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Objective To investigate the incidence and risk factors for hypogammaglobulinaemia and infectious complications associated with rituximab treatment in childhood-onset rheumatic diseases. Methods We performed a single-centre retrospective study of patients (n = 85) treated at Boston Children’s Hospital (BCH) from 2009 to 2019. Study subjects included patients (ages 6–24 years) who received rituximab for the treatment of a childhood-onset rheumatic disease. Results New-onset hypogammaglobulinaemia developed in 23 (27.1%) patients within 18 months of rituximab induction treatment. Twenty-two patients (25.9%) developed at least one infectious complication in the 18 months following the first rituximab infusion; of these, 11 (50%) had serious infections requiring inpatient treatment. After adjusting for potential confounders, exposure to pulse corticosteroid therapy in the month prior to rituximab use was a significant predictor of both new-onset hypogammaglobulinaemia (odds ratio [OR] 3.94; 95% CI: 1.07, 16.0; P = 0.044) and infectious complications (OR 15.3; 95% CI: 3.04, 126.8; P = 0.003). Post-rituximab hypogammaglobulinaemia was the strongest predictor of serious infectious complications (OR 7.89; 95% CI: 1.41, 65.6; P = 0.028). Younger age at rituximab use was also a significant predictor of new-onset hypogammaglobulinaemia (OR 0.83; 95% CI: 0.70, 0.97; P = 0.021). Compared with other rheumatic diseases, patients with vasculitis had a higher likelihood of developing infectious complications, including serious infections. Conclusion Although rituximab was well tolerated in terms of infectious complications in the majority of patients with childhood-onset rheumatic diseases, a substantial proportion developed new-onset hypogammaglobulinaemia and infectious complications following treatment. Our study highlights a role for heightened vigilance of rituximab-associated hypogammaglobulinaemia and infections in paediatric patients with rheumatic conditions.

Introduction Colorectal cancer is the second leading cause of cancer deaths in the USA, and screening tests are underutilized. The aim of this study was to determine the proportion of individuals at average risk who utilized a recommended initial screening test in a universal healthcare coverage system. Materials and Methods This is a retrospective cohort study of active duty and retired military members as well as civilian beneficiaries of the Military Health System. Individuals born from 1960 to 1962 and eligible for full benefits on their 50th birthday were evaluated. Military rank or rank of benefits sponsor was used to determine socioeconomic status. Adherence to the U.S. Preventive Services Task Force guidelines for initial colorectal cancer screening was determined using “Current Procedural Terminology” and “Healthcare Common Procedure Coding System” codes for colonoscopy, sigmoidoscopy, fecal occult blood test, and fecal immunohistochemistry test. Average risk individuals who obtained early screening ages 47 to 49 were also identified. Results This study identified 275,665 individuals at average risk. Of these, 105,957 (38.4%) adhered to screening guidelines. An additional 19,806 (7.2%) individuals were screened early. Colonoscopy (82.7%) was the most common screening procedure. Highest odds of screening were associated with being active duty military (odds ratio [OR] 3.63, 95% confidence interval [CI] 3.43 to 3.85), having highest socioeconomic status (OR 2.37, 95% CI 2.31 to 2.44), and having managed care insurance (OR 4.36, 95% CI 4.28 to 4.44). Conclusions Universal healthcare coverage does not ensure initial colorectal cancer screening utilization consistent with guidelines no does it eliminate disparities.

Background Comparative long-term trends in fatal accident rates in the UK’s most hazardous occupations have not been reported. Aims To compare trends in fatal accident rates in six of the most hazardous occupations (the three armed forces, merchant shipping, sea fishing and coal mining) and the general British workforce during peacetime years since 1900. Methods Examinations of annual mortality reports, returns, inquiry files and statistics. The main outcome measure was the fatal accident rate per 100 000 population employed. Results These six occupations accounted for ~40% of all fatal accidents in the British workforce. Fatal accident rates were highest in merchant shipping to 1914 (400–600 per 100 000) and in the Royal Air Force and sea fishing by the early 1920s (around 300 per 100 000). Since the 1950s sea fishing has remained the most hazardous occupation (50–200). Widespread reductions in fatal accident rates for each occupation have been greatest in recent years in the three armed forces and merchant shipping. Compared with the general workforce, relative risks of fatalities have increased in recent decades in all these occupations except shipping. Conclusions All six occupations still have high fatal accident rates. The greatly increased fatalities in sea fishing generally and in the Royal Air Force during its early years reflect, for different reasons, cultures of extreme risk-taking in these two sectors. Reductions in fatality rates in the armed forces over the last 20 years are due largely to decreases in land transport accidents.

The human placenta is hypomethylated compared to somatic tissues. However, the degree and specificity of placental hypomethylation across the genome is unclear. We assessed genome-wide methylation of the human placenta and compared it to that of the neutrophil, a representative homogeneous somatic cell. We observed global hypomethylation in placenta (relative reduction of 22%) compared to neutrophils. Placental hypomethylation was pronounced in intergenic regions and gene bodies, while the unmethylated state of the promoter remained conserved in both tissues. For every class of repeat elements, the placenta showed lower methylation but the degree of hypomethylation differed substantially between these classes. However, some retroelements, especially the evolutionarily younger Alu elements, retained high levels of placental methylation. Surprisingly, nonretrotransposon-containing sequences showed a greater degree of placental hypomethylation than retrotransposons in every genomic element (intergenic, introns, and exons) except promoters. The differentially methylated fragments (DMFs) in placenta and neutrophils were enriched in gene-poor and CpG-poor regions. The placentally hypomethylated DMFs were enriched in genomic regions that are usually inactive, whereas hypermethylated DMFs were enriched in active regions. Hypomethylation of the human placenta is not specific to retroelements, indicating that the evolutionary advantages of placental hypomethylation go beyond those provided by expression of retrotransposons and retrogenes.

