Transient Osteoporosis of Hip in A Middle-Aged Man 

Abstract

Introduction: Transient Osteoporosis of Hip is a benign, acute onset, self-limiting disorder of unknown aetiology commonly seen in middle aged men and pregnant females.

Case Report: We report a case of acute onset sharp pain in right hip in a physician without history of antecedent trauma. The diagnosis of Transient Osteoporosis of Right Hip was made based on clinical and MRI findings. The probable cause can be attributed to long standing working condition. There was complete resolution of symptoms by conservative treatment in the form of analgesics and non-weight bearing.

Conclusion: High level of suspicion should be kept in mind when dealing with patients with sudden onset non-traumatic joint pain to avoid unnecessary investigations and surgeries.

Abbrevation: Osteoporosis; Arthralgia; Hip; Acute pain

Introduction

Transient Osteoporosis of Hip (TOH) is an acute, idiopathic, benign, self-limiting entity, more commonly seen in middle-aged men and women in third trimester of pregnancy or immediate post-partum period [1-4]. This disorder of unknown aetiology has a sudden onset, usually without any antecedent history of trauma or injury. We hereby report a case of Transient osteoporosis of hip affecting a middle aged male physician.

Case Report

A 38 year old physician reported with sudden onset pain in right hip joint since 2 weeks. The pain was severe sharp sudden in onset, increased with activities like walking, standing for longer duration, getting up from bed and relieved completely on rest. Being a physician himself, he first neglected the pain and went to a physiotherapist to try local modalities with limited relief. There was no history to trauma/injury to right hip, no history of morning stiffness, anorexia, fever, weight loss, night cries, skin rashes or fever. There was no history of alcohol consumption or smoking. On examination, the patient was walking with an antalgic gait. The local temperature and the skin condition over right hip were normal. The affected hip had generalized tenderness with terminal restriction of movements. His haematological investigations revealed a haemoglobin of 12.3gm%, Total leukocyte count of 5800/mm³, ESR of 32mm at the end of one hour, all of which were within normal limits.

Initial radiographs in form of Pelvis with both hips Antero posterior view and frog leg lateral view revealed no bony abnormality with maintained joint space. His synovial aspiration was normal in appearance and was negative for acid fast bacilli, gram staining and was sterile with no growth on culture and sensitivity. With no conclusive diagnosis, MRI of right hip joint was done which showed low intensity signals of T1 weighted image and a high intensity on T2 weighted image covering the femoral head, neck and extending to the intertrochanteric region (Figure 1). Thus, with the aforementioned classical features, a diagnosis of Transient Osteoporosis of right Hip was made. The conservative treatment was started in the form of non-steroidal inflammatory drugs was started. The patient responded drastically to the conservative treatment within 3 weeks from the initiation of treatment. Regular monthly follow-up till 6 months followed by bi annual and annual follow-up till 2 years was done. The patient showed no signs of recurrence or worsening of the symptoms and was completely normal (Figure 2).

Figure 1: Transient Osteoporosis of Right Hip.

Figure 2: Complete Resolution at follow-up.

Discussion

Ever since Curtiss and Kincaid [5] described this entity among 3 pregnant females as transitory demineralization of the hip, this term has been a topic of interest due to its unknown aetiology. Albeit, the most commonly affected joint is Hip, other joints such as knee, foot and ankle has not been an exception6.

Various hypothesis and causes have been stated as the plausible explanation for this disease namely the neurogenic hypothesis, viral infection, disuse osteopenia, non-traumatic reflex sympathetic dystrophy and localized ischaemia, but none has proved to be conclusive [6,7]. However, women with decreased bone mass and parathyroid hormone related protein in pregnant females especially in the later trimester has been proved to be a cause for this disease [8]. Hadidy et al. [9] in their retrospective study of 17 patients in a span of 7 years, reported a higher incidence of TOH as compared to osteonecrosis and postulated it to be due to long hours of standing. There was no possible cause of TOH in the present case. Being a physician, long standing can be a possible cause. Scharpira [10] in their study mentioned that left hip is more commonly involved and that the male to female ratio is 3:1. He also identified three distinctive phases of TOH.

Initial rapid aggravating phase characterized by intense pain which increases on weight bearing with functional impairment during the first month after the onset of symptoms. This phase remains for another 1-2 months and later progresses to the second phase where there is demineralization of the femoral head, neck and the intertrochanteric region without affecting the joint space on plain radiograph. Magnetic resonance imaging serves to be an investigation of choice with high sensitivity in this stage with non-homogenous marrow involving the mentioned areas. The final spontaneous regression stage usually lasts for about 3-4 month where there is complete resolution of clinical as well as radiological features. The diagnosis of TOH on radiography is often late but typical with periarticular diffuse osteopenia affecting the femoral head, neck and even the intertrochanteric region. It rarely affects the pelvis and the joint space even in advanced stages which differentiates it from osteonecrosis. There is decreased joint space in osteonecrosis with involvement of the anterosuperior region of the femoral head and sparing the neck and trochanter. Bloem [11] described the MR finding in TOH as ill-defined area of decreased signal intensity is seen on T1 weighted images, with an area of increased signal intensity on T2 images suggestive of bone marrow edema.

In the present case, MR imaging led to a conclusive diagnosis of TOH. Radionuclide scan can be beneficial with diffuse and homogenous uptake initially with a gradual decrease in late stages. It has high sensitivity but low specificity [7]. No Scintigraphy scan was performed for the present case. Differential diagnosis of rheumatoid arthritis, infective arthritis, monoarticular conditions like idiopathic chondromatosis and pigmented villonodular synovitis, osteoarthritis, primary/secondary bone tumour and tuberculosis of the bone should be kept in mind while dealing with the patients with non-traumatic hip pain. A possibility of reflex sympathetic dystrophy (RSD) should also be kept in mind. However, RSD is associated with history of re-surgery, sensory disturbances with trophic changes with a predilection toward small bones and different MRI pattern than TOH. While it is difficult to differentiate TOH from osteonecrosis of the femoral head in the early stages, careful clinical assessment can help to rule out the diagnosis. Apart from acute onset pain and antalgic gait, patients with osteonecrosis have resting pain, differential rotation positive and painful range of movements. Radiologically, the lesion is typically confined to anterosuperior aspect of the femoral head with joint space narrowing and radiolucent areas with sclerosis in the head sparing the neck and trochanter region. Furthermore, MRI in osteonecrosis shows segmental well demarcated lesion in the femoral head with double line sign which is a pathognomic feature.

Various treatment options have been proposed for TOH with conservative methods being the mainstay of the same. Nonweight bearing with a course of non-steroidal anti-inflammatory medications and assurance is required I almost all the cases. Oral and intra-articular steroid therapy, calcitonin and sympathetic blocks have been proposed by few with limited results [7]. Medical management with different forms of oral and intravenousbisphosphonates like alendronate, pamidronate, ibandronate and zolebdronate have been tried by few in the past with good results [12-14]. Bisphosphonates reduces the increased bone destructive activities leading to restoration of the bone mineralization and decrease in pain dramatically. Although it provides symptomatic relief, it does not change the course of the disease. No form of bisphosphonates was used in the present case. Hoffman et al. [15] and Guerra et al. [16] in their studies have stressed upon surgical intervention using core decompression in patients with severe pain and in cases which do not respond to the conservative treatment.

Conclusion

Transient Osteoporosis of Hip should always be kept as a differential in cases with acute onset pain in joint in middle-aged males. Observation, reassurance, non-weight bearing and nonsteroidal anti-inflammatory drugs remain the mainstay of this self-limiting condition. High level of suspicion can help to avoid unnecessary investigations and surgeries.

For More Articles: Biomedical Journal Impact Factor : https://biomedres.us

Knowledge, Attitude and Practice Regarding Hepatitis B & C among Dental Surgeons of Khyber College of Dentistry (KCD) Peshawar and Bolan Medical College (BMC) Quetta

Abstract

Viral hepatitis B and C are a major health concern worldwide, with 170 million people chronically infected and at risk of liver cancer, cirrhosis or liver failure. The modes of transmission include intravenous drug use, blood products, body fluids, tattooing, surgical procedures and sexual intercourse. Thus Health Care Professionals have a high exposure to HBV and HCV infection and are at risk to it. A cross-sectional quantitative survey on 84 House Officers was conducted in Dental Surgeons of Khyber College of Dentistry and Bolan Medical College through a semi-structured questionnaire. Out of total 84 subjects 44 were male and 40 were female, with mean age 24.7+ 1.44. The subjects had good level of knowledge regarding disease transmission, prevention and treatment, which was from 85-90%, generally positive attitudes toward patient care was 67.9% and 59.5% consider doctors at risk of infection. Over all.53% consider media as most convenient source of information. Needle prick was high as 48.3%. 91.7% candidates were vaccinated and some of them attained few lectures regarding hepatitis. Good knowledge which can be improves by formal training and follow of the preventive measures in dental care procedures.

Keywords: Hepatitis B and C; Dental House Officers; Knowledge; Attitudes; Practices

Abbrevation: HIV: Human Immunodeficiency Virus; HCV: Hepatitis C Virus, HBV: Hepatitis B Virus; PPE: Personal Protective Equipment; KCD: Khyber College of Dentistry; BMC: Bolan Medical College

Introduction

Medical and dental health care professional are more vulnerable to various infections like hepatitis B and hepatitis C viruses, staphylococci, streptococci, herpes simplex virus types 1, human immunodeficiency virus (HIV), mumps, influenza, rubella and other prevalent infectious agents [1]. Hepatitis has become one of the major health care problem of the world with about 170 million patients are chronically infected with hepatitis C (HCV) with 3-4 million new infections each year and 8000-10000 death occur each year. About 3% of the world population is affected by hepatitis C virus [2]. Worldwide, an estimated two billion people have been infected with the hepatitis B virus (HBV), and more than 350 million have chronic liver infections [3]. World Hepatitis Day observed May 19th aims to raise global awareness of hepatitis B and hepatitis C and encourage prevention, diagnosis and treatment [4].

