Paternal contribution of HLA-G*0106 significantly increases risk for pre-eclampsia in multigravid pregnancies

Pre-eclampsia (PE) is a leading cause of maternal and fetal mortality and morbidity. Structural or functional alterations of human leukocyte antigen (HLA)-G present at the maternal-fetal interface may predispose women to PE. We tested the HLA-G gene for association with PE in a case-control study of 83 PE and 240 normotensive Malay women. HLA-G was amplified in a single-tube multiplex-PCR reaction and genotyped for 18 single nucleotide polymorphisms (SNPs) by multiplex-minisequencing. Case-control comparisons were performed, and associations with disease were expressed as odds ratios (ORs). Risk for PE was significantly associated with fetal allele G*0106 only in multigravid pregnancies (P = 0.002, OR = 5.0, 95% CI = 1.8-13.8). Among multigravid pregnancies, the frequency of PE babies heterozygous or homozygous for G*0106 was also significantly higher compared with normal control babies (P = 0.002, OR = 5.4, 95% CI = 1.9-15.4). Multivariate analyses with adjustment for factors associated with PE revealed similar results (P = 0.003, OR = 10.1, 95% CI = 2.2-46.8). Additionally, a significantly higher frequency of fetal-maternal G*0106 genotype mismatch was observed in PE compared with normal multigravid pregnancies (P = 0.001, OR = 9.6, 95% CI = 2.4-38.7). Thus, paternal HLA-G G*0106 contribution significantly increases risk for PE in multigravidas who do not carry this allele, potentially mediated by a gradual maternal alloimmune response to repeated exposure to the paternal HLA-G variant.     

The biopsychosocial model and spinal cord injury.

OBJECTIVE: To highlight the importance of taking the psychological, social and biological aspects into consideration when dealing with somatic complaints of spinal cord injured patients. SETTING: Supra-regional Spinal Injury Unit in the UK. STUDY DESIGN: Case study series. MATERIAL AND METHODS: The somatic complaints of four patients with spinal cord injury were assessed and their relationship to psychological and social issues were correlated. Two patients suffered unexplained pain, another excessive spasm uncontrolled with intrathecal Baclofen pump and the fourth with several pressure sores, constipation and other physical problems. The impact of psychosocial issues on the somatic complaints were analysed. RESULTS: In all four patients the resolution of their psychosocial issues resulted in significant gains vis-à-vis their somatic complaints. CONCLUSION: Psychological and social issues of spinal injury patients could have a serious impact on the resolution of somatic complaints. It is important to take these into consideration in their treatment.     

Roles of Lck,Syk and ZAP-70 tyrosine kinases in TCR-mediated phosphorylation of the adapter protein Shc

The adapter protein Shc has been implicated in mitogenic signaling via growth factor receptors, antigen receptors and cytokine receptors. Recent studies have suggested that tyrosine phosphorylation of Shc may play a key role in T lymphocyte proliferation via interaction of phosphorylated Shc with downstream molecules involved in activation of Ras and Myc proteins. However, the sites on Shc that are tyrosine phosphorylated in response to TCR engagement and the ability of different T cell tyrosine kinases to phosphorylate Shc have not been defined. In this report, we show that during TCR signaling, the tyrosines Y239, Y240 and Y317 of Shc are the primary sites of tyrosine phosphorylation. Mutation of all three tyrosines completely abolished tyrosine phosphorylation of Shc following TCR stimulation. Our data also suggest that multiple T cell tyrosine kinases contribute to tyrosine phosphorylation on Shc. In T cells, CD4/Lck-dependent tyrosine phosphorylation on Shc was markedly diminished when Y317 was mutated, suggesting a preference of Lck for the Y317 site. The syk-family kinases (Syk and ZAP-70) were able to phosphorylate the Y239 and Y240 sites, and less efficiently the Y317 site. Moreover, co-expression of Syk or ZAP-70 with Lck resulted in enhanced phosphorylation of Shc on all three sites, suggesting a synergy between the syk -family and scr -family kinases. Of the two potential Grb2 binding sites (Y239 and Y317), Y239 appears to play a greater role in recruiting Sos through Grb2. These studies have implications for Ras activation and mitogenic signaling during T cell activation.     

T2 olivary nuclei hyperintensities: A characteristic neuroimaging finding in FIG4-related leukoencephalopathy

FIG4 related leukoencephalopathy has recently been considered as an expanded spectrum of FIG4 related disorders characterized by upper and lower motor neuron involvement, dystonia, intellectual disability, bulbar symptoms with cerebellar atrophy. We report a 7-year-old girl who presented with classic clinical features of FIG4 related leukoencephalopathy and neuroimaging showed characteristic T2 olivary nuclei hyperintensities in addition to bilateral parietal lobe and thalamic hyperintensities and mild cerebellar atrophy. Trio exome sequencing with Sanger confirmation revealed a novel variant c.504C>G in the FIG4 gene. Phase contrast microscopy of skin fibroblast cultures detect enlarged vacuoles in 50% of patient's fibroblasts as opposed to 18.6% vacuolation in cultured control fibroblasts (p < 0.00001), a feature characteristic of fibroblasts with deleterious variants of FIG4. In addition, we have reviewed and compared the phenotypic features of published cases of FIG4 related leukoencephalopathy from literature. This case adds to the delineation of FIG4 related leukoencephalopathy phenotype. The radiological finding of T2 inferior olivary nuclei hyperintensities appear to be characteristic for the phenotype or at least for the cases due to variants in and around the 168th codon and active effort should be made to detect the same as it can add to the genotype phenotype spectrum.     

Linking changes in quality of life to haematologic response and survival in systemic immunoglobulin light-chain amyloidosis

This study reports health-related quality of life (HRQL) among newly-diagnosed immunoglobulin light-chain (AL) patients (n = 914) treated with a bortezomib-based regimen and its association with response depth and survival. Haematologic response/HRQL were assessed over 24 months in an ongoing, prospective study. HRQL change was calculated across haematologic/cardiac response levels. The relationship between baseline HRQL and survival was evaluated by the Cox proportional-hazard model (PH). Shared-random-effects models (SREMs) estimated time-to-death conditional on current HRQL/longitudinal HRQL trajectory. At 3 months, there was consistent decline in 5/8 HRQL domains across all haematologic response levels. By 12 months, 3/5 declining domains improved among complete response (CR) patients. In contrast, the mean change in less-than-CR patients did not indicate improvement. Under the Cox PH, having a baseline HRQL score five points higher than the sample mean was associated with 20% lower mortality risk. SREMs indicated a five-point greater HRQL score at the event time correlated with an approximately 30% decrease in mortality risk. For each one-point increase in HRQL score trajectory slope, mortality risk decreased by approximately 88%. Only CR patients had HRQL improvement, while partial response patients had less decline but no meaningful improvements. These data show the importance of HRQL serial assessments of AL patients and its importance as an end-point.