Effects of atipamezole on selected physiologic parameters in cynomolgus macaques (Macaca fascicularis).

BACKGROUND: Atipamezole, an α-2 adrenergic receptor antagonist, reverses the α-2 agonist anesthetic effects. There is a dearth of information on the physiological effects of these drugs in cynomolgus macaques (Macaca fascicularis). We assessed atipamezole's physiologic effects. We hypothesized atipamezole administration would alter anesthetic parameters. METHODS: Five cynomolgus macaques were sedated with ketamine/dexmedetomidine intramuscularly, followed 45 min later with atipamezole (0.5 mg/kg). Anesthetic parameters (heart rate, blood pressure [systolic (SAP), diastolic (DAP), and mean (MAP) blood pressure], body temperature, respiratory rate, and %SpO2) were monitored prior to and every 10 min (through 60 min) post atipamezole injection. RESULTS: While heart rate was significantly increased for 60 min; SAP, DAP, MAP, and temperature were significantly decreased at 10 min. CONCLUSIONS: This study indicates subcutaneous atipamezole results in increased heart rate and transient blood pressure decrease. These findings are clinically important to ensure anesthetist awareness to properly support and treat patients as needed.

Perinatal outcomes among young donor oocyte recipients.

STUDY QUESTION: Is the use of donor oocytes in women <35 years of age associated with an increased risk of adverse perinatal outcomes compared to use of autologous oocytes? SUMMARY ANSWER: Among fresh assisted reproductive technology (ART) cycles performed in women under age 35, donor oocyte use is associated with a higher risk of preterm birth, low birth weight and stillbirth (when zero embryos were cryopreserved) as compared to autologous oocytes. WHAT IS KNOWN ALREADY: Previous studies demonstrated elevated risk of poor perinatal outcomes with donor versus autologous oocytes during ART, primarily among older women. STUDY DESIGN, SIZE, DURATION: Retrospective cohort study using data reported to Centers for Disease Control and Prevention's National ART Surveillance System (NASS) during the period from 2010 to 2015 in order to best reflect advances in clinical practice. Approximately 98% of all US ART cycles are reported to NASS, and discrepancy rates were <6% for all fields evaluated in 2015. PARTICIPANTS/MATERIALS, SETTING, METHODS: We included all non-banking fresh and frozen ART cycles performed between 2010 and 2015 in women under age 35 using autologous or donor eggs. Cycles using cryopreserved eggs, donated embryos or a gestational carrier were excluded. Among fresh embryo transfer cycles, we calculated predicted marginal proportions to estimate the unadjusted and adjusted risk ratios (aRRs) and 95% confidence intervals (CIs) for the association between donor versus autologous oocyte use and stillbirth, spontaneous abortion, preterm delivery and low birth weight among singleton pregnancies or births. Stillbirth models were stratified by number of embryos cryopreserved. All models were adjusted for patient and treatment characteristics. MAIN RESULTS AND THE ROLE OF CHANCE: Among the 71 720 singleton pregnancies occurring during 2010-2015, singletons resulting from donor oocytes were more likely to be preterm (15.6% versus 11.0%; aRRs 1.39: CI 1.20-1.61) and have low birth weight (11.8% versus 8.8%; aRRs 1.34; CI 1.16-1.55) than those resulting from autologous oocytes. With zero embryos cryopreserved, donor versus autologous oocyte use was associated with increased risk for stillbirth (2.1% versus 0.6%; aRRs 3.73; CI 1.96-7.11); no association with stillbirth was found when ≥1 embryo was cryopreserved (0.54% versus 0.56%; aRR 1.15; CI 0.59-2.25). LIMITATIONS, REASONS FOR CAUTION: The data come from a national surveillance system and is thus limited by the accuracy of the data entered by individual providers and clinics. There may be unmeasured differences between women using donor eggs versus their own eggs that could be contributing to the reported associations. Given the large sample size, statistically significant findings may not reflect clinically important variations. WIDER IMPLICATIONS OF THE FINDINGS: Risks of preterm birth, low birth weight and stillbirth among singleton pregnancies using donor oocytes were increased compared to those using autologous oocytes. Further study regarding the pathophysiology of the potentially increased risks among donor oocyte recipient pregnancy is warranted. STUDY FUNDING/COMPETING INTEREST(S): None. TRIAL REGISTRATION NUMBER: N/A.