Pakistan is also facing the brunt of this disease and reported prevalence of HCV about 4-7% and that of HBV is about 3-4% by different surveys reported from country [5,6]. The incidence of new cases of HBV is decreasing worldwide after universal vaccination [7]. Lack of education and awareness regarding its spread are the main factors contributing to this disease [8]. An estimated 100 million individuals worldwide are chronically infected with HCV. High prevalence rates have been found in Southeast Asian countries, such as Thailand, Malaysia and India. In Pakistan, the sero-prevalence of HCV is 6.7% in women and 1.3% in children [9]. The virus is mainly transmitted through transfusion of contaminated blood and blood products, sexual contacts, intravenous drug users, traditional health practice is also common in the region. It is an occupational hazard for health care providers and require adherence to universal precautions [10]. The objective of the study was to assess the knowledge, attitude, and practices regarding Hepatitis B and C among Dental surgeons and to compare the Knowledge, attitudes and practices among house officers of the two different public Sector Medical/Dental colleges.

Methodology

The study design was Cross Sectional Descriptive Study-KAP Survey. Structured self-administered questionnaire which was pilot test in KCD only before was used for knowledge, attitudes andpractices of Dental house officers regarding the Hepatitis B and C. The survey was conduct from October 2011 to December 2011 on all the House Officers of both colleges. A Purposive sampling technique with size of 84 was used, 40 house officers were from Khyber College of Dentistry and 44 from Bolan Medical College, Dental Section. Data were analyzed using SPSS version 16.0. Mainly Descriptive statistics were used. Categorical variables like gender and questions about knowledge and practices were described as frequencies and percentages while Continuous variables were described as means and range. Chi square tests were used for significance.

Results

With a response rate of 87.5% (84), where 47.6% (40) house officers were from Khyber College of Dentistry and 52.4% (44) house officers participated from Bolan Medical College, Dental Section. Table 1 show the mean age and sex wise participant of study.

Table 1: Socio demographic characteristics of the study population (n = 84).

Knowledge about HBV and HCV

About 99% answered that hepatitis cannot be caused through casual contact, such as holding hands or hugging. Regarding the knowledge of the disease, 100% (n=84) of the house officers knew that a HBV and HCV positive person carrier are having the risk to infect others and spread it. About the dangerous route of infection of hepatitis was very good and mainly all house officers identify the prick from a contaminated instruments/syringe (81) 96.4%, while small percent 1.2% mark the Oro-fecal route. The best preventive method for it was marked 100% respondents that using the sterilize instrument/syringes (Figure 1) While some dentists also specify the blood product and the use of disposable instruments. Knowledge about treatment was (62)73.8% answer that the treatment of hepatitis is possible and its cure partially from it, while (12)14.3% answer that from treatment the patients cure totally and (10)11.9% answer in negative that treatment do not cure from HBV and HCV. Mass media was reported mainly by respondents (52.4%) as the main source of information about HBV and HCV, Medical institute (26.2 %) as shown in (Table 2).

Table 2: More convenient way for information about HBV and HCV.

Figure 1: General Knowledge about Hepatitis.

Attitudes toward HBV and HCV

The most important question about Vaccination of Hepatitis B was positive and 77 (91.7%) students are been vaccinated against it and 8.3% has not done the vaccination. The attitude toward the believe in vaccination protection against Hepatitis B was up to the mark, 92.9% answer in positive and 4.8% was not believe in the vaccination. As shown in the Table 3, the changing of gloves was also taken positive by many house officers and 96.4% said it’s not wastage of time and it important for their protection. The interesting question about the attitude was that if you personally get infected with hepatitis B or C whom will you tell about it, the answer mostly answer was doctor which show their trust and the right person for their problem, 51.2% trust in doctor and secondly 16.7% said that they would tell their parents about the infection of hepatitis.

Table 3: Answers about Attitude questions asked from house officers (n = 84).

Practices Regarding HBV and HCV

Hand washing with Plain water was reported 7.1% of the times, soap/water 45.2% and the use of antiseptic solution 36.9 %. At the same question about 8% said they do not wash hand after every patient and the reasons they show was the shortage of time and interrupted or short supplies of soap or anti-septic solution. The use of personal protective equipment (PPE) masks and apron or overall were reported 41.7% (35) of the times, the protective goggles in OT or MOS were marked less 3.6% while the 59.2% of the respondents reported. Forty one House Officers (48.8%) reported needle pricks during the last one year whereas 1.2% said they didn’t remember about the pricks. Of those 41 House Officer about 76 % of the sample responded with 1-3 pricks in their last year career, while 19% (08) show the results of 4-5 times of pricks and the alarming results was more than 5 times prick in the last year, (Figure 2) and it was 05% of the all (Table 4 ).

Table 4: Answers about Attitude questions asked from house officers (n = 84).

Figure 2: Bar chart showing different means of hands washing by house officers.

Comparison of Khyber College of Dentistry (KCD) with Bolan Medical College (BMC)

The knowledge about Hepatitis of both colleges was of good level, all house officers of both colleges were aware of Hepatitis and its risk from carrier. Protection through Vaccination in KCD dental house surgeons was 97.5% as compare to 87.6% of BMC which is significance with p-value 0.003. Changing of gloves for was masked by 97% of both institute house officer as not the wastage of time, which shown their behaviour to gloves changing and protection. Needle prick in the last one year was more and was alarming one, and was more about 61.5% in KCD and 36.4% in BMC house officers. (Figure 3) and (Figure 4) Exposure to HBV & HCV patients was high as about 82% in both hospitals house officer and they treated and expose to hepatitis positive patients from 1 to 20 or more than 20 no of patients. Screening policy of KCD was good and each and every patient was screen before any dental treatment and for minor or major oral surgeries, whereas in BMC there was no such screening policy for every patient (Table 5).

Table 5: KAP of Khyber college of Dentistry Vs Bolan Medical College.

Figure 3: House Officers exposed to No. of pricks in past one year.

Figure 4: Training on HBV and HCV at Khyber College of Dentistry and Bolan Medical College.

Discussion

There have been studies regarding the knowledge, awareness and practices of hepatitis B & C. However, the majority of these have reported a different level of knowledge and attitude, depending on their study population education and awareness, which limits the generalize ability of their results to the general population. On the other hand, cultural diversity in the different cities of Pakistan also necessitates the performing separate population-based studies in the various regions.

There have been studies [11-13]. Regarding the knowledge/ awareness, attitude and Practice or believes hepatitis B and C in Pakistan. The objective of this study was to determine level of knowledge and attitude about HCV and HBV in dental surgeons and practices with patients reporting for dental treatment. Regarding the availability of a successful treatment of HBV or HCV 15.4 % were aware about patients cure completely from it, where about 73.8% responses that they cure partially from treatment and 11.9% response that no such treatment exists for disease. This is much better than a study done among medical students of Karachi; their response was 48.2% [14]. Use of Sterilize instruments was chosen by 100% of working house officers and some also identified the use of disposable instruments.

Figure 5: Needle pricks in Khyber College of Dentistry Vs Bolan Medical College.

About 96.4% identified the prick from contaminated instruments as the dangerous risk for dentist (Figure 5). The knowledge about the route of transmission was almost 100% know the blood transfusion. The results of our study was even more knowledge then the study done by Abbasi Shaheed hospital on five dental institutes of Karachi as their knowledge about route of transmission was 86.16% [15]. 91.7% of the house officers were vaccinated against Hepatitis B and they believe that through vaccination the prevention is possible and respond was 92.9%, which can be comparing with study done on medical students in Bangladesh where 85% was aware of vaccination and 65.5% were vaccinated [16] and 63% was in south Korea dentist [17] which is less than our study. Similarly 96.4% don’t consider the changing of gloves as wastage of time and resources. About the doctor risk of infection while working at hospital/clinic was much positive as 59.5% said yes to the question and 29.8% responded that they are not at risk at all.

The use of personal protective equipment was good in practices; Gloves were used almost while treating patients but at same short supplies were reported by 5.7%. In study on dental care workers in Japan 25% deny to change gloves for every patient while 17% don’t wear it [18]. Mask and overall used in surgical procedures was 59.6%, while the remaining percent mark all the protective equipment’s i.e. gloves, mask, overall, goggles and rubber boots. The use of protective and barrier method in dentist of Durban, South Africa was also high as it were reported by our study respondents [19]. Quite a big percentage (82.1%) of our respondents was exposed to HBV and HCV patient/s in their professional career. About 1-30 patients with HBV and HCV positive are been exposed or treated by house officers. Mostly used mask, double gloves, goggles, sterilize/disposable instrument and apron, while masks, gloves and apron was used the most. This was in contrast with study done on Iranian surgeons who use double gloves only 24%.

Conclusion

A study was conducted to evaluate the magnitude of awareness regarding transmission of Hepatitis B and C amongst the Dental house surgeon. This study also focused on the practice of dental health care professionals regarding the protective and preventive measures to prevent the transmission of hepatitis and infection control. “Safe practices” would decrease the diseases burden and will save resources for the Public and Govt. Our health care planners need to understand it and our teaching and training programs need complete re-orientation to achieve this goal [20-25].

For More Articles: Biomedical Journal Impact Factor : https://biomedres.us

Salvage Therapy of Infected Wounds of the Extremities Using 5% Acetic Acid and Povidone Iodine

Abstract

Aim: Infected surgical wounds of extremities increase patient mortality and morbidity, with extended hospital stay and significant economic burden. Bone and joint infections pose a formidable challenge to the orthopedic surgeon. Salvage therapy of infected wounds of the extremities using 5% acetic acid and providone iodine.

Objective: To determine outcome of infected surgical wounds treated with 5% acetic acid and povidone iodine, and to reduce burden of costly systemic antibiotic therapy and find out an alternate way of infected wound management.

Method: 20 patients 16 male and 4 female average age 45years range 25 to 65yeras with infected extremities wounds were treated in which half of the patients were treated by 5% acetic acid (Group A) and half were treated with povidone iodine (Group B).

Results: The average age of patients was 45 years with male to female ratio 4:1. In-group A the wound healing was 76% and in-group B it was 54% after three weeks. But at the end of 6th week 98% healing was seen in group A while 83% healing was seen in group B.

