The role of size, sequence and haplotype in the stability of FRAXA and FRAXE alleles during transmission

Factors involved in the stability of trinucleotide repeats during transmission were studied in 139 families in which a full mutation, premutation or intermediate allele at either FRAXA or FRAXE was segregating. The transmission of alleles at FRAXA, FRAXE and four microsatellite loci were recorded for all individuals. Instability within the minimal and common ranges (0-40 repeats for FRAXA, 0-30 repeats for FRAXE) was extremely rare; only one example was observed, an increased in size at FRAXA from 29 to 39 repeats. Four FRAXA and three FRAXE alleles in the intermediate range (41-60) repeats for FRAXA, 31-60 for FRAXE) were unstably transmitted. Instability was more frequent for FRAXA intermediate alleles that had a tract of pure CGG greater than 37 although instability only occurred in two of 13 such transmissions: the changes observed were limited to only one or two repeats. Premutation FRAXA alleles over 100 repeats expanded to a full mutation during female transmission in 100% of cases, in agreement with other published series. There was no clear correlation between haplotype and probability of expansion of FRAXA premutations. Instability at FRAXA or FRAXE was more often observed in conjunction with a second instability at an independent locus suggesting genomic instability as a possible mechanism by which at least some FRAXA and FRAXE mutations arise.      

Preventable hospitalization and avoidable maternity outcomes: implications for access to health services for Medicaid recipients

This study demonstrates how readily available hospital discharge data and small area methods can be used to identify potential problems of access to primary and prenatal outpatient health services for Medicaid populations. We examine whether rates of preventable hospitalization and avoidable maternity outcomes differ across geographic areas by their concentration of Medicaid recipients. Five county and twenty-four intra-county areas in Upstate New York are examined. Individuals living in Medicaid intra-county areas had significantly higher rates of these hospitalizations than persons living in non-Medicaid areas. Public health managers can use these methods to identify and compare areas in which access problems exist and to target and evaluate programs designed to improve access.     

Respiratory syncytial virus genotypes and disease severity among children in hospital

OBJECTIVES: To determine the spectrum of N and G genotypes of respiratory syncytial virus (RSV) causing respiratory tract infection and whether particular genotypes are associated with severity of infection. PATIENTS AND METHODS: Nasopharyngeal aspirates (NPAs) were obtained from 114 infants with acute respiratory tract infection due to RSV over two seasons. Viral mRNA was extracted from NPAs or cultured virus, reverse transcribed, and the cDNA amplified by the polymerase chain reaction using primers directed to parts of the N and G gene respectively. Amplicons were separately digested with four different restriction endonucleases for each gene. The fragments were separated by agarose gel, electrophoresis, and the electrophoretic patterns used to assign the various genotypes. Disease severity was assessed as very mild (upper respiratory tract signs only), mild (coryza and signs of lower respiratory tract infection), moderate (requiring nasogastric or intravenous fluids), and severe (requiring oxygen or ventilation). RESULTS: Five of the six known N genotypes were detected, but NP4 and NP2 were found most frequently. There was no association between N genotype and disease severity. Six G (SHL) genotypes were detected. Significantly (p = 0.04) more of the infants infected with the SHL2 genotype had severe or moderate disease. CONCLUSIONS: During the seasonal peaks of RSV respiratory tract infection at least 10 different RSV genotypes cocirculated. While there is no association between N genotypes and disease severity, infection with the SHL2 G genotype appears to result in moderate to severe disease.     

Delivery Complications Associated With Prenatal Care Access for Medicaid-Insured Mothers in Rural and Urban Hospitals

