Genetic variation in the HLA region is associated with susceptibility to herpes zoster.

Herpes zoster, commonly referred to as shingles, is caused by the varicella zoster virus (VZV). VZV initially manifests as chicken pox, most commonly in childhood, can remain asymptomatically latent in nerve tissues for many years and often re-emerges as shingles. Although reactivation may be related to immune suppression, aging and female sex, most inter-individual variability in re-emergence risk has not been explained to date. We performed a genome-wide association analyses in 22,981 participants (2280 shingles cases) from the electronic Medical Records and Genomics Network. Using Cox survival and logistic regression, we identified a genomic region in the combined and European ancestry groups that has an age of onset effect reaching genome-wide significance (P>1.0 × 10(-8)). This region tags the non-coding gene HCP5 (HLA Complex P5) in the major histocompatibility complex. This gene is an endogenous retrovirus and likely influences viral activity through regulatory functions. Variants in this genetic region are known to be associated with delay in development of AIDS in people infected by HIV. Our study provides further suggestion that this region may have a critical role in viral suppression and could potentially harbor a clinically actionable variant for the shingles vaccine.

The structure of an essential splicing element: stem loop IIa from yeast U2 snRNA.

BACKGROUND: Eukaryotic genes are usually transcribed as precursor mRNAs which are then spliced, removing introns to produce functional mRNAs. Splicing is performed by the spliceosome and provides an important level of post-translational control of gene expression. Stem loop IIa from U2 small nuclear (sn)RNA is required for the efficient association of the U2 small nuclear ribonuclear protein (snRNP) with the nascent spliceosome in yeast. Genetic analysis suggests that stem loop IIa is involved in RNA-protein interactions early in splicing, and it may also interact with other RNA sequences in U2. The sequence of loop IIa is well conserved, consistent with the idea that this loop is important for function. RESULTS: We have solved the structure of U2A, a 20-base analogue of stem loop IIa from Saccharomyces cerevisiae, using NMR and restrained molecular dynamics. In the process, we have demonstrated the efficacy of a new structure calculation protocol, torsion angle molecular dynamics. The structure that has emerged, which is consistent with the in vivo chemical protection data available for stem loop IIa in the context of intact U2 snRNA, contains a sheared GA pair followed by a U-turn in the loop. The U-turn conformation, which resembles the U-turns in tRNA anticodon loops, makes this stretch of U2 snRNA an obvious target for interactions with proteins and/or other RNA sequences. CONCLUSIONS: The phenotypes of many stem loop IIa mutants can be rationalized assuming that the U-turn conformation in the loop must be preserved for efficient splicing. This observation, combined with the phylogenetic conservation of its sequence, suggests that the conformation of the loop of stem loop IIa is essential for its function in pre-mRNA splicing.

Genetic variation among 82 pharmacogenes: The PGRNseq data from the eMERGE network.

Genetic variation can affect drug response in multiple ways, although it remains unclear how rare genetic variants affect drug response. The electronic Medical Records and Genomics (eMERGE) Network, collaborating with the Pharmacogenomics Research Network, began eMERGE-PGx, a targeted sequencing study to assess genetic variation in 82 pharmacogenes critical for implementation of "precision medicine." The February 2015 eMERGE-PGx data release includes sequence-derived data from ∼5,000 clinical subjects. We present the variant frequency spectrum categorized by variant type, ancestry, and predicted function. We found 95.12% of genes have variants with a scaled Combined Annotation-Dependent Depletion score above 20, and 96.19% of all samples had one or more Clinical Pharmacogenetics Implementation Consortium Level A actionable variants. These data highlight the distribution and scope of genetic variation in relevant pharmacogenes, identifying challenges associated with implementing clinical sequencing for drug treatment at a broader level, underscoring the importance for multifaceted research in the execution of precision medicine.

New tool for presenting risk in obstetrics and gynecology.