Background Multisystem inflammatory syndrome in children (MIS-C) has been described in areas with high Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) burden. Clinical features included in the MIS-C case definition (e.g fever, elevated inflammatory markers) overlap with features of other childhood infections. The prevalence of non-SARS-CoV-2 infection in patients evaluated for MIS-C has not been described. Patients evaluated for MIS-C, and therapies administered. Methods Retrospective cohort study of patients < 21 years of age admitted to a freestanding children’s hospital in Boston, MA from May 14-June 6, 2020 who were evaluated for MIS-C. We identified patients undergoing Rheumatology consultation and echocardiogram (per the hospital’s protocol for evaluating children with suspicion for MIS-C). We tabulated patients evaluated for MIS-C found to have non-SARS-CoV-2 infection detected on standard microbiologic testing. Results 39 patients met inclusion criteria. Median age was 5 years (IQR 2–12 years). Of evaluated patients, 19/39 (49%) were diagnosed with MIS-C according to the Massachusetts Department of Public Health case definition; 10/39 (26%) required ICU admission. Non-SARS-CoV-2 infections were identified in 7/39 (18%), of whom 5/7 (71%) had bacterial infections, 1/7 (14%) had viral infection, and 1/7 (14%) had viral and bacterial co-infections; no fungal or parasitic infections were identified. Of patients diagnosed with MIS-C, 2/19 (11%) were found to have non-SARS-CoV-2 infection. Additionally, 5/19 (26%) had a positive polymerase chain reaction test for SARS-CoV-2 at time of MIS-C diagnosis, of whom 4/5 (80%) received remdesivir. Of patients evaluated for MIS-C, 17/39 (44%) received intravenous immune globulin, 14/39 (36%) aspirin, 4/39 (10%) anakinra, and 14/39 (36%) methylprednisolone. Additionally, 21/39 (54%) received antibacterial and 5/39 (13%) antiviral therapy (Table). Conclusion In this study, non-SARS-CoV-2 infections were diagnosed in 18% of children evaluated for MIS-C. Clinicians should consider alternative or concomitant infectious diagnoses in patients undergoing MIS-C evaluation. Research is needed to identify clinical and laboratory features that may distinguish patients with MIS-C from those with non-SARS-CoV-2 infection. Disclosures All Authors: No reported disclosures

Introduction Compared to the majority of non-Hispanic white ("white") cigarette smokers, many African American smokers demonstrate a later age of initiation. The goal of the present study was to examine African American late-onset smoking (ie, regular smoking beginning at age 18 or later) and determine whether late-onset (vs. early-onset) smoking is protective in terms of quit rates and health outcomes. Methods We used data from the National Survey of Midlife Development in the United States (MIDUS) because the wide age range of participants (20-75 at baseline) allowed the examination of smoking cessation and mortality incidence across the lifespan. Results Consistent with previous research, results indicated a later average age of smoking onset among African Americans, compared to whites. Disentangling effects of race from age-of-onset, we found that the cessation rate among late-onset African American smokers was 33%, whereas rates for early-onset African American smokers and early- and late-onset white smokers ranged from 52% to 57%. Finally, results showed that among white, low-socioeconomic status (SES) smokers, the hazard rate for mortality was greater among early- versus late-onset smokers; in contrast, among African American smokers (both low- and high-SES) hazard rates for mortality did not significantly differ among early- versus late-onset smokers. Conclusions Although late (vs. early) smoking onset may be protective for whites, the present results suggest that late-onset may not be similarly protective for African Americans. Tobacco programs and regulatory policies focused on prevention should expand their perspective to include later ages of initiation, in order to avoid widening tobacco-related health disparities. Implications This study indicates that late-onset smoking is not only the norm among African American adult smokers, but that late- versus early-onset smoking (ie, delaying onset) does not appear to afford any benefits for African Americans in terms of cessation or mortality. These results suggest that prevention and intervention efforts need to consider individual groups (not just overall averages) and that tobacco control efforts need to be targeted beyond the teenage years. Tobacco programs and regulatory policies focused on prevention should expand their perspective to include later ages of initiation, to avoid widening tobacco-related health disparities.

The WT1 gene encodes a zinc finger transcription factor important for normal kidney development. WT1 is a suppressor for Wilms tumour development and an oncogene for diverse malignant tumours. We recently established cell lines from primary Wilms tumours with different WT1 mutations. To investigate the function of mutant WT1 proteins, we performed WT1 knockdown experiments in cell lines with a frameshift/extension (p.V432fsX87 = Wilms3) and a stop mutation (p.P362X = Wilms2) of WT1, followed by genome-wide gene expression analysis. We also expressed wild-type and mutant WT1 proteins in human mesenchymal stem cells and established gene expression profiles. A detailed analysis of gene expression data enabled us to classify the WT1 mutations as gain-of-function mutations. The mutant WT1(Wilms2) and WT1(Wilms3) proteins acquired an ability to modulate the expression of a highly significant number of genes from the G2/M phase of the cell cycle, and WT1 knockdown experiments showed that they are required for Wilms tumour cell proliferation. p53 negatively regulates the activity of a large number of these genes that are also part of a core proliferation cluster in diverse human cancers. Our data strongly suggest that mutant WT1 proteins facilitate expression of these cell cycle genes by antagonizing transcriptional repression mediated by p53. We show that mutant WT1 can physically interact with p53. Together the findings show for the first time that mutant WT1 proteins have a gain-of-function and act as oncogenes for Wilms tumour development by regulating Wilms tumour cell proliferation.

A horizontal layer of Boussinesq fluid is known to be susceptible to vortex instability when the lower surface of the fluid is subjected to a time-periodic heating of sufficient strength. In this paper a quasi-steady technique is used to trace the stability of the layer right from a standard linear theory to the problem when the vortices are so strong so as to change the thermal profile at leading order. Furthermore, this system is used to assess the possible influence of the noise that inevitably arises in many physical and laboratory situations. Even though in many problems a fluid flow is assumed to be time-periodic with one dominant driving frequency, in practice many cases are actually contaminated by small components at higher frequencies, which are often multiples of the primary. Here we make a crude model of noise by taking the temperature of the lower surface of the fluid layer to be the sum of two time-dependent periodic functions of differing frequencies. It is shown that the presence of the second frequency can have a dramatic effect on the evolution of a vortex and only a small element of noise appears to be sufficient to generate vortices that penetrate as much as three times further into the layer compared with the situation when the noise is absent.

