A Pedagogical Description of Channel Interference in Multiphoton Absorption Processes

Abstract

In this mini-review, the author discusses a different view of two-photon absorption and in general any multi-photon absorption process in a molecular system in a very didactic way. This novel point of view is termed as “channel interference”. It connects the overall absorption cross section with the orientation of different transition dipole moment vectors that come into existence when a molecule undergoes two- or multiphoton absorption process. Therefore, channel interference provides an in-depth view of the process which can be used to control and fine tune the multi-photon activity in a molecular system for designing an efficient material.

Keywords: Two-photon absorption; Nonlinear optics; Response theory; Optical channels; Transition dipole moments

Abbreviations: TPA: Two-Photon Absorption; TP: Two-Photon; MPA: Multi-Photon Absorption; TDM: Transition Dipole Moment

Introduction

Light-Matter Interaction

When light interacts with matter, the electric field ofthe incident light causes a distortion of the electron cloud in the molecule, which is measured in terms of polarization. A stronger electric field and loosely bound electron cloud give larger polarization than a weaker electric field and a tightly bound electron cloud. In most of the molecules, the said polarization can be expressed as a linear function of the electric field and hence the optical processes associated with this linear polarization are called linear optical processes. The normal UV-Vis or IR absorption falls into this category. Most of the molecules show this kind of absorption with UV-Vis or IR source of radiation. However, when LASER is used as incident light, polarization becomes a non-linear function of the corresponding electric field.

The optical processes associated with such non-linear polarization are called non-linear optical processes. Two-photon or multi-photon absorption and hyper-polarizabilities are the two examples of non-linear optical processes. In this mini-review, we’ll discuss the multi-photon absorption process with an emphasis on two-photon absorption (2PA) caused by a linearly polarized light.

Linear and non-linear absorptions

Pictorially, a linear absorption process can be shown as in Figure 1 where, S₀ and S_f represent the initial and final states respectively. E₀ and E_f are the corresponding energies of the states and hν is the energy of the incoming photon. If an incident light of low intensity is used, absorption will occur if and only if hν matches the energy gap (ω_0f = |E_f– E₀|) between the two states. If the system is centrosymmetric, then an additional requirement for an allowed transition is that the two involved states should have the different symmetry. For example, if the absorption is taking place from ground state (having gerade symmetry), in a centro-symmetric molecule, then the final excited state should have gerade symmetry [1] this is the case of linear absorption, also called one-photon absorption (1PA). This is measured in terms of oscillator strength (δ^1p) which is directly proportional to the product of «_0f and square of transition dipole moment (TDM) vector (μ^of) between initial and final states [2,3].

Figure 1: Pictorial representation of 1PA process.

In contrast to the linear absorption, non-linear absorptions are more complicated in mechanistic way and hence in their theoretical descriptions. A pictorial representation of first two non-linear optical absorption processes i.e. 2PA and three- photon absorption (3PA) are shown in Figure 2. MPA (M≥2) is defined as the simultaneous absorption of M-photons of same or different frequencies by a system resulting in a transition from one state to another via one or more intermediate states (S_i, S_j). The intermediate states can be either a real or a virtual state [2]. The requirement of simultaneous absorption of more than one photon is the reason why one needs a high intensity light for achieving an MPA process. In order to have an idea about the complexity of the process, let us take the case of the simplest MPA process i.e. 2PA.

Figure 2: Pictorial representation of 2PA and 3PAprocesses.

The 2PA strength of a system is measured in terms of 2PA cross section, which depends upon the following quantities – two TDM vectors μ^oi and μ^if and energy gap between the states. Additionally, δ^2p depends upon the dipole moment of the ground- and the excited-states. Thus, in 2PA the system first absorbs a photon hVj and reaches the intermediate virtual state S_i (which has a negligibly small life time), but before relaxing back to the initial state S₀, the system absorbs the second photon hv₂ and reaches the final excited state S_f. For a successful 2PA to occur, both the TDMs i.e. μ^oi and μ^if should have large values and also the time-lag between the two photons should be smaller (that means high intensity) than the life-time of the intermediate state. The 3PA and other higher order multi-photon absorption processes require more photons to be absorbed simultaneously and hence are even more complicated and even more intense light is required for observing such processes. This is the reason why we do not encounter nonlinear optical absorptions in our daily life.

For 2PA, the requirement of high values of μ^oi and μ^if indicate that the 1PA for S₀ → S_i and S_i → S_f should be allowed transitions i.e. in centrosymmetric molecules the states (S₀ and S_i) and (S_i and S_f) should have different symmetries. This requirement is fulfilled if and only if S₀ and S_f have same symmetry and S_i have symmetry different from the other two states. Thus, a 2PA process, in a centrosymmetric molecule, is allowed between states of same symmetry. The TDM vectors are also called one-photon transition moments. Similar to this, we can also define two-photon, three- photon and other multi-photon transition moments. For 2PA, the corresponding transition moment is given as [4].

is the α^th component of TDM between p^th and q^th states and The summation in Eq. 2 runs over all the electronic states of the system including ground state and αβ ϵ {X,Y, Z}. The 2PA cross section, δ^2p for single beam of a linearly polarized light is related to transition moments, T_a by the following relation [5]

Origin of Channel Interference

So far, we have seen that both 1PA and 2PA depends upon the magnitudes of TDM vectors between the involved states. We have also seen that in case of 1PA, only one TDM is involved whereas, in case of 2PA (as in Eq. 2) and another multi-photon absorption processes several TDMs are involved. Since TDMs are vector quantities and hence these should contribute not only through their magnitudes but also through their orientations. Thus, δ^2p should depend upon the relative orientations of different TDM involved in the process. This should also be the case for 3PA and other higher order multi-photon absorption processes. But the question is how can we separate the contributions coming from the magnitude and those coming from the relative orientations of the TDM vectors? The quantum chemistry codes like DALTON [7], GAMESS [8], TURBOMOLE [9], etc. uses quadratic response theory (details about this theory can be found somewhere else [10,11] for calculating T_αβ and δ^2p .

Because of this approach, it is not possible to get the contribution from relative orientation of the TDM vectors as neither Eq. 2 nor Eq. 3 has any orientation related term. The orientation related terms or angles between TDM vectors appear when Eq. 2 is inserted into Eq. 3 and the terms are rearranged properly. This was first done by Cronstrand, Luo and Agren [12] in 2002 for 2PA process. However, their description was limited to two-dimensional cases that means when only two components of the TDM vectors contribute. In most of the molecules, all the three components of the TDM vectors have significant contributions, which require a general three-dimensional formula. This was done, again for 2PA only by Alam, Chattopadhyaya & Chakrabarti [13] in 2012. This is called generalized few-state model (GFSM), which reads as [13].

Where θ^rs_pq is the angle between two TDM vectors μ^pq and u”and other terms have their usual meanings. Eq. 5 has separated the contributions from the magnitude of the TDM vectors and those from their relative orientations. This formula, thus, can be used for studying the effect of orientation of different TDM vectors on δ^2p .

Some General Characteristics of Equation 5

It is interesting to discuss the characteristics of the generalized formula i.e. Eq. 5, because it can give important information regarding the symmetry in the process and it can also help to answer, whether such generalization is possible for other higher order MPA processes. It is interesting to note that Eq. 5 represents the overall δ^2p as a summation of interference between two channels S₀ → S_i → S_f and S₀ → S_j → S_f One can easily divide Eq. 5 into four contributions – (A) the pre-factor , (B) magnitudes of TDM vectors (numerator in the summation), (C) energy term (denominator in the summation) and (D) the orientation term (term in curly braces). Here, a brief discussion about different contributions is given.

A more comprehensive and full discussion can be found in [14]. Contribution (A) is same for all the molecules. Contribution (B) depends upon the magnitudes of a maximum of four TDMs (when i, j, and f represent different states). For a large value of , the corresponding TDMs should have large values for each state involved (i, j) in the summation. Note that, for 2PA, contribution (B) contains a maximum of four ^ terms. The third contribution i.e. (C) should have small value for a large value of δ^2p

This means, if the two incident photons have same frequency, then E_i and E. should be larger than E_f/2 i.e. the two states should lie above the mid-point between the initial and final states. Finally, contribution (D) has all cosine terms in it, each of which has a maximum value of+1. So, for a larger δ^2p, contribution (D) should be larger and close to its maximum value of +3. Note that there are altogether six cosine terms, which indicates that it includes orientation of each TDM vector relative to each of the others. The above partitioning scheme was further explored by Alam, Beerepoot and Ruud and using this, very recently, they came up with another generalization that can now be applied to any multiphoton absorption process.

Factors Affecting Channel Interference

Alam and co-workers have extensively studied [15-18] channel interference in several different kinds of molecules including both through-bond and through-space charge transfer molecules. They have shown that in general, channel interference is affected by donor-acceptor strength in the molecule, type of substitutions and their position in the molecule, polarity of the solvent, orientation of one part of the molecule relative to the other part etc. They have also studied the relative effect of donor and acceptors and concluded that donors may contribute more than acceptors [19].

Future Prospects

Channel interference is an interesting phenomenon that can be used to fine tune the two-photon activity in a molecule. Although several factors affecting channel interference has been studied, but still these studies are limited to specific systems. The phenomenon of channel interference in different types of molecules in various different solvents can provide interesting results, which can help to provide an effective design strategy for controlling channel interference. One of the main questions still unanswered about the channel interference is that how to visualize the different transition dipole moments in a molecule. For example, the ground and excited state dipole moment can be plotted in the molecular framework but how can one plot the TDM vectors between excited states? Answer to this question may help to visualize the channel interference in a real molecular framework.

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Broad Ligament Teratoma: A Rare Entity

Introduction

The broad ligament is a peritoneal fold that attaches the uterus, fallopian tubes, and ovaries to the pelvis. Disorders of the broad ligament are rare. Tumors of the broad ligaments are even rare. The most common solid tumor of the broad ligament is a leiomyoma. This case report is unique in world literature as first case has been documented till date.

Aim

This study was done to estimate the incidence of broad ligament tumors in our institute.

Case

A 19 year nullify porous presented in pod with abdominal mass for the last 4 months with irregular cycles .She had history of abortion 2 months back for which she underwent D&C .Per vaginal findings revealed normal anteverted uterus with large 10 by 8 cm mass in right annex non tender. Her menstrual cycles were regular with 5 days flow(LMP 8 days back). On abdominal examination 14 weeks size non tender mass with variegated texture was seen in right iliac fosse. Ultrasound findings revealed left ovarian dermoid cyst. Her biochemical parameters were normal. Tumor antigen study CA125 was<5.She was taken for explolatory laparotomy which revealed multiloculated cystic mass arising from left broad ligament10 by 7.5 by 6cm adherent to sigmoid colon, uterus and urinary bladder. Bilateral ovaries with tubes were normal. Excision of broad ligament mass was done in toot. Abdomen was closed in layers over suction drain. Postoperative period was uneventful [1- 3].

Conclusion

Tumors of the broad ligaments are rare. Gynecologists should be aware of the possibility of retroperitoneal broad ligament teratomatous tumors.

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Synthesis of Flavones

Introduction

Medicinal properties of the plants are attributed due to presence of various flavonoids. Flavone is one class of flavonoids which attracted the attention of researchers worldwide. These ‘yellow’ colored compounds have 2-phenylchromen-4-one backbone structure. Flavones contribute to various medicinal properties like anti diabetic [1], anti-inflammatory [2], anti-oxidant [3] and anti-cancer [4]. In some basic methods of synthesis of flavones aldehydes react with hydroxyl aceto phenones under claisensmith condensation. In this review we have tried to summarize the various methods of synthesis of flavones.

Allan-Robinson Strategy of synthesis flavones from chalcone

Allan J and Robinson R [5] carried out the reaction of o-hydroxyaryl ketones with aromatic anhydrides which results in the formation of flavones and isoflavones shown in (Figure 1).

Figure 1: Synthesis of flavoves by Allan Robinson reaction. O-benzoyloxyacetophenone is heated with glycerol at 2600 C for two hrs which leads to the formation of flvone.

a) Synthesis of flavones using O-benzoyloxyacetophenone

i. Method 1: T S Wheeler [6] carried out synthesis of flavones via two step synthesis method. In first step O-benzoyloxy aceto phenone was synthesized from reaction of O-hydroxy aceto phenone with benzoyl chloride in the presence of pyridine. In the second step O-benzoyloxy aceto phenone is heated with glycerol at 2600 C for two hrs which leads to the formation of flvone. The reaction is shown as (Figure 2).