BACKGROUND: The Paling Perspective Scale, a means of communicating risk in various settings, has been applied to diverse fields such as nuclear power, blood banking, and ophthalmology. TECHNIQUE: Statistics of risk for various events in obstetrics and gynecology were collected from the literature and directly applied to the risk scale. EXPERIENCE: The graphic simplicity and versatility of this scale make it adaptable for communicating risks to people of different technical and educational backgrounds. CONCLUSION: The Paling Perspective Scale might help obstetrician-gynecologists obtain informed consent for surgery, genetic counseling, and other topics.

Anthropometric measurements of white and black southern adolescent girls.

Anthropometric measurements of 691 white and 550 black 12-, 14-, and 16-year-old girls from three income groups, residing in the southern United States, were evaluated, Heights, weights, mid-upper arm circumferences, and arm muscle areas of 14-year-old girls were significantly higher than those of 12-year-old girls and significantly lower than those of girls 16 years of age; triceps skinfolds, arm fat areas, and body mass indexes of 12-year-olds were significantly lower than those of older subjects. Blacks had significantly higher weights, body mass indexes, and arm muscle areas than whites. Black 12-year-old girls were significantly taller than white 12-year-old girls but significantly shorter than older girls of either race; white 16-year-old girls were significantly taller than blacks of that age. Body mass indexes of black 12-year-olds and white 14-year-olds were significantly higher than those of white 12-year-olds, and significantly lower than those of black 14- and 16-year-olds. Medium-income blacks and whites of all income levels had lower (usually significantly) weights, body mass indexes, mid-upper arm circumferences, arm muscle areas, and arm fat areas than low- and high-income blacks did. Anthropometric values of white, but not of black, girls were generally similar to those reported in surveys of primarily white girls.

Rocky Mountain spotted fever and pregnancy: a case report and review of the literature.

The classic triad of fever, headache, and characteristic rash occurring 1 to 2 weeks after a tick bite in an endemic area should raise suspicions for Rocky Mountain spotted fever (RMSF). All providers with primary care responsibility for women should be familiar with the diagnosis and treatment of this illness. As a recent case illustrates, the diagnosis of Rocky Mountain spotted fever may be complicated by pregnancy. Several conditions of pregnancy have similar presentations to the initial, often nonspecific manifestations of RMSF. Although doxycycline is the recommended therapy for children and nonpregnant women, chloramphenicol remains the recommended therapy for women during pregnancy. The time of year, local prevalence, and patient's exposure history may be taken into account when deciding to treat during pregnancy. Vertical transmission of RMSF has not been documented in humans. Prevention of RMSF by avoidance of tick-infested areas or by the use of insect repellents and long clothing is recommended for all patients.

Behavior problems of children with Down syndrome and life events.

Behavior problems of 44 children with Down syndrome between the ages of 6 and 15 and 44 controls without mental retardation matched for age, sex, and socioeconomic status were compared on the basis of mother and teacher ratings. Ratings from both sources indicated that children with Down syndrome had more behavior problems, in particular attention deficit, noncompliance, thought disorder, and social withdrawal. Life events from the past year were significantly associated with mother but not teacher ratings of Down syndrome behavior problems.

Malignant hemangiopericytoma of the forearm.

Hemangiopericytoma is a tumor that arises from primitive perivascular cells in many sites of the body. A painless tumor may be present for years. Malignant hemangiopericytoma of the upper extremity is rare, with only 14 cases previously reported in the English literature. Because of the often unpredictable behavior of this tumor, extended follow-ups are strongly recommended.

Characterization of drug-related problems in elderly patients on admission to a medical ward.

The incidence, types, avoidability and risk factors associated with drug-related problems (DRPs) in geriatric patients on admission to a medical ward of the Toronto Hospital were assessed. The admission note and laboratory data of 150 consecutive admissions were reviewed for the presence of an adverse drug reaction, inappropriate dose, non-compliance, drug interaction, or lack of required medication. The avoidability (avoidable, possibly avoidable, or unavoidable) and contribution to hospitalization (major reason, contributing or non contributing) of each DRP was characterized. On admission, 41% of patients had a DRP identified, of which most were potentially avoidable (96.8%) and involved commonly prescribed drugs. The DRP was the major or contributing reason for admission in 31% of cases. Polypharmacy was a statistically significant risk factor for a DRP, particularly for male patients (p = 0.0010). In this elderly population, DRPs were not statistically correlated to age greater than 65 years, gender, renal function, native language, or duration of hospital stay. The incidence of DRPs and hospitalizations in the elderly can potentially be reduced by improving medication use. Enhanced communication, particularly between hospital and community pharmacists and their patients, may be a key mechanism.

