Regions of homozygosity and a novel variant in Steel syndrome: An added dilemma to diagnosis.

Steel syndrome is an autosomal recessive disorder that is caused by mutations in COL27A1 gene. The majority of reported cases have been of Puerto Rican origin, with few reports from India. The present case adds to the repertoire of homozygous recessive disorders from non-consanguineous Indian families. With the present case, a 4-year-old girl, we wish to signify that although mutations in several genes are known to cause skeletal abnormalities, identification of underlying mutations is important as it not only helps with the ascertainment of diagnosis but also aids in determining the role of surgical interventions which is particularly true for Steel syndrome, where the outcome of surgical intervention is usually dismal.

Clinical profile and outcomes of patients with Stage IV adenocarcinoma of lung: A tertiary cancer center experience.

BACKGROUND: There is limited Indian data on clinical profile and treatment outcomes for patients with Stage IV adenocarcinoma of lung. AIM: We aimed to prospectively study the clinical profile and treatment outcomes for patients with Stage IV adenocarcinoma of lung at a tertiary cancer center. MATERIALS AND METHODS: One hundred and ninetyfour patients with Stage IV adenocarcinoma of lung were prospectively analyzed for demographic and molecular profile (epidermal growth factor receptor [EGFR] and echinodermal microtubuleassociated proteinlike 4anaplastic lymphoma kinase [EML4ALK] mutations). Patients with EGFR and EML4ALK mutations were treated with tyrosine kinase inhibitors. Patients without these mutations were treated with standard chemotherapy regimens. Maintenance chemotherapy was offered to patients as per standard guidelines. Clinical outcomes measured were response rate (RR), progressionfree survival (PFS), and overall survival (OS). RESULTS: Median age of patients was 56 years (range, 26-82) with a male:female ratio of 2.3:1. EGFR and ALK mutation testing was feasible in 169 (87.1%) and 164 (84.5%), respectively, and detected in 37.9% and 5.5% patients, respectively. Overall RR, PFS and OS of whole cohort were 44.3%, 6.9, and 15.5 months, respectively. PFS and OS of mutated group (EGFR, EML4ALK) were longer than nonmutated group (10.5 vs. 5.4 months, P < 0.0001 and 21.5 vs. 11 months, P = 0.0001, respectively). PFS and OS of patients who received pemetrexed maintenance were longer than those who did not receive maintenance (8.5 vs. 6.5 months, P = 0.1613 and 18.5 vs. 12.5 months, P = 0.0219, respectively). CONCLUSIONS: Mutation testing at diagnosis is feasible in the vast majority of patients with Stage IV adenocarcinoma of the lung. Patients with EGFR or EML4ALK mutation and those who received pemetrexed maintenance had better clinical outcomes.

Anaplastic lymphoma kinase status in lung cancers: An immunohistochemistry and fluorescence in situ hybridization study from a tertiary cancer center in India.

BACKGROUND AND OBJECTIVES: Fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) have shown good concordance for the detection of echinoderm microtubule-associated protein-like 4 and anaplastic lymphoma kinase (ALK) rearrangement. Since studies reporting FISH/IHC concordance, clinicopathological features, and clinical outcomes of ALK-positive patients from India are lacking, this study was undertaken. MATERIALS AND METHODS: This is a retrospective, observational study of patients with adenocarcinoma of the lung on whom ALK test was performed between March 2013 and December 2015. ALK status was assessed in 341 patients by FISH using Vysis ALK Dual Color Break Apart Rearrangement Probe and IHC using ALK D5F3 clone. Clinicopathological features were noted. Patients were managed as per the standard guidelines. Clinical outcomes - response rate (RR) and progression-free survival (PFS) - were measured. RESULTS: ALK rearrangement was positive in 37 patients (10.9%). ALK positivity was observed more commonly in younger patients with no predilection for any gender or any specific histological subtype. ALK by IHC was highly sensitive (100%), compared to FISH with concordance rate of 94.4%. Thirty one of thirty seven (31 of 37) patients received therapy of which 3 patients received palliative chemotherapy and 28 patients received tyrosine kinase inhibitors (crizotinib/ceritinib). Overall RR observed was 77.4%, and median PFS had not been reached at a median follow-up of 12.5 months. INTERPRETATION AND CONCLUSIONS: We report higher frequency of ALK positivity (10.9%) in patients with adenocarcinoma of the lung. ALK by IHC is more sensitive than FISH for ALK detection with high concordance. These patients had good clinical outcome with TKIs targeting ALK fusion protein.

Assessment of intracranial collaterals on CT angiography in anterior circulation acute ischemic stroke.