Influence of clinical, societal, and treatment variables on racial differences in ER-/PR- breast cancer survival.

BACKGROUND: African American (AA) women with breast cancer have persistently higher mortality compared to whites. We evaluated racial disparities in mortality among women with estrogen receptor (ER)/progesterone receptor (PR)-negative breast cancer. METHODS: The study population included 542 women (45% AA) diagnosed with ER/PR-negative Stage I through III breast cancer treated at the Henry Ford Health System (HFHS) between 1996 and 2005. Linked datasets from HFHS, Metropolitan Detroit Cancer Surveillance System, and the U.S. Census Bureau were used to obtain demographic, socioeconomic, and clinical information. Economic deprivation was categorized using a previously validated deprivation index, which included 5 categories based on the quintile of census tract socioeconomic deprivation. Cox proportional hazards models were used to assess the relationship between race and mortality. RESULTS: AA women were more likely to have larger tumors, have higher Charlson Comorbidity Indices (CCI), and to reside in economically deprived areas. In an unadjusted analysis, AA women demonstrated a significantly higher risk of death compared to whites [hazard ratio (HR) 1.47, 95% confidence interval (CI) 1.09-2.00]. Following adjustment for clinical factors (age, stage, CCI) and treatment (radiation and chemotherapy), AA race continued to have a significant impact on mortality (HR 1.51, CI 1.10-2.08 and HR 1.63, CI 1.20-2.21). Only after adjusting for deprivation was race no longer significant (HR 1.26, CI 0.84-1.87). CONCLUSIONS: Social determinants of health play a large role in explaining racial disparities in breast cancer outcomes, especially among women with aggressive subtypes.

Evidence of Oxidative Injury in Pigs With Melanosis Coli.

Melanosis coli is a dark discoloration of the colon due to accumulation of pigment-laden macrophages in the lamina propria. Three case submissions were received where rectal discoloration was reported at slaughter in pigs from separate production systems and melanosis coli was confirmed microscopically. Tissues from affected and unaffected cohort pigs were evaluated for evidence of oxidative damage using immunohistochemical staining for 3-nitrotyrosine, 4-hyroxynonenol, and malondialdehyde. Affected colons had significantly greater immunolabeling for all 3 target compounds than unaffected colons (P ≤ .001, all analyses). Hepatic vitamin E levels were low in both affected and unaffected pigs, and there was a trend toward lower values in affected pigs. Given the limited number of slaughter-collected samples available for this investigation, further study is warranted to elucidate the possible association between low vitamin E concentrations and oxidative damage in cases of melanosis coli in pigs.

Mutations in the laminin alpha 2-chain gene (LAMA2) cause merosin-deficient congenital muscular dystrophy.

Congenital muscular dystrophies (CMDs), are heterogeneous autosomal recessive disorders. Their severe manifestations consist of early hypotonia and weakness, markedly delayed motor milestones and contractures, often associated with joint deformities. Histological changes seen in muscle biopsies consist of large variations in muscle fibre size, a few necrotic and regenerating fibres and a marked increase in endomysial collagen tissue. Diagnosis is based on clinical features and on morphological changes. In several CMD cases, we have demonstrated an absence of one of the components of the extracellular matrix around muscle fibres, the merosin M chain, now referred to as the alpha 2 chain of laminin-2 (ref.3). We localized this CMD locus to chromosome 6q2 by homozygosity mapping and linkage analysis. The laminin alpha 2 chain gene (LAMA2) maps to the same region on chromosome 6q22-23 (ref. 5). We therefore investigated LAMA2 for the presence of disease-causing mutations in laminin alpha 2 chain-deficient CMD families and now report splice site and nonsense mutations in two families leading presumably to a truncated laminin alpha 2 protein.

A novel mutation in the potassium channel gene KVLQT1 causes the Jervell and Lange-Nielsen cardioauditory syndrome.

