Role of DNA methylation in renal cell carcinoma.

Alterations in DNA methylation are seen in cancers and have also been examined in clear cell renal cell carcinoma (ccRCC). Numerous tumor suppressor genes have been reported to be partially or completely silenced due to hypermethylation of their promoters in single-locus studies, and the use of hypomethylating agents has been shown to restore the expression of many of these genes in vitro. In particular, members of the Wnt and TGF-beta pathways, pro-apoptotic genes such as APAF-1 and negative cell-cycle regulators such as KILLIN have been shown to be epigenetically silenced in numerous studies in ccRCC. Recently, TCGA analysis of a large cohort of ccRCC samples demonstrated that aberrant hypermethylation correlated with the stage and grade in kidney cancer. Our genome-wide studies also revealed aberrant widespread hypermethylation that affected regulatory regions of the kidney genome in ccRCC. We also observed that aberrant enhancer hypermethylation was predictive of adverse prognosis in ccRCC. Recent discovery of mutations affecting epigenetic regulators reinforces the importance of these changes in the pathophysiology of ccRCC and points to the potential of epigenetic modulators in the treatment of this malignancy.

Targeting chemokine pathways in esophageal adenocarcinoma.

Esophageal adenocarcinoma (EAC) is one of the fastest growing malignancies in the US and needs newer therapeutic and diagnostic strategies. Chronic inflammation plays a role in the pathogenesis of EAC and contributes to the dysplastic conversion of normal esophageal epithelium to Barrett's esophagus and frank adenocarcinoma. Chemokines play important roles in mediating inflammation and recent evidence implicates these ligands and their receptors in the development and spread of various tumors. We demonstrated that the chemokines IL8, CXCL1 and CXCL3 are significantly overexpressed during esophageal carcinogenesis and accompanied by amplification and demethylation of the chr4q21 gene locus. We also demonstrated that IL8 levels can be detected in serum of patients with EAC and can serve as potential biomarkers. We now demonstrate that inhibition of IL8 receptor, CXCR2, leads to decreased invasiveness of esophageal adenocarcinoma derived cells without affecting cellular proliferation. Taken together, these studies reveal the important roles that chemokines play in development of esophageal cancer and demonstrate that these pathways can serve as potential therapeutic targets.

Unusual cause of cholestatic jaundice in a patient with AIDS.

A 61-year-old man with AIDS on chronic highly active antiretroviral treatment (HAART) presented with lethargy and jaundice and was found to have abnormal liver function tests (LFTs). Investigations including viral/autoimmune markers and imaging were unrevealing, except for positive Epstein-Barr virus. HAART was held, however, transaminases and total bilirubin continued to rise. The liver biopsy revealed classical Hodgkin's lymphoma (HL). HL presenting only with liver findings without lymphadenopathy is rare. Extreme cases can lead to fulminant liver failure. The bone marrow biopsy and dramatic elevation in serum ferritin were consistent with haemophagocytic lymphohistiocytosis. Finding a chemotherapy regimen was challenging given abnormal LFTs and HAART interactions. Initial chemotherapy regimen has successfully decreased LFTs; however, it was limited by pancytopenia. The patient's regimen was changed, however second regimen was complicated by neuropathy. LFTs improved and the patient was able to receive the standard care chemotherapy for HL with significant clinical, laboratory and radiological improvement.

Acute disseminated encephalomyelitis--a prospective study of clinical profile and in-hospital outcome predictors.

INTRODUCTION: There is paucity of data on acute disseminated encephalomyelitis (ADEM) in adults in India. Recent reports indicate that demyelinating disorders in the eastern hemisphere are quite distinct from conventional western type multiple sclerosis. AIMS: This study aimed to study the clinical profile, laboratory and imaging parameters, in-hospital morbidity/ mortality and clinical and imaging predictors of in-hospital outcome in ADEM. RESULTS: A total of 29 patients were studied, gender ratio being not significantly different. Prior infection was present in 55.1% patients. Motor deficits (68.9%), bowel bladder abnormalities (65.5%) and sensory deficits (24.1%) were the commonest presenting features. Encephalopathy was seen in 24.1% patients. 10.3% patients had seizures and meningism. A polysymptomatic presentation was seen in 79.3% patients. Pure spinal cord affection (41.3%) was the commonest MRI pattern followed by subcortical (31%) and periventricular white matter involvement (24.1%). A normal MRI was seen in 17.2% of patients. 63% patients showed raised Cerebrospinal fluid (CSF) protein. The commonest in-hospital morbidity was urinary tract infection (18.5%). At admission; 81.4% patients had modified Rankin's score (MRS) between 4 and 6. At 6 weeks post admission, 90.4% patients had MRS score between 0-3, i.e, a favourable MRS. CONCLUSION: This short term, in-hospital study of ADEM showed preponderance of polysymptomatic onset with motor deficits, commonest MRI pattern being pure spinal cord involvement. A good prognosis for short-term recovery at 6 weeks was noted, despite moderate to severe disability at admission.

