A new autosomal recessive disorder of bilateral frontotemporal pachygyria without microcephaly: report of a case and review of literature

Pachygyria is a disorder of neuronal migration. We report an Indian family with four siblings with developmental delay, infrequent seizures, normal head size and mild to moderate mental retardation. Two of them had bilaterally symmetrical frontotemporal pachygyria. Dysmorphism and neurological signs were absent in the affected subjects. Affected male and female siblings with normal parents suggests autosomal recessive mode of inheritance. We believe these cases represent a new autosomal recessive disorder of neuronal migration. Other similar cases of lissencephaly are reviewed.     

Selection of replicon variants resistant to ACH-806, a novel hepatitis C virus inhibitor with no cross-resistance to NS3 protease and NS5B polymerase inhibitors

We have discovered a novel class of compounds active against hepatitis C virus (HCV), using a surrogate cellular system, HCV replicon cells. The leading compound in the series, ACH-806 (GS-9132), is a potent and specific inhibitor of HCV. The selection of resistance replicon variants against ACH-806 was performed to map the mutations conferring resistance to ACH-806 and to determine cross-resistance profiles with other classes of HCV inhibitors. Several clones emerged after the addition of ACH-806 to HCV replicon cells at frequencies and durations similar to that observed with NS3 protease inhibitors and NS5B polymerase inhibitors. Phenotypic analyses of these clones revealed that they are resistant to ACH-806 but remain sensitive to other classes of HCV inhibitors. Moreover, no significant change in the susceptibility to ACH-806 was found when the replicon cellular clones resistant to NS3 protease inhibitors and NS5B polymerase inhibitors were examined. Sequencing of the entire coding region of ACH-806-resistant replicon variants yielded several consensus mutations. Reverse genetics identified two single mutations in NS3, a cysteine-to-serine mutation at amino acid 16 and an alanine-to-valine mutation at amino acid 39, that are responsible for the resistance of the replicon variants to ACH-806. Both mutations are located at the N terminus of NS3 where extensive interactions with the central hydrophobic region of NS4A exist. These data provide evidence that ACH-806 inhibits HCV replication by a novel mechanism.     

Melanoma brain metastases: Biological basis and novel therapeutic strategies

The development of brain metastases is the deadliest complication of advanced melanoma and has long been associated with a dismal prognosis. The recent years have seen incredible progress in the development of therapies for melanoma brain metastases (MBM), with both targeted therapies (the BRAF-MEK inhibitor combination) and immune checkpoint inhibitors (the anti-CTLA-4, anti-PD-1 combination) showing impressive levels of activity. Despite this, durations of response for these therapies remain lower at intracranial sites of metastasis compared to extracranial metastases and it has been suggested that there are unique features of the brain microenvironment that contribute to therapeutic escape. In this review, we outline the latest research into the biology and pathophysiology of melanoma brain metastasis development and progression. We then discuss the current status of clinical trial that are open to patients with MBM and end by describing the ongoing challenges for the field.     

Epidemiology of multiple sclerosis in the north-east (Grampian region) of Scotland--an update.

The north-east of Scotland (Grampian Region) has undergone three incidence and prevalence surveys, including the present one, since 1970. Results from these indicate a true increase in the prevalence of the disease in the region. The incidence of the disease has remained continuously high and shows a slightly upward trend. Literature on the subject of repeated surveys in different regions of the world has been reviewed in detail. The need for a prevalence study from the south of the British Isles has been emphasised in order to enable one to judge if the increase in Scotland is in keeping with the pattern in the whole of the British Isles. The familial incidence of the disease was noted to be virtually unchanged between the three surveys. Certain other aspects of aetiological significance have been analysed, viz, clustering of patients at birth or at onset of the disease; ages of occurrence of childhood viral infections such as measles, mumps, chickenpox and rubella; and the role of canine distemper infection.     

Cerebral venous sinus thrombosis in a tertiary care setting in India

Sir, We read with interest the article on cerebral venous sinus thrombosis(CVST) in your journal.¹ CVST is reported to be commoner indeveloping countries, and has been linked to pregnancy, multiparityand infection.^2,3 Developments in imaging, immunology and geneticshave provided valuable information about risk factors and clinicalspectrum of CVST. We report our experience of CVST,     

The role of CC chemokine receptor 6 in host defense in a model of invasive pulmonary aspergillosis

RATIONALE: Invasive aspergillosis is a severe fungal infection afflicting immunocompromised patients, particularly patients with neutrophil defects. CCR6, a beta-chemokine receptor, mediates migration of dendritic cells (DCs) and several lymphocyte subsets to sites of epithelial inflammation, but its role in infections has not been examined extensively. OBJECTIVES: To test the hypothesis that CCR6-mediated leukocyte recruitment is necessary for effective host defense in neutropenic hosts with invasive pulmonary aspergillosis. METHODS: Neutropenic wild-type mice and mice with targeted deletion of CCR6 were infected with Aspergillus fumigatus. The host responses to the infection were compared in vivo and leukocyte responses to the fungus were examined in vitro. MEASUREMENTS AND MAIN RESULTS: In the context of infection, immature myeloid DCs were the major population of CCR6-expressing cells in the lungs. As compared with wild-type animals, CCR6-deficient mice developed a more severe infection when challenged with A. fumigatus conidia, as documented by a higher mortality rate and greater lung fungal burden. This was associated with reduced accumulation of DCs in the lungs. CCR6-deficient and wild-type DCs did not differ in their phagocytosis of conidia, cytokine response, or maturation in vitro. In adoptive transfer experiments, however, DCs from CCR6-deficient donors showed lesser accumulation in the lungs of infected mice as compared with wild-type cells, and transfer of wild-type, but not CCR6-deficient, DCs resulted in attenuated severity of infection in CCR6-deficient recipients. CONCLUSIONS: Taken together, these results implicate CCR6-mediated DC influx into the lung in the initial host defense in invasive aspergillosis.