Conclusion: Surgical infected wounds of extremities treated with 5% acetic acid reduce patient morbidity, hospital stay and economic burden.

Abbrevation: CDC: Centers for Disease Control

Introduction

Infected surgical wounds of extremities increase patient mortality and morbidity, with extended hospital stay and significant economic burden. Bone and joint infections pose a formidable challenge to the orthopedic surgeon [1]. The high success rate obtained with antibiotic therapy in most bacterial diseases has not been obtained in bone and joint infections because of the physiological and anatomical characteristics of bone. The overall surgical site infection rate has been estimated by the U.S. Centers for Disease Control and Prevention (CDC) to be 2.8% in the United States [2].

We evaluate the risk of infection in each patient by considering patient-dependent and surgeon-dependent factors. Patientdependent factors include nutrition, immunological status, and infection at a remote site. By physical and lab investigation. Surgeondependent factors include prophylactic antibiotics, skin and wound care, operating environment, surgical technique, and treatment of impending infections such as in open fractures. Simply stated, it is much easier to prevent an infection than it is to treat it. Most common pathogens responsible for wound infection in extremities are Staphylococcus aureas. Pseudomonas aeruginosa is a classic opportunistic pathogen with innate resistance to many antibiotics and disinfectants. It is the most difficult nosocomial pathogen to be eliminated from infection site [3]. The management of wound requires proper attention including medicinal and antiseptic dressings. This study was designed to see the role of 5% acetic acid and povidone iodine in extremities infected wounds.

Material and Methods

For this study total 20 hospitalized patients with wound infection in extremities not responding to traditional therapy for more than10 days were selected for the study. We equally divided our sample randomize in selection, and first half group A and second half group B. Group A were treated by 3%-5% acetic acid and Group B were treated by povidone iodine for 6 (six) weeks, and observe the healing. We used the Outcome parameters were as:

i. patient morbidity and mortality

ii. wound healing

iii. number of debridements

iv. wound culture results

v. white blood cell count > 10,000 cells/ dl)

vi. pyrexia > 100°F

vii. Infection site pain

a. Study Design: Prospective comparative study design was used.

b. Setting: Department of Orthopedic surgery and Traumatology International Medical College and Hospital, Gushulia, Tongi, Gazipure. Bangladesh [4] (Table 1).

Table 1: Details of patients.

Results

The average age of patients was 45 years with male to female ratio 4:1. In-group A the wound healing was 76% and in-group B it was 54% after three weeks. But at the end of 6th week 98% healing was seen in group a while 83% healing was seen in group B. Wounds were healed or were closed or were granulating follow-up. Number of debridements, wound cultures, white-blood-cells, and fever decreased after treatment began with 5% acetic acid [5-8].

Discussion

Wound infection in extremities in hospitalized patients has always been problem to the clinicians. Traditional therapies with anti microbial agents have their own limitations because of multiple antibiotic resistances. The use of acetic acid and providone iodine has been reported from time to time as a topical agent for the treatment of extremity wound infection. Topical use of acetic acid at concentrations between 0.5 to 5% eliminated microorganism responsible for extremity wound infection. From the result of this study it is concluded that 5% acetic acid is non-toxic and superior to providone iodine. It is the best alternative when infection is caused by multiple antibiotic resistant strains and where there is shortage of therapeutic options [9-11].

Conclusion

Dressings with 5% acetic acid for infected wounds of the extremities yield good results.

For More Articles: Biomedical Journal Impact Factor : https://biomedres.us

Oral Manifestations of a Patient with Epidermolysis Bullosa

Abstract

Epidermolysis bullosa acquisita (EBA) is a chronic autoimmune bullous disease characterized by the presence of IgG and IgM antibodies at the level of basement membrane. It is rare in humans and animals with an incidence ranging from 0.2 to 0.5 new cases per million and per year. This dermatological condition is a severe autoimmune disease. Scarring of the extensor surfaces of the extremities, hands and feet are typical; milia occur frequently; and nails often become thick and dystrophic or are lost. The disorder affects both sexes equally and occurs in all racial and ethnic groups.

Keywords: Adherent fingers; Absent nails; Microstomia; Bullae; Preventive care

Introduction

Epidermolysis Bullosa (EB) is a group of rare inherited disorders, usually detected at birth or early childhood [1-4]. Köbner coined the term ‘epidermolysis bullosa’ in 1886, but even before this time, Legg and Brocq had already provided a clinical description of the disease. Epidermolysis bullosa characterized by extreme fragility of the skin and mucous membranes, which gives rise to the formation of blisters following minor trauma [5]. This dermatological condition is a severe autoimmune disease [6,7]. Scarring of the extensor surfaces of the extremities, hands and feet are typical; milia occur frequently; and nails often become thick and dystrophic or are lost. The disorder affects both sexes equally and occurs in all racial and ethnic groups [8]. Epidermolysis bullosa has been classified into three major types depending upon the histological level of tissue separation [9]:

I. Epidermolysis bullosa simplex is characterized by discontinuities in the epithelial keratinocyte layer;

II. Junctional epidermolysis bullosa involves separation within the basement membrane; and

III. Dystrophic epidermolysis bullosa is characterized by discontinuities in the underlying connective tissue.

Each type of EB has various subtypes and these may vary in severity [10]. Skin biopsies are needed for appropriate diagnosis and classification for affected subjects.

Case Report

A 12-year-old female patient diagnosed with severe generalized junctional EB was referred to the Department of oral medicine and Radiology. The patient complaints of dental pain, halitosis, severe crustation of lips and limited mouth opening with ulcerations of buccal mucosa. The patient had one sister, aged 6 years old, who was unaffected by the disease. Her parents were also unaffected and were not consanguineous. Both sets of grandparents came from the nearby areas of same state. This type of illness had not previously appeared in the family Physical examination revealed generalized worn-out skin, blistering and scar formation, with blisters and vesicles present especially on the head and neck .The patient’s few fingers were adherent, and her nails were absent (Figures 1 & 2). Scar formation had resulted in the formation of microstomia (Figure 3). The patient’s maximum mouth opening was 14 mm. Clinical examination showed multiple missing teeth, decay and poor oral hygiene (Figure 4), due in part to a soft diet and hand contractures.

Figure 1: Nails absent.

Figure 2: Fingers adherent.

Figure 3: Crustations over lips[before] marked improvement [after].

The patient was a case of junctional epidermolysis bullosa which was confirmed by histopathology. Skin biopsy from fresh bulla showed a large dermo-epidermal bulla with mild chronic inflammatory infiltrate in dermis. Direct immuno fluorescence showed IgG IgM deposition at the level of basement membrane; all the features were suggestive of junctional epidermolysis bullosa. The goal of treatment in the present case was to prevent blisters from forming and its resulting complications. Topical steroids and antibiotics were used to promote healing and prevent secondary infection of blisters. Since restoration of teeth was not possible due to severe crown destruction, extraction of few teeth was done in two sittings under local anaesthesia. The use of an aloe vera containing tooth gel at home was suggested to soothe the burning feeling affecting the gums. A mouthwash was also prescribed to help the salivary immune system protect the mucosal surfaces. In this case, minimal intervention has so far preserved the oral cavity and monthly topic fluoride application helped to control dental caries. The patient maintains continuous contact with the health team to avoid complex treatments. Follow-up is advised after every 3 months for the evaluation of oral status.

Discussion

EB is a group of rare genetically determined disorders characterized by the development of blisters following minor or insignificant trauma or traction to the skin or mucosal surfaces [11-13].Oral manifestations and dental involvement of EB vary in frequency, in severity and according to subtype. Dental management of individuals with EB has been reported previously by several authors [14,15]. Examinations have shown that the caries prevalence among individuals with dystrophic EB and junctional EB is significantly higher than among healthy people [16]. Similar observations have been made with respect to the prevalence of plaque and gingivitis. However, the patients examined in these studies show no significantly higher prevalence of Candida albicans, Lactobacillus casei or Streptococcus mutans [17]. Wright et al .reported that none of their patients with EB showed any evidence of a decreased salivary flow rate [18]. Despite the severe cutaneous and extracutaneous involvement associated with inherited EB, the above authors found no evidence to support the hypothesis of abnormal salivary function or mucosal immunity in this disease. Taken together, these findings suggest that the rampant dental caries seen in the various forms of EB are more likely to be attributable to non salivary factors, such as enamel involvement, soft-tissue alterations and/or diet. Dental caries have a complex pathogenesis and may be influenced by a variety of genetic and environmental factors. Childhood EBA is a very rare disease and none of the previously described patients had dental abnormalities as a clinical manifestation of this disease. Interestingly, defects in enamel maturation and/or mineralization have been reported in dystrophic and junctional epidermolysis bullosa. The Col17_/_ mice, a model to study non-Herlitzjunctional epidermolysis bullosa enamel hypoplasia, exhibit imperfect amelogenesis demonstrated by malformed enamel rods and irregular enamel matrix [19].

Similar changes are observed in some cases of epidermolysis bullosa caused by mutations in laminin 5, a6b4 integrin or collagen VII [20]. The tooth abnormalities due to type VII collagen deficiency investigated in Col7a1_/_ and COL7-rescued humanized mice may be attributed to poorly differentiated ameloblasts [21]. Defective enamel structure may provide a flourishing local environment for cariogenic bacteria by providing more adhesive and colonization potential and being more acid soluble. Hence, defective enamel appears to be a favoring factor for dental caries of childhood. Epidermolysis bullosa treatment is generally focused on support. Perforating the blisters contributes to accelerating the healing process and prevents continued lateral spread of the blisters. Currently, researchers are focusing their attention on gene and cell therapy, recombinant protein infusions, intradermal injections of allogenic fibroblasts and stem cell transplantation. Other developing therapies are directed toward the enhancement of wound healing and better quality of life for EB patients [22]. Some difficulties complicate the rehabilitation treatment of thesepatients, as the fragility of the mucosa and the microstomia. The lesions in the oral mucous membrane can be so severe that they interfere with nutrition as a result of the difficulty of food due to pain as in present case. Thus, the treatment of the EB patient must be modified in order to decrease the effects of local trauma to the tissues.