Figure 2: Synthesis of flavones using O-benzoyloxyacetophenone.

ii. Method 2: In the second method7 first step is same as shown in method 1. Then in the second step O-benzoyloxyacetophenone was converted into di ketone using KOH and pyridine. Then diketone is refluxed with glacial acetic acid and sulphuric acid for 1 hr to obtain the final product as shown in (Figure 3).

Figure 3: Synthesis of flavones using diketone.

b) Synthesis of flavones involving cyclization via displacement of aromatic chlorine

In this method [8] O-chloro phenyl benzoyl acetylene in the presence of morpholine was refluxed for 10 hrs which ends up with the flavone as final product via removal of morpholine hydrochloride. The reaction mechanism is shown as (Figures 4 & 5).

Figure 4: Synthesis of flavones involving cyclization via displacement of aromatic chlorine.

Figure 5: Synthesis of flavones using ium chloropalladite or palladium (II) acetate catalysed reaction.

i. Lithium chloropalladite or palladium (II) acetate catalysed reaction: Initially benzene was stirred with sodium methoxide and then refluxed with Lithium chloropalladite or palladium (II) acetate and at the end reaction results in the formation of flavones [9].

ii. Using LiHDMs and acid catalysed cyclization reaction of O –hydroxyacetophenone: Reaction of O-hydroxyacetophenone with benzoyl chloride under acidic condition using LiHDMs leads to the formation of flavones in addition to the side product [10]. Reaction is shown in (Figure 6).

Figure 6: Synthesis of flavones using LiHDMs acid catalysed cyclization reaction of O –hydroxyacetophenone.

iii. Wells-Dawson method of synthesis of flavones using Heteropoly acid (HPA): In this method [11] synthesis was carried out using substituted 1,3 diketones dissolved in toluene or solvent free environment. Recation mixture was refluxed for 5hrs. at room temperature without catalyst (WD40/SiO2) no product was identified on TLC plate whereas use of just 1% mmol of HPA push the reaction in forward direction as shown in (Figure 7).

Figure 7: Wells-Dawson method of synthesis of flavones.

iv. From idophenol with alkynes in the presence of pladinum catalyst: Reaction of substituted idophenols with alkynes in the presence of carbon monoxide and pladinum catalyst yielded the flavones [12] as shown in (Figure 8).

Figure 8: Synthesis of flavones from idophenols and alkynes.

c) Synthesis of flavones from idophenols and alkynes

i. Iodine-alminium trioxide (I2/Al2O3) microwave assisted synthesis of flavones: In this method substituted O-hydroxyacetophenones was irradiated in microwave with carboxaldehyde in the presence of I2-Al2O3/NaOH [13]. Reaction mechanism is shown in (Figure 8).

ii. From the replacement of alkene hydrogen of 4H-chromen- 4-one: Reduction of 4H-chromen-4-one in presence of 2,2,6,6-Tetramethylpiperidine (TMP),Zn/ MgCl and THF gives the flavones as final product [14].

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A Review on the Reproduction and Development in Fish

Review

In order that survival of young be more than optimum, the timing of spawning by the mature adult fish is so adjusted that must be closely linked to the availability of maximum congenial environment added by increased food availability of food for the newly hatched young ones. The availability of food for the larvae and juveniles of most temperate and cold water fish species varies on a seasonal basis and following this fish are usually found to have a discrete and selective spawning season so perfectly timed that hatched out larvae will get readily available exogenous food from nature for their further development. Thus, in many temperate and cold water species, spawning is an annual event. Spawning culminates a series of preparatory events during which the gametes develop and the gonads increase in size. The annual cycle of fishesgenerally categorized into three major phases:

A. Post Spawning phase: Period when the gonads are thin and slender and appear to be in a resting phase.

B. Pre Spawning phase: Period in which the gonads begin production of gametes (gameto genesis) and incorporation of yolk into the oocytes (vitello genesis) which is accompanied by a process known as gonadal recrudescence i.e. gradual increase in gonad size.

C. Spawning phase: Period involving final maturation and ripening of the gametes; this phase culminates in spawning act, with the release of egg and milt which ensures fertilization.

Thus, gonadal development is considered to encompasses a series of interrelated phases, each requiring precise coordination and control if viable gametes are to be produced at the optimum time of the year for the subsequent survival of the young fish. The production of gametes involves the manufacture and incorporation of yolk into the developing oocytes (vitello genesis). During the early part of gonadal development, the oogonia, through the process of oogenesis produce mature eggs. Primarily, under the influence of GTHI, primary oogonium forms several primary follicles which ultimately develop into mature graffian follicle. It is within this graffwian follicle eggs mature and get associated with vitallogenin protein from liver known as yolk granule, acts as a readymade food for the growing embryo during development of larvae. Supported by this endogenous food gamete grow in size during post vitallogenic phase of development alin particular. In the salmonids, for example, the oocytes increase in diameter from about 50μm to 500-1000μm prior to the start of vitellogenesis. The incorporation of yolk that occurs during the vitellogenic phase leads to the diameter of the oocyte increasing to around 5000μm (5mm). Thus, there is an enormous increase in oocyte volume during post vitellogenic phase.

This observation supports the view that in majority of fishesthe gametic development is dependent on endogenous hormone and the nutrient protein from liver and its subsequent incorporation into egg cytoplasm. The yolk is derived from vitellogenin, a lipophosphorotein- calcium complex with a molecular weight of approximately 440, 000. Vitellogenin is synthesized in the liver and is then released into the blood system. The vitellogenin is then transported to the ovary through hepatic portal blood vessel from which it is sequestered by the oocyte. Following uptake into the oocyte the vitellogenin splits into two major components each having a molecular weight of 35 000, which form the yolk stores. The processes of gametic development and gonadal growth usually occur gradually and the prespawning phase of the cycle often continues for a considerable period of time, perhaps several months, before the actual spawning occurs. These indicate that the fish can ‘predict’ the arrival of spawning time several months in advance.

Environmental Influences on the Reproductive Cycle

In general, growth and development of gamete depends on different environmental cues in nature. The primary environmental cues are often linked to the annual cycles of day length and temperature variationsm Chattopadhyay et al. [1]. For example, in case of Cyprinus carpio and many other cyprinids, gonadal maturation begins in late winter after the vernal equinox (21^st March) when day length is in increasing manner and as a result water temperature is also in increasing trend. But in summer when temperature is high, cessation of spawning activity may occur due to inhibitory effects of high water temperature. Thus, it is thought that both photoperiod and temperature are major environmental cues responsible for the mediation of the reproductive cycle inseveral species of fish that inhabit temperate latitudes Devlin RH, Nagahama Y [2]. In temperate area salmon generally breed at temperature range of 8-10 oC i.e. during late autumn and early winter, but during autumn and winter when temperature of river water fal1.sto 1-2 oC, inhibition of oocyte growth and development may occur. In contrast to this fish are maintained under experimental condition of constant photoperiod (e.g. 12L: 12D -12h light and 12h dark each day) and temperature) the fish may still spawn at approximately yearly intervals. This means there is a strong autonomous component to the reproductive cycle, and under conditions this endogenous rhythm will have a periodicity of about 1 year.

In constant environment condition, fishes may spawn at intervals that are approximately but are significantly different from 1 year. Thus the periodicity of the rhythm is only approximately 1 year, i.e. it is circannual. As a result, many fish species rely on the seasonally changing cycle of day length to match their annual cycles of reproduction and these cyclic events will be mediated through a number of endocrine changes. Consequently, it is ultimately the neuro-endocrine system which directly controls the different phases of general development and the maturation of gametes. The general environmental cues that triggers maturation, gametice growth and development appears to be primarily environmental in nature followed subsequent endogenous rhythm. These environmental cues are often linked to the annual cycles of day length and temperature variations. For example, for in summer-spawning fish such as carp, Cyprinus carpio, and many other cyprinids, gonadal maturation begins in late winter or early spring. The start of the maturation process is thought to be triggered by a combination of increasing day length and the rise in water temperature with the commencement of spring. The extended spawning season, with a startup season in March–April continues up to the end of August through scientific management practice. Some authors are of the idea opinion that in certain fishes’ cessation of spawning activity may, in part, be due to inhibitory effects of high summer water temperatures on gonadal differentiation and maturation. For tropical fishes’ gonadal development and spawning stops with the fall of temperature that happen with the approach of winter. This provides a direct evidence that temperature along with photoperiod is the main controlling factor towards maturation and spawning in fish. S.

Again, some species such as the Tobinumeri dragonet and Repomucenusbeniteguri, resume spawning activities as water temperature falls during the course of autumn. These fish exhibit two distinct spawning seasons (May-July and September- November) during the course of the year. Spawning commences in spring when the water temperature reaches 18° C, but the spring spawning season comes to an end once temperature exceeds 28° C. Spawning that resumes in September when water temperature falls below 27 °C, and the autumn spawning season continues as long as temperature stays above 15 °C. Thus, gonadal development and maturation appear to be inhibited by temperatures lower than about 15 °C and higher than 27-28 °C. This suggests that water temperature is probably the major environmental cue for both inhibition and termination of the spawning seasons in the Tobinumeri dragonet. In the tropics changes in photoperiod and water temperature occurs after the vernal equinox that falls on 21st March every year. Gonadal recrudescence starts after this period for most of the fishes. Though these two environmental factors are unlikely to act as major cues for influencing the reproductive cycle in some fishes like tilapia and Cyprinus carpio. In some tropical species there does not appear to be any distinct spawning season and some members of the population can be found to be engaged in reproductive activities at almost any time of the year. In other species, spawning activities do seem to vary on a seasonal basis, with factors such as variations in rainfall and humidity possibly acting as the environmental cues triggering changes in gonadal development and maturation.

Endocrine Regulation of Fish Gonad Development

The development and maturation of fish gonads are controlled by genetic and environmental factors, and regulated by a molecular network of signals. As in other vertebrates, the HPG axis of the neuroendocrine system plays a central regulatory role on the reproductive development of fishes. Gonadotropin-releasing hormone (GnRH), lying upstream of the HPG axis, is a key regulatory factor. Once hypo- thalamus-secreted GnRH arrives at the pituitary gland, the cAMP signal pathway in gonadotrophs will be activated, transcription, synthesis and secreting of FSH and LH are all upregulated. Via blood circulation, FSH and LH enter the gonads to regulate gonad development and to promote sexual maturation by stimulating production of sex steroids. On the other hand, sex steroids can inhibit synthesis of GnRH in the hypothalamus through a negative feedback pathway. In recent years, the discoveries of kisspeptin, which can positively regulate GnRH, and GnIH, which can negatively regulate GnRH, have been praised as two remarkable breakthroughs in vertebrate neuro endocrinology Zohar Y [3]. They have become attractive topics in fish reproduction and physiological research.

Kisspeptin is a neuropeptide encoded by the kiss gene and act in conjugation with GPR54 as the receptor. The first research about kiss function was carried out in hypogonadism De Roux N [4]. The patients had delayed pubertal maturation and reproductive function due to a mutation in the gene encoding GPR54. Subsequent studies in mice, rats and monkeys further confirmed the functions of kiss peptin and GPR54 in reproductive development. Currently kiss peptin is thought to play a significant role on sexual differentiation of the brain, the initiation of puberty, secretion and release of GnRH, transmission of feedback signals of sex steroids and control of reproductive function by a photoperiodic factor Tena-Sempere M [5]. Currently, functional research of Kiss peptin and GPR54 in fish reproduction is developing rapidly. Parhar [6] found mRNA of GPR54 in GnRH neurons of tilapia, which suggested a direct effect of kisspeptin on GnRH neurons. Kitahashi [7] cloned and expressed the Kiss2 gene of zebrafish and medaka. Via intraperitoneal administration and real-time PCR, they observed a more important role of kiss2 than kiss1 in regulating zebra fish sex steroid synthesis. Li S [8] observed elevated levels of LH in goldfish serum after intraperitoneal administration of mature kisspeptinpeptides. However, Pasquier [9] confirmed an inhibitory effect of kisspeptin on LH levels of the eel, Anguilla anguilla. It is worth noting that two or three types of GnRH usually coexist in one fish species, and that two types of kisspeptin and GPR54, respectively, are also found. Thus, the relationship between the kisspeptin/ GPR54 signal system and GnRH, as well as regulatory mechanisms on reproduction, might differ between fishes and mammals.