The Jervell and Lange-Nielsen (JLN) syndrome (MIM 220400) is an inherited autosomal recessive disease characterized by a congenital bilateral deafness associated with a QT prolongation on the electrocardiogram, syncopal attacks due to ventricular arrhythmias and a high risk of sudden death. JLN syndrome is a rare disease, which seems to affect less than one percent of all deaf children. Linkage to chromosome 11p15.5 markers was found by analysing four consanguinous families. Recombinants allowed us to map the JLN gene between D11S922 and D11S4146, to a 6-cM interval where KVLQT1, a potassium channel gene causing Romano-Ward (RW) syndrome, the dominant form of long QT syndrome, has been previously localized. An homozygous deletion-insertion event (1244, -7 +8) in the C-terminal domain of this gene was detected in three affected children of two families. We found that KVLQT1 is expressed in the stria vascularis of mouse inner ear by in situ hybridization. Taken together, our data indicate that KVLQT1 is responsible for both JLN and RW syndromes and has a key role not only in the ventricular repolarization but also in normal hearing, probably via the control of endolymph homeostasis.

Mutations in the gene encoding lamin A/C cause autosomal dominant Emery-Dreifuss muscular dystrophy.

Emery-Dreifuss muscular dystrophy (EDMD) is characterized by early contractures of elbows and Achilles tendons, slowly progressive muscle wasting and weakness, and a cardiomyopathy with conduction blocks which is life-threatening. Two modes of inheritance exist, X-linked (OMIM 310300) and autosomal dominant (EDMD-AD; OMIM 181350). EDMD-AD is clinically identical to the X-linked forms of the disease. Mutations in EMD, the gene encoding emerin, are responsible for the X-linked form. We have mapped the locus for EDMD-AD to an 8-cM interval on chromosome 1q11-q23 in a large French pedigree, and found that the EMD phenotype in four other small families was potentially linked to this locus. This region contains the lamin A/C gene (LMNA), a candidate gene encoding two proteins of the nuclear lamina, lamins A and C, produced by alternative splicing. We identified four mutations in LMNA that co-segregate with the disease phenotype in the five families: one nonsense mutation and three missense mutations. These results are the first identification of mutations in a component of the nuclear lamina as a cause of inherited muscle disorder. Together with mutations in EMD (refs 5,6), they underscore the potential importance of the nuclear envelope components in the pathogenesis of neuromuscular disorders.

Cardiac myosin binding protein-C gene splice acceptor site mutation is associated with familial hypertrophic cardiomyopathy.

Familial hypertrophic cardiomyopathy (FHC) is an autosomal dominant disease characterized by a ventricular hypertrophy predominantly affecting the interventricular septum and associated with a large extent of myocardial and myofibrillar disarray. It is the most common cause of sudden death in the young. In the four disease loci found, three genes have been identified which code for beta-myosin heavy chain, cardiac troponin T and alpha-tropomyosin. Recently the human cardiac myosin binding protein-C (MyBP-C) gene was mapped to chromosome 11p11.2 (ref. 8), making this gene a good candidate for the fourth locus, CMH4 (ref. 5). Indeed, MyBP-C is a substantial component of the myofibrils that interacts with several proteins of the thick filament of the sarcomere. In two unrelated French families linked to CMH4, we found a mutation in a splice acceptor site of the MyBP-C gene, which causes the skipping of the associated exon and could produce truncated cardiac MyBP-Cs. Mutations in the cardiac MyBP-C gene likely cause chromosome 11-linked hypertrophic cardiomyopathy, further supporting the hypothesis that hypertrophic cardiomyopathy results from mutations in genes encoding contractile proteins.

Risk of renal cell carcinoma in relation to blood telomere length in a population-based case-control study.

BACKGROUND: There are few known risk factors for renal cell carcinoma (RCC). Two small hospital-based case-control studies suggested an association between short blood telomere length (TL) and increased RCC risk. METHODS: We conducted a large population-based case-control study in two metropolitan regions of the United States comparing relative TL in DNA derived from peripheral blood samples from 891 RCC cases and 894 controls. Odds ratios and 95% confidence intervals were estimated using unconditional logistic regression in both unadjusted and adjusted models. RESULTS: Median TL was 0.85 for both cases and controls (P=0.40), and no differences in RCC risk by quartiles of TL were observed. Results of analyses stratified by age, sex, race, tumour stage, and time from RCC diagnosis to blood collection were similarly null. In multivariate analyses among controls, increasing age and history of hypertension were associated with shorter TL (P<0.001 and P=0.07, respectively), and African Americans had longer TL than Caucasians (P<0.001). CONCLUSION: These data do not support the hypothesis that blood TL is associated with RCC. This population-based case-control study is, to our knowledge, the largest investigation to date of TL and RCC.