Carpal tunnel syndrome not always work related.

Carpal tunnel syndrome is all too frequently believed to be strictly a work related disease. A retrospective analysis of 1,884 carpal tunnel patients examined by one hand surgeon between 1977 and 1992 were evaluated for their rate of employment. Twenty-five percent of these CTS patients were not employed at the time their symptoms developed. We conclude that a significant rate of CTS illness exists in the nonemployed population.

Carpal tunnel syndrome. Effects of litigation on utilization of health care and physician workload.

We performed a study consisting of two parts to investigate the impact of litigation on patient recovery and physician workload. We received 556 replies from a questionnaire sent to hand surgeons and discovered that 98.20% of them felt that litigation increased the subjective complaints of patients. Most of these physicians (89.75%) also felt that litigation led to a worse result from treatment. Second, we undertook a retrospective chart review of 447 patients to see if there was a correlation between litigation, patient utilization of health care and physician workload. We found that workers' compensation patients with pending litigation went to the doctor's office more. They also had more letters, phone calls, and forms associated with their care, had more nerve conduction studies performed, and took longer to be discharged from care than patients with non-work-related carpal tunnel syndrome as well as workers' compensation patients who did not have pending litigation. These results indicated that litigation does affect patient utilization of health care and increases the workload on the physician.

Design and anticipated outcomes of the eMERGE-PGx project: a multicenter pilot for preemptive pharmacogenomics in electronic health record systems.

We describe here the design and initial implementation of the eMERGE-PGx project. eMERGE-PGx, a partnership of the Electronic Medical Records and Genomics Network and the Pharmacogenomics Research Network, has three objectives: (i) to deploy PGRNseq, a next-generation sequencing platform assessing sequence variation in 84 proposed pharmacogenes, in nearly 9,000 patients likely to be prescribed drugs of interest in a 1- to 3-year time frame across several clinical sites; (ii) to integrate well-established clinically validated pharmacogenetic genotypes into the electronic health record with associated clinical decision support and to assess process and clinical outcomes of implementation; and (iii) to develop a repository of pharmacogenetic variants of unknown significance linked to a repository of electronic health record-based clinical phenotype data for ongoing pharmacogenomics discovery. We describe site-specific project implementation and anticipated products, including genetic variant and phenotype data repositories, novel variant association studies, clinical decision support modules, clinical and process outcomes, approaches to managing incidental findings, and patient and clinician education methods.

Repeated dosing of digoxin-fragmented antibody in preterm eclampsia.

Early onset eclampsia has significant morbidity and mortality for both the mother and fetus. No effective treatment exists at present except delivery and seizure prophylaxis with magnesium sulfate. We report the novel use of a fragmented ovine antibody against digoxin for the treatment of eclampsia. A 16-year-old primagravida at 29 weeks 5/7 days gestation presented with clinical diagnosis of eclampsia and was treated with compassionate off-label use of digoxin-fragmented ovine antibody (Digibind Glaxo Smith Kline, Research Triangle Park, NC, USA). Improvement of her underlying disorder during a 48 h treatment window was noted without adverse maternal or neonatal outcome. We suggest digoxin-fragmented ovine antibody as a possible intervention in preterm pregnancies complicated by pre-eclampsia or eclampsia.

Correlation of head-to-body delivery intervals in shoulder dystocia and umbilical artery acidosis.