Lactocrine signaling is defi ned as transmission of bioactive factors from mother to offspring as a consequence of nursing. Lactocrine transmission of signaling molecules may be an evolutionarily conserved process through which bioactive factors necessary for support of neonatal development are delivered postnatally. Dependence on maternal resources for development in eutherian mammals extends into neonatal life for at least that period of time when nutrition is obtained solely from fi rst milk (i.e., colostrum). Data for the pig (Sus scrofa domesticus) provide evidence of lactocrine mediated effects on development of the female reproductive tract and other somatic tissues. Porcine uterine gland development, an estrogen receptor-alpha (ESR1)- dependent process, begins within 2 d of birth [postnatal day (PND) 0]. A lactocrine-driven, ESR1-mediated process was proposed as a regulatory mechanism governing onset of uterine gland development and endometrial maturation in the neonatal pig. Gilts maintained in a lactocrine-null state for 2 d from birth by milk-replacer feeding displayed altered patterns of endometrial gene expression and retarded uterine gland development by PND 14. In lactocrine-null gilts, inhibition of endometrial and cervical ESR1 and vascular endothelial growth factor (VEGFA) expression observed on PND 2 persisted to PND 14, even after gilts were returned to nursing on PND 2. Collectively, data support a role for lactocrine signaling in regulation of critical neonatal developmental events. Maternal lactocrine programming of postnatal development may help to insure healthy developmental outcomes. A systems biology approach will be required to define and understand mechanistic dynamics of lactocrine signaling events that may ultimately connect genotype to phenotype and establish the parameters of reproductive potential.

OBJECTIVES: Triazole antifungal drugs are the mainstay of treatment for patients with chronic pulmonary aspergillosis and are often used as steroid-sparing agents in patients with allergic aspergillosis. Peripheral neuropathy (PN) is a rare but reported side effect of triazole therapy in the acute management of invasive fungal infections, but its incidence during long-term triazole treatment for chronic aspergillosis is unknown. The goal of this study was to determine the incidence of PN in this context. PATIENTS AND METHODS: A retrospective cohort study was carried out to collect data on all patients with chronic aspergillosis commenced on long-term triazole therapy at the National Aspergillosis Centre in Manchester between 2007 and 2010. RESULTS: Two hundred and twenty-two patients were commenced on triazole therapy. Ten percent developed PN after an average of 4 months. Seventeen percent of patients taking itraconazole, 9% taking voriconazole and 3% taking posaconazole developed PN. This is the first report of posaconazole-induced PN. Twenty-two episodes of PN presented as numbness or tingling in the extremities, while four episodes presented as predominant leg weakness. The majority of cases were axonal, length-dependent neuropathies that recovered after triazole medication was discontinued. Two patients had non-progressive but irreversible PN. Two patients were diagnosed with mononeuropathies. CONCLUSIONS: A 10% incidence of PN was observed for patients commenced on triazole therapy for chronic aspergillosis. Patients on long-term triazole therapy should be monitored for neurological symptoms. If PN is suspected, diagnosis should include nerve conduction studies, exclusion of other causes and consideration of dose reduction or cessation of therapy.

In animals, microRNAs (miRNAs) generally repress gene expression by binding to sites in the 3'-untranslated region (UTR) of target mRNAs. miRNAs have also been reported to repress or activate gene expression by binding to 5'-UTR sites, but the extent of such regulation and the factors that govern these different responses are unknown. Liver-specific miR-122 binds to sites in the 5'-UTR of hepatitis C virus (HCV) RNA and positively regulates the viral life cycle, in part by stimulating HCV translation. Here, we characterize the features that allow miR-122 to activate translation via the HCV 5'-UTR. We find that this regulation is a highly specialized process that requires uncapped RNA, the HCV internal ribosome entry site (IRES) and the 3' region of miR-122. Translation activation does not involve a previously proposed structural transition in the HCV IRES and is mediated by Argonaute proteins. This study provides an important insight into the requirements for the miR-122-HCV interaction, and the broader consequences of miRNAs binding to 5'-UTR sites.

Little has been reported on suicides among seafarers and how they have changed over time.To establish the causes, rates and trends in suicides at work among seafarers in UK merchant shipping from 1919 to 2005 and to compare suicide rates with the general UK population and with seafarers employed in non-UK shipping.Examination of seafarers' death inquiry files, death registers and death returns (for a total population of 11.90 million seafarer-years); literature reviews and national suicide statistics.The suicide rate (for suicides at work and unexplained disappearances at sea) in UK shipping fell from 40-50 per 100,000 in the 1920s to10 per 100 000 in recent years, with an interim peak during the 1960s. Suicide rates were higher for ratings (all ranks below officers) than for officers, for Lascars (Asian seafarers) than for British seafarers and for older than for younger seafarers and were typically lower than those in Asian and Scandinavian merchant fleets. The suicide rate (for suicides at work) among seafarers was substantially higher than the overall suicide rate in the general British population from 1919 to the 1970s, but following reductions in suicide mortality among seafarers, it has become more comparable since.Although merchant seafaring was previously a high-risk occupation for suicides at work, there has been a sharp fall in the suicide rate in the past 40 years. Likely reasons for this include reductions over time in long intercontinental voyages and changes over time in seafarers' lifestyles.

