Intravenous Nicotine Simulation of Passive Smoking to Estimate Dosage to Exposed Non-Smokers

To estimate nicotine intake from passive smoking, six subjects received slow intravenous infusions of known doses of nicotine at a steady rate over one hour. The plasma and urinary nicotine concentrations produced by the infusions were compared with those found in previous studies of non-smokers exposed to tobacco smoke, in non-smokers in the general population, and in smokers during and after smoking their first cigarette of the day. It was estimated that the average rate of nicotine absorption was 0.23 mg/hr in a group of non-smokers exposed in a poorly ventilated public house, 0.36 mg/hr in non-smokers exposed to more extreme conditions in a smoke-filled unventilated room, and that the average daily-life exposure of a sample of 188 urban non-smokers was 0.014 mg nicotine per hour. In contrast, the dose absorbed by three smokers from their first cigarette of the day averaged 1.4 mg nicotine. The results indicate that when passive exposure of non-smokers results in carbon monoxide intake equivalent to the active smoking of one cigarette, the amount of nicotine absorbed is much less - equivalent to about one third of a cigarette dose. In view of the small samples and various assumptions in deriving these estimates, they can only be viewed as approximate.     

The Nottingham Prognostic Index: five- and ten-year data for all-cause Survival within a Screened Population

Introduction

The Nottingham Prognostic Index (NPI) is an established prognostication tool in the management of breast cancers (BCs). Latest ten-year survival data have demonstrated an improved outlook for each NPI category and the latest UK five- and ten-year survival from BC has been reported to be 85% and 77%, respectively. We compared survival of each NPI category for BCs diagnosed within the national breast screening service in Wales (Breast Test Wales (BTW)) to the latest data, and reviewed its validity in unselected cases within a screened population.

Methods

All women screened between 1998 and 2001 within BTW were included. The NPI score for each cancer was calculated using the size, nodal status, and grade of the primary tumour. Survival data (all-cause) were calculated after ten years of follow-up.

Results

In the three-year screening period, 199,082 women were screened. A total of 1,712 cancers were diagnosed, and 1,546 had data available for calculating the NPI. Overall five-year and ten-year survival was 94% and 82%, respectively.

Conclusions

Overall five-year and ten-year survival (all-cause) has improved even when compared with UK data for BC-specific survival. We found that the NPI remains valid for BC treatment, and that our data provide a reference for updating the all-cause survival of women diagnosed with BCs within a screened population.     

Unilateral hypoxic pulmonary vasoconstriction in the dog, pony and miniature swine

The hypoxic pulmonary vasoconstrictor response to unilateral hypoxia was analyzed in pentobarbital anesthetized dogs (n = 5), miniature swine (n = 5), and ponies (n = 5). The left and right lungs (LL, RL) were separately ventilated with the LL exposed to inspired oxygen concentrations (CIO2) of 100%, 12%, 8% or 4%, while the RL always received a CIO2 = 100%. Pulmonary blood flow distribution was measured using 15 microns radioactive microspheres. LL PAO2, and percent pulmonary blood flow diversion (%FD) were calculated at each CIO2. At CIO2 of 4% there were significant differences (P greater than or equal to 0.05) between the %FD responses of each species (mean +/- S.E.): the %FDswine (95.1 +/- 1.3) greater than %FDpony (76.0 +/- 4.6) greater than %FDdog (50.1 +/- 9.4). For all species, the %FD was inversely related to the level of regional hypoxia, but there were marked species differences in the magnitude and sensitivity of hypoxic pulmonary vasoconstriction with the swine being the strongest responder, the pony intermediate, and the dog the weakest responder.     

