Variable MHC class I engagement by Ly49 natural killer cell receptors demonstrated by the crystal structure of Ly49C bound to H-2K(b)

The Ly49 family of natural killer (NK) receptors regulates NK cell function by sensing major histocompatibility complex (MHC) class I. Ly49 receptors show complex patterns of MHC class I cross-reactivity and, in certain cases, peptide selectivity. To investigate whether specificity differences result from topological differences in MHC class I engagement, we determined the structure of the peptide-selective receptor Ly49C in complex with H-2K(b). The Ly49C homodimer binds two MHC class I molecules in symmetrical way, a mode distinct from that of Ly49A, which binds MHC class I asymmetrically. Ly49C does not directly contact the MHC-bound peptide. In addition, MHC crosslinking by Ly49C was demonstrated in solution. We propose a dynamic model for Ly49-MHC class I interactions involving conformational changes in the receptor, whereby variations in Ly49 dimerization mediate different MHC-binding modes.     

Redox regulation of reactive oxygen species-induced p38 MAP kinase activation and barrier dysfunction in lung microvascular endothelial cells

Reactive oxygen species (ROS)-mediated compromise of endothelial barrier integrity has been implicated in a number of pulmonary disorders, including adult respiratory distress syndrome, pulmonary edema, and vasculitis. The mechanisms by which ROS increase endothelial permeability are unclear. We hypothesized that ROS-induced changes in cellular redox status (thiols) may contribute to endothelial barrier dysfunction. To test this hypothesis, we used N-acetylcysteine (NAC) and diamide to modulate intracellular levels of cellular glutathione (GSH) and investigated hydrogen peroxide (H(2)O(2))-mediated mitogen-activated protein kinase (MAPK) activation and transendothelial electrical resistance (TER). Exposure of bovine lung microvascular endothelial cells (BLMVECs) to H(2)O(2), in a dose- and time-dependent fashion, increased endothelial permeability. Pretreatment of BLMVECs with NAC (5 mM) for 1 h resulted in partial attenuation of H(2)O(2)-induced TER (a measure of increase in permeability) and GSH. Furthermore, treatment of BLMVECs with diamide, which is known to reduce the intracellular GSH, resulted in significant reduction in TER, which was prevented by NAC. To understand further the role of MAPKs in ROS-induced barrier dysfunction, we examined the role of extracellular signal-regulated kinase (ERK) and p38 MAPK on H(2)O(2)- and diamide-mediated permeability changes. Both H(2)O(2) and diamide, in a dose-dependent manner, activated ERK and p38 MAPK in BLMVECs. However, SB203580, an inhibitor of p38 MAPK, but not PD98059, blocked H(2)O(2)- and diamide-induced TER. Also, NAC prevented H(2)O(2)- and diamide-induced p38 MAPK, but not ERK activation. These results suggest a role for redox regulation of p38 MAPK in ROS-dependent endothelial barrier dysfunction.     

The role of T regulatory cell-associated markers in monitoring tuberculosis treatment completion and failure

Monitoring tuberculosis (TB) treatment success is crucial for clinical decision-making. The only available tool in this regard is sputum microscopy, but it has demerits. Moreover, in case of smear negatives and extrapulmonary TB, an efficient tool is still sought for. Therefore, we evaluated T regulatory cell (Treg)-associated markers (CD25, CD39, and FoxP3) and cellular subsets in monitoring treatment success in treatment-completed groups. Expression profile of various markers and subsets were compared real time among treatment-naive pulmonary TB patients (TN-PTB), followed-up treatment-completed (TC-fu) cohort, and a not followed-up (TC-nfu) cohort. Peripheral blood mononuclear cells from various groups were incubated overnight and were stained with antibodies for specific markers and studied by flow cytometry. In both the treatment-completed groups, a decline in frequencies of CD25⁺ marker and CD4⁺CD25⁺, CD4⁺CD25⁺FoxP3, CD4⁺CD25⁺CD39⁺ Treg was observed with clearance of infection, indicating their potential in monitoring treatment success. However, in the case of treatment failure patient (Tfp), a drastic increase in frequency of CD4⁺CD25⁺FoxP3⁺ Treg subset was found, indicating its usefulness in predicting treatment failure. Although the investigation unveils markers useful in predicting treatment success or failure, the findings from this study needs to be validated in a larger cohort.     