Background: The mitral annulus (MA) is a dynamic structure that joins the left atrium (LA) and left ventricle (LV), but it is unknown whether MA motion is coupled to the LA or the LV or neither of the two. Since a well orchestrated coordination of LA, MA and LV septal-lateral (S-L) dynamics is essential for efficient valve closure, we assessed their functional coupling in an experimental ovine model. To assess the coupling under a wide range of physiological conditions, data were acquired in normal and acutely volume depleted hearts. Methods: In 10 sheep, radiopaque markers were placed in LA, MA and LV base (LV base ). Twelve weeks postoperatively, 4-D marker coordinates were obtained by stereo videofluoroscopy (60 frames/s) before (CTRL) and during acute inferior vena caval occlusion (VCO). Septal-lateral dimensions were calculated as distances between corresponding marker pairs in the LA, MA and LV base 5 frames before end-diastole (ED - 84 ms) and at end-diastole. Dynamics during late diastole are described as changes from ED - 84 ms versus end-diastole. To study the functional coupling between LA, MA and LV base we calculated slopes during late diastole from simple linear regressions on an animal-by-animal basis. Results: During late diastole in CTRL, the LA and MA both shortened along the S-L dimension (32.9 ± 6.6 mm vs 31.0 ± 5.5 mm, p = 0.026 and 27.3 ± 3.7 mm vs 24.6 ± 4.1 mm, p = 0.005, respectively) whereas the LV base lengthened (56.2 ± 9.3 mm vs 57.3 ± 9.3 mm, p = 0.012). VCO abolished septal―lateral dynamics of LA and LV base during late diastole (27.8 ± 4.3 mm vs 27.4 ± 3.9 mm, p = 0.155 and 49.4 ± 7.7 mm vs 49.5 ± 7.5 mm, p = 0. 752, respectively) while the MA still shortened (19.0 ± 2.9 vs 18.0 ± 2.8, p = 0.042). Under CTRL conditions LA dynamics were linearly dependent from MA dynamics (average coefficient 0.57, p = 0.001), suggesting that LA and MA are functionally coupled. With acute volume depletion, MA dynamics were linearly independent from both, LA and LV (average coefficient 0.28, p = 0.159 and 0.58, p = 0.192, respectively). Conclusion: Whereas MA and LA dynamics are coupled during late diastole in hearts with normal LV volumes, presystolic mitral annular septal-lateral shortening is independent from LA and LV dynamics with acute volume depletion. A better understanding of mitral annular dynamics and their functional coupling may help improve mitral valve repair strategies.

BACKGROUND: Historically, merchant seafaring was the most hazardous occupation in Britain. However, fatal accident rates have fallen sharply in the last 30 years. AIMS: To establish the causes of all fatal accidents and their trends among seafarers who were employed in UK merchant shipping from 1919 to 2005 and to compare with those in the general workforce and in other industries. METHODS: A historical study, based on examinations of death inquiry files from 1976 to 2005 and official mortality returns from 1919 to 1975, with a total population of 11.90 million seafarer-years at risk. RESULTS: From 1919 to 2005, there were 17,386 deaths from accidents in UK shipping, 6,074 from shipping disasters and 11,312 from personal accidents. Over time, there were large reductions in mortality rates for all the main types of fatal accident, except accidents on deck. Major causes of mortality from shipping disasters were vessels foundering in typhoons, storms and severe gales, explosions in cargo holds and collisions in poor visibility. Fatal accident rates were higher among British seafarers than among Lascars. The relative risk of an accident in UK shipping-compared with the general British workforce-was similar in 2001 to that in 1961. CONCLUSIONS: There have been major improvements in health and safety that have led to substantial reductions in fatal accident rates in UK merchant shipping throughout most of the last 90 years. This mirrors comparable improvements in the fatal accident rate among the general workforce of Great Britain. Language: en

The regulation of early follicular growth and development involves a complex interaction of autocrine, paracrine, and endocrine signals. The ability of these factors to regulate follicle growth may depend in part on the extent of vascular delivery to and perfusion of the ovary. Vascular endothelial growth factor A (VEGFA) is a major regulator of vascular physiology in the ovary. VEGFA is produced in numerous ovarian compartments and likely plays a role in the regulation of all phases of follicular growth, from preantral through preovulatory. The aim of the present study was to further evaluate the role of VEGF in early follicle growth by neutralization of endogenous VEGF or VEGF receptors. Adult mice were injected systemically and prepubertal mice were injected directly under the ovarian bursa with antibodies designed to neutralize VEGF or block interaction with its receptors in the ovary. Both systemic and intrabursal injections of VEGF antibody significantly reduced the number of primordial follicles within 1-3 days after administration without affecting primary or secondary follicle numbers. Primordial follicle numbers were not different from control levels by 30 days after VEGFA antibody administration. Administration of antibodies to the kinase domain receptor (KDR), but not the FMS-like tyrosine receptor (FLT1), for VEGF also resulted in a significant decrease in primordial follicles. These data suggest that VEGF plays a vital role in the maintenance and growth of the primordial follicle pool.

As part of a larger comparative phylogeographical study of Philippine fruit bats, I used fragments of the mitochondrial genes cytochrome b and ND2 to investigate phylogeography and diversification in Haplonycteris fischeri, a pteropodid bat endemic to the Philippines but widespread within the archipelago. Genetic diversity in H. fischeri was extremely high in these commonly studied genes, with 101 unique haplotypes in 123 sequenced individuals, although small, continuously isolated islands had less diversity than had large island complexes. Seven monophyletic groups and one paraphyletic group were restricted to individual islands, groups of islands, or parts of islands. Each Pleistocene island complex had a single resident monophyletic lineage; these five groups were separated by approximately 6-8% sequence divergence and apparently have been diverging for 4-6 Myr. Within island groups, monophyletic lineages on some individual islands suggest that current ocean channels have also been barriers to gene flow; in some cases, multiple allopatric clades were present on single islands. Basal divergence dates were estimated to be in the early Pliocene, and most diversification was apparently connected to the ongoing geological evolution of the Philippines. Geological history and current geography interact with ecology to cause substantial genetic differentiation within this primary forest-specialist species.

Background The aim of this study was to investigate trends in population-based mortality, hospital admission and case fatality rates for abdominal aortic aneurysm (AAA) from 1979 to 1999. Methods This was an analysis of routine statistics from 79 495 death certificates in England and Wales and 3217 hospital inpatient admissions in the Oxford Region. Results Mortality rates for all AAAs increased between 1979 and 1999 from 13 to 25 per million in women and from 80 to 115 per million in men. Admission rates increased in the same time interval from three to 22 admissions per million per year in women, and from 52 to 149 per million per year in men. Case fatality rates for all non-ruptured AAAs that were operated on decreased from 25·8 to 9·0 per cent and for all ruptured AAAs from 69·9 to 54·4 per cent. Conclusion Mortality rates and hospital admission rates for AAA rose in men and even more so in women between 1979 and 1999. Perioperative mortality for ruptured AAA declined a little during the study but nonetheless was still very high at the end. This reinforces the importance of detecting and treating AAA before rupture occurs.