Toxicity of Amphotericin B Deoxycholate-Based Induction Therapy in Patients with HIV-Associated Cryptococcal Meningitis

Amphotericin B deoxycholate (AmBd) is the recommended induction treatment for HIV-associated cryptococcal meningitis (CM). Its use is hampered by toxicities that include electrolyte abnormalities, nephrotoxicity, and anemia. Protocols to minimize toxicity are applied inconsistently. In a clinical trial cohort of AmBd-based CM induction treatment, a standardized protocol of preemptive hydration and electrolyte supplementation was applied. Changes in blood counts, electrolyte levels, and creatinine levels over 14 days were analyzed in relation to the AmBd dose, treatment duration (short course of 5 to 7 days or standard course of 14 days), addition of flucytosine (5FC), and outcome. In the 368 patients studied, the hemoglobin levels dropped by a mean of 1.5 g/dl (95% confidence interval [CI], 1.0 to 1.9 g/dl) following 7 days of AmBd and by a mean of 2.3 g/dl (95% CI, 1.1 to 3.6 g/dl) after 14 days. Serum creatinine levels increased by 37 μmol/liter (95% CI, 30 to 45 μmol/liter) by day 7 and by 49 μmol/liter (95% CI, 35 to 64μmol/liter) by day 14 of AmBd treatment. Overall, 33% of patients developed grade III/IV anemia, 5.6% developed grade III hypokalemia, 9.5% had creatinine levels that exceeded 220 μmol, and 6% discontinued AmBd prematurely. The addition of 5FC was associated with a slight increase in anemia but not neutropenia. Laboratory abnormalities stabilized or reversed during the second week in patients on short-course induction. Grade III/IV anemia (adjusted odds ratio [aOR], 2.2; 95% CI, 1.1 to 4.3; P = 0.028) and nephrotoxicity (aOR, 4.5; 95% CI, 1.8 to 11; P = 0.001) were risk factors for 10-week mortality. In summary, routine intravenous saline hydration and preemptive electrolyte replacement during AmBd-based induction regimens for HIV-associated CM minimized the incidence of hypokalemia and nephrotoxicity. Anemia remained a concerning adverse effect. The addition of flucytosine was not associated with increased neutropenia. Shorter AmBd courses were less toxic, with rapid reversibility.     

Testosterone and benign prostatic hyperplasia

The use of testosterone to treat the symptoms of late-onset hypogonadal men has increased recently due to patient and physician awareness. However, concerns regarding the effect of testosterone on the prostate, in particular any possible effect on the risk of prostate cancer have prompted further research in this regard. Surprisingly, numerous retrospective or small, randomized trials have pointed to a possible improvement in male lower urinary tract symptoms (LUTS) in patients treated with testosterone. The exact mechanism of this improvement is still debated but may have a close relationship to metabolic syndrome. For the clinician, the results of these studies are promising but do not constitute high levels of evidence. A thorough clinical examination (including history, examination and laboratory testing of testosterone) should be undertaken before considering the diagnosis of late-onset hypogonadism or instigating treatment for it. Warnings still remain on the testosterone supplement product labels regarding the risk of urinary retention and worsening LUTS, and these should be explained to patients.     

Using the Coriell Personalized Medicine Collaborative Data to conduct a genome‐wide association study of sleep duration

Sleep is critical to health and functionality, and several studies have investigated the inherited component of insomnia and other sleep disorders using genome‐wide association studies (GWAS). However, genome‐wide studies focused on sleep duration are less common. Here, we used data from participants in the Coriell Personalized Medicine Collaborative (CPMC) (n = 4,401) to examine putative associations between self‐reported sleep duration, demographic and lifestyle variables, and genome‐wide single nucleotide polymorphism (SNP) data to better understand genetic contributions to variation in sleep duration. We employed stepwise ordered logistic regression to select our model and retained the following predictive variables: age, gender, weight, physical activity, physical activity at work, smoking status, alcohol consumption, ethnicity, and ancestry (as measured by principal components analysis) in our association testing. Several of our strongest candidate genes were previously identified in GWAS related to sleep duration (TSHZ2, ABCC9, FBXO15) and narcolepsy (NFATC2, SALL4). In addition, we have identified novel candidate genes for involvement in sleep duration including SORCS1 and ELOVL2. Our results demonstrate that the self‐reported data collected through the CPMC are robust, and our genome‐wide association analysis has identified novel candidate genes involved in sleep duration. More generally, this study contributes to a better understanding of the complexity of human sleep. © 2015 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.     