Oral ulceration due to trauma during dental manipulation is unavoidable, but it could be limited by the mucosa lubrication before any manipulation with hydrocortisone cream, triamcinalone or petroleum jelly [23]. In addition, the use of small-sized instruments, short-shaft dental burs and hand pieces with a small-sized head is indicated. Dentures and restorations should be carefully adapted and highly polished; secondary infections should be prevented with the use of oral antiseptics or using topical antibiotics on existing bullous lesions. During the dental treatment in outpatient settings, the administration of local anaesthesia to patients with EB may also cause blister formation and should therefore be avoided whenever possible. Nevertheless, when necessary, local anesthetics should be injected slowly and deeply into the tissues to prevent mechanical tissue separation and blistering. Owing to the difficulties related to the restorative dental treatment of these patients, the emphasis on the oral health management must be on prevention beginning at an early age. Regular application of topical and systemic fluoride, oral hygiene instructions and dietary guidelines minimize caries development and improves overall oral health.

Conclusion

Early dental management and preventive care to minimize caries development and to improve oral health is very important for patients with EB. Furthermore, they are often advised to reduce their consumption of cariogenic foods. Topical fluoride applications at regular intervals are also indicated. Ongoing patient monitoring must be stressed to minimize the need for restorative treatment in patients with EB

For More Articles: Biomedical Journal Impact Factor : https://biomedres.us

Difficult Extraction of Post-Endodontic ally Treated Upper Second Molar : A Case Report

Abstract

The ideal tooth extraction is “the painless removal of the whole tooths, or roots, with minimal trauma to the investing tissues, so that the wound heals uneventfully & no post-operative prosthetic problem is created. The present article reports a case of difficult extraction in 39 years female. The aim of the article is to report a case of difficult extraction of post-endodontic ally treated upper second molar.

Case Report

A 39 years female patient was complaining of pain in the upper left back teeth region of jaw since 8 days. The patient was under root canal treatment with upper left second molar (Figures 1,2) and was complaining of pain with the same tooth [1]. On radiographic examination, it revealed that there is extended endodontic file in the molar’s mesial canal, which was extended beyond the root. This tooth had poor prognosis as well as patient was not ready to continue the root canal treatment due to pain, hence we decided to perform extraction of it. This extraction was challenging as there were more chances of breakage of endodontic file but we did it successfully. Maxillary cow-horn forceps was used for extraction. Tooth was extracted with minimal trauma and without breakage of endodontic file [2-6].

Figure 1: IOPA of left upper second molar.

Discussion

The ideal tooth extraction is “the painless removal of the whole tooths, or roots, with minimal trauma to the investing tissues, so that the wound heals uneventfully & no post-operative prosthetic problem is created.

Tooth extraction should be considered as a last option. Permanent teeth are extracted for various reasons such as dental caries, orthodontic reasons, periodontal disease, impacted teeth, failed dental treatments, pre-prosthetic considerations etc. [7]. Criterias which are taken into consideration before any extraction are tooth mobility, prosthetic planning ,severity of attachment loss, furcation involvement , endodontic-periodontal lesion, radiographic bone loss ( more than 50 % ) , grossly carious teeth [8].

Endodontic ally treated teeth are prone to extraction mainly due to non- restorable caries, endodontic failure, iatrogenic perforation, vertical root fractures [9]. Any endodontic treatment is been evaluated at several levels which starts at the success of treatment in preventing periapical lesions [10]. The complications which come across while performing extraction are tooth fracture, fracture of cortical plates, alveolar osteitis, trismus, postoperative pain, haemorrhage, wound dehiscence. Rare complications are luxation of adjacent teeth, maxillary tuberosity fracture, and displacement of tooth into adjacent tissue spaces [11]. Fcortical plates are fractured while doing extraction, it can lead to ridge narrowing and this may interfere with closure of extraction space [12]. The case mentioned in the article is a difficult case of extraction. But we performed it successfully and with fewer traumas to surrounding tissue.

For More Articles: Biomedical Journal Impact Factor : https://biomedres.us

Analytical Quality by Design: A Mini Review

Introduction

According to ICH Q8 guidelines, QBD is “A systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management.”

What is quality by design?

QbD incorporates planning, developing formulations and manufacturing procedures which ensures predefined product specifications. In 2002, the FDA announced a new initiative (cGMP for the 21st Century: A Risk based Approach). This initiative intended to modernize the FDAs regulation of pharmaceutical quality, and establish a new regulatory framework focused on QbD risk management, and quality system. The initiative has made the industry to look beyond quality by testing (QbT) for ensuring product quality and performance. An important aspect of QbD is to know how process and formulation parameters could affect the product characteristics and subsequent optimization of these parameters should be known in order to monitor these parameters online in the production process.

The use of QbD concepts results in a well-understood product and process that consistently delivers its intended performance. The knowledge acquired during development may support the formation of a design space and determines suitable process controls. These same QbD principles have been applied to the development of analytical methods, and are termed “Analytical QbD” (AQbD). Analogous to process QbD, the result of AQbD is a well understood, fit for purpose, and robust method that consistently delivers the intended performance throughout its lifecycle. The broad knowledge obtained from this process is used to establish a method operable design region (MODR), a multidimensional space based on the method factors and settings that provide suitable method performance.

AQbD helps in development of a robust and cost effective analytical method and facilitate the regulatory flexibility in analytical method i.e. the choice to change method parameters within a method’s design space, referred to as the method operable design region (MODR).

Regulatory perspective of AQbD

Analytical methods are key part of the control strategy in pharmaceutical quality system (ICH Q10). It includes various parameters and attributes related to drug substance and drug product including instrument operating conditions and their associated methods. Though cGMP regulation is in practice from a long time but many pharmaceutical giants are facing quality control related issues that are associated with the risk management system in analytical methods. Therefore looking the dependency of pharmaceutical development and manufacture on robust analytical data, need has come for implementation of AQbD in analytical method development, which is an indicator of quality process, product and robustness throughout the life cycle of the product. Below Figure 1 shows various stages in Qbd/AQbD

Figure 1: Regulatory perspective of QbDvsAQbD.

Comparison of Traditional approach VsQbD and AQbD

Traditional validation methods are usually one time evaluation. As a result chances of method failure during transfer are always high. Also the performance variables are not fully explored and understood. Therefore the below figure 2 summarizes the comparison of traditional and AQbD approach, which aims to handle the shortcomings of the traditional approach based on scientific understanding and knowledge repository.

Figure 2: Comparison of Traditional Approach vsQbD and AQbD.

Following are the advantages offered by AQbD in product development:

1. Scientific understanding of pharmaceutical process and method.

2. It involves product design and process development.

3. Science based risk assessment is carried.

4. Critical quality attributes are identified and their effect on final quality of product is analyzed.

5. It offers robust method or process.

6. It provides required design space for development.

7. Control strategy can be maintained throughout the analysis.

8. It allows continuous improvement till finished steps of method.

9. Flexibility in analysis of API, impurities in dosage forms, stability samples, and metabolites in biological samples.

10. Reduction in variability in analytical attributes for improving the method robustness.

11. Eliminate batch failures.

12. Minimize deviations and costly investigations.

13. Avoid regulatory compliance problems.

14. Better development decisions.

15. Empowerment of technical staff.

16. Smooth process of method transfer to the production level.

Elements of AQbD

Go to

AQbD/qbd comprises of all elements of pharmaceutical development described in ICH Q8 depicted in Figure 3.

Figure 3: Elements of Analytical Qbd.

Analytical target profile

ATP is way for method development or it is simply a tool for method development and has been mentioned in the ICH Q8 R (2) guidelines. It defines the method requirements which are expected to be measured that direct the method development process i.e.it is combination of all performance criteria required for the proposed analytical application. An ATP would be developed for each of the traits defined in the control strategy. The ATP defines what the method has to measure (i.e., acceptance criteria) and to what level the measurement is required (i.e., performance level characteristics, such as precision, accuracy, range, sensitivity, and the associated performance criterion). The ATP is defined with the help of knowledge and scientific understanding of the analytical process. Preliminary risk assessment should be carried out for expectation of the method requirements and analytical criticalities. ATP for analytical procedures comprises of

a) Selection of target analytes (API and impurities),

b) Selection of analytical technique (HPTLC, GC, HPLC, Ion Chromatography, chiral HPLC, etc.),

c) Choice of method requirements.

Accuracy and precision are the most important among the performance characteristics that provides the critical information needed to quantify an unknown amount of the substance using the proposed method. A method cannot be accurate and precise without acceptable specificity, linearity over a stated range, sufficient peak resolution for accurate integration, repeatability of injections, etc. To achieve an accurate and precise method the above important characteristics must be evaluated during method development as they provide an extensive data set for setting method controls.

CQA (Critical Quality Attributes)

ICH Q8 (8) defines CQA as a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality. CQA for analytical methods comprises of method attributes and method parameters. CQA can differ from one analytical technique to another.

a) CQA for HPLC (UV or RID) are buffers used in mobile phase, pH of mobile phase, diluent, column selection, organic modifier and elution method.

b) CQA for GC method is oven temperature and its program, injection temperature, flow rate of gas, sample diluent and concentration.

c) CQA for HPTLC is TLC plate, mobile phase, injection concentration and volume, time taken for plate development, reagent for color development, and detection methods.

Physical and chemical properties of the drug substance and impurities can also describe CQA for analytical method development such as polarity, charged functional groups, solubility, pH value, boiling point and solution stability.

Risk Assessment

Risk assessment strategy as specified in the ICHQ9 guideline: “it is systematic process for the assessment, control, communication and review of risks to the quality across the product lifecycle”. This step is vital in order to reach a confidence level that the method is reliable. Once the technique is identified, AQbD emphases on detailed risk assessment of the factors that may lead to possible variability in the method, like analyst methods, instrument configuration, measurement and method parameters, sample characteristics, sample preparation, and environmental conditions. Traditional method development relied on testing the method after transfer whereas Analytical QbD demands the risk assessment step before method transfer and throughout the product life cycle. According to ICH Q9, risk assessment can be carried out in three steps viz., risk identification, risk analysis and risk evaluation. One of the common ways to perform risk assessment is to use a Fishbone Diagram, also known as Ishikawa. Accordingly the risk factors are classified into the following categories:

a) High Risk Factors: e.g. Sample preparation methodology. These are to be fixed during the Method Development process.

b) Noise Factors: These are subjected to an MSA study. It can be done through staggered cross nested study design and variability plots, ANOVA etc. These factors are subjected to robustness testing.

c) Experimental Factors: e.g. Instrumentation and operation methods. Subjected to ruggedness testing and acceptable range is identified. The third step is Risk Evaluation which is done through Failure mode and effects analysis (FMEA) and the Matrix designs.