Meat-cooking mutagens and risk of renal cell carcinoma.

BACKGROUND: High-temperature cooked meat contains two families of carcinogens, heterocyclic amines (HCAs) and polycyclic aromatic hydrocarbons (PAHs). Given the kidneys' role in metabolism and urinary excretion of these compounds, we investigated meat-derived mutagens, as well as meat intake and cooking methods, in a population-based case-control study conducted in metropolitan Detroit and Chicago. METHODS: Newly diagnosed, histologically confirmed adenocarcinoma of the renal parenchyma (renal cell carcinoma (RCC)) cases (n=1192) were frequency matched on age, sex, and race to controls (n=1175). The interviewer-administered Diet History Questionnaire (DHQ) included queries for meat-cooking methods and doneness with photographic aids. Levels of meat mutagens were estimated using the DHQ in conjunction with the CHARRED database. RESULTS: The risk of RCC increased with intake of barbecued meat (P(trend)=0.04) and the PAH, benzo(a)pyrene (BaP) (multivariable-adjusted odds ratio and 95% confidence interval, highest vs lowest quartile: 1.50 (1.14, 1.95), P(trend)=0.001). With increasing BaP intake, the risk of RCC was more than twofold in African Americans and current smokers (P(interaction)<0.05). We found no association for HCAs or overall meat intake. CONCLUSION: BaP intake, a PAH in barbecued meat, was positively associated with RCC. These biologically plausible findings advocate further epidemiological investigation into dietary intake of BaP and risk of RCC.

Stroke in relation to use of raloxifene and other drugs against osteoporosis.

UNLABELLED: Prior studies have associated fatal stroke with raloxifene. In a cohort study, we found no excess risk of stroke with raloxifene; whereas, an excess risk of stroke and fatal stroke was seen with alendronate and etidronate. However, the excess risks were small. PURPOSE: We aim to study the association between use of raloxifene and other drugs against osteoporosis and risk of stroke. METHODS: This is a nationwide cohort study from Denmark. All users of bisphosphonates and other drugs against osteoporosis between 1996 and 2006 (n = 103,562) as exposed group and three age- and gender-matched controls from the general population (n = 310,683). RESULTS: Before the drugs were started, patients later initiating alendronate or raloxifene had fewer strokes than the controls. In contrast, patients who later did start clodronate have more strokes. Among the later users of other bisphosphonates, strontium ranelate or parathyroid hormone, no change in the risk of stroke was present. Patients who started raloxifene neither had an excess risk of strokes nor of fatal strokes. No dose-response relationship was present. Among users of alendronate, a decreasing overall risk of stroke was seen with increasing dose. However, for fatal strokes, the risk increased with increasing dose of alendronate. Among users of etidronate, no trend with dose was present for overall stroke risk; whereas for fatal strokes, an increasing risk was seen with increasing dose of etidronate. CONCLUSIONS: Raloxifene does not seem associated with an excess risk of strokes. The increase seen for alendronate did not seem to be causal as no classical dose-response relationship was present. The dose-response relationship for fatal strokes with alendronate and etidronate needs further examination. However, the excess risks were small and may be due to the underlying disease.

Socio-economic aspects of improved sanitation in slums: a review.

This socio-economic review provides an overview of the sanitation crisis in slum areas, and re-emphasizes the importance of sanitation. It highlights a lack of recognition of actual drivers for sanitation improvements, and the complexities in the provision of sanitation services in the context of urban slums with a mix of tenants and landlords. It elaborates how the drivers of demand for sanitation outlined in contemporary research are not universal but are rather context specific. The authors point out specific knowledge gaps for future research; for example, the need to establish a scientific basis for context-specific drivers of demand for sanitation improvements in slums, and a better understanding of associated complexities in order to set boundary conditions for achieving desired improvements.

Caregiving burden among informal caregivers of African American cancer survivors.