An unusual cause of flash pulmonary oedema.

We report a case of young woman who presented with acute cardiogenic pulmonary oedema and respiratory failure. She underwent emergent endotracheal intubation and was transferred to the intensive care unit. She responded to intravenous diuretics and positive pressure ventilation. Subsequent workup revealed that she had Graves' disease and was in thyrotoxic crisis. Therapy with propranolol and propylthiouracil was instituted to which she showed remarkable improvement.

Spontaneous occlusion of the circle of Willis in a young woman with epilepsy: epileptic-type Moyamoya disease.

The authors report a case of a 31-year-old woman from India with history of seizure disorder who presented with sudden onset right hemiparesis and right-sided upper motor neuron type facial palsy. No identifiable risk factors were noted on admission and all laboratory investigations were negative. MR angiography helped in arriving at the diagnosis of moyamoya disease as the aetiology of her symptoms.

Reversible steatohepatosis in a young boy with brittle type 1 diabetes mellitus: mauriac syndrome.

A 14-year-old male, diagnosed case of type 1 diabetes mellitus since 1 year, presented with uncontrolled blood glucose levels, non-compliance with insulin therapy and recurrent admissions with diabetic ketoacidosis. His blood glucose levels were difficult to control with wide fluctuations in insulin requirement. He had absent secondary sexual characteristics and hepatomegaly. Liver biopsy showed macrovesicularsteatosis without fibrosis or inflammation. Many glycogenated nuclei were present. He was started on intensive insulin therapy, whereby he showed subsequent regression of hepatomegaly and onset of pubertal spurt.

Pancreatic ascites in the setting of portal hypertension.

Pancreatic ascites is a rare cause of ascites and develops largely as a complication of chronic pancreatitis or sometimes due to duct injury during surgical procedures. The entity may mimic spontaneous bacterial peritonitis or ascites due to portal hypertension. Here, the authors discuss a case of pancreatic ascites developing in the setting of alcoholic liver disease with portal hypertension. The patient had features of chronic pancreatitis with pancreatic duct fistula and was managed with stenting of the pancreatic duct.

Dyselectrolytemia in acute kidney injury causing tetany and quadriparesis.

A 40-year-old female, presented with prerenal acute kidney injury secondary to diarrhoea. With appropriate hydration, she went into diuretic phase and subsequently developed hypokalemic quadriparesis with hypocalcaemic tetany due to hypomagnesemia and subclinical vitamin D deficiency. The patient improved with oral potassium, magnesium, calcium and vitamin D supplementation.

Renal tubular acidosis due to Wilson's disease presenting as metabolic bone disease.

Two sisters presented with lower limb deformity and difficulty in walking without support. Both had short stature; however, neurodevelopment and secondary sexual characters were normal. Abdominal examination revealed splenomegaly and ophthalmic examination showed presence of Kayser-Fleischer (K-F) rings. Diagnosis of Wilson's disease was confirmed with low serum copper and ceruloplasmin levels. Further investigations revealed urinary acidification defect with hypercalciuria pointing towards distal renal tubular acidosis. Both patients were started on copper chelation therapy and showed gradual radiographic improvement in osteopaenia.

Hydrocarbon pneumonitis masquerading as acute lung injury.

Hydrocarbon pneumonitis is an acute, intense pneumonitis resulting from aspiration/inhalation of volatile hydrocarbon compounds with low viscosity and surface tension. The authors describe the case of a 24-year-old male who aspirated diesel while siphoning it from heavy duty crane, developed bilateral pneumonitis and responded to 2-day therapy with non-invasive continuous positive airway pressure ventilation.

Acrocallosal syndrome in a young hypertensive male.

Acrocallosal syndrome is an extremely rare genetic disorder with autosomal recessive inheritance. It is characterised by moderate to severe mental retardation, hypotonia, agenesis of the corpus callosum and preaxial polydactyly involving both feet and the facial features like broad forehead and hypertelorism. The authors report a case of a young hypertensive male who presented with unprovoked seizures for the first time who had multiple craniofacial, digital dysmorphic features with moderate mental retardation. The diagnosis of acrocallosal syndrome was arrived at after neuroimaging showed agenesis of corpus callosum with interhemispheric cysts.

Sudden mono-ocular blindness with recurrent transient diplopia and ptosis in a middle-aged woman.

Sudden painless loss of vision is an ophthalmologic and a medical emergency resulting from various causes such as occlusion of retinal artery or vein, macular or vitreous haemorrhages, retinal detachment, and anterior and posterior ischaemic optic neuropathy. We report a 48-year-old woman presenting with right monocular blindness due to branch retinal artery occlusion whose vision recovered due to timely paracentesis coupled with treatment with adequate antiplatelet agents and anticoagulants. The patient had transient diplopia and ptosis despite adequate antiplatelet agents and anticoagulants. Thorough search for aetiology revealed the underlying cause to be aortoarteritis. Aortoarteritis is a rare disease, and ocular involvement occurs late in the disease. We review ophthalmologic manifestation of aortoarteritis and diagnostic utilities of various modalities for aortoarteritis.

