Fat mass, weight and body shape changes at menopause - causes and consequences: a narrative review.

In addition to age-related weight gain, menopause adds additional challenges for women with the occurrence of significant metabolic alterations and central and visceral fat redistribution. The changes in body composition then influence risks of cardiovascular disease, metabolic disruption, cancer, fracture, lung disease, sexual dysfunction, mental health disorders and dementia. They may also heighten the severity of vasomotor symptoms. Treatment of these changes requires a flexible long-term strategy. This narrative review explores the pathogenesis of the metabolic changes at menopause and effective management options.

A Photoactivated Protein Degrader for Optical Control of Synaptic Function.

Hundreds of proteins determine the function of synapses, and synapses define the neuronal circuits that subserve myriad brain, cognitive, and behavioral functions. It is thus necessary to precisely manipulate specific proteins at specific sub-cellular locations and times to elucidate the roles of particular proteins and synapses in brain function. We developed PHOtochemically TArgeting Chimeras (PHOTACs) as a strategy to optically degrade specific proteins with high spatial and temporal precision. PHOTACs are small molecules that, upon wavelength-selective illumination, catalyze ubiquitylation and degradation of target proteins through endogenous proteasomes. Here we describe the design and chemical properties of a PHOTAC that targets Ca 2+ /calmodulin-dependent protein kinase II alpha (CaMKIIα), which is abundant and crucial for baseline synaptic function of excitatory neurons. We validate the PHOTAC strategy, showing that the CaMKIIα-PHOTAC is effective in mouse brain tissue. Light activation of CaMKIIα-PHOTAC removed CaMKIIα from regions of the mouse hippocampus only within 25 µm of the illuminated brain surface. The optically-controlled degradation decreases synaptic function within minutes of light activation, measured by the light-initiated attenuation of evoked field excitatory postsynaptic potential (fEPSP) responses to physiological stimulation. The PHOTACs methodology should be broadly applicable to other key proteins implicated in synaptic function, especially for evaluating their precise roles in the maintenance of long-term potentiation and memory within subcellular dendritic domains.

Menopause status and climacteric symptoms in a birth cohort of mid-life New Zealand women.

BACKGROUND: There is little current research on the transition to natural menopause among contemporary groups of mid-life women at age 40 years. OBJECTIVE: This study reports on female members of the Christchurch Health and Development Study cohort. This research aimed to: document the menopause status, reproductive outcomes and climacteric symptoms of the women at age 40 years; examine the associations between menopause status and concurrent measures of psychosocial and economic well-being; and document the associations between menopause status and potential predictors of menopause reflecting childhood, family and individual factors prior to age 40 years. METHODS: The Christchurch Health and Development Study is a longitudinal, representative, prospective cohort of 1265 babies (630 females) born in New Zealand in 1977. At age 40 years, 470 women (who had not experienced surgical menopause) were interviewed on their menopause status, climacteric symptoms and associated factors. RESULTS: The majority of women were premenopausal, around 20% were perimenopausal and 2% were postmenopausal. Statistically significant associations were found reflecting higher rates of diagnosed reproductive disorder, climacteric symptoms, low occupational status, non-heterosexual sexuality and exposure to childhood sexual abuse amongst both perimenopausal and postmenopausal women at age 40 years. CONCLUSION: These data will inform directions for future data collection and analyses.

Broadening the ecology of fear: non-lethal effects arise from diverse responses to predation and parasitism.

Research on the 'ecology of fear' posits that defensive prey responses to avoid predation can cause non-lethal effects across ecological scales. Parasites also elicit defensive responses in hosts with associated non-lethal effects, which raises the longstanding, yet unresolved question of how non-lethal effects of parasites compare with those of predators. We developed a framework for systematically answering this question for all types of predator-prey and host-parasite systems. Our framework reveals likely differences in non-lethal effects not only between predators and parasites, but also between different types of predators and parasites. Trait responses should be strongest towards predators, parasitoids and parasitic castrators, but more numerous and perhaps more frequent for parasites than for predators. In a case study of larval amphibians, whose trait responses to both predators and parasites have been relatively well studied, existing data indicate that individuals generally respond more strongly and proactively to short-term predation risks than to parasitism. Apart from studies using amphibians, there have been few direct comparisons of responses to predation and parasitism, and none have incorporated responses to micropredators, parasitoids or parasitic castrators, or examined their long-term consequences. Addressing these and other data gaps highlighted by our framework can advance the field towards understanding how non-lethal effects impact prey/host population dynamics and shape food webs that contain multiple predator and parasite species.

Cytomegalovirus seropositivity is independently associated with cardiovascular disease in non-dialysis dependent chronic kidney disease.