GnIH (gonadotropin-inhibitory hormone) was first found in birds by Japanese scientists in 2000. Subsequent studies showed that GnIH might regulate reproduction of birds and mammals on every level of the HPG axis. It can inhibit synthesis and release of LH and FSH, induce apoptosis of testis cells, and might have a regulatory effect on the production of sex steroids as well as on the differentiation and maturation of germ cells by the way of autocrine or paracrine mechanisms Tsutsui K [10]. The functional study of GnIH in fishes has just started, and there are still many inconsistent findings. For instance, Zhang [11] detected lower levels of LH in the serum of mature female goldfish after intraperitoneal administration of zebra fish GnIH peptides, which demonstrated that GnIH could negatively regulate release of LH in goldfish. On the contrary, the results from intraperitoneal administration of GnIH to goldfish at developmental stages from early to late gonad recrudescence showed that GnIH increased pituitary LH-β and FSH-β mRNA levels as well as reduced serum LH and pituitary GnIH-R mRNA levels Moussavi M et al. [12] It has been suggested that GnIH has a seasonal effect on LH and FSH. This could change our understanding of the regulation of fish re- productive axis. It would also help us to study the function of GnIH in fish reproduction and explore new factors negatively regulating GnIH.

There are also types of molecules that can indirectly regulate fish reproductive development by affecting the HPGaxis. For example, in many teleosts the release of GtH can be inhibited by dopamine (DA) Trudeau VL [12], or be accelerated by γ-aminobutyric acid (GABA) Popesku JT [13], and secretion of GtH can be stimulated by neuropeptide Y (NPY) Zhang Y [11]. In our group, suppression subtractive hybridization (SSH) and cDNA microarray were applied to sterile females of the common carp with abnormal gonads and to wild type common carp Xu J [14-16]. We found more than 200 genes expressed differently at the hypothalamus, pituitary or gonad level, which included 87 unknown genes, whereas the other genes were associated with growth, organogenesis, energy metabolization, immune response, signal transduction and cell apoptosis. The results showed a very complex molecular network regulating fish reproductive development.

Fertilization and Post-Embryonic Development

Following fertilization, zygote undergoes meroblastic cleavage to form a ball of cells called morula, which subsequently transformed into blastula (Figures 1 & 2). The blastula, consists of a central dorsal blastodisc above the yolk sac, through continuous division forms three layer above the yolk – indicate the initiation gastrulation or cell movement. The dorsal layers, which contribute to the formation of embryo proper, by way of differentiation form a dorsal epiblast and ventral hypoblast. Below the hypoblast, a layer composed of loosely packed cell mass remains covering the yolk, called periblast. Gastrulation in bony fishes is accomplished by two processes; invagination and epiboly.At the beginning of gastrulation, the presumptive endodermal and mesodermal cells at the posterior and posterolateral end of the blastoderm turn inwards and migrate forwards under the blastoderm, so as to form the hypoblast. However, there is no in pushing of the epithelial layer and no true archenteron is formed. The presumptive endodermal cells lying along the posterior margin of the blastoderm, migrate inward along the surface of the yolk.

Figure 1: Water hardened eggs with developing eggs within.

Figure 2: Water hardened eggs with developing eggs within.

As these cells move inwards, they tend to be concentrated towards the middle of the blastoderm. The presumptive mesoderm cells also invaginate in a similar way and roll over the edge of the blastoderm. Although no true archenteron is formed, the edge of the blastoderm may be compared with the dorsal lip of the blastopore of amphibians. The mesodermal cells, after invagination, also converge towards the middle line, where the axial organs of the embryo are formed. Next, the precordial plates as well as the notochord cells also move inwards by rolling over along the posterior edge of the blastoderm, which corresponds with the dorsal lip of the blastopore. Notochord, prechordal plate and mesoderm are continuous with each other end, form the chord mesoderm. Initially, this involuted cell mass is called the hypoblast. The presumptive neural plate is now started stretching towards the posterior edge of the blastoderm and comes to occupy the areas vacated by the cells that have migrated to the inside. The presumptive neural cells also tend to be concentrated towards the midline and form a strip of tissue lying above the notochord and extend forward to from the posterior edge of the blastoderm. A peculiar feature in the development of fishes is that the formation of the primary organ rudiments begins in the anterior part of the embryo, long before the invagination is completed in the posteriorpart. The anterior part of the neural plate, corresponding to the forebrain appears first, and is followed by the mid brain region. The notochord gradually separated from the mesoderm, which becomes thickened due to concentration towards the midline, and is segmented into somite’s lying on either side of the notochord. The rest of the mesoderm remains un segmented and is called the lateral plate mesoderm. The endoderm also becomes separated from the mesoderm and endodermal plate in the middle line. This later forms the alimentary canals.

The process of neurolation in fishes is not like that of the amphibians. The neural plate does not roll into a tube but narrows gradually and sinks deeper into the underlying tissue. It then separates from epidermis, which grows over it and becomes continuous to form the dorsal surface of the embryo. The neural cavity is not formed by rolling over of the neural plate, but it appears later in the brain and the spinal cord by separation of cells in their middle region. During the process of involution, the cells of the blastoderm continue to grow over the yolk through the process of epiboly. During this, the presumptive ectoderm cells grow over and cover the yolk mass from outside, forming a layer of cells called epiblast. At the same time the periblast also grows and forms an inner covering of the yolk. The periblast and epiblast enclose the yolk in a yolk sac. Gastrulation is completed with the formation of yolk sac. At this stagethe the embryo proper can easily be distinguished from yolk sac.

Hatching and Post-Embryonic Development

After the completion of gastrulation, various organs of the body are formed resulting in a small embryo with more or less cylindrical and bilaterally symmetrical body. The body is raised up from the surface of the yolk, so that the embryo proper becomes distinct from the yolk sac. In this condition, the head of the embryo projects anteriorly from the yolk sac, the trunks lie over the yolk and the tail projects behind. The broad connection between the body and the yolk sac becomes constricted so as to form a stalk. Blood vessels develop in the wall of the yolk sac. Yolk is digested by the periblast and supplied to the body through blood vessels. The yolk sac gradually reduced in size and the embryo grows indicating the supply of nutrients to the growing embryo. Finally, on hatching a free swimming larva comes out. During this period of development, various organs of the body are formed from the ectoderm, mesoderm and endoderm. The ectoderm gives rise to the epidermis and its derivatives like the enamel of the teeth, olfactory epithelium, lens of the eye and the inner ear.

The neural plate which is also ectodermal in origin and gives rise to the brain, spinal cord, retina etc.The mesoderm divides into three parts- dorsal epimere, middle mesomere and ventral hypomere. The dorsal epimere becomes divided into smites at a very early stage. Each somite is subdivided into three parts- sclerotone, myotome and dermatome. The sclerotome collects round the notochord to form the vertebral column. The myotome gives rise to the muscles of the trunk, appendicular skeleton, appendages and their muscles. The dermatome gives rise to the connective tissue and muscles of the dermis and its derivatives i.e., scales. The middle part of the mesoderm (mesomere) gives rise to the kidneys, gonads and their ducts. The hypomere splits into somatic and splanchnic layers of the mesoderm and enclose the coelomic cavity. The splanchnic layers form the mesenchyme which forms the involuntary muscles and connective tissue of the gut. Heart and blood vessels also develop from the splanchnic mesoderm. Skeleton and musculature of the head, outer layers of the eye and the dentine of the teeth develop from the mesenchyme of the head region.

Larval Development

Young stages of fish, from hatchling stage to till they attain maturity are known as larvae or fry. The larval development period varies considerably in different fishes. A fish fry with a yolk sac (Figure 3) is known as the ‘sac fry’ but when the sac disappeared is known as ‘advanced fry. In some species the advanced fry closely resembles adult and develop into adult without any larval stage. This is called direct development and is seen in salmon, trout and many catfishes. On the other hand, an indirect development through larval stages takes place in several families of fishes like the Clupeidae, Cyprinidae, Lophiidae, Anguillidae, Scorpaenidae etc. In these fishes the larvae (fry) undergoes metamorphosis during which the larval characters are lost and the adult features appear. Through this development the larvae attain a miniature adult like appearance called ‘fingerling’. This enters into an active feeding stage which results in maturation of gonads to give rise to the adult. The females are usually larger in size than the males but the latter attain early sexual maturity.

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Neurological Complications after Pertussis Vaccine. The Enigma is Still Here

Mini Review

The significance of regular childhood vaccinations is universally accepted. However these vaccinations were reported to potentially have a long list of complications. This list includes disorders such as autism (measles vaccine), multiple sclerosis (hepatitis B vaccine) meningo encephalitis (Japanese encephalitis vaccine), Guillaine-Barre and giant cell arteritis (influenza vaccine), and more. Seizures and hypotonic/hypo responsive episodes following pertussis vaccination [1]. On the other side, public tolerance to adverse reactions is minimal. In the past, adverse reactions to vaccination drew significant public attention. A unique example to the problematic situation of such adverse events is the pertussis vaccine, which was along many years and still is a subject for many legal suits. Handicapped patients claimed that their medical difficulties, especially in the neurological field, are the result of the immunization, and thus they claim for an appropriate compensation. There were several phases in this process. Phase I may be represented by the article of Aicardi &Chevrie [2].

They described in 1975 twenty cases of acute neurological complications occurring within 7 days of pertussis immunization. Convulsions were present in every case and status epilepticus was observed in 5 infants. They concluded that the clustering of neurological complications in the 24 hours following immunizations is not consistent with the hypothesis of a mere temporal coincidence, but rather point towards the immunization as the cause. A debate took place for and against the vaccination as being the cause of potential neurological damage [3], sometimes with some background feeling that interest of major pharmaceutical companies to some degree involved n this debate, taking the “against” position. At this stage, the vaccination was of “whole cell” type, meaning that all the cell component of the Bordetella Pertussis were included in the vaccination. Phase II took place when it was decided to leave the former whole-cell pertussis vaccine, due to the consideration that cellular components of the Bordetella were responsible to the adverse events, mainly cell proteins. The vaccination was changed to an acellular form. It was found then that the acellular form lead to lower amount of complications although not eliminating them [4].

A 3^rd phase was defined when it was found that the pertussis vaccine in children with mutation in SCN1A gene, can lead them to present earlier than usually expected, with the epilepsy dictated by this gene Verbeek et al. [5] retrospectively analyzed data of children with Dravet syndrome and the pathogenic SCN1A mutation. They defined seizures within 24 hours after infant whole cell, acellular as “vaccination associated”. The risk of subsequent “vaccination associated” seizures was significantly lower for acellular pertussis 9% than whole-cell pertussis (37%). They conclude that subsequent vaccination associated seizures is probably vaccine-specific. Yet, the only factor by which any adverse event is considered as vaccination-related is the close time frame between its appearance and the immunization. And this time frame is not universally agreed upon. While Aicardi and Chevrie consider it to be 24 hours, others included in this category also children with much larger timeframes Huynh et al. [6] reviewed the appearance of acute disseminated encephalomyelitis (ADEM) as a post-vaccination phenomenon, which can appear after many vaccines including rabies, diphtheria-tetanus-polio, smallpox and more, including pertussis. They described a patient presenting with bilateral optic neuropathies within 3 weeks of inactivated influenza vaccination followed by delayed onset of ADEM 3 months post vaccination. It is clear from the above noted description that in spite of the universally accepted significance of childhood vaccinations in preventing serious diseases, one may not ignore the possibility that a small percentage of the vaccines will suffer from life-long disabilities caused by adverse events that were caused by these vaccinations. We have recently examined a 27-year-old young adult who is suffering from hemiparesis.

This started in infancy through a disease defined by a head CT scan as ADEM, which appeared in close relationship to the 4th pertussis vaccination. And now the dilemma is whether this can be related to the pertussis vaccination. If the answer is yes, the next consideration can be as follows: Young infants are getting vaccinated according to their country policy of childhood vaccinations. A very small proportion of the infants can be expected to develop neurological complications in close proximity to the vaccinationinjection. This morbidity seems to be directly associated with the recent vaccination. And the health authorities may be claimed to take responsibility for adverse events of the dictated vaccinations. It seems thus that the saga of vaccinations, side-effects and responsibility to that is still here.