TFIIB plays a pivotal role during assembly of the RNA polymerase II transcription preinitiation complex. TFIIB is composed of two domains that engage in an intramolecular interaction that can be disrupted by the VP16 activation domain. In this study, we describe a novel human TFIIB derivative harbouring two point mutations in the highly conserved N-terminal charged cluster domain. This mutant, TFIIB R53E:R66E, exhibits an enhanced affinity in its intramolecular interaction when compared with wild-type TFIIB. Consistent with this, the mutant displays a significantly reduced affinity for VP16. However, its ability to complex with TATA-binding protein at a model promoter is equivalent to that of wild-type TFIIB. Furthermore, this TFIIB derivative is able to support high order preinitiation complex assembly in the absence of an activator. Strikingly though, an activator fails to recruit the TFIIB mutant to the promoter. Taken together, our results show that a TFIIB conformational change is critical for the formation of activator-dependent transcription complexes.

The Naval Health Research Center developed and used a systematic process to review Marine Corps dental supply requirements. The approach (1) identified the dental procedures required to treat patients with dental conditions and (2) determined the consumable supplies and equipment needed to complete each procedure. By establishing the clinical requirement for each item pushed forward, the Naval Health Research Center model significantly reduced weight, cubic volume, and cost while enhancing far-forward dental capability. This effort produced a database that clarifies the relationship among dental conditions, dental procedures, consumables, and equipment when conducting authorized dental allowance list reviews, determining training requirements, and configuring supplies for future deployments.

Does obesity affect mental health? Two waves of data from a panel study of community residents 50 years and older were used to investigate the association between obesity and eight indicators of mental health: happiness, perceived mental health, life satisfaction, positive affect, negative affect, optimism, feeling loved and cared for, and depression. For none of the eight mental health outcomes examined did we observe a protective effect for obesity. Either no association was observed between obesity and psychological functioning, or the obese were worse off. Using 1994-1999 prospective data, the obese were at increased risk for poorer mental health on five of the outcomes examined using bivariate analyses. However, controlling for mental health problems at baseline and using statistical controls for covariates, the increased relative risk was limited to depression. There has been sufficient disparity of results thus far to justify further research on this question.

Background and Purpose. This study investigated the relationship between balance measures and ankle range of motion (ROM) in community-dwelling elderly women with no health problems. Identification of modifiable factors associated with balance may enable clinicians to design treatments to help reduce the risk of falls in elderly people. Subjects. The sample consisted of 34 women between the ages of 64 and 87 years (X̄=74.7, SD=6.0). Methods. Goniometry was used to determine bilateral ankle active-assistive range of motion (AAROM) and passive range of motion. Balance capabilities were measured with the Functional Reach Test (FRT) and the Tinetti Performance-Oriented Mobility Assessment (POMA). Balance data for the FRT, POMA balance subtest, POMA gait subtest, and POMA total score were correlated with ankle ROM using the Pearson product moment correlation coefficient (PCC). Results. Correlations between ROM and balance scores were found, ranging from .29 to .63. The POMA gait subtest and FRT resulted in higher correlations with ROM than did the POMA balance subtest (left total AAROM PCC=.63, .51, and .31). Correlations using composite ankle ROM scores were higher than individual motions. The strongest correlation existed between bilateral, total ankle AAROM and the POMA gait subtest scores (PCC=.63) Conclusion and Discussion. Correlations exist between ankle ROM and balance in community-dwelling elderly women. Additional research is needed to determine whether treatment directed at increasing ankle ROM can improve balance.

Two waves of data from a community-based study (Alameda County Study, 1994-1995) were used to investigate the association between obesity and depression. Depression was measured with 12 items covering Diagnostic and Statistical Manual of Mental Disorders: DSM-IV diagnostic criteria for major depressive episode. Following US Public Health Service criteria, obese subjects were defined as those with body mass index scores at the 85th percentile or higher. Covariates were age, sex, education, marital status, social isolation and social support, chronic medical conditions, functional impairment, life events, and financial strain. Results were mixed. In cross-sectional analyses, greater odds for depression in 1994 were observed for the obese, with and without adjustment for covariates. When obesity and depression were examined prospectively, controlling for other variables, obesity in 1994 predicted depression in 1995 (odds ratio (OR) = 1.73, 95% confidence interval (CI): 1.04, 2.87). When the data were analyzed with obesity defined as a body mass index of > or = 30, cross-sectional results were the same. However, the prospective multivariate analyses were not significant (OR = 1.43, 95% CI: 0.85, 2.43). Although these data do not resolve the role of obesity as a risk factor for depression, overall the results suggest an association between obesity and depression. The authors found no support for the "jolly fat" hypothesis (obesity reduces risk of depression). However, there has been sufficient disparity of results thus far to justify continued research.

Background Conventional treatment of mycotic aneurysms or graft infections of the aortoiliac segment by in situ or extra-anatomic prosthetic reconstruction has a high mortality and morbidity rate, with a substantial risk of persistent graft infection. The use of autologous vein may reduce this. Methods Eleven patients with suprainguinal arterial infections including two with mycotic aortic aneurysms, four with aortic graft infections, four infected femorofemoral grafts and an infected axillofemoral graft were treated by debridement and in situ reconstruction with autologous superficial femoropopliteal vein. All patients received appropriate antibiotic therapy and were followed by regular postoperative duplex imaging. Preoperative femoral vein duplex imaging was performed in eight of the 11 patients. Results Ten of the 11 patients survived with a functioning graft and without limb loss or evidence of infection at 4–33 months. One patient died from myocardial infarction after operation. Three patients had minor swelling of one leg. Four patients required subsequent angioplasty of anastomotic stenoses detected by duplex surveillance. Conclusion Superficial femoropopliteal vein is an excellent conduit for suprainguinal reconstruction in the presence of infection. Duplex imaging is useful for confirming the suitability of deep veins for use as a graft and for postoperative surveillance.