Increasing homogeneity in global food supplies and the implications for food security

The narrowing of diversity in crop species contributing to the world’s food supplies has been considered a potential threat to food security. However, changes in this diversity have not been quantified globally. We assess trends over the past 50 y in the richness, abundance, and composition of crop species in national food supplies worldwide. Over this period, national per capita food supplies expanded in total quantities of food calories, protein, fat, and weight, with increased proportions of those quantities sourcing from energy-dense foods. At the same time the number of measured crop commodities contributing to national food supplies increased, the relative contribution of these commodities within these supplies became more even, and the dominance of the most significant commodities decreased. As a consequence, national food supplies worldwide became more similar in composition, correlated particularly with an increased supply of a number of globally important cereal and oil crops, and a decline of other cereal, oil, and starchy root species. The increase in homogeneity worldwide portends the establishment of a global standard food supply, which is relatively species-rich in regard to measured crops at the national level, but species-poor globally. These changes in food supplies heighten interdependence among countries in regard to availability and access to these food sources and the genetic resources supporting their production, and give further urgency to nutrition development priorities aimed at bolstering food security.A shared axiom of ecology and nutrition is that, within certain ranges, diversity enhances the health and function of complex biological systems. Species diversity has been shown to stimulate productivity, stability, ecosystem services, and resilience in natural (1–5) and in agricultural ecosystems (6–13). Likewise, variation in food species contributing to diet has been associated with nutritional adequacy (14–17) and food security (18).The development of sedentary agricultural societies and further rise of modern agriculture is generally considered to have led to a decline in the total number of plant species upon which humans depend for food (19, 20), particularly the wild, semidomesticated, and cultivated vegetables and fruits, spices, and other food plants that supplemented staple crops with the provision of micronutrients and that bolstered food security historically during crop failures (21). Harlan (20) warned that

most of the food for mankind comes from a small number of crops and the total number is decreasing steadily. In the United States in the past 40 years, many vegetables and fruits have disappeared from the diet, and the trend is going on all over the world. More and more people will be fed by fewer and fewer crops.

More recent analyses of dietary transition in developing countries in association with globalization have noted increases in the diversity of plants contributing to diets locally, along with a Westernization transition in preference of energy-dense foods (i.e., animal products, plant oils, and sugars) over cereals, pulses, and vegetables, and of particular major crop plants within these food categories over traditional crops (22, 23). The impact of such changes on overall crop diversity worldwide has not been comprehensively documented, although recent changes in varietal and allelic level diversity of some crops have been investigated (24–26). Given the potential food security implications of narrowing of the diversity of crop species both in production systems and in food supplies, an assessment of the global state of crop plant species diversity is warranted.Here we examine changes in the diversity of the portfolio of crop species upon which humans primarily depend for food security in regard to calories, protein, fat, and food weight. Using national per capita food supply data published by the Food and Agriculture Organization (FAO) of the United Nations, we analyzed trends in the richness, abundance, and composition of measured crop commodities in the food supplies of 152 countries comprising 98% of the world’s population from 1961 to 2009.     

Evolving specialization of the arthropod nervous system

The diverse array of body plans possessed by arthropods is created by generating variations upon a design of repeated segments formed during development, using a relatively small "toolbox" of conserved patterning genes. These attributes make the arthropod body plan a valuable model for elucidating how changes in development create diversity of form. As increasingly specialized segments and appendages evolved in arthropods, the nervous systems of these animals also evolved to control the function of these structures. Although there is a remarkable degree of conservation in neural development both between individual segments in any given species and between the nervous systems of different arthropod groups, the differences that do exist are informative for inferring general principles about the holistic evolution of body plans. This review describes developmental processes controlling neural segmentation and regionalization, highlighting segmentation mechanisms that create both ectodermal and neural segments, as well as recent studies of the role of Hox genes in generating regional specification within the central nervous system. We argue that this system generates a modular design that allows the nervous system to evolve in concert with the body segments and their associated appendages. This information will be useful in future studies of macroevolutionary changes in arthropod body plans, especially in understanding how these transformations can be made in a way that retains the function of appendages during evolutionary transitions in morphology.