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Farm-To-Fork Food Surveillance System: A Call for Public Health Education

Abstract

Objective: This paper aims to present a generalized farm-to-fork surveillance system framework with a focus on education for improving health and controlling and preventing food borne illnesses.

Method: A brief literature search compiled some of the existing surveillance systems with special attention to the Canadian context. The Public Health Agency of Canada conceptual model for food borne surveillance was used to develop a framework focused on educating the public on controlling and preventing food borne illnesses.

Result: The farm-to-fork surveillance system presented focuses on the end-user as well as producers and food handlers, with special attention on how to keep illness-causing pathogens out of food, destroy them once they have contaminated the food, and control their growth in already contaminated food. There are many local and worldwide efforts on how to properly hand-sanitize before, during and after food preparation in restaurants/eateries and at home so that food borne illnesses are prevented.

Conclusion: A food borne illness surveillance system is needed in Canada focusing on introducing a harmonious and standardized surveillance system across the country; strengthening local and provincial capacity for implementing such surveillance and in responding to food borne illnesses through networking; and enhancing the surveillance capacity along the entire farm-to-fork chain.

Introduction

Food borne illnesses result from consuming contaminated food or beverage with infections (bacteria, viruses, parasites, and prions) and non-infectious (poisonings – fungi and their toxins, heavy metals, chemical, and so on) contaminants at any stage from farm-to-fork chain [1,2] Every year in the U.S.A, food borne illnesses cost more than US$150 billion in medical expenses and economy loss due to days of work missed; cause 5000 fatalities and more than 76 million reports of illness-related symptoms. It is believed that one in every six Americans (or 48 million people) gets sick with foodborne diseases from 31 known pathogens annually [3] Between 1990 and 2004, there were 639 outbreak reports linked to contaminated produce in the US, including those related to tomatoes with Salmonella served in restaurants, and lettuce with E. coli O157: H7 served at the Taco Bell© fast food chain. In Canada, readyto- eat meat products contaminated with Listeria monocytogenes resulted in 57 confirmed illnesses and 22 deaths across the country in 2011 [4] In order to respond faster, more efficiently and more effectively to national and international foodborne outbreaks, the Food-borne Illness Outbreak Response Protocol (FIORP) was updated by the Public Health Agency of Canada in 2010 [5] After the FIORP updated, there were at least four outbreaks in 2016 and 2015, two involving Salmonella infection, one involving Listeria from packaged salad products from the Dole processing plant in Springfield, Ohio and another involving Vibrio para haemo lyticus linked to raw shellfish [6].

Contaminated foods commonly associated with food borne illness are [7].

a. Animal in origin (beef, poultry, eggs, milk, soft cheese, seafood, and so on);

b. Raw fruits and vegetables;

c. Canned products (canned goods, juices, cider, and so on).

Since 2009, the Government of Canada offers an annual food recall report which, for the first six months of 2011, for example, this report showed seven recalls on products contaminated with E. coli O157: H7, 18 recalls on products contaminated with Listeria, 23 recalls on products contaminated with Salmonella, just to namea few [8]. Although American and Canadian data might be alarming, food borne illnesses are still underreported locally and worldwide, and go undiagnosed as people fail to come forward about all food poisonings and do not always seek a doctor when feeling ill. When people seek care, the medical system fails to issue a specific diagnosis [9]. Once the source of contamination is identified following a report, food recall occurs. In general, public companies affected by a recalled product can experience share price volatility, and have their stock price dropping 30% within the first week of recalls.

In 2009 the Kellogg’s© lost nearly $70 million worth of peanut butter crackers and cookies recalled contaminated with Salmonella [10] In 2017, Thomas concluded that on average, an initial recall involving meat and poultry products for example, is associated with short-term reductions in shareholder wealth of up to $236 million, 5 days after the recall announcement [11] The primary sources of pathogens found in foods are from a variety of sources: feces (intestinal tracks of animals and humans), soil and water, plants and plant products, food equipment and utensils, animal feeds, animal hides, food handlers, processing plant air and dust, and more. With such a variety of contact points in which food can get contaminated, people are both the main cause and the victims in food borne illnesses. Once contaminated foods are ingested, people can be highly contagious before any symptoms appear and even after symptoms disappear. Hence, about half of healthy food handlers are carriers of disease agents. Improper handling and sanitation in food preparation (in restaurants and other eateries, and at home) are critical to preventing food borne illnesses and yet, many people do not know how to properly do it. As a result, educating the public about food safety (handling, storage and preparation) is the outcome focus of the surveillance system presented in this paper for use in a public health action to reduce morbidity and mortality and to improve health [12].

Surveillance: A call for Education in Canada.

Surveillance is ‘the ongoing and systematic collection, analysis, interpretation, and dissemination of data about health-related event for use in a public health action to reduce morbidity and mortality and to improve health [13] and it is necessary to determine any significant change in frequency (outbreaks) and distribution of cases [14]. Although food borne illnesses are underreported, there are various worldwide surveillance systems in place aimed at interrupting the transmission of food-related pathogens [9,15,16]. Unfortunately, ‘the need for a Canadian food and nutrition surveillance system has been recognized for some time’ despite of the existence of a conceptual model on surveillance proposed by Health Canada [17] and its FIORP [5]. Hence, there is an inconsistency on how and what to report, which adds difficulties in comparing the different surveillance systems despite the existence of guidelines [11] and worksheets [9].

A framework for Education on Food Handling

Based on the different foodborne illnesses surveillance systems available [12,18] the following framework is suggested (Figure 1). A suggested food borne illness surveillance system involving data collection, analysis, dissemination and application (Figure 1) highlights four main components of a surveillance system: data collection (who, when, what and where – case definition), analysis (what food and contaminants are implicated, and the need for laboratory confirmation), dissemination (to health authorities and the public), and application (the means used to prevent further spread, and can include education, food recalls, inspections and regulations).The art in surveillance lies in collecting appropriate and timely information and in interpreting it correctly, which might lead to controlling the outbreak [9]. Upon analysis of all the information gathered, a suspicion of a foodborne illness case can be raised and the local health authority notified (either from thehealth care provider, laboratory, or other source) (Figure 1). The public is then made aware of the potential outbreak, and food recall occurs. Despite the effort, however, food borne illnesses remain under reported because, for each case that gets identified through clinical laboratory analysis, another 29 are estimated to go unreported [19]. Moreover, them is understanding of the food handling or consumption, changes in consumption patterns due to food shortages, mass food recalls and regulatory changes in food safety can only make food borne illness surveillance fallible [10,20].

Figure 1: A suggested food borne illness surveillance system involving data collection, analysis, dissemination and application.

Educating the Public: Variables and Indicators

The success of the application aspect of a surveillance system has to go beyond food recalls, government fines, and lawsuits to include public education on how to prevent the contamination and spread of food borne illnesses. This education involves the preparation and dissemination of information on food safety to the public at large. Information can be provided to advise the public on: how to keep illness-causing pathogens out of food, how to destroy illness-causing pathogens or how to control their growth once they have contaminated the food, as follows:

Keeping Pathogens Out of Food

Information should focus on building sanitary barriers between food handlers/consumers and the foodthey manipulate/eat and educate them on how to proper handle food. The ‘Food-Safe School Action Guide’ in the [21] US educates school children and staff on washing produces under running water; removing and discarding outer leaves from lettuce and cabbage; washing hands before preparing food, when switching from one type or food handling to another, and after preparing food; and regularly cleaning and disinfecting the refrigerator, freezer, and counters. The guide does reinforce hand-washing as the single most important method of preventing food contamination [22,23]. In fact, the United Nations has declared the 15th of October as the Global Hand-washing Day to improve hygiene practices worldwide. In order to avoid food contamination by employees, many public eateries have a reminder in their washrooms advising their employers about a step-by-step process on how to properly wash and dry all areas of their hands before returning to the kitchen or counter area. In New Zealand, campaigns are more direct with respect to the consequences of poor hand-washing by mentioning diarrhoea and vomiting.

These campaigns have been emphasizing that there is no need to use an antibacterial soap to do a good job and hand sanitizers should not replace of plain soap and water. However, the WHO recently suggested alcohol-based handrubs as the best option to fulfill the highest standards of safety in relation to the prevention of cross-infection when focusing on point of care [24] alcoholbased handrubs have to yet be proven efficacious and safe in handling food and food products. At the farm level as well as in commercial food operations and distribution plants, best practice guidelines on food production and handling should include inspection of fields and packing plants; utilization of third party audits to monitor workers’ hygiene; testing dairy, meat, and food products for microbial contamination regularly; inspect plant after an outbreak; coordinate food recalls carried out by industry; and so on. Health agencies have regular food handling inspections for food establishments, and food handlers must have a valid Food Safe BC certificate to ensure that proper food handling procedures are observed and practiced in British Columbia, Canada [25]. It is noted that despite these efforts, there is no guarantee that proper food handling procedures are followed accordingly.

Destroying Pathogens once they have Already Contaminated the Food

The main focus here is in eliminating pathogens that have already contaminated food during production, storage or preparation. Such destruction can takes place via thermal processing (mainly cooking-heat temperature at recommended levels accordingly for different foods); non-thermal processing (irradiation, pulsed electric fields, oscillating magnetic fields, high pressure processing, pulse light technology, and freezing at commercial level); antimicrobial and sanitizers (ozone, chlorine, iodine, and organic acids at commercial level); or hurdle technology (combine interventions methods to prevent bacterial growth at commercial level). The Canadian Food Inspection Agency has an online document alerting the population about the proper way to cook meat and poultry products while other online resources offer food storage guidelines for cupboard, refrigerator and freezer [26,27], in various languages such as Dari, Cambodian and Zulu [28]. The ‘Food-Safe School Action Guide’ [15] reinforces cooking time and temperatures, and the importance in maintaining heat in hot foods; separation of raw meat from cooked foods and vegetables including cleaning cutting boards that contacted raw meat; chilling food by refrigerating leftovers promptly and at right temperature; keeping purchased (refrigerated) food chilled until getting home; and reheating leftovers properly.

Controlling the Growth of Pathogens in already Contaminated Food

Bacterial growth is a major source for food borne illnesses either from raw, uncooked, and improperly cooked food, or from not appropriately stored cooked food. Although there are various factors affecting bacterial growth (type of food, acidity of food, time and temperature, oxygen and moisture), the existing guidelines reinforce the need for refrigerating foods at 40o Fahrenheit (about 4.4o Celsius) or lower within two hours or less after cooking, and not leaving standing water in sinks. The World Health Organization has developed the ‘five keys to safer food’ campaign [28] that is available in more than 50 languages and reinforces the above points as well as the need to remind consumers and eateries to not thaw frozen food at room temperature, but in the fridge. Hence, getting information from government websites [5] and from numerous web pages including ‘Livestrong’ [29] and online blogs might further help to reinforce food safety practices. Food blogs such as the ‘food buglady’ [30] offers updated lists of food safety recalls in Canada, while the ‘Gainesville’s Lunch out Blog’ [31] discusses issues of contamination in the U.S fast food chains. Despite the efforts outlined above, a foodborne outbreak can still happen, and it remains up to those affected individual to seek medical attention to disseminate information, which can be used to identify or warn others of potential contaminations. For example, in 2007, participants from a muddy BC cross-country mountain bike race commented on a race-related web forum that they were feeling ill with similar symptoms. Such internet activity prompted the race organizers to contact the local public health unit, which then received 13 laboratory reports of Campylobacter jejuni outbreak infection in the racers who ingested mud [32].

Limitations and Barriers

Aside from the variation of food contaminants and case definition, the underreported status of food borne illnesses, the lack of a firm Canadian surveillance system, other barriers exist in making the public aware of food borne illness. For example, there are unanswered questions about the influences of the social, cultural and physical environments in which the social aspects of food consumption and eating behaviour occur [33] including:

a. How do advertising and the mass media affect the nutritional knowledge and perceptions of Canadians?

b. What is the relationship between socio-cultural and economic status and diet?

c. What are the interactions between the individual and collective determinants of healthy eating that are unique to older adults?

d. How are the dietary habits of Aboriginal people influenced by concerns over pollutants in their local food sources?

e. What impact do self-esteem and body image have on food selection and eating behavior?

f. Another barrier regards to the perception of food borne illness risk. The lay perspective of health risk is personal and differs markedly from the expert view which tends to focus on a more impartial point of view in regards to food hazards [34]. The public’s perceptions are important to be considered by health agencies when tailoring information on how to minimize the risks and public health burden of food borne illness, and on how to promote confidence in the food chain supply.

