Eye disease in multibacillary leprosy patients at the time of their leprosy diagnosis: findings from the Longitudinal Study of Ocular Leprosy (LOSOL) in India,the Philippines and Ethiopia

Existing prevalence surveys do not provide adequate information to estimate the magnitude of ocular pathology or vision loss in leprosy patients. We sought to determine the prevalence of ocular findings and related risk factors in leprosy patients at the time of their disease diagnosis. We also sought to determine if there were geographic differences and whether these were due to different demographic characteristics of the populations. The study was undertaken at Schieffelin Leprosy Research & Training Centre (Karigiri, India), Leonard Wood Memorial Leprosy Institute (Cebu, Philippines), and (for 3 years only) ALERT (Addis Ababa, Ethiopia). Newly diagnosed multibacillary (MB) leprosy patients as well as MB cases relapsed after dapsone monotherapy were eligible for enrollment. In each study site, the target population was 300. Standardized examinations were conducted between 1991 and 1998. Patient enrollment included 301 patients in Karigiri, 289 patients in Cebu, and 101 patients in Addis Ababa. The age-adjusted prevalence of blindness (< 6/60 in the better eye) and visual impairment (6/24-6/60) was 2.8% and 5.2%, respectively. Lagophthalmos and leprosy related uveal changes were detected in 3.3% (95% CI 2.0-4.7%) and 4.1% (95% CI 2.4-5.7) of patients, respectively. Overall, 11% (95% CI 8.5-13.2%) of newly enrolled MB patients had potentially blinding leprosy related ocular pathology. Lagophthalmos was associated with increasing age, a short duration between onset and diagnosis, and a previous reaction involving the face. Uveal conditions were associated with increasing age. Overall, eye disease was more common in Indian and Ethiopian patients compared to Filipino patients; however, differences were not significant when controlling for age and clinical (non-ocular) factors. Patients with potentially blinding leprosy related pathology were over three times more likely to have other (hand and foot) disabilities than patients without pathology. Differences in the prevalence of blindness and potentially blinding leprosy related ocular pathology between the sites could be accounted for by the differences in age and other clinical factors of the patients at the different sites. Findings suggest that, even in the face of active leprosy control efforts, around 11% of patients will have potentially blinding pathology at the time of their diagnosis and 2.8% will be blind. If those patients with lagophthalmos or blindness are considered appropriate for referral for more detailed assessment, approximately 4% of newly diagnosed leprosy patients will require active follow-up for eye care; including those with reaction involving the face will result in 9.4% of patients requiring active follow-up. These people are likely to be older, with a reaction involving the face, and/or with other disabilities than those not requiring active follow-up.     

Modeling time-to-cure from severe acute malnutrition: application of various parametric frailty models

Background

In developing countries about 3.5% of children aged 0–5 years are victims of severe acute malnutrition (SAM). Once the morbidity has developed the cure process takes variable period depending on various factors. Knowledge of time-to-cure from SAM will enable health care providers to plan resources and monitor the progress of cases with SAM. The current analysis presents modeling time-to-cure from SAM starting from the day of diagnosis in Wolisso St. Luke Catholic hospital, southwest Ethiopia.

Methods

With the aim of coming up with appropriate survival (time-to-event) model that describes the SAM dataset, various parametric clustered time-to-event (frailty) models were compared. Frailty model, which is an extension of the proportional hazards Cox survival model, was used to analyze time-to-cure from SAM. Kebeles (villages) of the children were considered as the clustering variable in all the models. We used exponential, weibull and log-logistic as baseline hazard functions and the gamma as well as inverse Gaussian for the frailty distributions and then based on AIC criteria, all models were compared for their performance.

Results

The median time-to-cure from SAM cases was 14 days with the maximum of 63 days of which about 83% were cured. The log-logistic model with inverse Gaussian frailty has the minimum AIC value among the models compared. The clustering effect was significant in modeling time-to-cure from SAM. The results showed that age of a child and co-infection were the determinant prognostic factors for SAM, but sex of the child and the type of malnutrition were not significant.