MODR (Method Operational Design Region)

MODR used to develop operational region for routine operation (e.g., analysis time, procedure and limits). In accordance with the requirement of ICH Q8 guidelines, regarding “design space” in product development, method operable design region (MODR) can also be established in method development phase, which could serve as a source for robust and cost effective method. Understanding of method performance regions helps to establish the desired operational conditions. Critical method parameters and analytes sensitivities should be evaluated. MODR is the operating range for the critical method input variable (similar to CQAs) that produces results which consistently meet the goals set out in the ATP. MODR permits the flexibility in various input method parameters to provide the expected method performance criteria and method response without resubmission to FDA. It is based on a science, risk based and multivariate approach to evaluate effects of various factors on method performance.

Method Control Strategy

Establishing a control strategy is of utmost importance while ensuring that the method is performing as intended on a routinebasis as goals described in ATP. Basically it’s a planned set of controls aimed at minimizing the variability in the process. The strategy is data dependent. Data generated during method development and method verification forms the basis of the control strategy. A factor identified to have risk has to be controlled. More attention is given to the high risk factors. If the risk are low and manageable then the method control strategy can be defined, which generally consists of appropriate system suitability check and verified time to time by having control over it so that method delivers the desirable method attributes. Interestingly, the control strategy of AQbD is not different from the traditional control strategy.

Lifecycle Management

Going through all the elements of AQbD for a particular analytical method the key steps that ensure fitness of the method for its intended use includes the method validation, verification and transfer. Combining all together is termed as ‘lifecycle management of analytical procedure’, which commence with establishment of ATP and continues till the methods are in use. The resultant confirmation with respect to ATP is the main focus of performance qualification e.g., precision study at the site of routine use. Continual verification involves activities, which provide the assurance that the method is under control throughout its lifecycle.

Applications OF AQbD

Numerous applications of AQbD have been reported in the field of Pharmaceutical analysis. We have tried to put some of the examples of chromatographic methods especially liquid chromatography in various areas of analysis that have utilized not all steps shown in Figure 1, but have implemented some aspects of AQbD in their approach. Below Table 1 summarizes some of the application area (Table 1).

Table 1: Few applications applying AQbD approach.

Conclusion

Analytical Quality by Design (AQbD) plays a key role in the pharmaceutical industry for ensuring the method reliability and non-variability in results. The outcome of AQbD is the understanding from method development to method transfer. AQbD tools are ATP, CQA, Method Optimization and Development with DoE, MODR, and Control Strategy with Risk Assessment, Method validation, and continuous improvement. During method development, all potential factors (the inputs) and all critical analytical responses (the outputs) are studied to determine the relationships. Critical analytical factors are identified in an approach that parallels what is described for process development in ICH Q8 and Q9. The AQbD approach plays an active role between analytical scientists during development and operational laboratories as methods are being developed and as factors that lead to potential method failures are identified and controlled. Thus all elements of Aqbd altogether will provide better understanding of the method performance and for its continuous improvement throughout the life cycle.

For More Articles: Biomedical Journal Impact Factor : https://biomedres.us

Benign Migratory Glossitis: Case Report and Literature Review

Abstract

Benign migratory Glossitis (BMG) is a benign, usually asymptomatic mucosal lesion of dorsal surface of the tongue, characterized by depapillated erythematous patches separated by white irregular borders. Etiology of BMG is unknown. Risk factors include psoriasis, fissured tongue, diabetes mellitus, hypersensitivity and psychological factors. We report BMG in an Egyptian soldier of UN peace keeping force, with stress as a possible etiological factor and provide literature review of this disorder.

Keywords: Geographic tongue; Benign migratory Glossitis; Erythema migrans

Introduction

Benign migratory Glossitis (BMG) is a benign, immunemediated, chronic inflammatory lesion of unknown etiology, usually characterized by asymptomatic erythematous patches with whitish margins across the surface of the tongue. This condition is also known as geographic tongue, erythema migrans, Glossitis exfoliativa and wandering rash of the tongue. The central erythematous patch represents atrophy of the filiform papillae. The white border is composed of regenerating filiform papillae and a mixture of keratin and neutrophil aggregates within the epithelium. The most frequently reported prevalence is 1-2.5% with no gender predilection. It commonly occurs on the tip, lateral borders, and dorsum of the tongue; extending sometimes to the ventral surface as well. BMG shows periods of exacerbation and remission with recovery in one area and appearance in other area; thus explaining the typical migratory nature of this lesion [1-3].

Etiology of BMG is not well established. Various studies have found association of BMG with psoriasis, diabetes mellitus, Reiter’s syndrome, Down’s syndrome, pregnancy, psychological factors, genetic factors, hypersensitivity, fissured tongue [3] and consumption of oral contraceptive pills and lithium carbonate [4]. The diagnosis is based on history and clinical presentation. Though usually asymptomatic in nature; pain and burning sensation in the affected area of the tongue has been reported on consumption of spicy/salty food and/or alcoholic drinks [4,5].The lesion typically changes its shape with time owing to the change in pattern of depapillation.

Similar lesions may also be seen in atrophic candidiasis, local chemical or mechanical trauma, drug induced reactions, psoriasis and atrophic lichen planus [6]. Asymptomatic BMG needs no therapy. Treatment of symptomatic BMG aims at provision of symptomatic relief by means of topical application of corticosteroids, local anesthetic agents, anti-inflammatory mouthwashes and systemic use of antihistamines and Zinc supplements [7]. We report a 26-year-old patient, an Egyptian soldier of UN peace keeping force, suffering from BMG; with stress as a possible etiological factor.

Case Report

A 26-year-old male patient, an Egyptian soldier performing his duties in United Nations-African Union Mission in Darfur (UNAMID), reported to Pakistani Field Hospital Darfur, Sudan; complaining of pain and burning sensation in his tongue for last two months. The patient was asymptomatic two months back when he developed burning sensation in his tongue on taking spicy food and hot drinks. After a few days the severity of burning increased in response to the same stimuli. In addition to it, he developed mild continuous pain and discomfort in tongue which aggravated during speech and mastication. He took multivitamin tablets and systemic antifungalmedication (capsules) on the advice of a general practitioner but was not relieved of his symptoms. He also complained of disturbed sleep and loss of appetite. The patient related his symptoms with composite filling of his upper molar tooth which had been done one month before appearance of his symptoms.

His medical history was not significant. Currently he was not taking any medication and denied allergy to any medication or food item. According to the patient, no member of his family ever experienced such problem. He was nonalcoholic and remained nonsmoker until recently when he started smoking since last two weeks, about 10 cigarettes per day, without any known reason. He was unmarried and engaged to a lady about 18 months back. His marriage was delayed because of his job/service commitments. He was the eldest son of the family, having two sisters, two brothers and two parents; all dependent upon him. In mission area, his job was procurement and logistics management.

On clinical examination, he was a young male of average built and height with mesofacial profile. TMJ examination and mouth opening were normal. Intraoral examination showed satisfactory oral hygiene with all teeth intact. There were wear facets on lower anterior teeth. Examination of tongue revealed characteristic morphological features of geographic tongue. Multiple flat, smooth, erythematous patches of depapillated mucosa with yellowish white, slightly elevated, irregular peripheral borders were visible on dorsum and lateral margins of the tongue (Figure 1). No ulceration, bleeding or pus discharge was observed. Systemic examinations were unremarkable.

Figure 1: Initial clinical presentation of geographic tongue.

As the clinical diagnosis was straightforward, a biopsy was not deemed necessary. Other investigations included blood complete picture with RBC indices, serum glucose level, serum folate, vitamin B12 and albumin level and total Iron binding capacity; to distinguish from Glossitis associated with anemia or other nutritional deficiencies. Patient was reassured of the benign nature of the lesion. For symptomatic relief, he was advised topical application of Triamcinolone acetonide (Kenalog in orabaseointment) and use of Benzydamine mouth wash for 10 days. He was also advised tablet Paroxetine, 10 mg once daily for 3 months, by our Psychiatrist. The patient was reviewed after 2 weeks who reported significant reduction in severity of his symptoms with only mild discomfort during eating. On examination of the tongue, the peripheral white zones on lateral margins of the tongue had disappeared. (Figure 2) Patient was advised to observe fortnightly follow up visits for the rest of his stay in mission area.

Figure 2: 10 days post-treatment.

Discussion

BMG is one of the most prevalent oral mucosal lesions (1- 2.5 %, usually adults) [7]. Our patient demonstrated typical appearance and location of BMG, though it may occur on other sites of oral mucosa than on the dorsum of the tongue where it is called geographic stomatitis [7,8]. BMG is usually asymptomatic. However, itching, foreign body sensa¬tion, mild pain and mild to severe burning sensation, which may occasionally interfere with eating or sleep¬ing, have also been reported. The severity of symptoms varies at different times, depending on the disease activity. Our patient reported disturbed sleep owing to pain and burning sensations which aggravated on taking spicy food and hot drinks. Cancer phobia has been reported in patients of BMG, due to which they, sometimes, seek medical help even in asymptomatic cases [2].

Etiology of BMG could not be established in our patient. No association was found between his disease and the reported risk factors like inheritance, diabetes mellitus, nutritional deficiency, Reiter’s syndrome etc. His family and past medical history was not contributory. Allergy has been proposed as a major causative factor in BMG. An association has also been reported between the BMG and asthma, eczema, hay fever, elevated serum immunoglobulin E (IgE) and atopic patients [4,9]. Our patient denied allergy to any medication Various studies have demonstrated an association between BMG and psoriasis on the bases of microscopic similarity between the two conditions and the presence of a common genetic marker, HLA-C*06.Its prevalenceina population of psoriasis patients is approximately 5% [1,4,8]. Our patient had no psoriasis.