Another limitation happens in terms of food recall. According to Maple Leaf Foods, many Canadian small markets do not have a food recall plan to readily identify the immediate previous supplier and the immediate subsequent recipient of food in case of an outbreak [35]. Larger companies such as Safeway Inc, Loblaw Companies Limited, Save-on-Foods© and Costco Wholesale Corporation use personalized membership or loyalty cards to offer discounts to their loyal customers. These companies can trace purchases through the loyalty cards, which can assist in identifying purchasers of a recalled product and promptly inform the consumers.

Conclusion and Future Direction

A national food borne illness surveillance system focusing on educating the public at large is needed to monitor patterns of diseases that occur within the farm-to-fork chain. Such education should include proper hand sanitation, food storage and food preparation since the globalization of the food supply also brings the globalization of food borne illnesses. In Canada, a food borne illness [36] surveillance system could be modeled on the framework presented in (Figure 1), focusing on [28]:

a. Introducing a harmonic and standardized surveillance system across the country;

b. Strengthening local and provincial capacity for implementing such surveillance and in responding to food borne illnesses through networking; and

c. Enhancing the surveillance capacity along the entire farm-to-fork chain.

In addition, careful attention has to be placed on the eating habits of a multicultural and multi-language society such as that in Canada and in British Columbia while encouraging the public to engage more proactively in coming forward and reporting their food borne illness symptoms to a health provider/authority. The authors would like to caution the readers that (Figure 1) has not been tested or evaluated.

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The Association of Chronic Obstructive Pulmonary Disease and Osteoporotic Fracture in Older Patients

Abstract

Recent epidemiological studies have demonstrated a close association between osteoporotic fractures and common chronic diseases such as chronic obstructive pulmonary disease (COPD), hypertension, chronic kidney disor¬ders, and diabetes. COPD is a chronic inflammatory airway disease, and it well known that osteoporotic fractures are common in patients with COPD. However, reports on the association between COPD and osteoporotic fractures have been inconsistent in the literature. The objective of this review is to discuss the existing literature on the potential association between COPD and osteoporotic fractures in older adults. A PubMed search was conducted to identify studies evaluating the potential association between COPD and osteoporotic fractures in older adults. Overall, the results of these studies showed a non beneficial effect. COPDs have been associated with an increased risk of osteoporotic fractures. Further research is needed on algorithms to identify COPD patients with a high risk of osteoporotic fractures and the beneficial effects of preventing osteoporotic fractures in older patients with COPD.

Keywords: Chronic obstructive pulmonary disease; Osteoporosis fracture; Mechanism

Introduction

Chronic obstructive pulmonary disease is the most common chronic respiratory disease in the world and results in increasing economic costs [1]. The prevalence of osteoporotic fractures, which is more common in older patients than in younger patients, has been estimated to be 9 million worldwide in 2000 [2]. By 2030, COPD has been projected to be the third leading cause of death caused by an increase in cigarette smoking [3,4]. Hence, concerns about the health care of COPD, particularly in terms of the related comorbidity with osteoporotic fractures, have gradually increased worldwide. Recently, several observational studies have opened a debate about whether COPD is associated with osteoporotic fractures in treated COPD patients [5-8]. A cross-sectional study conducted by Watanabe et al. reported that the prevalence of vertebral osteoporotic fractures is as high as 79.4% in Japanese men with COPD [5]. Similarly, a nationwide population-based cohort study conducted by Lee et al. on 44,812 patients with a depressive disorder aged 28.6-50.9 years with or without COPD reported that the adjusted relative risk of vertebral osteoporotic fractures in individuals with COPD was 1.24 (95% CI, 1.02–1.51) compared with that in the non-COPD patients [6].

Previous studies have also demonstrated a positive relationship between COPD and a higher risk of osteoporotic fractures in the hip [7,8]. Reyes et al. reported that an independent association exists between COPD and increased risk of hip OF in Catalonians [8]. However, none of the abovementioned studies had used a prospective design method. A prospective study conducted by Dam et al. to examine the association between COPD or asthma and NOF revealed that male patients with COPD or asthma had 42% and 164% greater risk of sustaining non vertebral and vertebral NOF, respectively [9].The association between COPD and NOF in older patients observed in these studies may be attributable to the shared risks between both conditions, such as advanced age, smoking, physical inactivity, osteoporosis, drugs, dementia, alcohol consumption, estrogen deficiency, impaired eyesight, low body weight, dietary calcium deficiency, susceptibility to falling, and uncontrolled inflammation [6,10].

Statin use has been shown to be independently associated with a decreased risk of osteoporotic fractures [11,12]. Statins are effective agents in controlling dyslipidemia and are widely used in the prevention of cardiovascular diseases [13]. In particular, statins may influence bone metabolism by increasing bone formation [14]. It should be noted that osteoporotic fractures in older patients may result from accidents and events such as falls. Patients with COPD have muscle weakness, mobility impairment, and exerciseintolerance that make them susceptible to falls. An observational cohort study reported a significant association between COPD and increased risk (adjusted OR, 1.12; 95% CI, 1.01–1.24) of falls compared to that in non-COPD patients [15]There are no guidelines available on the prevention of osteoporotic fractures in older COPD patients.

Only one previous report has developed a five-step clinical approach for preventing fractures in patients with COPD. This five-step clinical approach consists of clinical case finding, risk evaluation, differential diagnosis, treatment, and follow-up. This clinical approach was developed considering the risk factors for fractures, including classical risk factors (older age, low body mass index, personal and family history of fractures, immobility, smoking, alcohol intake, use of glucocorticoids, and increased fall risk) and COPD-specific risk factors (severe airflow obstruction, pulmonary exacerbations, and oxygen therapy). However, this fivestep clinical approach for preventing fractures has not yet been validated. Further research is needed on algorithms to identify patients with COPD at a high risk of osteoporotic fractures and the beneficial effects of preventing osteoporotic fractures in older patients with COPD.

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Küttner’s Tumour – Chronic Sclerosing Sialadenitis of the Submandibular Gland

Introduction

Chronic sclerosing sialadenitis, originally described by H. Küttner in 1896, is a rare cause of salivary gland enlargement [1]. Its clinical and radiographic presentations can mimic other conditions such as, lymphoma or infectious causes and can only be correctly diagnosed following removal of the gland. This “Küttner’s Tumour” is now classified as an IgG4 related disease, with characteristic dense infiltrate of immunoglobulin (Ig) G4- positive plasma cells. However, the exact aetiology of IgG4 related disease remains unknown with no known role of the IgG4 molecule itself [2]. Other IgG 4 related diseases include Riedel‘s thyroiditis, Mikulicz’s disease and idiopathic retroperitoneal fibrosis [3]. This case demonstrates the diagnostic difficulty of this presentation, with multiple differential diagnoses that cannot be excluded until the final histopathological examination.

Case Report

The patient was a 63-year-old man who presented with bilateral submandibular swelling, which were present for four months. Physical examination showed firm, non-tender enlarged submandibular glands. The laboratory values showed a normal leukocyte count (10.6 x 109/L), haemoglobin level 14.2 g/dL), and platelet count (292 x 109/L). Nasoendoscopy examination to the level of the vocal cords was unremarkable. Ultrasound showed the submandibular glands contained a number of hypoechoic nodules which were well defined with attenuated echogenic strands internally. Fine needle aspiration cytology showed a mixed population of lymphoid cells. Contrast-enhanced computerised tomography scan revealed bilateral asymmetrical enlargement of right and left submandibular glands (Figure 1). No sialolithiasis was found. There was no significant cervical lymphadenopathy. As the diagnosis of lymphoma could not be excluded a decision was made to remove the right submandibular gland. Final pathology revealed the submandibular gland measured 55x38x25 mm. Histologically the lesion was composed of well-defined areas showing stromal fibrosis associated with acinar atrophy, florid chronic inflammation that includes conspicuous germinal centres, but also prominent numbers of interstitial plasma cells and vascular changes (Figures 2 & 3).

Figure 1: Head and neck Ct study image showing bilateral enlargement of sub mandibular glands measuring 3.3cm x2.5cm right and 3 cm x 2.2cm left.

Figure 2: [H +E x 10] The low power slide shows normal salivary gland in the upper left corner of the slide and shows a very well demarcated lesion of chronic sclerasingsialadenitis.

Figure 3: [H+E x 20] The high power view shows atrophic acini, stromal fibrosis, and lymphoid aggregates with germinal centers.

Discussion

Chronic sclerosing sialadenitis (Küttner’s tumour) is a nonneoplastic, chronic inflammatory disease of the submandibular gland first described by Küttner in 1896 [1]. A predominance of male sex has been recognised in the sixth to eighth decades [4]. Two factors appear important in the aetiology of Küttner’s tumour: an initial disturbance in saliva flow causing an obstructive sialadenitis and an immune reaction of the salivary duct system causing an obstructive progressive sialadenitis. Chronic sclerosing sialadenitis has been classified into four histological stages depending on the degree of inflammation;

a. Stage 1: focal sialadenitis;

b. Stage 2: diffuse lymphocytic sialadenitis with salivary gland fibrosis;

c. Stage 3: chronic sclerosing sialadenitis with salivary gland sclerosis;

d. Stage 4: chronic progressive sialadenitis with salivary gland cirrhosis [4];

Histologically, the disease is characterised by acinar atrophy, dense lymphocytic infiltration and fibrosis [5,6].

Recently, more than 90% of cases of Küttner’s tumour has been regarded as an immunoglobulin G4 (IgG4) related idiopathic sclerosing lesion [3,7]. IgG 4 constitutes only 3-6 % of the total IgG fraction in the plasma of healthy patients and is the smallest component among the IgG subclasses and its biologic function remains uncertain. IgG 4 related sclerosing disease has been identified in a wide variety of organs, including pancreas, biliary tree, liver, gallbladder, lacrimal gland, salivary gland, kidney, lung pleura and lymph nodes [8].Currently, the histologic diagnosis of IgG4 related disease is based primarily on IgG4 positive to IgG containing cell ratio of > 50% and the number of IgG4 positive cells per high powered field (30) [6].

Elevated serum IgG4 level and marked improvement with steroid therapy are other common diagnostic features [2]. It is important to distinguish between chronic sclerosing sialadenitis and sialolithiasis-associated sialadenitis as the treatment is markedly different. Chronic sclerosing sialadenitis shows a dense chronic inflammatory infiltrate composed of fibroblasts, lymphocytes and plasma cells. This is differentiated from sialolithiasis-associated sialadenitis by an interlobular fibrosis with less cellularity. However in up to 40% of cases of chronic sclerosing sialadenitis, a sialolith occurs simultaneously [4]. IgG4 related sclerosing disease has been shown to have a good response to steroid treatment with full remission rates of 90% with medical therapy alone [2]. However most commonly chronic sclerosing sialadenitis will be surgically excised and diagnosed by the histopathologist as it can mimic submandibular gland malignancy [8]. Prognosis is very good as these are benign lesions that do not tend to recur [9].

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How to Approach Internal Jugular Vein Aneurysm; A Rare Cause of Neck Mass

Abstract

Venous aneurysms are rare entities especially while presenting neck mass. Internal Jugular vein anuerysms comprise a small part of all venous aneurysms.Natural history of the pathology depends on anatomic location. Surgical intervention is spared for symptomatic cases. We present a15 year old male who admitted to otorhinolaryngology clinic with expansile right lateral neck mass with out any pulsation. Physical examination revealed a normal morphology of cervial region. When the patient was asked to strain, an expansing soft painless mass appeared in the right supraclavicular region. The mass disappeared when the patient breathed normally. Lateral cervical cyst was suspected. Ultrasonography and magnetic resonance imaging with venography sequences were ordered. Dynamic measurements showed enlargement of right internal juguler vein with cross sectional diameter of 39 mm at proximal segment of the vein and reaching 59 mm vertically. Echocardiographic evaluation and thorax imaging showed no accompanying pathology. Doppler ultrasound showed well mucosal lining with substantial muscular layer without any thrombotic focus. Direction of flow was toward subclavian vein. Conservative approach was preffered for the case. Patient was followed up on for 1 year with no additonal symptom.