BACKGROUND AND PURPOSE: Intracranial collaterals influence the prognosis of patients treated with intravenous tissue plasminogen activator in acute anterior circulation ischemic stroke. We compared the methods of scoring collaterals on pre-tPA brain CT angiography for predicting functional outcomes in acute anterior circulation ischemic stroke. MATERIALS AND METHODS: Two hundred consecutive patients with acute anterior circulation ischemic stroke treated with IV-tPA during 2010-2012 were included. Two independent neuroradiologists evaluated intracranial collaterals by using the Miteff system, Maas system, the modified Tan scale, and the Alberta Stroke Program Early CT Score 20-point methodology. Good and extremely poor outcomes at 3 months were defined by modified Rankin Scale scores of 0-1 and 5-6 points, respectively. RESULTS: Factors associated with good outcome on univariable analysis were younger age, female sex, hypertension, diabetes mellitus, atrial fibrillation, small infarct core (ASPECTS ≥8), vessel recanalization, lower pre-tPA NIHSS scores, and good collaterals according to Tan methodology, ASPECTS methodology, and Miteff methodology. On multivariable logistic regression, only lower NIHSS scores (OR, 1.186 per point; 95% CI, 1.079-1.302; P = .001), recanalization (OR, 5.599; 95% CI, 1.560-20.010; P = .008), and good collaterals by the Miteff method (OR, 3.341; 95% CI, 1.203-5.099; P = .014) were independent predictors of good outcome. Poor collaterals by the Miteff system (OR, 2.592; 95% CI, 1.113-6.038; P = .027), Maas system (OR, 2.580; 95% CI, 1.075-6.187; P = .034), and ASPECTS method ≤5 points (OR, 2.685; 95% CI, 1.156-6.237; P = .022) were independent predictors of extremely poor outcomes. CONCLUSIONS: Only the Miteff scoring system for intracranial collaterals is reliable for predicting favorable outcome in thrombolyzed acute anterior circulation ischemic stroke. However, poor outcomes can be predicted by most of the existing methods of scoring intracranial collaterals.

Does measuring the median nerve at the carpal tunnel outlet improve ultrasound CTS diagnosis?

INTRODUCTION: Nerve conduction is often regarded as more sensitive than ultrasonography (US) for diagnosing carpal tunnel syndrome (CTS). The diagnostic value of US derives from median nerve enlargement occurring at both ends of the carpal tunnel resulting in a dumbbell-like swelling from carpal tunnel pressure. An important reason for the inferior sensitivity of US may be because measurements are restricted to the carpal tunnel inlet. We investigate the value of including median nerve enlargement at the carpal tunnel outlet for diagnosing CTS. METHODS: Retrospective cohort study of nerve conduction verified CTS, determining sensitivity, specificity, and positive and negative predictive values of carpal tunnel inlet and outlet median nerve cross sectional area as determined by US for the diagnosis of CTS. Nerve conduction graded CTS severity. RESULTS: 127 hands from 77 patients with CTS and 35 control healthy hands were assessed. US sensitivity for diagnosing CTS increased from 65% to 84% by including outlet enlargement of the median nerve. Specificity changed from 94% to 86%, positive predictive value from 98% to 96% and the negative predictive value from 43% to 60%. 25 hands out of the 127 from CTS patients showed enlargement restricted to the outlet and mainly occurred in moderate CTS. CONCLUSION: In our population, the use of carpal tunnel outlet median nerve enlargement in addition to inlet median nerve size increases sensitivity for diagnosing CTS by 19%.

Complex partial status epilepticus associated with adult H1N1 infection.

In the wake of the worldwide H1N1 pandemic, there has been evidence that the H1N1 influenza virus is associated with neurological complications. This is the first report describing status epilepticus in an adult patient with H1N1 virus infection, to our knowledge. This patient had no prior history of epilepsy and presented with complex partial status epilepticus. This was further illustrated on electroencephalographs and MRI brain changes that corresponded with the patient's clinical state and which subsequently resolved on follow-up. Although uncommon, H1N1 infections may result in central nervous system complications in adults and it is crucial to treat such patients with urgency.

Identification of a novel mutation in an Indian patient with CAII deficiency syndrome.

Carbonic anhydrase II (CAII) deficiency syndrome characterized by osteopetrosis (OP), renal tubular acidosis (RTA), and cerebral calcifications is caused by mutations in the carbonic anhydrase 2 (CA2) gene. Severity of this disorder varies depending on the nature of the mutation and its effect on the protein. We present here, the clinical and radiographic details along with, results of mutational analysis of the CA2 gene in an individual clinically diagnosed with renal tubular acidosis, osteopetrosis and mental retardation and his family members to establish genotype-phenotype correlation. A novel homozygous deletion mutation c.251delT was seen in the patient resulting in a frameshift and a premature stop codon at amino acid position 90 generating a truncated protein leading to a complete loss of function and a consequential deficiency of the enzyme making this a pathogenic mutation. Confirmation of clinical diagnosis by molecular methods is essential as the clinical features of the CAII deficiency syndrome are similar to other forms of OP but the treatment modalities are different. Genetic confirmation of the diagnosis at an early age leads to the timely institution of therapy improving the growth potential, reduces other complications like fractures, and aids in providing prenatal testing and genetic counseling to the parents planning a pregnancy.

