Changes in clinical & biochemical presentations of primary hyperparathyroidism in India over a period of 20 years.

Background & objectives: With the advent of serum chemistry autoanalyzer and routine estimation of serum calcium as a part of annual physical examination, there has been a dramatic change in the presentation of primary hyperparathyroidism (PHPT) from symptomatic to asymptomatic disease in the United States. However, such trend has not been documented from India. We carried out this retrospective study to analyse the changes in clinical presentations of PHPT patients over a period of two decades in a tertiary care centre in north India. Methods: This retrospective study included patients with PHPT treated at a single centre of north India between March1990 and October 2010. Two decades were divided into four different time periods, i.e. 1990 to 1994, 1995 to 1999, 2000 to 2004 and 2005 to 2010. Clinical presentations, biochemical parameters and surgical outcomes were compared between different time periods using appropriate statistical methods. Results: Data of 202 patients with PHPT with male: female ratio of 3:7 were analyzed. There was a rise in the number of cases of PHPT diagnosed in the last decade compared to the previous decade (28 cases vs 174 cases, P<0.001). Change in the mean age, male: female ratio, lag time for the diagnosis of PHPT and clinical presentations of PHPT (predominance of bone and stone symptoms) did not differ across different time periods. Non-significant decrease in serum calcium levels at the time of diagnosis of PHPT and a significant, decline in the serum alkaline phosphatase levels (P<0.01) were found in the last decade, however, iPTH levels were higher in the last decade (pP<0.05). There was no change in the site and size of parathyroid adenoma in the two decades, however, postoperative symptomatic hypocalcemia was less frequent in the last decade. Interpretation & conclusions: The findings of this retrospective analysis show that the PHPT still remains symptomatic disease with increasing awareness over the last two decades in our center. There was not much change in the clinical presentation, in the past two decades.

The impact of VKORC1-1639 G>A polymorphism on the maintenance dose of oral anticoagulants for thromboembolic prophylaxis in North India: A pilot study.

BACKGROUND: The dose requirements for oral anticoagulants in thromboembolic events are influenced by promoter polymorphism in the VKORC1 gene. However, limited data are available on the influence of the polymorphism in various Indian populations. The present study aimed at determining the relationship between the VKORC1-1639 G>A genotypes and maintenance doses of oral anticoagulants for therapeutically stable INR values in patients taking Acitrom after valve replacement surgery. MATERIALS AND METHODS: Fifty patients from the northern Indian region were genotyped for VKORC1-1639 G>A by polymerase chain reaction and restriction fragment length polymorphism. Means of the weight-normalized daily Acitrom dose were calculated for every patient. RESULTS AND DISCUSSION: The VKORC1 1639G>A minor allele frequency in the study population (n = 50) was found to be 22%. The patients with a wild type genotype required the maximum drug dose as suggested for full functionality of the enzyme. Heterozygous patients were found to have an intermediate drug dose and the patients with a variant homozygous genotype had the minimum maintenance drug dose requirement. These findings are in concurrence with the effect of the promoter polymorphism on vitamin K epoxide reductase activity.1639G>A minor allele frequency in the study population (n = 50) was found to be 22%. The patients with a wild type genotype required the maximum drug dose as suggested for full functionality of the enzyme. Heterozygous patients were found to have an intermediate drug dose and the patients with a variant homozygous genotype had the minimum maintenance drug dose requirement. These findings are in concurrence with the effect of the promoter polymorphism on vitamin K epoxide reductase activity. CONCLUSION: The VKORC1-1639 G>A status can be indicative of establishing the therapeutic dose of oral anticoagulants in Indian patients.

Fibrous dysplasia & McCune-Albright syndrome: An experience from a tertiary care centre in north India.