An association between BMG and the fissured tongue has been reported in literature [1,4,10,11]. The fissured tongue is an asymptomatic, benign condition characterized by fissures or grooves on dorsal surface of the tongue. Fissured tongue should be interpreted as an end stage of BMG.7 In our patient; BMG was notaccompanied by fissured tongue. Various studies support the role of emotional stress, as a causative agent, in the development and/or exacerbation of BMG [4,12,13]. Redman et al. [12] investigated the association of emotional stress and BMG in a population of students and found evidence to suggest emotional stress as an etiological factor in BMG. They also suggested that in a person with signs of psychological disturbance, the appearance of geographic tongue might be considered as additional evidence of the disturbance.

After exclusion of other risk factors, as mentioned in the literature, we suggest work/emotional stress to be a factor in development and/or exacerbation of BMG in our patient. Being the eldest son of the family with lot of familial responsibilities on his shoulders, who was away from his family for last 10 months, performing his duties in a Foreign country; coupled with requirements of commitment to his job might have put him under lot of stress which could develop BMG in our patient. Moreover; there is a possibility of the presence of an asymptomatic lesion which was diagnosed only after the appearance and exacerbation of symptoms during the period of stress.

Conclusion

In this case the lesion was readily identifiable clinically so biopsy was not considered. If biopsy is considered, it should involve the peripheral zone to include the typical microscopic features of this lesion; parakeratosis, acanthosis and sub epithelial Tlymphocytic inflammation [4]. Symptomatic treatment with topical corticosteroids, topical local anesthetic agents, antiinflammatory mouthwashes, antihistamines and anxiolytic dugs is documented in literature [6]. Our patient responded well to a 10 days course of topical corticosteroids (triamcinoloneacetonide) with significant reduction of his symptoms and disappearance of Peripheral zone of the lesion, which is a sign of recovering mucosa [6,7]. In conclusion, BMG is a completely benign mucosal lesion that shows periods of exacerbation and remission. In asymptomatic cases, its diagnosis is important to relieve cancer anxiety of the patient. In symptomatic cases, symptomatic treatment should be provided by use of corticosteroids along with correction of the cause. Possible role of stress in development of symptomatic BMG has been observed in this case report which may be confirmed by further investigations.

For More Articles: Biomedical Journal Impact Factor : https://biomedres.us

Outcome of Surgical Repair of Complete Rupture of Distal Biceps Tendon: A Clinical Series

Abstract

Complete distal biceps rupture is a rare injury as compared to proximal biceps tendon rupture. It is usually caused by an eccentric contraction of the muscle, often seen with a sudden unintentional pull or jerk. An epidemiological study showed an incidence of 1.2 ruptures per 100,000 patients per year with an average age of 47 years. It is important not to miss the diagnosis initially, since delay in surgery does affect the outcome. In low-demand patients with complete distal biceps tendon tears, non-operative treatment may be entertained provided the patient understands the potential for residual weakness, particularly of forearm supination. The surgical repair is the treatment of choice especially in high demand male patients. There are a variety of fixation methods including bone anchors, suspension techniques, bone tunnels with interference screws, and transosseus sutures. No one technique has emerged as the gold standard and the choice remains that of surgeon. In this case series we present couple of patients with distal biceps tendon rupture one with acute rupture and another with chronic rupture treated surgically. We conclude patients do benefit from surgical repair.

Keywords: Distal biceps tendon; Acute; Chronic; Tendon tear; Elbow; Repair

Abbreviations: USG: Ultra Sono Gram; MRI: Magnetic Resonance imaging ; ASES: American Shoulder and Elbow Surgeons; LABC: Lateral Ante Brachial Cutaneous; PREE: Patient-Rated Elbow Evaluation

Introduction

Nearly 90% of biceps tendon ruptures occur in the proximal biceps and involve the long head of biceps. The remaining ruptures occur in the distal biceps tendon representing only 3% of biceps muscle injuries. The mechanism of injury in distal rupture involves a strong eccentric contraction of the biceps tendon against unanticipated resistance. The injury is most common in the dominant arm of middle-aged men. Symptoms include weakness in elbow flexion (by 30%) and forearm supination (by 40%) [1].

Some individuals may maintain reasonable function after non-operative treatment of a ruptured distal biceps tendon, biomechanical and clinical studies suggest that most individuals benefit from surgical repair or reconstruction [2]. The surgical treatment of distal biceps tendon tears has been studied extensively. The techniques available for repair involve a three-level distinction: anatomic versus non-anatomic repair, single-incision versus double-incision exposure and fixation method (most commonly the use of cortical button, interference screws, transosseous sutures or suture anchors) [2,3].

The number of reported distal biceps tendon tears seems to have increased over the last few years, likely related to better understanding and improved diagnostic methods [4] However in a number of instances, the diagnosis is initially missed. In this case series we present couple of patients with complete distal biceps tendon rupture; one with acute rupture and another with chronic rupture. We discuss the diagnosis, treatment, outcome and complications of surgical repair of the tendon using suture anchor.

Clinical Series

Case 1

63 year old left dominant handed male patient sustained injury to left elbow at work site one month before he presented to us,- while he was trying to cut a banana tree it was about to fall on his feet, while he tried to catch the tree before it fell. He had a painful ‘pop’ at the time of injury. He noticed painful range of movement of left elbow and difficulty in using left elbow. Initially he consulted an orthopaedic surgeon and was managed with a sling and analgesics, when he presented to us he had developed painful restriction of range of movement and was so unhappy about the initial treatment. On inspection there was flattening of the distal contour of the arm as compared to opposite arm (Figure 1), mild tenderness at anticubital fossa. He had weakness of flexion and supination.

On ‘hook test’ (Figure 2) we could not hook finger around any anterior structures with elbow in flexed and supinated position. Pre operative quick DASH score was 57. X-ray showed no bony abnormality and an MRI confirmed complete rupture (Figure 3) and marked retraction of distal biceps tendon from bicipital tuberosity of the radius. Since the duration of injury was just one month we planned for reinsertion of tendon to bicipital tuberosity using fibre wire and an anchor screw. After pre anaesthesia evaluation patient was taken up for surgery. We went through anterior approach using a curved single incision over antecubital fossa without a tourniquet, and retrieved the tendon from the superior part of the incision (Figure 4).

Figure 2: The hook test for distal biceps tendon, as described by O’Driscoll [6]. a. The normal test in which the examiner’s fingers can be hooked under the biceps tendon. b. The abnormal test, in which the examiner is unable to hook the distal biceps tendon. c. Demonstration of a normal hook test. As shown, a cord-like structure is felt under the index finger. d. Clinical picture demonstrating an abnormal hook test. The examiner is unable to feel the cord-like structure corresponding to the distal biceps tendon.

Figure 3: MRI showing complete rupture and marked retraction of distal beceps tendon from bicipital tuberosity of radius.

Figure 4: Retrieval of the ruptured tendon from the proximal part of incision.

On the distal part of the incision further dissection was done and recurrent branch of radial artery was ligated (Figure 5) to avoid injury to it. Bicepital tuberosity on radius was identified and bed prepared (Figure 6). An anchor screw was passed into it and with the fibre wire, tendon was re attached (Figure 7), as we expected there was enormous tension on tendon and hence a long arm slab in 1100 of flexion and supination was given. Patient was discharged on second post op day and at one month follow up slab and sutures were removed, elbow mobilisation started (Figure 8). Wound was healed well and at 2 months post of he had near normal range of movement and without any pain and quick DASH score improved to 11 at 2 months post op and it is improving further.

Figure 8: At 1 month follow up POP slab was removed and sutures removed wound healed well.

Case 2

A 44 year old right hand dominant male farmer patient sustained distal bicepital tendon rupture following a fall from tree while he was trying to cut a branch of tree and he lost control and fell down and tried to catch another branch of the tree to save himself and he heard a painful pop at that time and finally he fell on the ground. Fortunately he did not have any major fractures but noticed pain and swelling around the elbow. On the same day he presented to us. On examination swelling and ecchymosis in the distal arm and proximal forearm. Severe tenderness was noted. X ray of right elbow was normal and an MRI showed complete tear of distal biceps tendon. He was treated similarly as described in case one and biceps was reattached using fibre wire and suture anchor. Post operative protocol was also similar as case one and at 3 months follows up his quick DASH score improved to zero and he returned back to work.

Discussion

Distal biceps rupture is a rare injury as compared to proximal biceps tendon rupture usually caused by an eccentric contraction of the muscle, often seen with a sudden unintentional pull or jerk. An epidemiological study showed an incidence of 1.2 ruptures per 100,000 patients per year with an average age of 47 years [5]. Unlike proximal biceps tendon rupture which leave only a cosmetic deformity (with little or no functional disability), the distal biceps tendon injury affects functional outcome of elbow resulting in stiffness, chronic pain, weakness of flexion and supination. Unfortunately, the implications of this injury are high, in demanding male labourers. In a number of instances, the diagnosis is initially missed. In such situations patients are extremely unhappy. As seen in our patient (case one) his diagnosis was missed initially and when he presented to us at one month post injury he was very unhappy about initial treatment and outcome.

The diagnosis of complete distal biceps tendon tears can be established based on patient history and physical examination. X ray elbow may be normal; Ultra sonogram (USG) and magnetic resonance imaging (MRI) provide more valuable information. Patients may report a painful ‘pop’ at the time of injury. A useful clinical test was described by O’Driscoll et al. [6,7], the so-called ‘hook test’. The patient is asked to look at the palm of his hand on the affected side with the shoulder elevated, the elbow flexed at 90° and the forearm in supination. An intact distal biceps tendon allows the examiner to hook his fingers around the cord-like structure. If the bicep is torn, since the distal brachial is is flat, the examiner will not be able to hook his finger around any anterior structures. This test was elicited in patient with chronic distal biceps tendon rupture (case 1) We did not try this test in other patient with acute tendon rupture because it was painful (Figure 2).