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of early death in patients with chronic kidney disease (CKD). Previous work has described an association between Cytomegalovirus (CMV) seropositivity and CVD amongst patients with dialysis dependent end stage renal disease. Whether CMV seropositivity is associated with CVD in non-dialysis dependent CKD has not been established. AIM: Investigate whether past CMV infection is associated with prevalent CVD in patients with non-dialysis dependent CKD. DESIGN: A retrospective observational study using the Renal Impairment in Secondary Care cohort, a study evaluating bio-clinical determinants of outcomes in patients with progressive CKD. METHODS: We assayed cryopreserved serum samples collected at inception for anti-CMV IgG antibodies from 764 patients with stages 2 to 5 CKD (pre-dialysis) and investigated its relationship with prevalent CVD. RESULTS: Median estimated glomerular filtration was 24 ml/min/1.73 m2 (IQR 19-32). Sixty-eight percent of patients were CMV seropositive. CMV seropositivity was associated with older age, non-Caucasian ethnicity, diabetes and higher social deprivation index score. On univariable analysis, CMV seropositivity correlated with higher systolic blood pressure (P = 0.044), prevalent CVD (P < 0.001), ischaemic heart disease (P < 0.001) and cerebrovascular disease (P = 0.022). On multivariable analysis, CMV seropositive patients nearly twice as likely to have CVD compared to seronegative patients [Odds Ratio (OR) = 1.998, CI 1.231-3.242, P = 0.005]. CONCLUSIONS: In patients with non-dialysis CKD, CMV seropositivity is independently associated with a higher prevalence of CVD.

Dorsal hippocampal damage disrupts the auditory context-dependent attenuation of taste neophobia in mice.

Rodents exhibit neophobia for novel tastes, demonstrated by an initial reluctance to drink novel-tasting, potentially-aversive solutions. Taste neophobia attenuates across days if the solution is not aversive, demonstrated by increased consumption as the solution becomes familiar. This attenuation of taste neophobia is context dependent, which has been demonstrated by maintained reluctance to drink the novel tasting solution if the subject has to drink it after being brought to a novel environment. This spatial context-dependent attenuation of taste neophobia has been described and likely depends on the integrity of the dorsal hippocampus because this brain area is crucial for representing space and spatial context associations, but is unnecessary for processing taste memories per se. Whether changing the non-spatial auditory context causes a similar effect on attenuation of taste neophobia and the potential role of the dorsal hippocampus in processing this decidedly non-spatial information has not been determined. Here we demonstrate that changing the non-spatial auditory context affects the attenuation of taste neophobia in mice, and investigate the consequence of hippocampal lesion. The results demonstrate that the non-spatial auditory context-dependent attenuation of taste neophobia in mice is lost following NMDA excitotoxic lesions of the CA1 region of the dorsal hippocampus. These findings demonstrate that the dorsal hippocampus is crucial for the modulation non-associative taste learning by auditory context, neither of which provide information about space.

Infections on the move: how transient phases of host movement influence disease spread.

Animal movement impacts the spread of human and wildlife diseases, and there is significant interest in understanding the role of migrations, biological invasions and other wildlife movements in spatial infection dynamics. However, the influence of processes acting on infections during transient phases of host movement is poorly understood. We propose a conceptual framework that explicitly considers infection dynamics during transient phases of host movement to better predict infection spread through spatial host networks. Accounting for host transient movement captures key processes that occur while hosts move between locations, which together determine the rate at which hosts spread infections through networks. We review theoretical and empirical studies of host movement and infection spread, highlighting the multiple factors that impact the infection status of hosts. We then outline characteristics of hosts, parasites and the environment that influence these dynamics. Recent technological advances provide disease ecologists unprecedented ability to track the fine-scale movement of organisms. These, in conjunction with experimental testing of the factors driving infection dynamics during host movement, can inform models of infection spread based on constituent biological processes.

2016 IMS Recommendations on women's midlife health and menopause hormone therapy.

The International Menopause Society (IMS) has produced these new 2016 recommendations on women's midlife health and menopause hormone therapy (MHT) to help guide health-care professionals in optimizing their management of women in the menopause transition and beyond. The term MHT has been used to cover therapies including estrogens, progestogens and combined regimens. For the first time, the 2016 IMS recommendations now include grades of recommendations, levels of evidence and 'good practice points', in addition to section-specific references. Where possible, the recommendations are based on and linked to the evidence that supports them, unless good-quality evidence is absent. Particular attention has been paid to published evidence from 2013 onwards, the last time the IMS recommendations were updated. Databases have been extensively searched for relevant publications using key terms specific to each specialist area within menopause physiology and medicine. Information has also been drawn from international consensus statements published by bodies such as the IMS, the European Menopause and Andropause Society and the North American Menopause Society. The recommendations have been produced by experts derived mainly from the IMS, with the assistance of key collaborators where deemed advantageous. In preparing these international recommendations, experts have taken into account geographical variations in medical care, prevalence of diseases, and country-specific attitudes of the public, medical community and health authorities towards menopause management. The variation in availability and licensing of MHT and other products has also been considered.