Background & objectives Fibrous dysplasia (FD) is a rare metabolic bone disease and information available from India is limited to only anecdotal case reports. We describe the clinical profile and therapeutic outcome of 25 patients with FD observed over a period of 14 yr in a tertiary care centre from north India. Methods In this retrospective study patients (n = 25) with diagnosis of fibrous dysplasia based on either classical radiological features and/or histological evidence on bone biopsy, were analyzed. Associated endocrinopathies if any, were evaluated. The diagnosis of McCune Albright syndrome (MAS) was considered when fibrous dysplasia was accompanied by either café-au-lait macules and/or endocrinopathies. The clinical presentation, biochemical parameters and imaging were analysed. Seven patients received bisphosphonate therapy. The final outcome and side effects were noted. Results Age of the patients ranged from 7 to 48 yr (mean ± SD, 24.2 ± 11.4 yr) with a lag time between onset of symptoms and presentation ranging from 1 to 20 yr (mean ± SD, 6.6 ± 6.2 yr). The mean duration of follow up was 3.5 ± 2.1 yr. Eighteen (72%) patients had polyostotic disease while the remaining had monostotic FD. Eight patients had endocrinopathies: five had acromegaly, one each had gonadotropin independent precocious puberty (GIPP), hyperthyroidism and hypophosphatemic rickets. One child with GIPP later developed hyperthyroidism. McCune Albright syndrome was observed in 10 (40%) patients. A majority of the patients underwent various minor or major surgical procedures and seven patients received bisphosphonates for recurrent pathological fractures. Bone pain was reduced in all bisphosphonate treated patients with a decrease in subsequent fractures. Interpretation & conclusions This series of FD patients from north India shows the varying presentations of this rare disease. Medical treatment with bisphosphonates appears to be potentially rewarding.

Computed tomographic pulmonary angiography: Utility in acute pulmonary embolism in providing additional information and making alternative clinical diagnosis.

Objective: To evaluate the role of computed tomographic (CT) pulmonary angiography (CT-PA) in detecting additional information that may help in making an alternative clinical diagnosis in patients referred to CT for a suspected acute pulmonary embolism (PE). Materials and Methods: 50 patients (34 males, 16 females) in the age group of 18-72 years (mean 42.3 years), having high clinical suspicion of PE, underwent CTPA over a 2 year period. Chest x-ray, arterial blood gas (ABG) analysis, echocardiography were done in all patients. All patients underwent at least one other imaging examination besides CTPA: ventilation perfusion scan, Doppler ultrasound or compression ultrasound (for DVT). All patients were followed for 3 months after completion of the diagnostic work up at baseline. The final diagnosis was achieved by a combination of clinical, imaging, and laboratory analysis, after adequate imaging, laboratory tests, and follow up. Result: CTPA helped correctly identify 29 of 30 patients with PE. In the remaining 20 patients (with no evidence of PE), CT-PA provided additional information (that suggested or confirmed alternate clinical diagnosis) in 15 patients (75%): pleural effusion (n=8), mediastinal or hilar lymphadenopathy (6), pneumonia/airspace consolidation (5), atelectasis/collapse (2), aspergilloma (1), malignancy (1), and others (2). Conclusion: CT-PA is highly specific and sensitive for diagnosis of PE. In addition, in a majority of patients who do not have PE, it also provides important ancillary additional information and helps in making an alternative clinical diagnosis.

A pilot study on hypothalamo-pituitary-adrenocortical axis in primary hyperparathyroidism.