Nonoperative treatment in symptomatic patients has been shown to result in a 30–50% loss in supination strength and 20% loss in elbow flexion strength [8]. Thus the surgical repair is the treatment of choice especially in high demand male patients. So, the consensus of opinion is that acute ruptures should be repaired primarily if possible, and there are a variety of fixation methods including bone anchors, suspension techniques, bone tunnels with interference screws, and transosseus sutures [9]. No one technique has emerged as the gold standard and the choice remains that of surgeon.

The techniques available for repair involve a three-level distinction: anatomic versus non-anatomic repair, single-incision versus double-incision exposure and various fixation methods. Randomised controlled trial was conducted to compare acute DBT tears treated surgically with a single-incision technique (fixation with two suture anchors) or double-incision technique (fixation with transosseous bone tunnels) [10]. The authors found that both techniques provided similar results in terms of pain, American Shoulder and Elbow Surgeons (ASES) elbow scores, and functional sub-scores, DASH score, patient-rated elbow evaluation (PREE) score, and isometric extension, pronation or supination strength.

However, the double-incision technique resulted in significantly higher strength for elbow flexion when compared to the singleincision technique (104% Vs 94%, respectively). We have used single incision technique in both cases and used anchor screw for fixation. In acute cases this approach gives excellent exposure for retrieval, preparation and fixation at radial tuberosity. In chronic cases if there is associated lacertus fibrosus tear, tendon retracts so much and generates lot of tension when it is brought down and hence it requires immobilisation in flexion and supination. In situation where severe retraction of tendon requires reconstruction this is best done with auto graft. Outcome of our patients is excellent. Quick DASH score improved from 57 to 11 at 2 months post op and it is improving further in patient with chronic rupture and quick DASH score improved to 0 at 3 months post-op in patient with acute rupture (Figures 9 & 10).

Figure 9: At 2 months follow up.

Figure 10: At 2 months follow up.

Injuries to posterior interosseous nerve and the lateral ante brachial cutaneous (LABC) nerve have been reported in 5% to 40% of elbows respectively, more commonly with a single anterior incision [10,11]. Heterotrophic ossification may be seen on radiographs after distal biceps tendon repair using any exposure or fixation technique, but it seems to be more common and tends to interfere more with forearm rotation using a two-incision technique. Care should be taken not to expose the ulna to prevent cross union [3]. We don’t have such complication in either case.

Conclusion

Distal biceps tendon rupture is a relatively rare injury usually caused by an eccentric contraction of the muscle in middle aged men. It is common on the dominant side. It is important not to miss the diagnosis initially, since delay in surgery does affect the outcome. In low-demand individuals acute complete tears are occasionally treated non-operatively, but most patients benefit from surgical repair.

For More Articles: Biomedical Journal Impact Factor : https://biomedres.us

Ewing’s Sarcoma/Pnet Presenting as Breast Mass

Abstract

Introduction: Ewing’s sarcoma family of tumours (ESFT) are uncommon, aggressive malignant tumours that usually arise in soft tissues or bones in children and young adults. Long bones of the lower limbs are most commonly involved. Occurrence at atypical sites can pose a diagnostic challenge. We report an exceptional case of this tumour presenting as a breast mass in a male patient.

Case Report: A 23-year-old male patient was referred to our centre with complaint of a progressively enlarging breast lump. This was initially suspected to be carcinoma, breast. On re-evaluation at our centre, FNAC yielded a diagnosis of small round cell malignancy and a possibility of Ewing’s/PNET was suggested which was confirmed on trucut biopsy and immune histochemistry. Chest CT scan subsequently performed revealed a left sided heterogeneous soft tissue mass involving a large part of thorax, causing contra lateral meditational shift. Understanding the nature and extent of disease and expecting a dismal outcome the patient refused any further investigation and treatment.

Discussion: ESFT are aggressive fast growing tumours which require urgent diagnosis for swift commencement of therapy. Occurrence at unusual sites or uncommon presentations can lead to consideration of alternative clinical diagnoses and make the evaluation challenging. This case highlights the need for careful evaluation of cytology smears, keeping in mind the unexpected, avoiding the unnecessary diagnostic delay.

Abbreviations: ESFT: Ewing Sarcoma Family of Tumours; PNET: Peripheral Neuro Ectodermal Tumour; FNAC: Fine Needle Aspiration Cytology; CT: Computed Tomography

Introduction

Ewing Sarcoma Family of Tumours (ESFT) is uncommon, aggressive, malignant tumours that usually arise in soft tissue or bones in children and young adults. The term ESFT includes typical Ewing’s Sarcoma, the Peripheral Neuro ectodermal tumour (PNET) or Askin’stumor of the chest wall [1]. It is the second most malignant tumour in the 10-20 year age group [2]. ESFTs arise from migrating embryonic cells of the neural crest showing variable neuro ectodermal differentiation. The differentiation pattern forms the basis of differentiating each individual type of ESFT though these features commonly overlap. This tumour family most commonly involves long bones of lower limbs, however, atypical presentations have been studied, which can present a diagnostic challenge [3,4]. Here we present an exceptional case of Ewing’s Sarcoma presenting as a breast mass in a male patient.

Case Report

A 23 year old male presented with a four month history of a progressively enlarging lump in his left breast. Physical examination revealed a firm, fixed and non tender mass measuring approximately 8X7 centimetres in his left breast. It was unattached to the overlying skin. The contra lateral breast and both axilla were normal. A Fine Needle Aspiration Cytology (FNAC) performed at another tertiary centre concluded in the diagnosis of breast carcinoma and the patient was referred to our centre for further management. With a clinical suspicion of breast carcinoma in mind, a repeat FNAC was performed at our centre. Cytology smears showed loosely cohesive clusters of small to medium sized monomorphic round cells which were, at places arranged around blood vessels, against a background of necrotic debris. Cells had pale, vacuolated, fragile cytoplasm, round nuclei with opened up chromatin and 2-3 conspicuous nucleoli (Figures 1a & 1b).

Figure 1A: Loosely cohesive clusters of small to medium sized monomorphic round cells against a necrotic background.

Figure 1B: These cells have pale, vacuolated, round nuclei with opened up chromatin and 2-3 conspicuous nucleoli.

Based on these features a diagnosis of small round cell malignancy with a possibility of Ewing’s Sarcoma/PNET was suspected. Trucut biopsy was performed and showed small round tumour cells arranged around blood vessels with occasional rosette formation and areas of necrosis (Figure 2a). On immune histochemistry cells stained positive for CD 99, NSE and vimentin (Figures 2b-2d) while they were negative for LCA, synaptophysin, cytokeratin and desmin. This confirmed the diagnosis of Ewing’s Sarcoma/ PNET. Computed tomography (CT) scan showed a large, heterogeneously enhancing, solid left chest wall mass with internal necrosis arising from anterior fourth rib, with extension into left breast, mediastinal shift and complete atelectasis of the left lung (Figure 3).

Figure 2a: Small round tumor cells arranged around blood vessels with occasional rosette formation and areas of necrosis.

Figure 2b: Positivity for CD99.

Figure 2c: Positivity for vimentin.

Figure 2d: Positivity for NSE.

Figure 3: Computed tomography(CT) Scan showed a large, heterogeneously enhancing, solid left chest wall mass with internal necrosis arising from anterior fourth rib, with extension into left breast, mediastinal shift and complete atelectasis of the left lung.

Discussion

ESFTs form a single group of bone and soft tissue tumours with undifferentiated Ewing’s at one end of the spectrum and Peripheral neuro ectodermal tumour (PNET) showing clear signs of neural differentiation at the other [5]. The most common sites of Ewing’s sarcoma are chest wall, Para vertebral region, retroperitoneal space, lower extremities, and gluteal region. However, few cases have been reported in the kidney, breast, gastrointestinal tract, prostate, endometrium, the adrenal glands, brain, and lung [6]. The breast is uncommonly involved and only 5-6 cases have been reported inEnglish literature, all of them in females [7]. This case is probably the first case of this tumour presenting as a breast mass in a male patient. Occurrence at unusual sites or uncommon presentations can lead to consideration of alternative clinical diagnoses and make the evaluation challenging. The index case had a tumorprobably arising from a rib, extending into thorax posteriorly and presenting as a breast mass anteriorly. This resulted in an initial confounding diagnosis of carcinoma breast.

A delay in the correct diagnosis resulted in expansion of the tumour into the mediastinum, thus upstaging the disease. It has been reported that those with localized non pelvic disease treated with multimodal therapeutic modalities including concomitant chemoradiation, have a5-year disease-free survival rate of approximately 70%. This, however, comes down significantly when the tumour spreads into the body cavities, as was seen in this case. The patient belonged to a low socio economic background and understanding the poor prognosis, he refused any further investigations and treatment. On FNAC, the differential diagnoses consists of other small round cell tumours like lymphoma, plasmacytoma, as well as small cell variants of the various epithelial and soft tissue tumours. Careful evaluation of the cytology smears, keeping in mind the unexpected, and supplementing it with immune histochemical marker studies, is, therefore, of utmost importance.

This group of tumours is characterized by the presence of the typical translocation t (11; 22) (q24; q12), the EWS-FLI1 chimeric transcript on molecular analysis and the expression of CD99 antigen (MIC-2) at immune histochemistry [8]. Other markers, like vimentin and NSE, show variable positivity. Imaging modalities usually present findings that are non specific. The diagnosis is usually made on histopathology, immunohistochemistry and the characteristic translocation t (11;22) found on molecular analysis. This case, however, highlights the importance of thorough evaluation of FNAC smears in guiding towards diagnosis and also the need for an early diagnosis in such cases.

Conclusion

ESFTs are aggressive, fast growing tumours which require urgent diagnosis for swift commencement of therapy. Occurrence at unusual sites or uncommon clinical presentations can lead to consideration of alternate clinical diagnosis, making the management challenging. The delay in diagnosis in the index case might have led to the spread of disease and a dismal prognosis, which should be avoided.