CONTEXT: Pregnancy complications affect many women. It is likely that some complications can be avoided through routine primary and prenatal care of reasonable quality. PURPOSE: The authors examined access to health care during pregnancy for mothers insured by Medicaid. The access indicator is potentially avoidable maternity complications (PAMCs). Potentially avoidable maternity complications are often preventable through routine prenatal care, such as infection screening and treatment. The authors examined the risks of potentially avoidable maternity complications among rural and urban hospital deliveries for groups of mothers defined by race or ethnicity. METHODS: Data are from the year 2000 Nationwide Inpatient Sample (NIS). The stratified sample represents all discharges from 20.5% of community hospitals in the United States. The Nationwide Inpatient Sample identifies hospital locations, but not patients' areas of residence. Analyses, which accounted for the sample design, included calculation of potentially avoidable maternity complication rates by race or ethnicity, chi2, t tests, and multivariate logistic regression. FINDINGS: Within groups defined by race or ethnicity, unadjusted rates for potentially avoidable maternity complications did not differ significantly by hospital location. Holding other factors constant, potentially avoidable maternity complications were less common in rural hospitals than in urban hospitals (odds ratio, 0.78; CI, 0.62 to 0.99). In rural hospitals, African Americans had notably higher risk for potentially avoidable maternity complications than did non-Hispanic whites (odds ratio, 1.72; CI, 1.26 to 2.36). In urban hospitals, risk of potentially avoidable maternity complications was not significantly higher for African Americans. Hispanics and Asians had notably lower risks of potentially avoidable maternity complications in urban hospitals than did non-Hispanic whites. CONCLUSIONS: Providers and policymakers should work to reduce the risks of potentially avoidable maternity complications for African American women in rural areas who are insured by Medicaid.     

Enhancement of chemotactic factor-stimulated neutrophil oxidative metabolism by leukotriene B4

Leukotriene B4 (LTB4) is a potent primary stimulator of neutrophil chemotaxis, aggregation, and degranulation and induces superoxide production at higher concentrations. In order to determine whether LTB4 modulates neutrophil responses to oxidative stimuli, human neutrophils (PMNs) were incubated with LTB4 prior to stimulation with f-Met-Leu-Phe (fMLP, 10(-7) mol/L), opsonized zymosan (OZ, 250 micrograms/mL), or phorbol myristate acetate (PMA, 32 nmol/L). Superoxide (O2-) production by stimulated PMNs was assessed by the superoxide dismutase-inhibitable reduction of cytochrome c. LTB4 alone did not stimulate O2- production in concentrations below 10(-7) mol/L and had no effect on the O2- assay. In the concentration range of 10(-12) to 10(-8) mol/L, LTB4 did not alter O2- release induced by OZ or PMA. In contrast, LTB4-treated cells demonstrated enhanced O2- production following exposure to fMLP, and in the presence of 10 nmol/LLTB4, generated 180% +/- 41% of O-2 quantities produced by control cells (n = 23). Enhancement was LTB4 dose-dependent, was maximal in the range of 1 to 10 nmol/L LTB4, was not reversed by removal of the lipid from the medium prior to fMLP stimulation, and was not dependent on the presence of Ca++ or Mg++ in the suspending medium. Chemiluminescence of fMLP-stimulated neutrophils was increased to 323% of controls in neutrophils preincubated with 10 nmol/L LTB4. Unlike augmentation of oxidative responses to fMLP seen with other degranulating stimuli, enhancement by LTB4 was not correlated with an increase in 3H-fMLP receptor binding. These results indicate that, in addition to its primary effects on neutrophil function, LTB4 modulates PMN oxidative responses to the chemotactic peptide and, thus, may amplify the release of oxygen metabolites at inflammatory foci.     

Physical and functional interactions between Stat5 and the tyrosine- phosphorylated receptors for erythropoietin and interleukin-3

Erythropoietin (Epo) and interleukin-3 (IL-3) stimulate activation of the Jak2 tyrosine kinase and induce tyrosine phosphorylation and activation of Stat5. In the present study, we have shown that Epo or IL- 3 stimulation induces binding of Stat5 to the tyrosine-phosphorylated Epo receptor (EpoR) or IL-3 receptor beta subunit (betaIL3), respectively, in IL-3-dependent 32D cells expressing the EpoR. The binding of Stat5 to these cytokine receptors was shown to be rapid and transient, occurring within 1 minute of stimulation of cells and significantly decreasing after 5 minutes of cell treatment. In vivo binding experiments in COS cells showed that binding of Stat5 to the EpoR was mediated through the Stat5 Src homology 2 (SH2) domain. In vitro binding studies further showed that Stat5, but not other Stats examined, bound specifically to tyrosine-phosphorylated recombinant EpoR fusion proteins. In these in vivo and in vitro binding studies, Stat5 bound, albeit to a lesser degree, to truncated EpoR mutants in which all the intracellular tyrosines except Y-343 were removed. Furthermore, EpoR-derived synthetic phosphotyrosine peptides corresponding to Y-343, Y-401, Y-431, and Y-479 inhibited the in vitro binding of Stat5. When expressed in 32D cells, a mutant EpoR in which all the intracellular tyrosines were removed by carboxy-terminal truncation showed a significantly impaired ability to induce tyrosine phosphorylation of Stat5, particularly at low concentrations of Epo, but exhibited an increased sensitivity to Epo for growth signaling as compared with the wild-type EpoR. These results indicate that Stat5 specifically and transiently binds to the EpoR through the interaction between the Stat5 SH2 domain and specific phosphorylated tyrosines, including Y-343, in the EpoR cytoplasmic domain. It was implied that betaIL3 may also have similar Stat5 docking sites. The Stat5 docking sites in the EpoR were shown to facilitate specific activation of Stat5, which, however, may not be required for the EpoR-mediated growth signaling.     

