The spectrum of neurological manifestations and genotype–phenotype correlation in Indian children with Gaucher disease

Gaucher disease (GD), one of the most frequent autosomal recessive lysosomal storage disorders, occurs due to bi-allelic pathogenic variants in the GBA1. Worldwide, the c.1448T>C (L483P) homozygous pathogenic variant is reported to be associated with neurological GD phenotype. Clinical distinction between GD1 and GD3 may be challenging due to subtle neurological features. Objective methods to evaluate neurological signs and saccades may help in early diagnosis. This study was conducted to assess the neurological phenotype, and its severity using a modified severity scoring tool (mSST), and the genotype–phenotype correlation. A total of 45 children aged 2 years 6 months to 15 years with a confirmed enzymatic and molecular diagnosis of GD with or without therapy were recruited. mSST tool was used to assess the severity of the neurological phenotype. A digital eye movement tracker (View Point Tracker) was used to assess eye movements. Clinical and genetic findings were analyzed. Out of 45 patients, 39 (86.7%) had at least one neurological phenotype detected using the mSST tool, with impairment of cognitive function (68.8%, 31/45) being the commonest feature. Thirty-two of 45 (71%) were assessed for saccadic eye movements using the eye tracker. Of these, 62.5% (20/32) had absent saccades. Four children (8.9%, 4/32) without clinical oculomotor apraxia had absent saccades on the viewpoint eye tracker. Overall, 77.7% (35/45), had homozygosity for c.1448T>C in GBA1 of which 91.4% (32/35) had neurological manifestations. Other alleles associated with neurological phenotype included c.1603C>T(p.R535C), c.1184C>T (p.S395F), c.115+1G>A (g.4234G>A), c.260G>A (p.R87Q) and c.1352A>G (p.Y451C). To conclude, in India, the c.1448T>C pathogenic variant in GBA1 is the commonest  and is associated with neurological phenotype of GD. Therefore, every patient of GD should be assessed using the mSST scoring tool for an early pick up of neurological features. The routine use of a viewpoint eye tracker in children with GD would be useful for early recognition of saccadic abnormalities.     

Expression of short chain fatty acid receptors and pro-inflammatory cytokines in utero-placental tissues is altered in cows developing retention of fetal membranes

Introduction

Retention of fetal membranes (RFM) is an economically important condition in dairy cattle disturbing the health and production in affected animals. In spite of extensive research, pathogenesis for RFM and identification of a predictive marker for the condition still remains elusive. Since expulsion of fetal membranes in an inflammatory process, studying the expression of inflammatory molecules is expected to give an idea about the pathogenesis of RFM.

Methods

Expression of pro-inflammatory cytokines, short chain fatty acid (SCFA) receptors and adhesion molecules was studied using qRT-PCR in the utero-placental tissues obtained from the cows that expelled fetal membranes normally (n = 12) and from the cows that developed RFM (n = 12). Concentrations of SCFAs were estimated in the utero-placental tissues using Gas Chromatography.

Results

The concentration of butyrate in the utero-placental tissue extract was 3–4 times lower, and GPR41 and GPR43 mRNA expression was 7.7–10.0 and 3.4–4.4 folds lower (p < 0.05) in cows that developed RFM compared to those that expelled the fetal membranes normally. The expression of IL-1, IL-6, IL-8, TNF-α, ICAM and PECAM was higher (p < 0.05) in the cows that normally expelled the fetal membranes compared to those that developed RFM.

Discussion

Since a clear association of butyrate levels, expression of pro-inflammatory cytokines, adhesion molecules and SCFAs receptors was observed with expulsion of fetal membranes, modulating the levels of these molecules prior to parturition might help in reducing the incidence of RFM in cows.

Conclusion

Inflammatory response is essential for normal expulsion of fetal membranes and that inadequate or altered expression of pro-inflammatory cytokines, adhesion molecules and SCFA receptors is associated with RFM in cows.     