Novel pregnancy‐triggered episodes of CAPOS syndrome

Cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndrome (OMIM# 601338) is a rare autosomal dominant disorder characterized by episodic, fever‐induced ataxic encephalopathy in childhood with residual symptoms. All identified patients have the same heterozygous missense variant c.2452G>A (p.Glu818Lys) in the ATP1A3 gene, encoding Na⁺/K⁺ ATPase α3. We describe a large CAPOS pedigree with three generations of affected members, the first ascertained in the United States. Deafness, optic atrophy, and pes cavus were present in all three members of the family evaluated. In addition, one of the affected individuals experienced markedly worsening features during her three pregnancies and in the immediate postpartum period, a potential element of the natural history of CAPOS previously unreported. We conclude that the triggering factors and clinical spectrum of pathogenic ATP1A3 variants may be broader than previously described. Targeted sequencing of ATP1A3 should be considered in any patient presenting with cerebellar ataxia triggered by febrile illness, or pregnancy and delivery, especially in the presence of sensorineural hearing loss, optic atrophy, pes cavus, or early childhood history of acute encephalopathic ataxia. Prophylactic administration of acetazolamide or flunarizine may prevent acute episodes of ataxia or mitigate neurologic symptoms, although their efficacies have not been well studied.     

A right-to-left or bidirectional ductal shunt in preterm neonates: grave implication?

We delineate the natural history of a right-to-left or bidirectional (RL/BD) patent ductus arteriosus (PDA) in preterm infants and compare outcomes of an RL/BD and a left-to-right (LR) ductal shunt. We performed a retrospective chart review of preterm infants (< 32 weeks), who, between 2 and 30 days of age, had an RL/BD PDA > 1.5 mm (study group; N = 74) or an LR PDA (N = 87) on echocardiogram (ECHO). In the study group, 27% of infants who were of significantly lower gestational age and birth weight had a "prolonged" RL/BD PDA on two or more ECHOs. Infants with RL/BD PDA required significantly greater surfactant (98.6% versus 94.2%) and less PDA therapy (27% versus 92%) and had higher mortality (48.6% versus 21.8%) compared with those with LR PDA. On regression analysis, lower gestation (odds ratio [OR] 1.45; 95% confidence interval [CI]: 1.15 to 1.83) and RL/BD PDA (OR 4.74; 95% CI: 2.18 to 10.3) were significantly associated with mortality. The independent association between an RL/BD PDA shunt and mortality warrants further investigation. Insights into the etiology of pulmonary hypertension may optimize outcomes in this population.     

Direct determination of metallic impurities in graphite by EDXRF

Energy dispersive X-ray fluorescence (EDXRF) methods have been developed for the direct determination of 14 trace metallic impurities in graphite powder without any need for sample dissolution. Using synthetic standards, calibration curves were established for different elements after optimizing the spectrometer parameters. Two synthetic samples were analyzed to evaluate the performance of the developed analytical methods. The estimates for most of the analytes were in good agreement with the added amounts. Three graphite powder samples were analyzed by the present method as well as by D.C. arc emission spectrometric technique for comparison and the agreement between the analyte values determined, using both methods was good. Samples in pellet form were analyzed using a separate calibration with standards in pellet form. The present method is rapid, as it alleviates the need for any chemical treatment and gives good precision.     

Primary cardiac lymphoma masquerading as right atrial myxoma causing complete heart block—a case report

Secondary involvement of the heart and pericardium by systemic lymphoma is well documented. Primary Cardiac lymphomas (PCL) are extremely rare. Incidence of PCL is increasing in immunocompromised patients. However PCL in immunocompetent is much rarer. We report such a case of PCL in an immunocompetent elderly female masquerading as right atrial myxoma causing complete heart block which was surgically debulked successfully. Her rhythm resumed to Sinus rhythm following surgical debulking. Immunohistochemistry of the excised tumour revealed Diffuse Large B cell lymphoma. With combination chemotherapy, she is symptom free on six months follow up.     

Parotid lipoblastoma in a child: Rare presentation as huge infratemporal mass with cervical extension

Lipoblastomas arising within the parotid gland and extending into the infratemporal fossa are very rare. They are common in children <3 years of age. Access to the tumour requires careful planning and interpretation of imaging studies. Lipoblastomas tend to recur. Meticulous dissection of the tumour is needed to prevent recurrence. By adopting the appropriate approach, complete removal is possible with minimal morbidity.     

Preysyrinx state and shunt dysfunction: an under recognized entity?

Presyrinx state is a relatively recently recognized condition. Prompt identification of this condition and appropriate treatment leads to reversal of the radiological and clinical findings with a good prognosis. Failure to identify this condition in a timely fashion leads to fully established syringomyelia. To date, presyrinx state has not been described as a feature of shunt dysfunction. One such rare case is being reported. A 14-year-old boy who was shunted for postmeningitic hydrocephalus at the age of 2 years and subsequently underwent shunt revision presented for routine follow-up and was found to have shunt dysfunction. CT scan showed panventriculomegaly and MRI studies showed panventriculomegaly with a “presyrinx” state extending from the fourth ventricle up to the thoracic region. Shunt revision led to prompt radiological reversal of the presyrinx state. This case is being reported to highlight the hitherto unreported association of shunt dysfunction and presyrinx state. The literature on presyrinx state is being reviewed with reference to the 20 cases reported earlier.