Background & objectives: Parathormone (PTH) and calcium, both have been shown to stimulate adrenal steroidogenesis in animal models and in vitro experiments. This is attributed to structural similarity between 15-25 amino acid region of the parathyroid hormone (PTH) and 1-11 amino acid region of adrenocorticotropin (ACTH). However, there are no in vivo human data regarding the effect of PTHcalcium axis on adrenocortical function. Materials: Ten patients with primary hyperparathyroidism underwent evaluation for cortisol dynamics including 0800 h and 2000 h plasma cortisol on day 1, cortisol response to insulin induced hypoglycaemia (IIH) on day 2, and 1 mg overnight dexamethasone suppression test (ONDST) on day 4. Serum aldosterone was also measured at 0800 h in fasting state on salt ad libitum for three days. These parameters were repeated 3 months after curative parathyroidectomy. Results: Basal plasma cortisol level at 0800 h and 2000 h were within upper normal range and loss of circadian rhythm in cortisol secretion was observed in half and forty per cent of patients had nonsuppressibility with ONDST. The defined peak cortisol response to insulin induced hypoglycaemia (>550 nmol/l) was achieved in all and nearly one third of patients had exaggerated response (>2000 nmol/l). After curative parathyroidectomy, the abnormalities in circadian rhythm and non-suppressibility with ONDST continued to prevail in 40 per cent of patients. The peak cortisol response to IIH showed a decrement but remained higher than normal. No correlation was observed between circulating parathyroid hormone and calcium with cortisol levels. Serum aldosterone was in upper normal range pre - and postoperatively, though it decreased postoperatively, but it could not attain a statistical significance (p = 0.5). Interpretation & conclusion: Abnormalities in hypothalamo-pituitary-adrenocortical axis in primary hyperparathyroidism do occur, however these are inconsistent and do not recover in majority of patients even after 3 months of curative parathyroidectomy.

Mutation analysis in Indian children with achondroplasia - utility of molecular diagnosis.

OBJECTIVE: Mutation analysis in Indian children with achondroplasia. METHODS: We studied 11 sporadic cases of achondroplasia. Mutation analysis was done by PCR/RFLP (Polymerase chain reaction/Restriction fragment length polymorphism) method. RESULTS: Nine of the 11 cases had mutation G-->A at 1138 nucleotide position in transmembrane domain of fibroblast growth-factor receptor 3 (FGFR3) gene. Substitution G-->A is a common recurrent mutation reported worldwide. In two cases we could not detect any common mutation and also in entire region of transmembrane domain sequenced. There is possibility of mutation in the other regions of FGFR3 gene in these two cases. CONCLUSION: Further study of these two cases is needed in order to define other genotypes resulting in achondroplasia. Postnatal diagnosis of achondroplasia depends on clinical and radiological features. Mutation detection is mainly useful for prenatal diagnosis.

Risk factors for renal injury in patients with meningomyelocele.

PATIENTS AND METHODS: Thirty operated patients of myelodysplasia were clinically evaluated for the age at presentation, the extent of lesion and neurological deficit. Urological assessment was done with urine cultures, serum creatinine, radiological (ultrasound of kidney, ureters and bladder, voiding cystourethrogram) and urodynamic (water cystometry) parameters. An objective scoring for bladder (Galloway, et al.) was applied. Dimercapto-succinic acid (DMSA) scan was done in all the patients for evidence of renal scars. The results of above investigations were correlated with presence or absence of renal scars (renal injury) on DMSA scan. None of the patients had received any prior bladder care. RESULTS: Twenty one patients had no renal scars and 9 patients had evidence of renal scarring. Patients with renal scars were older at presentation, they had greater degree of hydroureteronephrosis (P < or = 0.001) and vesicoureteric reflux (P < or = 0.005). The incidence of high leak pressures (>25 cm of water, P < or = 0.05), unacceptable bladder volumes (maximum cystometric capacity < 60% for age, P < or = 0.005) and high risk Galloway's score (> 5, P < or = 0.05) was high in patients with associated renal scarring as compared to their nonscarred counterparts. Three of these patients had serum creatinine >1 mg/dl (P < or = 0.005). The incidence of urinary complaints and positive urine cultures was also higher in these patients (NS). CONCLUSION: Increasing age, evidence of hydroureteronephrosis and vesicoureteric reflux, high leak pressures, low bladder volume and high combined Galloway score (>5) define a high risk bladder in our population and predispose to renal injury in patients of myelodysplasia. Early referral for bladder risk assessment and management of all myelodysplasia patients is recommended.

Clinical profile, diagnosis and management of patients presenting with symptomatic pulmonary embolism.