Exposure to disease or injury often results in impaired reproductive activity accompanied by decreased testosterone levels. After immune activation, the cytokine interleukin 1-β (IL-1β) circulates in high concentrations, and its exogenous administration evokes many of the sequelae of immune activation. Previously, we have shown that the administration of this cytokine into the cerebral ventricles blunts hCG-stimulated testosterone secretion. This effect, though time-dependent, occurs before significant elevation of interleukin 6 in the peripheral bloodstream, does not depend on adrenal activation, and/or changes in LH concentrations, leading us to hypothesize a direct connection between the brain and testis. To explore this mechanism further, we isolated testicular tissue from rats treated intracerebroventricularly (icv) with vehicle or IL-1β 30 or 90 min before they were killed. We found that in vivo cytokine treatment blunted ex vivo testosterone secretion in response to hCG, showing that the mechanism is independent of circulating cytokines. Though hCG binding was moderately reduced by icv IL-1β in these preparations, the extent of this inhibition did not explain our observations. As the first acutely and hormonally regulated step in the biosynthesis of testosterone is the transfer of cholesterol into the inner mitochondrial membrane, which is mediated by steroidogenic acute regulatory (StAR) protein, we hypothesized that the rapid effects of icv IL-1β on testicular responsiveness to hCG might be due to reduced levels of StAR. We report here that StAR protein was indeed reduced in Leydig cells isolated from rats treated in vivo with IL-1β. Furthermore, treatment with a water-permeable form of cholesterol that bypasses the requirement for StAR partially restored hCG-stimulated testosterone secretion from testes isolated from rats treated icv with IL-1β. Taken together, our data indicate that StAR plays a role in the suppression of testicular function evoked by central administration of IL-1β.

Slowing the expansion of the range of the gypsy moth, Lymantria dispar (L.), in North America will reduce the area affected by gypsy moth populations in the future and hence may be economically justified. The rate of range expansion can be reduced by eradication of isolated gypsy moth infestations in a barrier zone that is located just beyond the expanding population front and is slowly shifted in the direction of population spread. We developed a model to optimize the allocation of resources for monitoring and treatment of isolated colonies in a barrier zone. Model parameters were estimated using data collected in the central Appalachian Mountains. The model predicted that the cost of slowing population spread is minimized when the density of pheromone traps and eradication activity within the barrier zone decrease with increasing distance from the population front. Sensitivity analysis indicated that the output was most sensitive to the change of the maximum distance from the population front at which colonies can become established. The present value of predicted costs of all monitoring and treatment in the barrier zone were

A method for the synthesis of polypeptides using co-polymers as solid supports (called solid phase synthesis) has drawn the attention of medicinal chemists because of its utility in combinatorial chemistry and parallel synthesis. The small sample sizes and compound concentrations present unique challenges to analytical chemists. This thesis presents some results of the application of energy dispersive x-ray spectrometry (EDS) in the environmental scanning electron microscope (ESEM) to this problem. The use ofEDS in the ESEM has advantages of minimal sample size, speed and simplicity because the analyses are performed without special specimen preparation. The reaction products and intermediates of two model two-step syntheses were evaluated using EDS-ESEM. The fIrst synthetic scheme was followed by the removal of CI and addition of a S functional group in the fIrst step and by the addition of a Br functional group in the second step. The second synthesis was followed by the removal of CI in the ftrst step and the subsequent addition of a Br functional group in the fmal step. The EDS-ESEM results confIrmed that the reactions occurred as expected with the exception that some CI was present in all of the reaction products of the fIrst synthesis. The synthetic products were also evaluated by infrared microspectroscopy and by elemental analysis (ion chromatography). All three techniques gave similar qualitative analyses. In general, the results from a single bead were sufficient to characterize the whole sample. These tests demonstrate that EDS-ESEM has the potential to be a useful analytical technique in solid phase synthesis.

Data on symptoms of major depressive episodes were examined for the 1994 cohort (n = 2,417) of the Alameda County Study (mean age = 65). In addition to age, we examined gender, education, marital status, social isolation and social support, perceived physical and mental health, chronic medical conditions, functional impairment, life events, financial strain, and neighborhood quality. The point prevalence of symptoms of major depressive episodes was 6.6 percent for men and 10.1 percent for women, with a trend for prevalence to increase with age. When the effects of the other psychosocial risk factors were controlled, there were no significant age effects. Multivariate analyses demonstrated that apparent initial age effects were due almost entirely to chronic health problems and functional impairment. The implications are clear: Healthy, normal-functioning older adults are at no greater risk of depression than younger adults. Apparent age-related effects on depression are attributable to physical health problems and related disability.

Objective : To investigate whether fetal platelets in immune thrombocytopenia purpura (ITP) may be predicted by antepartum assessment. Methods : A prospective analysis was conducted of 28 pregnant women with ITP out of 8,056 deliveries. Of the 28 patients, 13 were evaluated by fetal scalp sampling and 11 were evaluated by percutaneous umbilical blood sampling (PUBS). Results : The mean fetal and maternal platelet counts prior to delivery were 146,000 and 176,000, respectively. The mean fetal and maternal platelet counts after delivery were 245,000 and 149,000, respectively. Fetal cord platelet counts could not be predicted by maternal platelet count, the presence/absence of maternal direct/indirect anti-platelet antibodies, steroid therapy, or history of splenectomy. PUBS for fetal platelet assessment correlated well with fetal postdelivery counts. Conclusions : Patients with ITP rarely exhibit complications. No antepartum characteristic enhances reliable prediction of neonatal outcome. Method of delivery should be based on obstetric guidelines.

