The persistence of interleukin-6 is regulated by a blood buffer system derived from dendritic cells

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Two novel presenilin-1 mutations (Y256S and Q222H) are associated with early-onset Alzheimer's disease

Mutations in the gene encoding presenilin 1 (PS-1) account for 50% of early-onset familial Alzheimer's disease (EOFAD) cases. In this study, we identified two missense mutations in the coding sequence of the presenilin (PS-1) gene in two EOFAD pedigrees. AD was confirmed in one pedigree by autopsy. Mutation analysis of PCR products amplified from genomic DNA templates showed two novel PS-1 mutations resulting in Gln222His and Tyr256Ser. The two novel mutations are located within predicted transmembrane domains five (TM-5) and six (TM-6), respectively, and are associated with very early ages of onset. The Tyr256Ser is associated with one of the youngest age of AD onset, 25 years, which is consistent with a drastic change in function of the altered PS-1 protein. A morphometric analysis of the cortical degenerative changes of the Tyr256Ser case, showed severe involvement of the primary motor cortex, which correlated well with the pyramidal changes, including tetraspasticity. Immunoblot analysis showed the Tyr256Ser case had the greatest expression of Abeta(1-40) and Abeta(1-42), which was confirmed by ELISA, compared to other PS-1 mutant FAD cases and age-matched controls and, thus, contributes to the severity of the disease pathology.     

Ca2+-activated K+ (BK) channel inactivation contributes to spike broadening during repetitive firing in the rat lateral amygdala

In many neurons, trains of action potentials show frequency-dependent broadening. This broadening results from the voltage-dependent inactivation of K⁺ currents that contribute to action potential repolarisation. In different neuronal cell types these K⁺ currents have been shown to be either slowly inactivating delayed rectifier type currents or rapidly inactivating A-type voltage-gated K⁺ currents. Recent findings show that inactivation of a Ca²⁺-dependent K⁺ current, mediated by large conductance BK-type channels, also contributes to spike broadening. Here, using whole-cell recordings in acute slices, we examine spike broadening in lateral amygdala projection neurons. Spike broadening is frequency dependent and is reversed by brief hyperpolarisations. This broadening is reduced by blockade of voltage-gated Ca²⁺ channels and BK channels. In contrast, broadening is not blocked by high concentrations of 4-aminopyridine (4-AP) or α-dendrotoxin. We conclude that while inactivation of BK-type Ca²⁺-activated K⁺ channels contributes to spike broadening in lateral amygdala neurons, inactivation of another as yet unidentified outward current also plays a role.     

Prospects of electrochemical immunosensors for early diagnosis of preeclampsia

Preeclampsia is a vascular multisystem disorder that accounts for varying degree of morbidity and mortality of mother and the fetus. This can be significantly averted if diagnosed at an early (18‐20 weeks) stage of gestation, as there is no known way to prevent preeclampsia. In spite of extensive work on biomarker discovery, the existing method for its detection is mostly based on colorimetric immunoassays whose sensitivity is ranging in nanomolar range. Further, it has also been observed that change in the expression of a single biomarker is not sufficient to diagnose this condition. So, for early diagnosis (by 18‐20 weeks), an immuno‐diagnostic platform with detection limits in picomolar range and beyond along with the ability to do simultaneous detection of multiple analyte would be of great importance. A nano‐immunosensors with an electrochemical readout system can be a potential alternative that promises for the ultrasensitive detection of analyte with high specificity as well as suitability for on‐site analysis. Coupling the lateral flow technology with immunosensors would make it feasible to detect more than one biomarker simultaneously on a microchip. This review intends to summarize the potential preeclampsia biomarkers, limitations of existing diagnostic methods along with the recent advancements, and prospects to develop electrochemical immunosensors for early clinical diagnosis.     

Computational modelling of motion at the bone–implant interface after total knee arthroplasty: The role of implant design and surgical fit

Background

Aseptic loosening, osteolysis, and infection are the most commonly reported reasons for revision total knee arthroplasty (TKA). This study examined the role of implant design features (e.g. condylar box, pegs) and stems in resisting loosening, and also explored the sensitivity of the implants to a loose surgical fit due to saw blade oscillation.