High-dose etoposide and cyclophosphamide without bone marrow transplantation for resistant hematologic malignancy

Seventy-five patients with resistant acute leukemia or lymphoma received high-dose cyclophosphamide and etoposide to explore the activity of this combination in resistant hematologic malignancies, and to determine the maximum doses of these drugs that can be combined without bone marrow transplantation. Etoposide was administered over 29 to 69 hours by continuous infusion corresponding to total doses of 1.8 g/m2 to 4.8 g/m2. Cyclophosphamide, 50 mg/kg/d, was administered on 3 or 4 consecutive days total 150 to 200 mg/kg ideal body weight). At all dose levels myelosuppression was severe but reversible. Mucosal toxicity was dose-limiting with the maximum tolerated dose level combining etoposide 4.2 g/m2 with cyclophosphamide 200 mg/kg. Continuous etoposide infusion produced stable plasma levels that were lower than would be achieved after administration by short intravenous infusion, and this could explain our ability to escalate etoposide above the previously reported maximum tolerated dose. There were 28 complete (35%) and 12 partial (16%) responses. Median duration of complete response (CR) was 3.5 months (range 1.1 to 20+). Seventeen of 40 patients (42%) with acute myelogenous leukemia (AML) achieved CR, including 6 of 20 (30%) with high-dose cytosine arabinoside resistance. We conclude that bone marrow transplantation is not required after maximum tolerated doses of etoposide and cyclophosphamide. This regimen is active in resistant hematologic neoplasms, and the occurrence of CR in patients with high-dose cytosine arabinoside-resistant AML indicates a lack of complete cross-resistance between these regimens.     

Associations of multiple chronic health conditions with active life expectancy in the United States

Purpose: To estimate associations of eight common health conditions with life expectancy (LE) and disabled life expectancy (DLE), the percentage of life disabled in an activity of daily living. Methods: Data from the Panel Study of Income Dynamics represented Americans ages 55+ (1999–2011, n?=?2118, mean baseline age 63.3, 19?447 person-years). We estimated probabilities of death and disability with multinomial logistic Markov models adjusted for age, sex, race/ethnicity and education. We used the probabilities to create large populations with microsimulations, each individual having a known monthly disability status, age 55 through death. We calculated LE and DLE for the populations, repeating each microsimulation 100 times for confidence intervals. Results: Nearly half (48.8%) of the participants had two or more conditions, 24.7% had three or more, 11.5% had four or more. Having any one condition significantly reduced LE. For example, white women lived to age 87.3 (95% confidence interval 86.5–88.1) with no conditions, 75.8 (70.9–80.7) with heart disease. Multiple conditions did not further reduce LE but often increased DLE, which for white women was 12.2% (11.1–13.2) with no conditions, 39.1% (28.3–49.8) with heart disease and 47.0% (46.9–47.1) with heart disease, diabetes and hypertension. Conclusion: The increasing prevalence of multiple chronic conditions may substantially increase disability.

• Implications for Rehabilitation

• The growing number of individuals with multiple chronic conditions will greatly increase the prevalence of disability in later life.

• It is important for rehabilitation science, practice and policy to address this emerging epidemiological transition.

• Rehabilitation is especially important for people with pre-diabetes, developing heart disease or early stages of other cardiovascular-related diseases as avoiding the development of multiple chronic diseases through increased activity may greatly reduce disability and mortality.