Keywords: Jugular vein; Aneurysm; Neck mass

Introduction

Internal jugular vein aneurysms and phlebectasias are the most common venous malformations in the head and neck region. Venous aneurysms are divided into two as primary and secondary aneurysms [1]. Secondary ones are mainly due to trauma, infection, inflammation, venous valve insufficiency and arteriovenous malformations. Primary ones are rare and focal saccular or fusiform dilatations of the veins. No incidence was reported in the literature but it is known to be equal between male and female. A venous aneurysm can yield symptoms at any age.

The pathology is rather benign, owing to the localization, they can lead serious complications such as thrombosis, pulmonary embolism, rupture and bleeding and pressure over neighbouring structures. A clear aetiology has not been yet established. Recent literature states that structural changes take place in the vessel wall due to increased matrix metalloproteinases [1]. The most common location for a venous aneurysm is lower extremities with popliteal vein is the leading one. Deeper locations are prone to be related with thrombosis and pulmonary embolism [2]. The symptomatology of the entity includes mass with pain and swelling. Surgical intervention for asymptomatic internal juguler vein aneuryms is generally due to cosmetic expectations opposing aneurysms of deep venous systems.

Case Report

15 year old male applied to otorhinolaryngology clinic with expansile right lateral neck mass with out any pulsation. Physical examination revealed a normal morphology of cervial region. When patient is asked to strain an expansing soft painless mass appeared in the right supraclavicular region (Figures 1 & 2). As the Valsalva manuever was prolonged, the mass continued to swell. Nevertheless swelling disappeared when the patient breathed normally. Initially a lateral cervical cyst was suspected. Ultrasonography and magnetic resonance imaging with venography sequences were ordered. Static magnetic resonance imaging of neck did not reveal any pathology. Dynamic measurements showed enlargement of right internal juguler vein with cross sectional diameter of 39 mm at the proximal segment of the vein and reaching 59 mm vertically (Figures 2 & 3). Evaluation of thorax was achieved with computed tomography which also showed dilatation at the proximal part of the jugular vein (Figure 4). Echocardiographic evaluation and thorax imaging showed no accompanying pathology. Doppler ultrasound showed well mucosal lining with substantial muscular layer without any thrombotic focus (Figure 5). The lesion was reported as fusiform internal jugular vein aneurysm. Consultation with cardiovascular surgery was done and conservative approach was preffered. Patientwas followed up on for 1 year with no additonal symptom (Figures 1-5).

Figure 1: Doppler and classical ultrasound view of the lesion when it was not dilated.

Figure 2: Doppler and classical ultrasound view of the lesion when the patient was asked to strain.

Figure 3: Magnetic resonance imaging of the patient with venography revealed dilated vein.

Figure 4: Evaluation of thorax was achieved with computed tomography which also showed dilatation at the proximal part of the jugular vein.

Figure 5: Patient’s external appearance was shown in the photo.

Discussion

Patients who admit to otorhinolaryngology clinic with neck masses are applied a series of examinations. After physical examination ordering ulstrasonography generally gives enlightening information about the nature of the mass. Sometimes the mass can be dynamic such as laryngoceles, communicating cysts or blood vessels. In such cases patients should be asked to strain to swell the mass. Cervical adenitis, cystic hygroma, thyroglossal duct cysts, dermoid cysts, branchial cleft cysts and arterial– venous malformations are the most common pathologies which sould be kept in mind for differential diagnosis. Cervial masses could emerge due to a long list of diseases, however laryngoceles, superior mediastinal tumors or cysts and jugular vein aneurysms swell with the Valsalva maneuver [3]. If an asymptomatic jugular vein aneurysm starts causing symptoms such as pain, the clinician should suspect thrombosis.

Paleri et al. stated that up to 10 % percent of the jugular aneurysms can be bilateral, therefore bilateral neck should be evaluated and followed up with doppler ultrasound [4]. According to the liaterature because of risk of thrombosis in IJV aneurysm is less than 1%, in most of the cases conservative approach is preffered [5,6]. Because accompanying jugular vein thrombosis can complicate the case, due to increased risk for massive pulmonary embolism, some prophylactic measures, such as major venous vessel trunk isolation, can be taken.

Differentiating that whether the lesion is primary or secondary is the most important part because while the primary ones are more likely to be congential anomalies, a secondary anerysm is most likely due to highly mortal pathologies such as tumoral compression, thrombosis of vessel or other causes of vascular occlusion. According to the literature venous dilatation in pediatric age groups are generally fusiform in structure and symptomatic.

Conclusion

Primary venous aneurysms are rare and generally congenital. Careful follow up is an appropriate treatment. In case of complications such as thrombosis or rupture occur, interventions should be held. Nevertheless secondary ones should be intervened immediately due to the fact that they can be presenting symptoms of highly mortal conditions such as tumoral compression etc.

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Review on Euphorbia neriifolia Plant

Abstract

The present review is an attempt to highlight of Euphorbia neriifolia – Indian ethno-medicinal plant which was to be scientifically proved with different pharmacological activities such as laxative, carminative, bronchitis, tumors, leucoderma, piles, inflammation, enlargement of spleen, anemia, ulcers, fever and for wound healing along with some harmful effect to human being especially latex of plant.

Keywords: Euphorbia neriifolia; Herbal drugs; Medicinal plants; Wound management, Latex

Introduction

Medicinal plant usage is as old as humankind in the therapeutics. There are about 45,000 medicinal plants species in India. The officially documented plants with medicinal potential are 3000 but traditional practitioners use more than 6000. Bioactive compounds in plants have also been utilized for additional purposes, namely as arrow and dart poisons for hunting (several Aconitum species), poisons for murder, hallucinogens used for ritualistic purposes, stimulants for endurance, and hunger suppression, as well as inebriants and medicines. The plant chemicals (bioactive compounds) used for pharmacological or toxicological effects are largely the secondary metabolites. These secondary metabolites called bioactive compounds can be classified into several groups according to their chemical classes, such alkaloids, terpenoids, cardiac glycosides, saponins, steroids, limonoid, tannins, flavonoids, and phenolics [1]. In 18^th century and before that, the plants are major source for the treatment of different diseases and infections.

Now a day’s some of the plant derived natural products that includes vinblastine, vincristine, taxol, podophyllotoxin, camptothecin, digitoxigenin, gitoxigenin, digoxigenin, tubocurarine, morphine, codeine, aspirin, atropine, pilocarpine, capscicine, allicin, curcumin, artemesinin and ephedrine among others are also used as drug in pure form or in crude form or mixture. Some of them are synthesized synthetically but about 121 (45 tropical and 76 subtropical) major plant drugs have been identified for which no synthetic route is currently available (Figure 1).

Figure 1:

According to the World Health Organization (WHO) till 2003 about 80% of the population of developing countries are unable to afford pharmaceutical drugs, so they goes to plant based medicines to sustain their primary health care needs [2]. 252 drugs are considered as basic and essential by the WHO and out of those 11% are exclusively of plant origin and a significant number are synthetic drugs obtained from natural precursors. India has an official recorded list of more than 45,000 plants species and estimated list of more than 7,500 species of medicinal plants growing in its 16 agroclimatic zones under nearly 63.7 million hectares of forest courage [3].

Euphorbiaceae, the spurge family, comprises five subfamily, 49 tribes, some 7300 species and 283 genera of flowering plants distributed primarily in the tropical regions [4,5]. The largest genus of family Euphorbiaceae is Euphorbia with about 1600 species. They range from annual weeds, vines, succulents, herbs (Phyllanthus amarus), shrubs (Ricinus communis) and trees (Phyllanthus emblica). In several species of Euphorbia, the stem is modified to perform photosynthesis. There are more than 35 species are found in tropical, subtropical and warm temperate regions of South-East Asia; Vietnam has more than 24 species, Thailand has 25, Sumatra has 6, Java has 5, Borneo has 5, Philippines has 6, Sulawesi has 5, Lesser Sunda Islands has 11, Moluccas has 7 and New Guinea 15, Australia has 45 species [6]. In our country, the family is represented by several genera such as Euphorbia, Ricinus, Phyllanthus, Croton, Pedilanthus, etc. It is characterized by the presence of white milky latex that exudes when broken and which is more or less toxic, and some are useful as a source of oil or wax. The flowers are always unisexual. The leaves are stipulate or exstipulate, petiolate, alternate (e.g. Ricinus communis), simple, entire or deeply lobed or trifoliately compound (e.g. Hevea brasiliensis) and with unicostate or multicostate reticulate venation. In xerophytic species of Euphorbia, leaves are reduced or absent.

The Euphorbia is named after a Greek surgeon called Euphorbus. He was physician of Juba II who was the Romanised king of a North African kingdom, and is supposed to have used their milky latex as an ingredient for his potions. The latex of these species has different medicinal application along with some poisonous effect. Euphorbia neriifolia Linn (Indian Spurge tree, Hedge Euphorbia commonly known as Snuhi) belong to the family Euphorbiaceae, is one of the different species of Euphorbia genus plants, with wide range of local medicinal uses throughout the areas in which it is grown. This is one of the herbs extensively used in the Indian system of medicine. They all have latex and a unique flower structure. Euphorbia neriifolia plant is reported to contain sugar, tannins, flavonoids, alkaloids, 24-methylene cycloartenol, triterpennoidal saponins, etc. As Euphorbia neriifolia plant is selected for the review because of wide variety applications in the traditional medicines such as for the treatment of abdominal troubles, bronchitis, tumors, leucoderma, piles, inflammation, enlargement of spleen, anemia, ulcers, fever and in chronic respiratory trobles [7]. It used as analgesic, hepatoprotective, immunostimulant, anti-inflammatory, mild CNS depressant, wound healing, redioprotective agent [7]. A significant percentage is succulent, but they are mostly originating from Africa and Madagascar.

Different Names of The Plant

a) Hindi name – Sehund, Danda thukar [8].

b) English name – Common milk hedge, Holy Milk Hedge, Dog’s Tongue

c) Arabic name – Jakum

d) Kannada name – Male kalli

e) Marathi name – Thor, Tridhara Nivdunga

f) Malayalam name – Illa kalli

g) Punjabi name – Thor

h) Telugu name – Akujemuddu

i) Tamil name – Ilaikalli

j) Sanskrit – Snuhi

k) Latin – Euphorbia neriifolia

l) Ayurveda – Sthavara visha varga, Upavisha

Plant Profile

a. Botanical name: Euphorbia neriifolia

b. Family: Euphorbiaceae

Scientific Classification

A. Kingdom: Plantae

B. Subkingdom: Tracheobionta (Vascular plants)

C. Superdivision: Spermatophyta (Seed plants)

D. Division: Magnoliophyta (Flowering plants)

E. Subfamily: Euphorbioideae

F. Tribe: Euphorbieae

G. Class: Magnoliopsida (Dicotyledons)

H. Subclass: Rosidae

I. Order: Malpighiales (Figure 2)

Figure 2: Genus: Euphorbia

Species [9]:

a) E. nerifolia linn – Patra Snuhi

b) E. nivulia Buch – Ham

c) E. antiquorum Linn – Tridhara Sehunda

d) E. trigona Haw – Tridhara Sehunda bheda

e) E. royleana Boiss – Thuhara

f) E. Tirucalli– Kanda snuhi

Distribution

Euphorbia neriifolia grows widely around the dry, rocky and hilly areas of north, central and South India mostly in Deccan Peninsula and Orissa. It is indigenous plant of South Asia, but now locally cultivated and naturalizing in Sri Lanka, India, Burma (Myanmar), Bangladesh, Thailand and throughout the Malaysian region except for Borneo; also occasionally cultivated in other topical regions. It is also found in E. Asia – S. China, Vietnam, and New Guinea [6]. Euphorbia is an herb and deciduous. The parts of the plant that grow above the ground are used to make medicine.

Morphological Description

Euphorbia neriifolia is cultivated in gardens, and is apparently spontaneous. Small erect fleshy glabrous shrub, erect, branches ¾ in diameter jointed cylindric or obscurely 5-angled with sharp stipular thorns arising from thick subconfluent tubercles in 5 irregular rows like cactus. The branches are 2-4 meters high, the trunk and older branches are grayish and cylindrical; medium branches are being slightly twisted, stoud, freshy, and 4 or 5 angled or winged; younger ones are usually 3-winged, wings labulate with a pair of stout, sharp, 2- to 4- mm long spines rising from the thickened bases at each leaf of petioles-scar [7]. Leaves are succulent, deciduous, 6-12 inch long, terminal on the branches, waved narrowed into a very short petiole. The leaves are arise from the sides of wings towards the end of the branches, are fleshy, oblong-obviate, 5-15cm long, or in young plants somewhat longer, painted or blunt at the tip [7]. This plant is leafless for most part of the year, except during monsoon when fresh leaves appear.