Time trends in breast cancer and menopause hormone therapy use in New Zealand.

OBJECTIVE: The publication of preliminary findings from the Women's Health Initiative (WHI) Study in 2002 suggested an increased risk of breast cancer among users of menopause hormone therapy (MHT). This resulted world-wide in a rapid and significant decline in the use of hormone therapy. It was later claimed that breast cancer incidence rates had fallen as a result of lower rates of hormone therapy use. Our aim was to investigate whether there was an association between changes in the use of hormone therapy and rates of breast cancer diagnosis in New Zealand subsequent to the publication of the WHI. METHOD: Validated prescription usage data along with breast cancer screening and cancer registration data were accessed. Time trends extending for 8 years after the publication of the WHI were assessed. RESULTS: The use of hormone therapy for managing menopausal symptoms fell by about 70% following the controversy about its safety. Breast cancer registration rates among women aged 50-59 years had started to fall in advance of this change in prescribing. Changes in other age groups appear to coincide with changes in the screening eligibility for the national breast screening program rather than use of hormone therapy. CONCLUSION: The time trend analysis does not support an association between changes in hormone therapy use and the incidence rate of breast cancer.

Reported co-infection deaths are more common in early adulthood and among similar infections.

BACKGROUND: Many people have multiple infections at the same time, but the combined contribution of those infections to disease-related mortality is unknown. Registered causes of death offer a unique opportunity to study associations between multiple infections. METHODS: We analysed over 900,000 death certificates that reported infectious causes of death. We tested whether reports of multiple infections (i.e., co-infections) differed across individuals' age or sex. We also tested whether each pair of infections were reported together more or less often than expected by chance, and whether this co-reporting was associated with the number of biological characteristics they had in common. RESULTS: In England and Wales, and the USA, 10 and 6 % respectively of infection-related deaths involved co-infection. Co-infection was reported reported most often in young adults; 30 % of infection-related deaths among those aged 25-44 from the USA, and 20 % of infection-related deaths among those aged 30-39 from England and Wales, reported multiple infections. The proportion of infection-related deaths involving co-infection declined with age more slowly in males than females, to less than 10 % among those aged >65. Most associated pairs of infections co-occurred more often than expected from their frequency of being reported alone (488/683 [71 %] in the USA, 129/233 [55 %] in England and Wales), and tended to share biological characteristics (taxonomy, transmission mode, tropism or timescale). CONCLUSIONS: Age, sex, and biologically similar infections are associated with death from co-infection, and may help indicate patients at risk of severe co-infection.

Intravenous antiarrhythmic doses of lidocaine increase the survival rate of CA1 neurons and improve cognitive outcome after transient global cerebral ischemia in rats.

Brain ischemia is often a consequence of cardiac or neurologic surgery. Prophylactic pharmacological neuroprotection would be beneficial for patients undergoing surgery to reduce brain damage due to ischemia. We examined the effects of two antiarrhythmic doses of lidocaine (2 or 4 mg/kg) on rats in a model of transient global cerebral ischemia. The occlusion of both common carotid arteries combined with hypotension for 10 min induced neuronal loss in the CA1 region of the hippocampus (18±12 vs. 31±4 neurons/200 µm linear distance of the cell body layer, X±SD; P<0.01). Lidocaine (4 mg/kg) 30 min before, during and 60 min after ischemia increased dorsal hippocampal CA1 neuronal survival 4 weeks after global cerebral ischemia (30±9 vs. 18±12 neurons/200 µm; P<0.01). There was no significant cell loss after 10 min of ischemia in the CA3 region, the dentate region or the amygdalae; these regions were less sensitive than the CA1 region to ischemic damage. Lidocaine not only increased hippocampal CA1 neuronal survival, but also preserved cognitive function associated with the CA1 region. Using an active place avoidance task, there were fewer entrances into an avoidance zone, defined by relevant distal room-bound cues, in the lidocaine groups. The untreated ischemic group had an average, over the nine sessions, of 21±12 (X±SD) entrances into the avoidance zone per session; the 4 mg/kg lidocaine group had 7±8 entrances (P<0.05 vs. untreated ischemic) and the non-ischemic control group 7±5 entrances (P<0.01 vs. untreated ischemic). Thus, a clinical antiarrhythmic dose of lidocaine increased the number of surviving CA1 pyramidal neurons and preserved cognitive function; this indicates that lidocaine is a good candidate for clinical brain protection.