Xanthogranulomatous pyelonephritis in a young postpartal female.

Xanthogranulomatous pyelonephritis (XGP) is a rare chronic inflammatory disorder of the kidney characterised by an infectious phlegmon arising in the renal parenchyma. It is seen in patients who have urolithiasis, urinary tract infection and immunocompromised status. The clinical presentation is variable and renal neoplasm is considered as a differential due to its characteristic extrarenal visceral invasion. The treatment is almost universally extirpative and can pose a formidable challenge to the treating physician and surgeon. The authors report a rare case of XGP in a postpartal woman who presented with multiple visceral abscesses whose diagnosis was arrived on histopathological examination.

Early predisposition to osteomalacia in Indian adults on phenytoin or valproate monotherapy and effective prophylaxis by simultaneous supplementation with calcium and 25-hydroxy vitamin D at recommended daily allowance dosage: a prospective study.

BACKGROUND: Long-term therapy with antiepileptic drugs (AED) may be associated with increased total serum alkaline phosphatase (ALP) levels and reduced serum calcium, inorganic phosphorous, and vitamin D levels. These adverse biochemical alterations have an adverse effect on bone health. OBJECTIVE: To determine (a) onset of derangements in serum total ALP and its isoenzymes (liver, bone), calcium and 25-hydroxy vitamin D (25-OHD) concentrations after initiation of treatment with phenytoin or valproic acid monotherapy and (b) the effect of simultaneous supplementation with calcium and 25-OHD at recommended daily allowance (RDA) dosage, on these biochemical parameters. MATERIALS AND METHODS: Study was a prospective, case-controlled study in adults. Serum biochemical parameters were estimated at baseline, 30, 60, and 90 days of starting AED treatment in the study subjects: Groups--A (only calcium supplementation) and Group B (both calcium and 25-OHD supplementation). STATISTICAL ANALYSIS: Mean+/-SD, and students' paired t test (between groups A and B) unpaired students' t test (drug-wise). RESULTS: At 60 days of AED therapy Group A showed a significant increase in serum total ALP (78.83+/-11.04 to 101.75 +/- 9.56 IU/l) (P < 0.001), ALP-liver isoenzyme, (41.97+/- 10.81 to 68.83 +/-7.81 IU/L) (P < 0.001), significant decrease in calcium (9.30 +/- 0.36 to 8.80 +/- 0.38 mg%) (P < 0.001), ALP-bone isoenyzme (36.84 +/- 5.01 to 32.92 +/- 6.46 IU/L) (P < 0.001), and a significant decrease in 25-OHD (25.19 +/- 5.98 to 19.76 +/- 5.35 ng/ml) (P < 0.001) at 90 days. In contrast Group B, at 60 days, showed a significant decrease in serum total ALP (81.92 +/- 19.63 to 54.77. +/- 11.53 IU/L) (P < 0.0001), ALP-liver isoenzyme (48.01. +/- 13.53 to 28.12. +/- 5.88 IU/L) (P < 0.0001), significant increase in calcium ((9.24 +/- 0.31 to 9.93 +/- 0.26 mg%) (P < 0.001) and ALP-bone isoenzyme levels (33.93 +/- 12.2 to 26.25 +/- 8.23 IU/L). In Group B, 25-OHD levels showed a significant increase at 90 days (24.36 +/- 3.42 to 31.53 +/- 327 ng/ml) (P < 0.0001). CONCLUSION: Biochemical derangements in calcium metabolism involving the bone are seen by 60 days after starting AED monotherapy, indicating predisposition to development of osteomalacia in these patients. This is preventable by simultaneous oral supplementation with calcium and 25-OHD.

Monocular blindness during therapy for cerebral neurocysticercosis.

Neurocysticercosis is endemic in India, cerebral and ocular manifestations being common. A 32 yr old man on treatment with Albendazole for cerebral neurocysticercosis for 10 days presented with 3 days of painful uniocular blindness. He had only light perception in the left eye, left pupil was non-reactive to light and left disc was edematous. B-scan of eye revealed retinal detachment due to sub retinal cyst and CT brain showed multiple parenchymal cysticerci. The natural history of ocular neurocysticercosis or enhanced sub-retinal inflammation due to Albendazole therapy could have resulted in the retinal detachment in this case.

Experience with patients with anti-MUSK antibody positive myasthenia gravis.

The association of muscle tyrosine kinase (Musk) antibody with recurrent bulbar weakness in acetylcholine receptor antibody (Ach-R Ab) negative myasthenia gravis (MG) has been well documented. We describe 2 patients, a middle aged man and a 9-year-old girl, both seronegative for Ach R antibody who had recurrent bulbar weakness and MUSK antibody positivity. Patients made a full recovery from the acute episode with intravenous immunoglobulin (IV Ig) therapy. The peculiar clinical features of this condition and its management are discussed.