Rare finding of 2n/4n mixoploidy in mother and fetus with severe immune hydrops.

The findings of diploid-tetraploid mosaicism in cultured amniotic fluid cells is considered a culture artifact. On rare occasions its presence indicates a chromosomally abnormal fetus with multiple congenital defects. We present here a patient who in her previous pregnancies had delivered one hydrops and two macerated fetuses. The reported pregnancy also resulted in a fetus with severe hydrops. Cytogenetic analysis of cultured amniotic fluid cells revealed diploid-tetraploid mosaicism in the fetus also confirmed in fetal cord blood and skin fibroblasts. Chromosomal analysis of the parents revealed mixoploidy in the mother. These findings are extremely important for prenatal diagnosis and prompt us to not uniformly dismiss tetraploidy as artifactual but to confirm it especially in cases with ultrasound abnormalities.

Error-specific medial cortical and subcortical activity during the stop signal task: a functional magnetic resonance imaging study.

The ability to detect errors and adjust behavior accordingly is essential for maneuvering in an uncertain environment. Errors are particularly prone to occur when multiple, conflicting responses are registered in a situation that requires flexible behavioral outputs. Previous studies have provided evidence indicating the importance of the medial cortical brain regions including the cingulate cortex in processing conflicting information. However, conflicting situations can be successfully resolved, or lead to errors, prompting a behavioral change in the observers. In particular, how does the brain use error signals specifically to adjust behavior on the fly? Here we employ a stop signal task (SST) to elicit errors approximately half of the time in high-conflict trials despite constant behavioral adjustment of the observers. Using functional magnetic resonance imaging, we show greater and, sequentially, less activation in the medial cortical regions when observers made an error, compared with when they successfully resolved high-conflict responses. Errors also evoked greater activity in the cuneus, retrosplenial cortex, insula, and subcortical structures including the thalamus and the region of the epithalamus (the habenula). We further showed that the error-related medial cortical activities are not correlated with post-error behavioral adjustment, as indexed by post-error slowing (PES) in go trial reaction time. These results delineate an error-specific pattern of brain activation during the SST. The results also suggest that the relationship between error-related activity and post-error behavioral adjustment may be more complicated than has been conceptualized by the conflict monitoring hypothesis.

Difficulties in emotion regulation and impulse control during cocaine abstinence.

RATIONALE: Prior research has shown that cocaine dependence is associated with dysfunction of brain systems involved in emotions and motivational states. OBJECTIVES: To examine whether difficulties in emotion regulation are associated with early cocaine abstinence using the recently validated Difficulties in Emotion Regulation Scale (DERS). METHOD: Recently abstinent treatment-seeking cocaine patients (n=60) completed the DERS during their first week of inpatient treatment and at discharge (3-4 weeks later), and scores were compared with community controls (n=50). RESULTS: Compared with controls, cocaine-dependent individuals reported difficulties relating to understanding emotions, managing emotions and impulse control in the first week of abstinence. With continued abstinence, cocaine-dependent individuals showed continued difficulties only in impulse control. CONCLUSION: Cocaine-dependent individuals report emotion regulation difficulties, particularly during early abstinence. Additionally, protracted distress-related impulse control problems suggest potential relapse vulnerability.

Modulation in the photosensitivity of albumin-bound bilirubin.

Exposure of BR-albumin complexes to visible light at pH 8.0 led to a change in the fluorescence intensity at 525 nm, which was found to be different for different serum albumins. Whereas a complex of BR with human serum albumin (HSA) showed a marked increase in fluorescence upon photoirradiation, BR-sheep serum albumin (SSA) complex failed to produce a marked increase. On the other hand, a complex of pig serum albumin (PSA) with BR produced a remarkable decrease in fluorescence upon photoirradiation. Equilibration of these complexes with approximately 20 mM chloroform for 1 h resulted in alteration in the photoinduced fluorescence. These photoinduced fluorescence modulations were found to be concentration dependent. Photoirradiation of BR-HSA complex led to a significant decrease in the positive CDCEs of the bisignate CD spectra in a time dependent manner that can be reconciled, to a significant extent, in the presence of chloroform. Taken together, all these results suggest that chiroptical properties/stability of albumin-bound BR varies with albumin species, protein concentration and the presence of chloroform.