Occupation and task as risk factors for asthma-related outcomes among healthcare workers in New York City

Background

Previous studies have suggested an association of asthma onset and exacerbation with cleaning and disinfecting activities in a number of industries, including healthcare. The objective of the current study was to investigate the association of asthma and related outcomes with occupations and tasks in urban healthcare workers in the United States.

Clinical Features and Long-Term Outcome of Nephrotic Syndrome Associated with Heterozygous NPHS1 and NPHS2 Mutations

Background and objectives: Mutations in nephrin (NPHS1) and podocin (NPHS2) genes represent a major cause of idiopathic nephrotic syndrome (NS) in children. It is not yet clear whether the presence of a single mutation acts as a modifier of the clinical course of NS.Design, setting, participants, & measurements: We reviewed the clinical features of 40 patients with NS associated with heterozygous mutations or variants in NPHS1 (n = 7) or NPHS2 (n = 33). Long-term renal survival probabilities were compared with those of a concurrent cohort with idiopathic NS.Results: Patients with a single mutation in NPHS1 received a diagnosis before those with potentially nongenetic NS and had a good response to therapies. Renal function was normal in all cases. For NPHS2, six patients had single heterozygous mutations, six had a p.P20L variant, and 21 had a p.R229Q variant. Age at diagnosis and the response to drugs were comparable in all NS subgroups. Overall, they had similar renal survival probabilities as non-NPHS1/NPHS2 cases (log-rank χ² 0.84, P = 0.656) that decreased in presence of resistance to therapy (P < 0.001) and in cases with renal lesions of glomerulosclerosis and IgM deposition (P < 0.001). Cox regression confirmed that the only significant predictor of dialysis was resistance to therapy.Conclusions: Our data indicate that single mutation or variant in NPHS1 and NPHS2 does not modify the outcome of primary NS. These patients should be treated following consolidated schemes and have good chances for a good long-term outcome.The discovery of podocyte genes that cause familial nephrotic syndrome (NS) allows a more appropriate approach to patients with NS, especially in children with a familial history of proteinuria (1,2). There is growing evidence that mutations in genes coding for slit diaphragm proteins frequently also occur in sporadic NS and are associated with potentially variable clinical outcome (3–9). Most reports have focused on monogenic diseases involving two major genes—nephrin (NPHS1) and podocin (NPHS2)—that together cause almost 60% of the cases of NS in those who are younger than 1 yr and in adolescents (10). A still unresolved issue is the clinical impact of heterozygous mutations and/or variants of NPHS1/NPHS2 because the contribution of heterozygous alleles to NS has received heterogeneous interpretation (3,9,11–16). In particular, it is unknown whether patients who carry a single mutation represent a separate clinical entity, because no data on response to drugs and on the long-term clinical outcome are available.The reason for an association of NPHS1 and NPHS2 heterozygous mutations with NS remains elusive, because these are recessive conditions that require a molecular defect on both alleles to determine a pathologic effect. One explanation may be a digenic inheritance whereby a mutation of another gene affects the slit diaphragm assembly. Moreover, the presence of a heterozygous mutation or variant in NPHS1 or NPHS2 may act as a modifier of the phenotype and represent a clinical problem in terms of prognosis, drug response, and long-term outcome. Data on this aspect are scattered and offer no practical opportunity for discussion (3,9,11–16).This article reports the clinical features of 40 patients with NS associated with heterozygous mutations/variants of NPHS1 or NPHS2. Renal survival probabilities of these children were compared with those of a concurrent cohort of children with classical idiopathic NS.     

crv4, a mouse model for human ataxia associated with kyphoscoliosis caused by an mRNA splicing mutation of the metabotropic glutamate receptor 1 (Grm1)

We describe a novel spontaneous autosomal recessive mutation, cervelet-4 (crv4), which arose in a BALB/c strain. Mice homozygous for the mutation exhibit principally a reduced body size, a congenital neurological phenotype characterized by ataxic gait and intention tremor, with no gross anomalies observed in brain or cerebellum, and skeletal anomalies. Using linkage analysis, we mapped the crv4 locus to the proximal region of chromosome 10, at the location of the Grm1 gene. Genetic complementation crosses between crv4 and Grm1 KO mice confirmed that crv4 is a new allele of Grm1. Molecular analysis of the Grm1 gene in mutant mice revealed the insertion of a 190-bp LTR fragment in intron 4. Our results also indicated that the presence of the LTR fragment caused the disruption of the Grm1 normal splicing process and complete absence of the wild-type protein. crv4 is an interesting model to extend the study of Grm1 function and the pathological effects of Grm1 deficiency in vivo.