Inflorescence or the arrangement of flowers in a bunch on the plant is “cyathium” type, means one female and several male flowers are found on a same bunch. Female flowers consist of a trichambered ovary, which usually elongates in fruits. Male flowers many, bracts linear. Female flowers rarely developed. Each chamber contains an ovum. Involucres are yellowish 3-nate, the lateral ones of the cymes shortly thickly pedicelled, central sessile; lobes large, erect, roundish, cordate, fimbriate; glands transversely oblong; bracteoles most abundant, fimbriate. Fruits are three chambered, tricoccaus, but so deeply divided that it has the appearance of 3 radiating slender follicles.

Botanical Description [10]

Euphorbia neriifolia, is a bitter, xerophytic, prickly, succulent shrubby, fleshy, large, erect much branched shrub, which sometimes grows into a small tree of 2-8 meters height or more with rounded branches cactus like plant. The tree looks somewhat like a cactus but with large, persistent leaves on younger parts of the plant, and growing up to 8 meters [4,11].

Stem: Green and cylindrical stem and large branches also being round and terete, spiral ridge portion, Sharp stipular thorns, with hollow space in centre containing white reticulate mass. The younger branchlets are somewhat verticillate, with two or more whorls without articulations, fleshy, cactus-like, swirled, light-green, glabrous, 8-30 (-40) mm thick, often leafless, and spine shield in 5 distinct rows on more or less distinct angles (not winged) which are visible for a long time [12]. The trunk and older branches are being grayish and cylinder. Bunches of succulent thick leaves occurs on the branches [4]. Central meristem is prominent throughout plastochronic phases. There is close histogenic relationship between central and peripheral meristem [13]. The leaves arise from the sides of wings towards the end of the branches.

Leaves: The fresh young leaves are simple, dark green in colour having leathery texture. The surface is glabrous with reticulate venation. The average leaf size is (8-14±2) cm (length) and (4- 8±2) cm (breadth) and (1.3±0.2) mm (thickness) with pointed and acute tip [14]. Peri-clinical divisions in the third and fourth layers of peripheral meristem initiate the leaf [4]. During vegetation period they are deciduous but in the late summer they fall.

Stippular thorns: The spines are short, about 4-12 mm long arising from the ribs, grayish brown to black in color, sharp, persistent, from low conical truncate distant, spirally arranged tubercles 2-5 mm height and 2-3 cm apart [4,12].

Flowers (terminal, corymbose): Both male and female flowers are found in the same bunches of the herb. Flowers when viewed as a whole, looks like a single flower. 3 to 7 flowered cymes or panicles appearing laterally in the axils of the upper leaves on short, rigid and forked peduncles, Flattened-globose, 1.5-2 mm x 4-5 mm, reddish, prominent in groups of tree, the central one is subsessile, the lateral ones with apeduncle of 6-7 mm, cyathial glands 5 oblong, 1-3 mm broad. Corolla absent but the involucres has two nearly round to ovate, bright red bracts 3-7 mm long. Inflorescence or the arrangement of flowers in a bunch on the plant is cyathium type (one female and several male flowers are found on a same bunch) [12]. Basically, male flowers many, bracts linear while female flowers rarely developed. Flowers and fruits occurs during the month of December to May [4].

Fruits: Fruits (capsules) are three chambered or 3-lobed, smooth, stigmas slightly dilated and minutely toothed with 10-12 mm in diameter [4].

Latex: Latex is a milky-sap-like fluid found in cells or vessels and usually executed after tissue injuries that make up the laticiferous system [13].

Cultivation Needs: Needs full exposure to the sun but can also succeed to grow in light shade. They prefer rocky areas for the growth. They need well drained soil. Grows well in dry place and rocky area in villages of all over India [15-17]. It needs no maintenance. It is a moderately fast grower, and will quickly become large landscape masterpieces in just 3-5 years. Water regularly during the active growing season (at least weekly) from March toSeptember but no water should ever be allowed to stand around the roots. Keep almost completely dry in winter.

Chemical Constituents

Phytochemical investigations on Euphorbia neriifolia yielded in the isolation of several classes of secondary metabolites, many of which expressed biological activities such as Euphol (8,24- euphadien-3β-ol), monohydroxy triterpenes, nerifoliol, taraxerol, flavonoids, steroidal saponins, sugar, tannins, alkaloids, β-amyrion, glut-5(10)-en-1-one, cycloartenol, 9,9-cylolanost- 20(21)ene-24-ol- 3-one (neriifolione), and triterpenoidal saponin [18,19]. Chemical constituent present in different part of plant: Euphol (Whole plant, bark, latex, root); friedelan-3 and 3β-ol, D:B-friedoolen- 5(10)-en-1-one, glut-5(10)-en-1-one and taraxerol (stem, leaves); n-hexacosanol, euphorbol, hexacosanoate, 12-deoxy-4β- hydroxyphorbol-13-dode-canoate-20-acetate and pelargonidin- 3,5-diglucoside (bark); 24-methylenecycloartenol and tulipanindiglucoside (bark, root); nerifoliol (latex), cycloartenol, euphorbol, ingenol triacetate, 12-deoxyphorbol-13,20-diacetate, delphinidin- 3,5-diglucoside (root) [19-21] (Figures 3 & 4).

Figure 3:

Figure 4:

Latex portion contain 69 – 93.3% water and water soluble and 0.2 – 2.6% caoutchouc [22,23]. The latex of E. neriifolia is an active ingredient of many Ayurvedic formulations like Abhaya lavana, Avittoladi bhasma, Citrakadi taila, Jatyadi varti, Snuhidugdhadi varti, Snuhi ghrta and Jalodarari ras. It (gum resin) was found to contain Euphol, neriifoliol, neriifolene, Euphorbon, Resin, gum, caoutchouc, malate of calcium, monohydroxy triterpene, taraxerol, β-amyrion, glut- 5-(10)-en-1-one, neriifolione and cycloartenol [24].

Fresh latex yields 10.95% solid with 18.32% total resinous matter, and 24.50% and 16.23% of total diterpene and triterpene respectively. A gum resin which is the active principle, traces of an alkaloid; wax, caoutchouc, chlorophyll, resin (2.40%), tannin, sugar, mucilage, calcium oxalate, carbohydrates albuminoids, “gallic acid quercetin, a new phenolic substance and traces of an essential oil”. Neriifolin-S and neriifolin, 9,19-cyclolanost-22(22’),24-diene- 3β-ol (Neriifoliene), 5-eupha-8,24-diaene-3β-ol (Euphol), Neriifoliene and euphol, 9,19-cyclolanost-20 (21)-en-24- ol-3-one (Neriifolione), cycloartenol, Neriifoliol, Lectin, etc are the chemical constituents extracted from fresh [25-29] or dried latex [30,31] of E. neriifolia. The leaves of Euphorbia neriifolia L. were found to be highly fibrous (nearly 15.36%). It may contain suberin or cutin, some amount of carbohydrates, cellulose and lignin. It contains higher amount of calcium oxalate crystals and starch than stem and leaves. It contain high values of total ash, and smaller values of acid insoluble and water soluble ashes. The leaves of Euphorbia neriifolia L. were found to be rich in calcium and potassium [32]. The results of phytochemical screenings of hydro-ethanolic, petroleum ether, benzene, chloroform, ethyl acetate, ethanol and aqueous extracts of leaves mainly revealed the presence of proteins, glycosides, alkaloids, phenolics, flavonoids, saponins and terpenoids in appreciable, moderate and trace amount. The proteins and amino acids were possessed in negligible amount [14].

In one of the study, the hydroalcoholic extract of E. neriifolia was found to contain sugar, tannins, flavonoids, alkaloids, 24-methylene cycloartenol, and triterpennoidal saponins on preliminary phytochemical analysis and there is absence of fixed oils and glycosides. Several triterpenoids like Glut-5-en-3β-ol, Glut-5(10)-en-1-one, taraxerol and β-amyrin have been isolated from the powdered plant, stem and leaves of E. neriifolia. The leaf extracts in the water and organic solvents such as chloroform, ethanol, ethyl acetate, and butanol of E. neriifolia were found phlobotannins, flavonoids, saponins, tannins, terpenoids, phenols and cardenoloids [33,34].

a) Moisture content: Leaf 73.8%, Stem 62.4%, Bark 86.9% Whole plant 78.6 [35]./p>

b) Oil content: Leaf 2.46%, Stem: 3.56%, Bark 4.95%, Whole plant 3.87% [35].

c) Polyphenol content: leaf 4.67%, Stem 9.63% Bark 12.68% Whole plant 11.49% [35].

d) Hydrocarbon content: leaf 0.42%, Stem 2.58%, Bark 2.93, Whole plant 2.28% [35].

Pharmacological Uses

Plants are bitter, laxative, carminative, acrid, pungent, improves appetite, abortifacient, digestive, expectorant, depurative, febrifuge, stomachic, vermifuge, useful in abdominal troubles, bronchitis, tumors, loss of consciousness, asthma, leucoderma, piles, inflammation, enlargement of spleen, anemia, ulcers, cutaneous diseases, dropsy, dyspepsia, pain, flatulence intermittent fever, fever and in chronic respiratory troubles [36-38].

a. The leaves are diuretic. The leaves are heated, squeezed, and the sap taken, sometimes with salt, to treat asthma, wheezing in babies, colds, aphrodisiac, and stomach upset. The leaves are also used to treat fevers, coughs and colds, carminative, stomachic and expectorant, chronic respiratory troubles, bleeding piles and diabetes [34,39,40]. Applied externally, the sap is used to treat infected nails and to relieve earaches. The expressed juice of the leaves is reported as very effectual in relieving the paroxyms of spasmodic asthma. The anti-inflammatory and analgesic activity of hydro alcoholic leaves extract of Euphorbia neriifolia is due to the presence of flavonoids [41].

b. In a study, E. neriifolia leaf extract was found to be a potent analgesic, anti-inflammatory, mild CNS depressant, wound healing activity along with humoral and cell mediated immunostimulating activity [42]. E. neriifolia reduced serum lipid profile and glucose signifying catabolic property with added in vivo and in vitro antioxidant activity.

c. The bark has been used as a strong purgative. The root is considered antiseptic, antispasmodic, purgative and local rubefacient activity [34]. Mixed with black pepper, it is employed in the treatment of snake bites both internally and externally.

d. The latex also reported its oral efficacy and safety on adjuvant arthritis, skin warts, and earache [37]. In a 14-day repeated dose sub-acute toxicity study, the drug showed to possess striking anti-arthritic activity. The white, acrid, milky juice (latex) is internally a purgative and externally it has rubefacient properties. As drastic purgative, it is given in combination with other medicines such as chebulic myrobalan, longpepper, trivrit root and which are kept steeped in it in cases of ascites, anasarca and tympanitis. The latex juice is also applied to remove warts and similar excrescences and to afford relief in earache; mixed with shoot it is used as an anjan in ophthalmia; mixed with margosa oil it is used as an application in rheumatic affections. The juice is largely used with clarified or fresh butter as an application to unhealthy ulcer and scabies and applied to glandular swellings to prevent and suppuration. It is expectorant, pungent and is thus used in treating tumors, arthritis and abdominal pains. Turmeric powder mixed with the milky juice of Euphorbia neriifolia is recommended to be applied to piles. The tribal population of Chattishgarh region uses the milky latex as an ingredient of aphrodisiac mixture [37,43].

e. 0.5% and 1% sterile water soluble fraction of E. neriifolia latex was evaluated for wound healing activity in guinea pig. E. neriifolia latex showed increase in collagen and DNA content improving the tensile strength. It also showed increased epithelization and angiogenesis indicating potential wound healing property [7,44]. There is report of its anti-inflammatory and antiarthritic activity of a novel triterpene (Nerifolione) isolated from the latex of E. neriifolia along with total extract of latex in acetone.

f. Antibacterial effect was found of the leaf extract of E.neriifolia in the ethanol and chloroform when was tested against the different bacterial organisms and it was believed to be due to the presence of tannins, phlobatannins, saponin, cadenoids, phenol, terpenoids and flavonoids which have been shown to possess antibacterial properties. The water and ethyl acetate extract exhibited very less activity [31].