The stability of pethidine 2.5mg/ml, and of a mixture of bupivacaine hydrochloride 1.25mg/ml and diamorphine hydrochloride 125μg/ml, in 500ml 0.9 per cent sodium chloride infusion bags was determined. Samples of the solutions were stored uncovered at room temperature, exposed to natural and artificial light, for 24 and 28 days, respectively. No colour change, crystallisation or precipitation was observed, and although the mean pH of the bupivacaine and diamorphine mixtures increased slightly, the mean pH of the pethidine samples remained essentially unchanged. The only significant (P < 0.05) change in potency was a reduction in diamorphine concentration by a mean of 8.22 per cent after 28 days, which is in accordance with other reports on diamorphine degradation. Thus pethidine 2.5mg/ml in 500ml 0.9 per cent sodium chloride infusion bags is stable for at least 24 days at room temperature, and a mixture of bupivacaine hydrochloride 1.25mg/ml and diamorphine hydrochloride 125μg/ml in 500ml 0.9 per cent sodium chloride infusion bags is stable (less than 10 per cent loss of potency) for 28 days at room temperature. Both these solutions could, therefore, be prepared in pharmacy central intravenous additive units and supplied to hospital wards as 500ml infusion bags for use in epidural analgesia following surgery. As each bag would provide nearly three days' worth of analgesic, the risk of infection and the nursing workload should both be reduced.

This paper reviews three interconnected issues that have been central to the controversial problem of describing the relationship between class and gender. First, the matter of taxonomy, and whether or not extant class schemes are suitable for the study of women's employment. Second, the question of how sex segregation in the occupational structure relates to regimes of class inequality and class mobility; more specifically, of the connections between absolute mobility rates and relative mobility chances. Finally, the attempt to identify the unit of class composition, in particular the so-called asymmetry hypothesis concerning the pattern of relationships among the class positions of spouses and the attributes that are said to comprise socio-political class formation. We argue that the last of these provides the most important strand to the debate, and present new cross-national data on the relationships between class identities, voting behaviour, and the social class standing of male and female partners. The findings for advanced capitalist societies support the conventional view that the unit of class composition is the household. However, those for post-communist states are contrary to conventional expectations, suggesting that processes of sociopolitical class formation may be different in East and West.

Examined the association between otitis media with effusion (OME) during the first 3 years of life and cognitive and academic performance and behavioral outcomes at 12 years of age in 56 socioeconomically disadvantaged children attending a research childcare program. OME history was prospectively documented from birth through 3 years during well and illness periods. Standardized tests of intelligence and academic achievement and measures of behavior were administered when children were 12 years of age. OME during early childhood was not related to intellectual performance, academic achievement, behavior, or attention. Results do not support a long-term relationship between a history of OME and later developmental outcomes. Generalizations of these findings to other populations should be done cautiously.

Mutations in the nuclear-encoded mitochondrial maintenance gene RRM2B are an important cause of familial mitochondrial disease in both adults and children and represent the third most common cause of multiple mitochondrial DNA deletions in adults, following POLG [polymerase (DNA directed), gamma] and PEO1 (now called C10ORF2, encoding the Twinkle helicase) mutations. However, the clinico-pathological and molecular features of adults with RRM2B-related disease have not been clearly defined. In this multicentre study of 26 adult patients from 22 independent families, including five additional cases published in the literature, we show that extra-ocular neurological complications are common in adults with genetically confirmed RRM2B mutations. We also demonstrate a clear correlation between the clinical phenotype and the underlying genetic defect. Myopathy was a prominent manifestation, followed by bulbar dysfunction and fatigue. Sensorineural hearing loss and gastrointestinal disturbance were also important findings. Severe multisystem neurological disease was associated with recessively inherited compound heterozygous mutations with a mean age of disease onset at 7 years. Dominantly inherited heterozygous mutations were associated with a milder predominantly myopathic phenotype with a later mean age of disease onset at 46 years. Skeletal muscle biopsies revealed subsarcolemmal accumulation of mitochondria and/or cytochrome c oxidase-deficient fibres. Multiple mitochondrial DNA deletions were universally present in patients who underwent a muscle biopsy. We identified 18 different heterozygous RRM2B mutations within our cohort of patients, including five novel mutations that have not previously been reported. Despite marked clinical overlap between the mitochondrial maintenance genes, key clinical features such as bulbar dysfunction, hearing loss and gastrointestinal disturbance should help prioritize genetic testing towards RRM2B analysis, and sequencing of the gene may preclude performance of a muscle biopsy.

Extremely cold environments are a challenge to military field feeding operations due to freezing and inadequate intakes of rations and water. The U.S. Army Research Institute of Environmental Medicine conducted a series of three cold-weather field feeding studies to test, modify, and contribute data for the development of Cold-Weather Feeding Doctrine. Conclusions from these studies show that command emphasis is essential for ration and water storage and distribution to prevent freezing, and adequate ration and water consumption to prevent weight loss and dehydration. Since any ration mix can be configured to meet cold-weather feeding requirements, the decision of which ration to use should be based on logistical support and constraints, mission requirements, and water availability.

Darier's disease is a dominantly inherited skin disorder in which there is abnormal adhesion between keratinocytes. We and others have recently mapped the disease gene to chromosome 12q23-q 24.1. In the present study we have established that the disease gene lies between the loci D12S78 and D12S79 which are 12cM apart. We have also obtained direct evidence that the disease is unlikely to result from a mutation in one of the members of the keratin gene cluster on chromosome 12q.

The objective of this study was to determine if maternal sleeping position around the time of implantation influences eventual placental implantation site. Between November 1997 and April 1999, women with singleton pregnancies between gestational ages of 15 and 20 weeks presenting for ultrasound examinations were prospectively queried regarding their usual position of sleep during early gestation. Dominant position of sleep was noted as prone, supine, right side, or left side. At ultrasound examination, placental location was categorized as (1) fundal, (2) left high, (3) right high, (4) anterior high, (5) posterior high, (6) anterior low, (7) posterior low, (8) right low, (9) left low, or (10) central low. During the 18 months of this study, data were obtained from 1,500 patients. At the time of conception, front or prone sleeping was the most common (497 of 1,500, 33.1%), followed by right side (439 of 1,500, 29.3%) and left side (360 of 1,500, 24%), with the back being the least frequent position of sleep (204 of 1,500, 13.6%). Women who usually slept supine at the time of conception and implantation were significantly more likely to have a high or fundal placental location compared with those who usually slept in the prone position (p = 0.041). In addition, women who slept exclusively on their right side early in pregnancy were significantly more likely to have a right-sided placental location compared with women who slept exclusively on their left side (p = 0.025). The data from this investigation indicate that sleeping position early in gestation may influence the ultimate placental implantation site.