An unusual case of Plasmodium vivax malaria monoinfection associated with crescentic glomerulonephritis: a need for vigilance

Plasmodium vivax infection is increasingly a major public health burden and the second most frequent human malaria. Higher levels of clinical severity and chloroquine resistance are major factors responsible for such increases. Malarial glomerular injury is uncommon and mainly observed in Plasmodium malariae-infected patients. Occasionally, transient immune complex-mediated glomerulonephritis is associated with Plasmodium falciparum infection. Coexistent crescentic glomerulonephritis and vivax malaria have not previously been reported. We report a fatal case of P. vivax malaria, who presented with acute renal failure. P. vivax monoinfection status was diagnosed with peripheral blood smear and rapid antigen test. Further evaluation for renal failure related to systemic illness and immunological markers were inconclusive. He was treated with antimalarial drugs, hemodialysis, and supportive therapy. Renal biopsy performed for nonrecovering renal failure reveled crescentic glomerulonephritis. This case highlights the need to thoroughly search for malaria-associated crescentic glomerulonephritis using renal biopsy after nonrecovering renal failure.     

TP53 polymorphisms in gliomas from Indian patients: Study of codon 72 genotype, rs1642785, rs1800370 and 16 base pair insertion in intron-3

Several single nucleotide polymorphisms of the TP53 gene have been reported, amongst which polymorphism in codon 72 (rs1042522) has received significant attention and shown to be associated with disease susceptibility in different cancer types. However, there are variable reports on this polymorphism in gliomas from worldwide with inconsistent results. In addition, the implications of other polymorphic loci are not much explored in gliomas. Hence, in the present study the TP53 sequence was analyzed for all polymorphism and mutations in a total of 84 gliomas of different types and grades from patients of Indian origin. The complete sequence of all coding exons (2 to 11) and introns 2, 3, 5 and 8 of TP53 gene were studied while for introns 1, 4, 6, 7, 9 and 10, only exon flanking regions could be studied. The polymorphic loci were compared with control population. In addition to the well known codon 72 polymorphism (rs1042522), three other polymorphisms rs1642785, rs1800370 and a 16 base pair insertion in intron-3 were found. At codon 72, our study showed higher Arg/Arg genotype in gliomas compared to normal population (38% versus 13%). The Arg allele frequency in glioma patients was comparatively higher than controls (0.55 versus 0.45; P = 0.037). The Arg allele frequency was also high in adult glioblastomas compared to paediatric counterparts (0.55 versus 0.36). However, there was no significant association of TP53 mutations with any genotype of codon 72. At rs1642785, the G allele frequency was significantly higher in gliomas than in control population (0.55 versus 0.36, P = 0.005). The genotype at a 16 base pair insertion in intron-3 was almost similar in case and control. However, the polymorphism at rs1800370 was exclusive to gliomas. This is the first report of TP53 gene polymorphism in glioma patients from India. Our study also delineates the frequency of four polymorphisms in gliomas for the first time. The codon 72 variant (rs1042522) and rs1642785 polymorphisms possibly poses risk to glioma development in Indian population. However, the functional significance of these polymorphism needs further elucidation.     