Conclusions

The log-logistic with inverse Gaussian frailty model described the SAM dataset better than other distributions used in this study. There is heterogeneity between the kebeles in the time-to-cure from SAM, indicating that one needs to account for this clustering variable using appropriate clustered time-to-event frailty models.     

Type 1 versus Type 2 calreticulin mutations in essential thrombocythemia: A collaborative study of 1027 patients

CALR (calreticulin) trails JAK2 as the second most mutated gene in essential thrombocythemia (ET). Mutant CALR in ET is a result of frameshift mutations, caused by exon 9 deletions or insertions; type‐1, 52‐bp deletion (p.L367fs*46), and type‐2, 5‐bp TTGTC insertion (p.K385fs*47) variants constitute more than 80% of these mutations. The current study includes a total of 1027 patients divided into test (n = 402) and validation (n = 625) cohorts. Among the 402 ET patients in the test cohort, 227 (57%) harbored JAK2, 11 (3%) Myeloproliferative leukemia virus oncogene (MPL), and 114 (28%) CALR mutations; 12% were wild‐type for all three mutations (i.e., triple‐negative). Among the 114 patients with CALR mutations, 51 (45%) displayed type‐1 and 44 (39%) type‐2 variants; compared to mutant JAK2, both variants were associated with higher platelet and lower hemoglobin and leukocyte counts. However, male sex was associated with only type‐1 (P = 0.005) and younger age with type‐2 (P = 0.001) variants. Notably, platelet count was significantly higher in type‐2 vs. type‐1 CALR‐mutated patients (P = 0.03) and the particular observation was validated in the validation cohort that included 111 CALR‐mutated ET patients (P = 0.002). These findings, coupled with the recent demonstration of preferential expression of mutant and wild‐type CALR in megakaryocytes, suggest differential effects of CALR variants on thrombopoiesis. Am. J. Hematol. 89:E121–E124, 2014. © 2014 Wiley Periodicals, Inc.     

Glycine triggers an intracellular calcium influx in oligodendrocyte progenitor cells which is mediated by the activation of both the ionotropic glycine receptor and Na+-dependent transporters

Using fluo-3 calcium imaging, we demonstrate that glycine induces an increase in intracellular calcium concentration ([Ca2+]i) in cortical oligodendrocyte progenitor (OP) cells. This effect results from a calcium entry through voltage-gated calcium channels (VGCC), as it is observed only in OP cells expressing such channels, and it is abolished either by removal of calcium from the extracellular medium or by application of an L-type VGCC blocker. Glycine-triggered Ca2+ influx in OP cells actually results from an initial depolarization that is the consequence of the activation of both the ionotropic glycine receptor (GlyR) and Na+-dependent transporters, most probably the glycine transporters 1 (GLYT1) and/or 2 (GLYT2) which are colocalized in these cells. Through this GlyR- and transporter-mediated effect on OP intrcellular calcium concentration [Ca2+]i, glycine released by neurons may, as well as other neurotransmitters, serve as a signal between neurons and OP during development.     

Oligodendrocyte development and myelinogenesis are not impaired by high concentrations of phenylalanine or its metabolites

Phenylketonuria (PKU) is a metabolic genetic disease characterized by deficient phenylalanine hydroxylase (PAH) enzymatic activity. Brain hypomyelination has been reported in untreated patients, but its mechanism remains unclear. We therefore investigated the influence of phenylalanine (Phe), phenylpyruvate (PP), and phenylacetate (PA) on oligodendrocytes. We fisrt showed in a mouse model of PKU that the number of oligodendrocytes is not different in corpus callosum sections from adult mutants or from control brains. Then, using enriched oligodendroglial cultures, we detected no cytotoxic effect of high concentrations of Phe, PP, or PA. Finally, we analyzed the impact of Phe, PP, and PA on the myelination process in myelinating cocultures using both an in vitro index of myelination, based on activation of the myelin basic protein (MBP) promoter, and the direct quantification of myelin sheaths by both optical measurement and a bioinformatics method. None of these parameters was affected by the increased levels of Phe or its derivatives. Taken together, our data demonstrate that high levels of Phe, such as in PKU, are unlikely to directly induce brain hypomyelination, suggesting involvement of alternative mechanisms in this myelination defect.