The Army Field Feeding System was evaluated for its ability to provide adequate nutrition and hydration during a 10-day cold weather field exercise. Soldiers consumed the 18-Man Arctic Tray Pack Ration Module with either a wet-pack (Meal, Ready-to-Eat) or a dehydrated (Long Life Ration Packet) individual ration. Both feeding regimens were acceptable, meeting protein and micronutrients requirements. However, the soldiers consumed only 70% of their energy requirement, thus losing an average of 0.9% of body weight. This weight loss, although not excessive, underscores the importance of maintaining an adequate food intake during extended cold weather military field operations.

Nineteen male soldiers participated in a study of the effectiveness of two antiperspirants (aluminum chlorohydrate and aluminum zirconium tetrachlorohydrex glycine) in reducing foot-sweat accumulation and injuries. Each subject was tested before and after antiperspirant application, with a 1-hour treadmill march at 5.6 km/hour in a warm environment. Both antiperspirants decreased (p less than 0.05) foot-sweat accumulation over 50%. There was also a tendency, although not statistically significant, for subjects to incur fewer blisters with antiperspirant use. However, the antiperspirants also increased (p less than 0.05) the incidence of irritant dermatitis. Nevertheless, these data suggest that the application of antiperspirants to the feet has merit in reducing serious foot injuries (blisters, trench foot) exacerbated by wet feet.

There is a dichotomy between calories issued to soldiers in their daily field rations and the amounts actually consumed. Soldiers frequently consume insufficient calories to maintain body weight. A supplemental pack (740 kcal) was developed, to increase field calorie consumption, and tested with the old and new versions of the Meal, Ready-to-Eat on a 10-day field study in Alaska. Initial and final measurements included body weights, heights, blood, and urine parameters. Daily measurements included the collection of urine samples and completion of a dietary intake log. Energy intakes of the supplemented groups were 4%-11% higher (p less than 0.05) although the calorie intakes were still below the recommended 4,500 kcal/day for cold weather operations. Mean body weight loss ranged from 3.0 lb (1.7%) to 4.8 lb (2.8%). Two groups of the four groups became hypohydrated by day 3, due to low water intake, and only improved after direct intervention to increase drinking. Water and food intakes were strongly correlated (p less than 0.05). Results confirm the success of the supplemental pack as a means of increasing food intake and underscore the importance of water discipline in a cold environment.

Findings of pesticide and related chemical residues are presented for 27 065 samples of foods collected and analyzed in 10 state food laboratories over 1988 and 1989 (fiscal years (FY) 88 and 89). These laboratories conduct food regulatory programs compatible with national programs of the U.S. Food and Drug Administration. Of the findings, 6325 samples contained detectable levels of 1 or more pesticide analytes and 418 (or 1.5%) of the total number of samples were deemed to be of regulatory significance

Patients with adult periodontitis (AP) exhibit elevated serum antibody levels to Porphyromonas (Bacteroides) gingivalis; however, it is not known whether these antibodies originate from plasma cells in the local disease site or from peripheral lymphoid tissues. We studied the isotype and subclass levels and origin of antibodies to P. gingivalis fimbriae, since elevated serum anti-fimbriae responses were seen when compared with sera of healthy controls. IgG anti-fibriae titres were dominant and the subclass response was IgG3 much greater than IgG1 greater than IgG2 much greater than IgG4; however, some IgA anti-fimbriae antibodies were also seen. The IgA subclass fimbriae-specific response was mainly IgA1; however, significant IgA2 anti-fimbrae antibodies were seen. We also assessed numbers of anti-fimbriae antibody producing cells from peripheral blood mononuclear cells (PMBC) and from either healthy or inflamed gingiva of AP subjects. Gingival mononuclear cells (GMC) of AP patients exhibited high numbers of immunoglobulin-producing (spot-forming) cells (SFC) including fimbriae-specific antibody secreting cells in a pattern of IgG greater than IgA greater than greater than greater than IgM. However, low numbers of SFC were seen in GMC from healthy gingiva; further, no anti-fimbriae SFC responses were noted in healthy GMC. Although no fimbriae-specific immunoglobulin-producing cells were seen in PBMC, low numbers of antigen-specific SFC were found in pokeweed mitogen-triggered PBMC from AP subjects. Treatment of AP patients for plaque and surgical removal of inflamed gingiva resulted in significant reductions in serum anti-fimbriae responses. These studies show that AP patients exhibit brisk serum IgG and IgA subclass anti-fimbriae antibodies, whose origin appear to be the plasma cells present in the localized inflamed tissues.

Acrylonitrile (ACN) has been shown to cause tumors of the brain, stomach and Zymbal's gland in rats in several bioassays, but it has not been tested in other species. The carcinogenic risk of humans exposed to ACN is unclear. ACN is metabolized in the liver to 2-cyanoethylene oxide (CEO), which is believed to be the proximate or ultimate carcinogenic species. Therefore, the kinetics of CEO formation were studied with liver and lung microsomes from mice and humans using a GC-MS assay for CEO, and the data were compared with previously obtained kinetic parameters for rat microsomal enzymes. The rate of CEO formation by human liver microsomes was comparable to that of rat liver microsomes, but less than that of mouse liver microsomes. Liver microsomes produced more CEO than lung microsomes with all three species. CEO formation by microsomes from mice was approximately 4 times greater than that by microsomes from rats or humans, suggesting that mice would have higher CEO concentrations in blood than rats after ACN exposure. However, after oral administration of ACN, the concentration of CEO in mouse blood was one-third that in rat blood at all doses and time points examined. These results show that CEO circulates via the blood, providing exposure to distant sites. The blood concentrations of CEO do not appear to correlate with rates of microsomal CEO formation. This suggests that species differences in the detoxication of CEO may play an important role in determining circulating CEO concentrations and distant organ exposure.

Extended abstract of a paper presented at Microscopy and Microanalysis 2012 in Phoenix, Arizona, USA, July 29 – August 2, 2012.