PURPOSE: Relatively little is known about caregivers of African American cancer survivors. Our goal was to identify the extent of burden among this group of caregivers. METHODS: Responses from 560 informal caregivers of African American participants of the Research on Cancer Survivors (ROCS) study in Detroit, MI, were analyzed including demographics, assistance provided including activities of daily living (ADLs) and instrumental activities of daily living (IADLs), time spent in caregiving, and caregiver burden (CGB). We assessed relationships between CGB and demographic variables, ADLs/IADLs, and level of care. Multivariable logistic regression determined which ADLs and IADLs were associated with high CGB. RESULTS: Over 75% of caregivers were female and 97% identified as African American. Mean age was 52.6 years. Fifty-six percent were employed outside the home, and 90% were related to the survivor. Caregivers averaged 35.7 h/week providing care, assisting with on average 2.8 ADLs and 5.0 IADLs. Despite the many hours and activities reported, no caregivers rated CGB as severe; only 4% rated it moderate to severe. ADLs associated with the top quartile of CGB were feeding and toileting; IADLs were finances, telephoning, housework, and medications. CONCLUSIONS: Caregivers for African American cancer survivors provide many hours of care, yet most describe their CGB as low. Although ADL assistance is often available through the healthcare system, assistance with IADLs presents an opportunity to lessen the burden for these caregivers and their care recipients. IMPLICATIONS FOR CANCER SURVIVORS: African American cancer survivors receive much care from informal family caregivers, who assist with multiple ADLs and IADLs. Formal IADL assistance programs, similar to those available for ADLs, would benefit both survivors and caregivers.

Family history of cancer and renal cell cancer risk in Caucasians and African Americans.

BACKGROUND: The association between renal cell carcinoma (RCC) risk and family history of cancer has not been examined with an adequate number of African Americans (AAs). METHODS: In a population-based case-control study, unconditional logistic regression was used to calculate the association between RCC risk and a family history of cancer among 1217 RCC cases and 1235 controls. RESULTS: Increased RCC risk was shown for subjects with at least one first-degree relative with kidney cancer (odds ratio=2.29; 95% confidence interval=1.31-4.00). No differences in risk were observed when analyses were stratified by race. For Caucasians, excess risk was observed among those reporting a sibling with kidney cancer, whereas for AAs, increased risk occurred among subjects reporting either a sibling or parent affected with the disease. A family history of non-renal cancers, and those related to smoking or to the von Hippel-Lindau syndrome, revealed no association with RCC risk. CONCLUSION: The RCC risk associated with a family history of kidney cancer is similar among Caucasians and AAs.

Use of bisphosphonates and raloxifene and risk of deep venous thromboembolism and pulmonary embolism.

SUMMARY: Prior studies have associated raloxifene and strontium ranelate with deep venous thromboembolism and pulmonary embolism. In a cohort study, we observed an increased risk also with the bisphosphonates. However, the increase was present already before the start of bisphosphonates pointing at an effect of the underlying condition. INTRODUCTION: We seek to study the association between use of drugs against osteoporosis and risk of deep venous thromboembolism (DVT) and pulmonary embolism (PE). METHODS: Nationwide register-based cohort study from Denmark with all users of bisphosphonates and other drugs against osteoporosis between 1996 and 2006 (n = 103,562) as cases and three age- and gender-matched controls from the general population (n = 310,683). RESULTS: Before start of a drug against osteoporosis, an increased risk of DVT/PE was present in the crude analysis for alendronate, etidronate, and risedronate. However, upon adjustment, this increase in risk disappeared. Before start of raloxifene, a decreased risk of DVT/PE was present (odds ratio (OR) = 0.53, 95% confidence interval (CI), 0.39-0.71). After start of a drug, alendronate (HR = 1.20, 95% CI, 1.00-1.43), clodronate (HR = 4.06, 95% CI, 1.47-11.2), and etidronate (HR = 1-37, 95% CI, 1.23-1.51) were all associated with an increased risk of DVT/PE, while raloxifene was only borderline, significantly associated with risk of DVT/PE (HR = 1.64, 95% CI, 0.97-2.77). No dose-response relationship was present except for alendronate, where the risk was inversely associated with dose, i.e., the risk of DVT/PE decreased with increasing average daily dose. The HR for DVT/PE was higher with clodronate and etidronate than with alendronate. Alendronate and raloxifene carried the same risk for DVT/PE. CONCLUSION: Bisphosphonates seem associated with an increased risk of DVT/PE. However, the association does not seem to be causal.