OBJECTIVE: To study the clinical profile and diagnostic methods in patients with symptomatic pulmonary embolism (PE). METHODS: Prospective assessment of clinical features, radiology and outcome of patients presenting with symptomatic PE over an 18-month period. RESULTS: During study period, 24 patients with a mean age of 39 +/- 12.1 years were diagnosed to have symptomatic pulmonary embolism. Dyspnoea (91.7%) and cough (58.3%) were the predominant complaints. Spiral computed tomographic pulmonary angiography (CTPA) was performed in 21 (87.5%) patients and perfusion scans in 14 (58.4%) patients. Echocardiography performed in all patients revealed evidence of pulmonary artery hypertension and right ventricular dyskinesia in 20 (83.3%) and 15 (62.5%) patients, respectively. Thrombolysis with streptokinase was performed in 14 (58.3%) patients. All patients received low molecular weight heparin followed by warfarin. Of the 24 patients, 20 (83.3%) were discharged and are under regular follow-up; four patients died. CONCLUSIONS: Pulmonary embolism is a common problem and can be easily diagnosed provided it is clinically suspected. Early diagnosis and aggressive management is the key to successful outcome.

Polymorphism of GSTM1 and GSTT1 genes in prostate cancer: a study from North India.

BACKGROUND: Glutathione-S-transferases (GSTs) are active in the detoxification of wide variety of endogenous or exogenous carcinogens. The genetic polymorphisms of GSTM1 and GSTT1 genes have been studied earlier to evaluate the relative risk of various cancers. AIM, SETTING AND DESIGN: In the present study, we examined the association of the GSTM1 and GSTT1 gene polymorphisms with sporadic prostate cancer patients in north Indian population. MATERIAL AND METHODS: This case control study was undertaken over a period of 24 months and included 103 prostate cancer patients and 117 controls; both patients and controls originated from northern part of India. The GSTT1 and GSTM1 genotypes were identified by multiplex PCR in peripheral blood DNA samples. STATISTICAL ANALYSIS: Difference in genotype prevalence and association between case and control group were assessed by the Chi square and Fisher Exact tests. RESULTS: Frequencies of null genotypes in GSTT1 and GSTM1, was 11% (13/117) and 30% (35/117) respectively in control individuals. The frequencies of GSTT1 and GSTM1 null genotypes in prostate cancer patients were 34% (35/103) and 53% (55/103) respectively. CONCLUSION: Our study demonstrates that the null genotypes of GSTT1 and GSTM1 are substantially at higher risk for prostate carcinoma as compared to the normal healthy controls. The GSTT1 and GSTM1 null genotypes did not show significant association with tobacco usage in prostate cancer patients. However, the null genotypes were significantly stratified in 50-60 year-old patients when incidence of prostate cancer is high.

Bone scan in diagnosis of lymphoma with extensive bone marrow necrosis--a case report.

Bone marrow necrosis (BMN) is a relatively uncommon clinicopathologic entity with diverse etiology. We describe a case of BMN in a 11 1/2 year old male child with an underlying non Hodgkin's lymphoma T-cell type. With the help of 99m Tc-MDP (methylene diphosphonate) bone scan we were able to find out the etiologic factor in this case.

Bronchial transection: delayed diagnosis and successful repair.

Traumatic bronchial transection is usually recognized and repaired immediately after injury. Bronchial transection has a variety of clinical presentations due to air leak into the pleural cavity and it is very rare to have total absence of air leak from the transected bronchus at presentation. We present one such case of main right bronchus injury with total absence of initial clinical signs and symptoms, leading to a delay in the diagnosis. However, the surgical repair eight months after injury showed excellent recovery of the chronically collapsed lung.

Molecular diagnosis and genetic counseling for fragile X mental retardation.