Filarial infection is resisted differentially by subjects having different blood group phenotypes

This study was aimed to elucidate the relationship between major blood group antigens (BGAs) and susceptibility or resistance to human lymphatic filariasis. A total of 492 human subjects, living in Raipur city of Chhattisgarh, endemic for bancroftian filariasis in Central India, were screened for the presence of Wuchereria bancrofti microfilariae and disease manifestations. The frequency of BGAs was tabulated as a function of the status of filariasis, namely normal (no infection), mf carrier (presence of microfilariae in blood), and elephantiasis (confirmed clinical manifestations). The comparison of ABO phenotype distributions among all the three groups clearly indicated that disease status has a significant relationship with the blood group attributes. The result of χ² analysis of the frequencies of ABO phenotypes observed in microfilaraemic and elephantiasis groups (observed frequency vs. expected frequency computed based on the distribution of the normal population) revealed that there has been a significant alteration in the distribution of ABO phenotypes in microfilaraemic, but not in elephantiasis, group. The susceptibility to filarial infection was computed as a function of blood group phenotypes in the population. The susceptibility and conditional susceptibility for elephantiasis were the least among the subjects with AB phenotypes. The mechanism of association between filariasis and ABO antigens needs to be further explored to understand how the distribution of BGAs affects susceptibility/resistance to infection. J. Clin. Lab. Anal. 23:186–191, 2009. © 2009 Wiley‐Liss, Inc.     

Food allergy is associated with an increased risk of asthma

Background The atopic march is well documented, but the interrelationship of food allergy (FA) and asthma is not well understood.
Objective The aim of this study was to examine the strength of the association and temporal relationships between FA and asthma.
Methods This analysis included 271 children 6 years (older group) and 296 children <6 years (younger group) from a family-based FA cohort in Chicago, IL. Asthma was determined by parental report of physician diagnosis. FA status was determined based on the type and timing of clinical symptoms after ingestion of a specific food, and results of prick skin test (Multi-Test II) and allergen-specific IgE (Phadia ImmunoCAP). Analyses were carried out using logistic regression accounting for important covariates and auto-correlations among siblings. Kaplan–Meier curves were used to compare the time to onset of asthma with the FA status.
Results Symptomatic FA was associated with asthma in both older [odds ratio (OR)=4.9, 95% confidence interval (CI): 2.5–9.5] and younger children (OR=5.3, 95% CI: 1.7–16.2). The association was stronger among children with multiple or severe food allergies, especially in older children. Children with FA developed asthma earlier and at higher prevalence than children without FA (Cox proportional hazard ratio=3.7, 95% CI: 2.2–6.3 for children 6 years, and hazard ratio=3.3, 95% CI: 1.1–10 for children <6 years of age). No associations were seen between asymptomatic food sensitization and asthma.
Conclusions Independent of markers of atopy such as aeroallergen sensitization and family history of asthma, there was a significant association between FA and asthma. This association was even stronger in subjects with multiple food allergies or severe FA.     

Intensity-modulated radiation therapy (IMRT) for inoperable non-small cell lung cancer: the Memorial Sloan-Kettering Cancer Center (MSKCC) experience.

INTRODUCTION: Intensity-modulated radiation therapy (IMRT) is an advanced treatment delivery technique that can improve the therapeutic dose ratio. Its use in the treatment of inoperable non-small cell lung cancer (NSCLC) has not been well studied. This report reviews our experience with IMRT for patients with inoperable NSCLC. METHODS AND MATERIALS: We performed a retrospective review of 55 patients with stage I-IIIB inoperable NSCLC treated with IMRT at our institution between 2001 and 2005. The study endpoints were toxicity, local control, and overall survival. RESULTS: With a median follow-up of 26 months, the 2-year local control and overall survival rates for stage I/II patients were 50% and 55%, respectively. For the stage III patients, 2-year local control and overall survival rates were 58% and 58%, respectively, with a median survival time of 25 months. Six patients (11%) experienced grade 3 acute pulmonary toxicity. There were no acute treatment-related deaths. Two patients (4%) had grade 3 or worse late treatment-related pulmonary toxicity. CONCLUSIONS: IMRT treatment resulted in promising outcomes for inoperable NSCLC patients.     

Management protocols of Allergic Fungal Sinusitis

Controversy surrounds the appropriate surgical approach and the appropriate medical therapy for Allergic Fungal Sinusitis. The present prospective study aims to assess the impact of these factors on the treatment outcome of Allergic Fungal Sinusitis. In the present study 34 cases with AFS were randomized into one of 3 methods of post operative therapy i.e. systemic itraconazole (group A, n=11), topical steroids (group B, n=12) and nasal alkaline douches only (group C, n=11). Outcome was assessed at 6 months post-operative by the Kupferberg grading system for assessment of nasal and sinus mucosa. Grade ‘3’ mucosal disease was defined as recurrence. Complete pre-operative opacification of sphenoid and frontal sinus was a predictor of poorer outcome. Postoperative systemic itraconazole therapy demonstrated a trend towards a better outcome but was not statistically significant. Larger trials are required to conclusively evaluate the merit of various post-operative treatment regimens for AFS.