Enalapril dosage in steroid-resistant nephrotic syndrome

We have examined, in a randomized crossover trial, the antiproteinuric effect of treatment with low- (0.2 mg/kg daily) and high-dose (0.6 mg/kg daily) enalapril in 25 consecutive patients with steroid-resistant nephrotic syndrome (SRNS). Patients in group A (n=11) received enalapril at low doses for 8 weeks, followed by 2 weeks of washout and then at high doses for 8 weeks. Those in group B (n=14) initially received enalapril at high and then low doses. Patients continued to receive treatment with tapering doses of prednisolone; none received concomitant therapy with daily oral or intravenous steroids, alkylating agents, cyclosporine, non-steroidal anti-inflammatory drugs, and other antihypertensive medications. The urine albumin-to-creatinine (Ua/Uc) ratio and the percentage reduction were determined for each phase of therapy. Baseline clinical, biochemical, and histological features were comparable in the two groups. In the first phase, treatment with low-dose enalapril (group A) resulted in median 34.8% Ua/Uc reduction compared with 62.9% with high doses (group B) (P<0.01). High-dose enalapril was associated with a significant reduction in Ua/Uc ratio in both groups. The combined median Ua/Uc (95% confidence interval) reduction in the low-dose phase was 33% (–10.3% to 72.4%) and in the high-dose 52% (15.4%–70.4%) (P<0.05). The median Ua/Uc ratio at the end of 20 weeks was 1.1 and 1.8 in groups A and B, respectively (P>0.05). Systolic and diastolic blood pressure reductions were similar in both groups. No period or carry-over effect was found. Prolonged treatment with enalapril thus resulted in a dose-related reduction in nephrotic-range proteinuria. Titration of the dose of enalapril may be a useful strategy for achieving substantial reduction of proteinuria in children with SRNS.     

Management of Neglected Upper Cervical Spine Injuries

BackgroundInjuries involving upper cervical spine are serious and fatal injuries which are associated with alteration of normal occipital–cervical anatomy. These injuries may result in permanent neurologic deficits or neck deformity if not treated in a timely and appropriate manner.ObjectiveTo evaluate the outcomes of neglected upper cervical spine injuries treated by various methods.Study designRetrospective study.Materials and methodsTwelve patients attending ER or OPD with a history of neck trauma and who were diagnosed with fractures and fracture dislocations C1 and C2 were included in the study. Fresh injuries sustained within a week were excluded from study. The outcomes were measured in terms of improvement in VAS, ODI Scores and correction of the neck deformity. Surgical parameters like duration of surgery and blood loss were also observed.ResultsEleven males and one female. The mean age was 40.9 ± 16.9 (07–67 years). Eleven patients underwent posterior instrumentation, while one patient was treated anteriorly. The mean delay in presentation was 28 ± 8.67 days (15–42 days). The mean duration of surgery was 188.3 ± 34.35 min (120–240 min), average blood loss was 350 ± 111.8 ml (150–600 ml). The mean VAS improved from 8.45 ± 0.89 to 3.9 ± 0.51 (p < 0.05). The mean ODI Pre-operatively was 88.45 ± 5.89 which improved to 31.9 ± 4.01 (p < 0.05). The neck deformity/torticollis was corrected in all the patients.ConclusionsNeglected upper cervical spine injuries are difficult to treat and a posterior approach is helpful in reducing the subluxations indirectly and to obtain a posterior fusion.     

Targeted exome sequencing in anti-factor H antibody negative HUS reveals multiple variations

Background

Genetic susceptibility to atypical hemolytic uremic syndrome (aHUS) may lie within genes regulating or activating the alternate complement and related pathways converging on endothelial cell activation.

Methods

We tested 32 Indian patients of aHUS negative for antibodies to complement factor H for genetic variations in a panel of 15 genes, i.e., CFH, CFHR1-5, CFI, CFB, C3, CD46, MASP2, DGKE, ADAMTS13, THBD and PLG using next-generation DNA sequencing and for copy number variation in CFHR1-3.

Results

Despite absence of a public database of exome variations in the Indian population and limited functional studies, we could establish a genetic diagnosis in 6 (18.8%) patients using a stringent scheme of prioritization. One patient carried a likely pathogenic variation. The number of patients carrying possibly pathogenic variation was as follows: 1 variation: 5 patients, 2 variations: 9 patients, 3 variations: 5 patients, 4 variations: 9 patients, 5 variations: 2 patients and 6 variations: 2 patients. Homozygous deletion of CFHR1-3 was present in five patients; none of these carried a diagnostic genetic variation. Patients with or without diagnostic variation did not differ significantly in terms of enrichment of genetic variations that were rare/novel or predicted deleterious, or for possible environmental triggers.

Conclusion

We conclude that genetic testing for multiple genes in patients with aHUS negative for anti-FH antibodies reveals multiple candidate variations that require prioritization. Population data on variation frequency of the Indian population and supportive functional studies are likely to improve diagnostic yield.