g. Analgesic and Anti-inflammatory study had been carried out of the 70% hydroalcoholic leaves extract of E.neiifolia by using tail flick method and the Carrageen induced hind paw edema method, which had led to the confirmation of the analgesic and anti-inflammatory activity of E.neriifolia. The analgesic effect of leaf hydroalcoholic extract was also evaluated using Eddy’s hot plate method in albino rats. It shows significant analgesic and Anti-inflammatory activity as compared to the standard drugs, diclofenac sodium and indomethacin respectively [7,45]. The anti-inflammatory activity of petroleum ether fraction of latex of E.neriifolia is also studied on the rat by paw edema method. The pet. Ether fraction contains triterpenes euphol, nerifoliol and cycloartenol having anti-inflammatory and analgesic activity [7,46].

h. E. neriifolia leaf extract was found to be mild depressant on central nervous system at higher doses. E. neriifolia leaf extract at 400 mg/kg dose potentiates pentobarbitoneinduced duration of sleep. Leaf extract did not have any motor in coordination or ataxia on muscle grip performance in mice effect in rota rod test and showed statistically insignificant reduction in locomotor activity. The elevated plus-maze introduced by Lister for mice is based on the apparent natural aversion of rodent to open and high spaces which forms the basis for its use in the measurement of anxiety as well as short-term memory. E. neriifolia at 400 mg/kg dose exhibited pronounced antianxiety activity by significantly increasing preference to open arm percent number of open arm entries and percent time spent in open arm. The results of the present study showed that the mice spent a significantly higher time in the open arm and also entered them more frequently signifying the anti-anxiety activity.

i. The E. neriifolia leaves extract and isolated flavanoid significantly restored the antioxidant enzyme level in the kidney and exhibited significant dose dependent protective effect against DENA induced nephrotoxicity, which can be mainly attributed to the antioxidant property of the extract. This study paid way for the use of hydroethanolic extract of E. neriifolia as anti-carcinogenic potential and for protection of ENF against DENA induced renal cancer [47]. DENA exposed animals showed alterations in normal hepatic histo-architecture, which comprised of necrosis (N), dilated sinusoids and vacuolization of the cells. Mice treated with E. neriifolia lower (ENL) and higher (ENH) dose and ENF before intoxicated with DENA showed that the liver cells were normal, with very little necrosis. The ENH and ENF protect the hepatic tissue against DENA-induced hepatic carcinoma [48].

j. The extract of E. neriifolia leaves possesses antioxidant properties and could serve as free radical inhibitors or scavengers, acting possibly as primary antioxidants. The antioxidant activity of ethanolic extract of E. neriifolia was evaluated by various antioxidant assays such as TAC, FRAP, FTC, TBA and non specific activity. All the result of anti oxidant activities found were compared with standard antioxidants. The highest antioxidant property was found for the ethanolic leaf extract of E. neriifolia [7,49]. The catabolic and antioxidant effect of the extract may be due to presence of saponins and flavanoids [50].

k. The hydro-alcoholic extract of dried leaves of Euphorbia neriifolia possessing significant protection against E.coli induced abdominal sepsis, significant increase in total leucocyte count, differential leucocyte count and phygocytic index were determined. It shows significant activity [51].

l. Different doses of aqueous extract E. neriifolia were administrated to both sex of Wister albino rats along with standard frusemide. The collected urine sample were tested for concentration of Na+ and K+ by flame photometer, the tested samples increases the urine volume as an effective hypermatraemic and hypercholaemic diuretic [7,52].

m. The anti-diabetic and anti-hyperlipidemic activity of ethanolic extract of leaves of E. neriifolia was studied on the type-2 diabetic rats. After 21 days of oral administration of 200 – 400 mg per kg of etanolic extract produced decrease on fasting blood glucose, triglyceride, cholesterol, LDL levels in HFD-STZ induced type-2 diabetic rats, on the other hand there was significant increase in HDL levels. It indicates that the ethanolic extract exhibits anti-diabetic potential along with potent lipid lowering effect after repeated oral administration [53].

n. Psychopharmacological profile of hydroalcoholic extracts of E. neriifolia leaves in mice and rats was studied and the result suggested that the leaf extract significantly reduces apomorphine induced stereotypyin mice at all doses. The result also suggested that, the leaf extract shows antipsychotic, anti antianxiety, anti-convulsant activity in mice and rats [7,54].

o. The hepatoprotective effect of saponin fraction of isolated from the leaf extract of E. neriifolia was studied on CCl4-induced hepatotoxicity on rat. During the study they found that cytosolic enzymes like SGPT, SGOT and ALP elevates in the blood and hepatic glutathione and SOD decreases [55].

Traditional Uses of E. neriifolia [34]

The plant has been used in Ayurveda, Unani and Sidha. A traditional uses of E. neriifolia (Sehund) as per Ayurveda are – to improve digestion strength (deepana); induces server purgation (rechana); useful in treating disorders of veta-dosha imbalance such as neuralgia, paralysis, constipation, bloating, etc; unctuous oily (snigdha); light to digest (leghu); etc [56].

a. The leaf of E. neriifolia is heated and tied over the area affected with pain and inflammation.

b. The fresh juice from the leaf is poured inside the ears to treat earache, to defrost skin warts, and in arthritis. The milk latex of Euphorbia neriifolia is applied over warts as part of treatment.

c. Oil processed from the leaf of E. neriifolia and sesame oil is used for external application to treat joint pain.

d. The paste of the leaf of E. neriifolia is applied over the skin to treat skin diseases.

e. The vaidhyas from ancient times used to use the milky juice exuded from the injured stems as drastic cathartic and to relieve earache. They are used as a drastic purgative in the enlargement of liver and spleen, syphilis, dropsy, general anasarca, leprosy, etc. It has been found beneficial for Asthma [6,34]. The method as found by a Ayurvedic doctor is by the prepared succus consisting of equal parts of the juice of this plant and simple syrup; administered in doses of 10 – 20 drops three times a day; has been found to relieve asthma attacks completely.

f. Latex is acrid, laxative, pungent and good for tumours, abdominal troubles and leucoderma. It is also used as a purgative, rubefacient, carminative, expectorant, whooping cough, gonorrhoea, dropsy, leprosy, asthma, dyspepsia, jaundice, enlargement of the spleen, colic and stone in the bladder. It is use to remove cutaneous eruptions and warts. It is liable to cause dermatitis [4,15]. The dried juice with some other ingredients used as a drastic purgative in the enlargement of liver and spleen, syphilis, dropsy, general anasarca, leprosy, etc. Juice is largely used with clarified or fresh butter as an application to unhealthy ulcers and scabies i.e. it is used for cleansing the abdomen in cases of poisoning and in severe constipation. When applied to glandular swellings it prevents suppuration. Mixed with Margosa oil it is applied to rheumatic limbs. The fresh milk latex of Euphorbia neriifolia is used in the preparation of ‘Kshara sutra’, applied for the medicated thread useful to treat piles and fistula or over external pile mass to reduce it. Turmeric powder mixed with the juice of Euphorbia neriifolia is recommended to be applied on piles. Thread steeped in the above mentioned mixture is used in ligaturing external Haemorrhoids [6,34]. Normally, as found by the survey, Asthma patients take the latex by mixing it with honey. Juice mixed with ghee is given in syphilis, in visceral obstructions and in spleen and liver enlargements due to long continued intermittent fevers. Externally the juice is applied to remove warts.

g. Root- bark boiled in rice-water and arrack is given in dropsy [6,34,57]. Root and stem is used as symptomatic treatment of snake bite, scorpion sting and as a antispasmodic. Root and milky juice mixed with black-pepper is employed in scorpion- stings and snake bites, both internally and externally but large dose causes irradiation and determatitis. The stem is roasted in ashes and the expressed juice with honey and borax is given in small doses to promote expectoration of phlegm and juice from fresh stem of E. neriifolia is added with honey and borax to treat cough and sore throat. Pulp of the stem mixed with fresh ginger is used to prevent hydrophobia [57].

h. Euphorbia is used for breathing disorders including asthma, bronchitis, and chest congestion. It is also used for mucus in the nose and throat, throat spasms, hay fever, piles, and tumors. Some people use it to cause vomiting. In India, it is also used for treating worms, severe diarrhea (dysentery), gonorrhea, and digestive problems [4].

i. The tribal population of Chhattisgarh region uses the milky latex as an ingredient of aphrodisiac mixture [7]. The juice of the plant is used in Gujarat for smearing cuts made by tapers on Borassus flabellifer (Linn) in order to prevent the palm from the attack of red weevil. Stem or leaf juice is used in case of cough and cold mixed with honey [58].

j. E. neriifolia latex is one of the constituents of “Kshaarasootra”, which is used in Indian medicine to heal analfistula. A multicentric randomized controlled trial carried out by Indian Council of Medical Research revealed that the long term out come with “Kshaarasootra” was better than with the surgery offering an effective, ambulatory and safe treatment for patients with fistula-in-ano [59].

k. Euphorbia neriifolia Plant used in different Ayurvedic medicines, some of them are listed here – Agnivrana Taila (for burns, boils, etc), Ayaskirti (for anemia, weight loss therapy, skin diseases, etc), Vishatinduka taila (for gout, numbness, skin diseases), Abhaya lavana (for liver and spleen disorder), Madhusnuhi rasayana (for skin diseases like eczema, psoriasis, diabetics, carbuncles, piles, tumors, goiter, iching, rheumatoid arthritis, etc), Shanka dravaka (for ascites, indigestion, liver and spleen diseases), etc.

Harmful Effects

The latex portion of the plant is actually regarded as the toxic part in the plant [10].

a. The plant is poisonous and skin contact with the sap can cause blistering: The milky latex or sap of Euphorbia species is found to be toxic and may cause intense inflammation of the skin and the eye. Ocular toxic reaction ranges from mild conjunctivitis to severe kerato-uveitis. Corneal involvement generally follows a typical sequence with worsening of edema with epithelial sloughing on the second day. It is believed that some species are more toxic than the others. Few cases have also been reported about the permanent blindness occurring due to the accidental inoculation of the Euphorbia neriifolialatex. When treated early and managed meticulously, the inflammation generally resolves without sequelae [60].

b. The leaves and roots is used as a fish poison [60].

c. The injection of the latex causes Irritation, Vomiting, Diarrhoea, Burning sensation in the abdomen, Convulsions and Coma. On contact with the skin there will be Burning of skin and vesication [61].

d. There will be Inflammation of eye and temporally Blindness if the milk of plant falls to the eye. Treatment for the person who has been come in contact with the latex can be washing the contact part with running water. It holds good even for the contact with the eyes [54].

The symptomatic treatment includes [12]:

a. On ingestion: Gastric lavage is recommended with normal saline or Activated charcoal.

b. On contact: with the skin – Topical corticosteroids are used, with Eye- Antibiotic eye drops, Tears substitute, IOP (Intra ocular pressure) lowering medications.

The post mortem investigation showed the Signs of inflammation of contact part, gangrenous patches in the stomach and rotten spleen. The medico-legal importance includes accidental poisoning, Homicidal and suicidal purposes, which are very rare and used for procuring criminal abortions [12].

Conclusion

Utilization of plants for medicinal purposes in India has been documented long back in ancient literature because they are essential for human survival. Traditional medicinal system is widely distributed in India. A major proportion of population mostly belonging to rural areas is still dependent on traditional system of medicines for their various health needs. Therefore, traditional and cultural medical knowledge has a catalyzing effect in meeting health care demands. From the available literature survey, it should clearly show that Euphorbia neriifolia L. serve as an important source of many therapeutic efficient chemicals. It is extensively used in an Indian medicine system in combination with other plants and natural products. This plant is useful in abdominal troubles, bronchitis, tumors, loss of consciousness, asthma, leucoderma, piles, inflammation, enlargement of spleen, anemia, ulcers, cutaneous diseases, dropsy, dyspepsia, pain, flatulence intermittent fever, fever and in chronic respiratory troubles due to present of different natural products as Euphol, monohydroxy triterpenes, nerifoliol, taraxerol, flavonoids, steroidal saponins, sugar, tannins, alkaloids, β-amyrion, proteins, glycosides, alkaloids, phenolics in appreciable, moderate and trace amount. This is one plant has been successfully used in many health problem since a long period of time for the treatment of wide variety of health issues. There is scope for developing newer drug molecule or mixture for the treatment of multiple diseases only by changing the dosage. The Euphorbia neriifolia L. is poisonous and skin contact with the sap can causes blistering.

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