A real-world assessment of procalcitonin combined with antimicrobial stewardship in a community ICU.

PURPOSE: We evaluated the feasibility and impact of PCT-guided antibiotic duration combined with an established antibiotic stewardship program (ASP) in a community hospital intensive care unit (ICU). METHODS: We implemented daily PCT levels for ICU patients receiving antibiotics. Our protocol recommended stopping antibiotic therapy if PCT met an absolute or relative stopping threshold. We evaluated the adherence to stopping criteria within 48 h, antibiotic use [days of therapy (DOT) per 1000 patient-days (PD)], length of stay and ICU-mortality. We performed interrupted time series analysis to compare 24 months before and 12 months after implementation. RESULTS: A total of 297 antibiotic courses were monitored with PCT in 217 patients. Protocol adherence was 34% (absolute threshold: 39%, relative threshold: 12%). Antibiotic use pre-PCT was 935 DOTs/1000 PDs and post-PCT was 817 DOTs/1000 PDs (RRadj 0.73, 95% CI: 0.62 to 0.86). No statistically significant changes in clinical outcomes were noted. CONCLUSION: In the context of an established ASP in a community hospital ICU, PCT monitoring was feasible and associated with an adjusted overall decrease of 27% in antibiotic use with no adverse impact on clinical outcomes. Incorporating PCT testing to guide antibiotic duration can be successful if integrated into workflow and paired with ASP guidance.

Polarized magnetic field fluctuations at the apollo 15 site: possible regional influence on lunar induction.

High-frequency (5 to 40 millihertz) induced lunar magnetic fields, observed at the Apollo 15 site near the southeastern boundary of Mare Imbrium and the southwestern boundary of Mare Serenitatis, show a strong tendency toward linear polarization in a direction radial to the Imbrium basin and circumferential to the Serenitatis basin, a property that could be indicative of a possible regional influence on the induction.

The second-hand effects of antibiotics: communicating the public health risks of drug resistance.

Antimicrobial resistance (AMR) poses a threat to modern medicine, but there are challenges in communicating its urgency and scope and potential solutions to this growing problem. It is recognized that AMR has a 'language problem' and the way in which healthcare professionals communicate about AMR may not always resonate with patients. Many patients are unaware that antibiotics can have detrimental effects to those beyond the recipient, due to transmission of drug-resistant organisms. The overestimation of benefits and underestimation of risks helps to fuel demand for antibiotic use in situations where they may be of little or no benefit. To better communicate risks, clinicians may borrow the term 'second-hand' from efforts to reduce smoking cessation. We present several examples where antibiotics themselves have second-hand effects beyond the individual recipient in hospitals, long-term care homes and the community. Incorporation of the concept of the second-hand effects of antibiotics into patient counselling, mass messaging and future research may help facilitate a more balanced discussion about the benefits and risks of antibiotic use in order to use these agents more appropriately.

Spatially resolved characterization of heavy ion irradiated crystals using static field gradient nuclear magnetic resonance.

Static magnetic field gradient NMR has been used for one-dimensional spatial (19)F spin-lattice relaxation profile studies (resolution of the order of 10 µm) in a LiF crystal irradiated with U ions. Technical aspects of the use of large static magnetic field gradients are discussed as well as a special data acquisition mode allowing for effectively measuring spatially resolved spin-lattice relaxation rates as low as 10(-3) s(-1). In addition to the expected enhanced spin-lattice relaxation rate within the ion range, also an enhanced rate beyond the ion range has been found.

Spatially resolved characterization of Xe ion irradiated LiF crystals using static field gradient NMR.

Spatially resolved (19)F and (7)Li nuclear magnetic resonance (NMR) spin-lattice relaxation rates have been measured in LiF crystals irradiated with 1.44 GeV Xe ions at fluences from 10(10) to 10(12) ions cm(-2). In addition, the F-centre concentration has been measured by optical absorption spectroscopy and the concentration of paramagnetic centres by electron paramagnetic resonance (EPR). Within the ion range, the relaxation rate turns out to increase linearly with the concentration of paramagnetic centres but super-linearly with the F-centre concentration. Beyond the ion range, the relaxation rate is still significantly enhanced compared to non-irradiated LiF.