The fragile X syndrome is the most frequent cause of inherited mental retardation. It is caused by a dynamic mutation: the progressive expansion of polymorphic (CGG)n trinucleotide repeats located in the promoter region of the FMRI gene at Xq27.3. The cloning of the FMRI gene and the elucidation of the molecular basis of the fragile X syndrome is of great importance for the diagnosis and understanding of this unusual type of mutation. Although extensively studied, the mechanism behind the transition from stable normal (CGG)n alleles to the carrier state (an unstable premutation) and from premutation to mutation is partially understood. The clinical diagnosis of fragile X mental retardation (FXMR) is not possible as dysmorphic features are subtle. Molecular diagnosis by Southern Blot is the confirmatory test that makes carrier detection and prenatal diagnosis possible. As the risk of recurrence of FXMR is high in the family and carrier relatives, an identification of fragile X positive children, and offering carrier detection and prenatal diagnosis to the families is very important. It is possible by screening mentally retarded children and adults even if there is no family history of mental retardation or typical behavioral or physical features associated with the fragile X phenotype. In this review we have discussed the method for the diagnosis and counseling of the families. The complexities due to premutation and the variable severity of manifestations in carrier females need to be understood while counseling fragile X families.

Re-evaluation of reading frame-shift hypothesis in Duchenne and Becker muscular dystrophy.

The reading frame hypothesis has been proposed to explain the molecular basis of two allelic forms of muscular dystrophies, Duchenne/Becker muscular dystrophy (D/BMD). To evaluate the hypothesis in Indian D/BMD patients, we analyzed deletion of dystrophin exons in 147 DMD and 19 BMD patients. Our studies showed deviation of more than 30% from the reading frame hypothesis in DMD patients (47/147). The present results implicate a need to reevaluate the reading frame hypothesis.

DNA mismatch repair, microsatellite instability and cancer.

Mismatch (MMR) repair system plays a significant role in restoration of stability in the genome. Mutations in mismatch repair genes hamper their activity thus bring about a defect in mismatch repair (MMR) mechanism thereby conferring instability in the microsatellite sequences of both the coding and non-coding regions of the genome. Mutated mismatch repair genes result in the expansion or contraction of microsatellite sequence and confer microsatellite unstable or replication error positive phenotype. Hypermethylation of promoter regions of some of the MMR genes also causes inactivation of these genes and thus contribute to MSI. Microsatellite instability is an indicator of MMR deficiency and is a prime cause of varied tumorogenesis.

Effect of erythromycin and cisapride on emptying of the vagally denervated intrathoracic stomach.

BACKGROUND: Subsequent to esophagectomy and reconstruction among patients with esophageal cancers, the intrathoracic denervated stomach acts as a passive conduit without peristalsis. OBJECTIVE: The study was designed to assess the impact of two prokinetic drugs viz. erythromycin and cisapride on the emptying of vagally denervated intrathoracic stomach. METHODS: Twenty consecutive patients of carcinoma esophagus, who had undergone one stage transhiatal oesophagectomy with cervical esophagogastrostomy and were disease free at three months postoperative follow-up, were included in the study. These patients were randomised into two groups of ten each. The patients in group A received erythromycin, while patients in group B received cisapride. The gastric emptying was studied by scintigraphy, using a standard test meal containing 99m Tc sulphur colloid labelled 'IDLIS' [rice based radio labelled food] before and after the drug treatment. RESULTS: The pre and post treatment mean gastric half emptying time of the patients in the erythromycin group was 52.6 min and 49.7 min (p > 0.1) and in cisapride group it was 53.76 and 26.4 min respectively (p < 0.05). Intergroup comparison of the difference was not statistically significant. CONCLUSION: Cisapride is an effective prokinetic agent in the treatment of gastric stasis of the vagally denervated intrathoracic stomach.

Clinical and molecular diagnosis of spinal muscular atrophy.

The spinal muscular atrophies are a group of disorders characterized by flaccid limb weakness. It is necessary to differentiate these from other causes and identify the SMA variants. In classical SMA, majority of the patients shows homozygous deletion of the telomeric SMN gene (SMN1) on chromosome 5q. The availability of DNA analysis has allowed proper genetic counseling and prenatal diagnosis in the affected families. Application of newer techniques has enabled more accurate carrier detection. Our objective is to stress the variability in the clinical features and recent advances in the molecular diagnosis for SMA.