OBJECTIVE: Our goal was to determine the effect of shoulder dystocia on umbilical artery acidosis. STUDY DESIGN: We performed a retrospective analysis of 134 mother-infant pairs of shoulder dystocia cases at our institution from January 1, 1994, through December 31, 1997. Cases were identified from the obstetric database, and charts were abstracted for demographics, head-to-body delivery interval, umbilical blood gas parameters, and neonatal outcome. Pooled student t tests were used to compare mean blood gas values with data previously reported from our patient population. Regression analysis was performed regarding head-to-body delivery interval and blood gas parameters. RESULTS: The mean umbilical artery pH of shoulder dystocia cases (7.23 +/-.082) was less than the mean arterial pH of all vaginal deliveries in our institution (7.27 +/-.069), P <.001. Head-to-body delivery intervals (available for 44 cases) were not associated with statistically significant alterations in umbilical artery pH (r(2) =.0004), PCO(2) (r(2) =.011), or base deficit (r(2) =.006). Increasing head-to-body delivery interval was also not significantly correlated with decreasing 5-minute Apgar score (r =.0278). CONCLUSION: In our study population, shoulder dystocia resulted in statistically significant but clinically insignificant reductions in mean umbilical artery blood gas parameters. No statistically significant linear relationship was identified between the head-to-body delivery interval and fetal acid-base status.

Erythropoietin in the cerebrospinal fluid of neonates who sustained CNS injury.

We previously reported that erythropoietin (Epo) is present in human cerebrospinal fluid (CSF). It is not known whether CSF Epo concentrations change under conditions of CNS injury or, if so, whether this change reflects loss of blood-brain barrier integrity or increased CNS Epo synthesis. We hypothesized that CSF Epo increases in conditions of neural injury including hypoxia, meningitis, and intraventricular hemorrhage (IVH) and that CSF Epo concentrations are independent of plasma Epo concentrations. To test these hypotheses, Epo concentrations were measured in 122 paired CSF and blood samples obtained from neonates and children categorized as follows: 16, asphyxia; 31, meningitis; 11, IVH; 41, controls. Twelve infants treated with recombinant Epo (rEpo) and 11 additional samples from children with miscellaneous neurologic problems were also evaluated. CSF and plasma Epo concentrations were significantly higher in asphyxiated infants than in controls (225.0+/-155.0 versus 4.5+/-0.5 mU/mL; mean +/- SEM, p < 0.05, respectively, in CSF; 1806.7+/-1254 versus 5.2+/-0.5, p < 0.05 in plasma). Neonates with IVH had higher CSF Epo concentrations than controls (p < 0.01) but did not have higher plasma Epo concentrations than controls. Patients with meningitis did not have elevated CSF or plasma Epo concentrations. There was no correlation between CSF and plasma Epo concentrations in infants treated with rEpo. We conclude that Epo is selectively increased in the CSF by hypoxia, less so by IVH, and not at all by meningitis. rEpo treatment does not elevate CSF Epo. These findings suggest that rEpo does not cross the blood-brain barrier and that hypoxia induces increased CNS synthesis of Epo.

Comparison of natriuretic and diuretic effects of single and divided doses of furosemide.

The natriuretic and diuretic effectiveness of once-daily and twice-daily furosemide administration schedules was compared in a two-way crossover study using six normal subjects. Urine was collected for 24hours before and after administration of the first dose of furosemide. Patients received one 40-mg dose or two 20-mg doses of the drug administered six hours apart. Sodium and potassium urine concentrations were measured through flame emission photometry using lithium as an internal standard. Chloride urine concentrations were determined using colorimetric measurement with mercuric thiocyanate. Results were statistically evaluated by a one-way analysis of variance. Results showed no statistically significant differences (p greater than 0.7) between the two regimens in the cumulative 24-hour excretion of sodium, potassium, chloride or water. The average 24-hour sodium excretion following a single 40-mg furosemide dose was 268.9 mEq, while that following administration of the two 20-mg doses was 294.2 mEq. Differences during various intervals within the 24-hour collection period were consistent with the relative sizes of doses administered. It would appear that single daily dose administration regimens would be a logical beginning for furosemide therapy, particularly when lower doses are being considered.