For More Articles: Biomedical Journal Impact Factor : https://biomedres.us

FLT3 Receptor Heterogeneity Strictly Specifies the Dimensions of Malignant Transformation Events in Acute Myeloid Leukemia

Abstract

Qualitative mutational events act synergistically with increases in mutated FLT3 receptors in the plasma-membrane in inducing constitutive activation of the receptors in terms of such indices as auto phosphorylation of the tyrosine kinase domains. Dimerization of the FLT3 sub-units and diminished “repulsive” dysfunctions of the juxtamembrane domain allow for permissive receptor activation. Incremental numbers of mutated receptors may strictly characterize the nature of origin of the malignant transformation event in terms of both synergic and compensatory mechanisms that directly modulate and further impact the hematopoietic progenitor cell subpopulations and also renewal of the hematopoietic stem populations in the bone marrow. Blast cell generation proliferation and impaired differentiation programs come to account for a great degree of heterogeneity in hematopoietic ally-related cell types in response to agents with tyrosine kinase inhibitory action.

Abbreviations: AML: Acute Myeloid Leukemia; ITDs: Internal Tandem Duplications; TKIs: Tyrosine kinase inhibitors; WT: Wild Type; GFI: Growth Factor Independence; SKY: Spleen Tyrosine kinase

Introduction

Stem cell hematopoietic replacement or renewal, and inhibitory effects on proliferation or contrasting maturation of progenitor cells are distinct stages and essentially highly distinctive process mechanisms in leukemogenesis. As such, the development of Internal Tandem Duplications (ITDs) in the FLT3 mutant cell juxtamembrane domain, in a large subset of Acute Myeloid Leukemia (AML) patients, has to be considered within such a differential context that is reflected in complete remission, disease-free survival, relapse rate and overall survival of AML patients with ITDs. FLT3- ITDs account for up to 25% of AML cases; the transcription factor ATF4 in these patients is essential for FLT3-ITD-induced autophagy [1]. The development of FLT3-targeted inhibitors constitutes an important paradigm shift in managing patients with very aggressive FLT3-mutated AML [2]. AML is highly heterogeneous and involves immature myeloid cell proliferation and bone marrow failure [3]. Allogeneic stem-cell transplantation decreases the risk of AML recurrence compared to standard chemotherapy but is associated with the risk of serious complications [4]. AML is the most common acute leukemia in adults, and treatment options, particularly in the elderly, are limited [5].

Autophosphorylation

Oncogenic forms of FLT3 are important therapeutic targets in AML but clinical responses to small-molecule kinase inhibitors are short-lived due to rapid emergence of resistance arising from point mutations or compensatory increases in FLT3 expression [6]. The complexity of autophosphorylation events in the two intra-cellular tyrosine kinase domains implicates both FLT3-ITD mutant cells and also cells with wild-type FLT3 in the development of constitutive activation of the FLT3 receptors. It is hypothesized that FLT3-ITD leukemia cells exhibit mechanisms of intrinsic signaling adaptation to TKI treatment that are related to an incomplete response [7]. It is further to such considerations that various different adaptor proteins are also involved in the activation of different cellular pathways and activators that lead to impaired maturation and increased proliferation of progenitor cells.

The ITDs are associated with preserved reading frame and involve non-ligand activation of the FLT3 receptors in a contextual referential system that involves often groups of three or more duplicated head-to-tail insertions of tandem duplications withthe stabilization of phosphorylation or open configuration of the tyrosine kinase domains. The ITDs are located to the juxtamembrane domain of the individual receptor in a manner that also implicates Dimerization of FLT3 receptor homodimers.

Constitutional Activation

The prognosis in AML patients could be further stratified by different mutation combinations and hence the value of nextgeneration sequencing for genomic classification [8]. Dimensions of constitutive activation of the FLT3-ITDs are also reflected in other tyrosine-kinase receptor type III family in a manner that wellillustrates the high levels of homology between various members of this large receptor family. Such high degrees of mechanistic variability in down-stream pathway effects indicate a range of nonspecific targeting of mediators within the potential scope of biologic and clinical consequences of tyrosine kinase activation modulation.

Systems of therapeutic intervention with tyrosine kinase inhibitors (TKIs) indicate that FLT3-WT (wild-type), as constitutively activated, is highly significant in terms comparable to FLT3-ITDs mutant receptors. As such, concepts of constitutive activation of the FLT3 receptors in general and of FLT3-WT/ITD receptors, in particular, also include excessive numbers of these receptors traversing the plasma-membrane of the cells. Within further realization model systems, the signal transmutations of the FLT3 receptors are profoundly influenced by numerous potential parameters of control and modulation in signal transduction. FLT3- ITD AML usually responds poorly to conventional therapies and may become resistant to TKIs due to molecular bypass mechanisms [9].

Tyrosine Kinase Domains

The tyrosine kinase domains that are autophosphorylated and activated lead to an essential stage model that mechanistically can affect proliferation, maturation and even apoptosis of blast cells in both the bone marrow and peripheral blood of AML patients. Degrees of synergism may also include FLT3-ITD and FLT3-TKD (where mutations are present in the tyrosine kinase domains) and are generally exclusive phenomena and appear not generally applicable to the biology of FLT3-mutant AML cells. TKI treatment increases the surface expression through up-regulation of FLT3 and glycosylation of FLT3-ITD and FLT3-D935 Y mutants [10].

FLT3-ITDs are a negative prognostic factor in AML patients particularly in patients over 60 years of age; such a modulated series of effects is reflected in results of studies examining the potential therapeutic benefits of administered TKIs as single agents or when combined with standard chemotherapy. The use of allogeneic stem cell transplantation has improved outcome in FLT3- ITDs patients especially in terms of relapse rates, including also AML patients treated immediately after first relapse. Growth Factor Independence 1 (GFI1) is a negative indicator of AML progression and high levels of GFI1 expression are paralleled by higher FLT3 expression and exhibit a FLT3-ITD signature of gene expression; knock-down of GFI1 expression in vitro leads to decreased FLT3 RNA and down-regulation of FLT3-ITD signaturegenes [11].

Multi-Components

Considered response of FLT3-mutated hematopoietic cells to small molecule inhibitors is, hence, an overall index of participation of multiple pathways that originate from autophosphorylation of the tyrosine kinase domains and that are reflected in such pathways as inhibited apoptosis and in the activation of intra-nuclear catenin. The multi-component systems of adaptor proteins in particular allow for signal response in the evolutionary course of AML cell proliferation and of impaired maturation beyond the hematopoietic blast stage. Spleen tyrosine kinase (SYK) is activated and increases in FLT3-ITD-positive AML patients and is critical for transformation and maintenance of the leukemia clone in these patients [12].

A critical stage of differentiation appears to be the transition of (CD34+/CD33-) subpopulations of progenitor cells to the (CD34+/CD33+) cell population when considering FLT3 precursor cells in AML patients. The three main groups of mutated FLT3 hematopoietic cells include FLT3-ITDs, and also FLT3-point mutations in the juxtamembrane domain, and the tyrosine kinase domain mutations. FLT3-TKD-mutated AML patients have a more favorable prognosis clinically when compared with patients with FLT3-ITD mutations [13]. As such, an essentially significant degree of heterogeneity is found within the complex phenomenon of FLT3- mutated hematopoietic progenitor cell populations considered and is contributory to AML leukemogenesis. The complex heterogeneity of AML has seriously hampered the development of a curative treatment; mono-therapy is associated with resistance due to the parallel signaling circuitry involving also MAPK and mTOR [14]. Whereas FLT3-ITD cells tend to target myeloid-type cells, FLT3- TKDs are associated with a preferential selection of lymphoid-type precursor cells.

Autophosphorylation

The essential absence of stop-codons in both FLT3-ITD and FLT3-TKD cells affecting especially the internal tandem duplications in the former group of mutated receptors is fully consistent with excessive signaling as a hallmark of the constitutive receptor activation and tyrosine kinase autophosphorylation. Dynamics of constitutive phosphorylation of the FLT3-mutated receptors are reflected within contexts of auto-stimulation that primarily include excessive suppression of the “repulsive forces” that affect the juxtamembrane domain of the receptor in patients with FLT3-ITDs. Also, glycosylation of the extra-cellular domain of the FLT3 cells, whether FLT3-ITD or WT, may possibly be implicated not only in the trans-membrane insertion of the FLT3 receptors but also as implemented component in response to extra-cellular stimuli that may synergistically cooperate with constitutive receptor activation and phosphorylation of the tyrosine kinase domains.

Andrographolide (an active component of Andrographis paniculata) suppresses MV4-11 cell proliferation through inhibition of FLT3 signaling with also inhibition of fatty acid synthesis and cellular iron uptake [15]. FLT3 LIGAND The FLT3 receptor ligand FL functionality is mechanistically homologous to the KIT receptor and dynamics of each ligand type and is projected towards thefurther creation of established states of autophosphorylation of the tyrosine kinase domain. In this sense, TKIs may be expected to impact the constitutive activation of the blast cells in terms of ongoing dimensions of proliferation and impaired maturation of the hematopoietic progenitor cells in patients with AML.

Results of the non-responsive sub-populations of hematopoietic progenitor cells may in part arise from the marked heterogeneity of pathway response and inclusion as terms of effect arising from constitutive activation and autophosphorylation of the FLT3 receptors. High expression of proviral integration site for Moloney murine leukemia virus-1 (PIM-1), a serine/threonine kinase, is a high risk independent prognostic factor in AML [16]. The SOX4 transcription factor is not only an independent prognostic factor in AML but also an important molecular oncogenic agent in leukemogenesis [17].

High expression of Inhibin-Beta A (a ligand of the transforming growth factor Beta super family) is an adverse prognostic marker for de novo AML [18]. As such, incremental numbers of FLT3 receptors that traverse the cell membrane may potentially prove a dynamic interplay with tyrosine kinase activation in further oncogenesis and synergistically potentiate ongoing progression of the AML cell subpopulations. Indeed, further synergistic compensatory increases in FLT3-ITDs may prove instrumental in augmenting dimensions of malignant transformation events that include stem cell subpopulations generating mutated progenitor hematopoietic cells.

or More Articles: Biomedical Journal Impact Factor : https://biomedres.us