Shadowing the actions of a predator: backlit fluorescent microscopy reveals synchronous nonbinary septation of predatory Bdellovibrio inside prey and exit through discrete bdelloplast pores.

The Bdellovibrio are miniature "living antibiotic" predatory bacteria which invade, reseal, and digest other larger Gram-negative bacteria, including pathogens. Nutrients for the replication of Bdellovibrio bacteria come entirely from the digestion of the single invaded bacterium, now called a bdelloplast, which is bound by the original prey outer membrane. Bdellovibrio bacteria are efficient digesters of prey cells, yielding on average 4 to 6 progeny from digestion of a single prey cell of a genome size similar to that of the Bdellovibrio cell itself. The developmental intrabacterial cycle of Bdellovibrio is largely unknown and has never been visualized "live." Using the latest motorized xy stage with a very defined z-axis control and engineered periplasmically fluorescent prey allows, for the first time, accurate return and visualization without prey bleaching of developing Bdellovibrio cells using solely the inner resources of a prey cell over several hours. We show that Bdellovibrio bacteria do not follow the familiar pattern of bacterial cell division by binary fission. Instead, they septate synchronously to produce both odd and even numbers of progeny, even when two separate Bdellovibrio cells have invaded and develop within a single prey bacterium, producing two different amounts of progeny. Evolution of this novel septation pattern, allowing odd progeny yields, allows optimal use of the finite prey cell resources to produce maximal replicated, predatory bacteria. When replication is complete, Bdellovibrio cells exit the exhausted prey and are seen leaving via discrete pores rather than by breakdown of the entire outer membrane of the prey.

Responses to a conjugate pneumococcal vaccine in preterm infants immunized at 2, 3, and 4 months of age.

Preterm infants are at an increased risk of invasive pneumococcal disease infection and, additionally, have a diminished response to Haemophilus influenzae type b (Hib) conjugate vaccines. There are little data examining the response of preterm infants to a seven-valent pneumococcal conjugate vaccine (PCV7). We examined the responses of preterm infants immunized at 2, 3, and 4 months of age to PCV7. A total of 133 preterm and 54 term infants were immunized with PCV7 and the Neisseria meningitidis group C (MCC), diphtheria, tetanus, pertussis, polio, and Hib vaccines. Pneumococcal serotype-specific IgG was measured by enzyme-linked immunosorbent assay (ELISA) pre- and postimmunization and at 12 months or following a booster of PCV7. Term and preterm responses were compared using linear and logistic regression analyses. Term infants had higher preimmunization geometric mean concentrations (GMCs) for all serotypes. Preterm infants had lower postimmunization GMCs for serotype 23F. Gestational age affected postimmunization GMCs for serotypes 4, 6B, and 23F. Preterm infants were as likely to have levels of ≥0.35 µg/ml as term infants for all serotypes except 23F. The proportions of infants with titers of ≥0.35 µg/ml for all 7 serotypes were comparable between groups. A total of 28 of 29 term infants who received a booster had levels of ≥0.35 µg/ml for all serotypes. One infant had undetectable levels for serotype 6B. Of the 32 preterm infants boosted, 9 had levels of <0.35 µg/ml for 1 serotype, and 1 had levels of <0.35 µg/ml for 2 serotypes. In nonboosted infants, GMCs for all serotypes except 6B had fallen by 12 months of age. These results support the need for a booster dose in the second year of life.

Effects of Snail Density on Growth, Reproduction and Survival of Biomphalaria alexandrina Exposed to Schistosoma mansoni.

The effects of snail density on Biomphalaria alexandrina parasitized with Schistosoma mansoni were investigated. Laboratory experiments were used to quantify the impact of high density on snail growth, fecundity, and survival. Density-dependent birth rates of snails were determined to inform mathematical models, which, until now, have assumed a linear relationship between density and fecundity. The experiments show that the rate of egg-laying followed a negative exponential distribution with increasing density and this was significantly affected by exposure to parasitic infection. High density also affected the weight of snails and survival to a greater degree than exposure to parasitic infection. Although snail growth rates were initially constrained by high density, they retained the potential for growth suggesting a reversible density-dependent mechanism. These experimental data can be used to parameterise models and confirm that snail populations are regulated by nonlinear density-dependent mechanisms.

Immunogenicity of a heptavalent conjugate pneumococcal vaccine administered concurrently with a combination diphtheria, tetanus, five-component acellular pertussis, inactivated polio, and Haemophilus influenzae type B vaccine and a meningococcal group C conjugate vaccine at 2, 3, and 4 months of age.

The immunogenicities of conjugate pneumococcal vaccines have been demonstrated when they are administered at 2, 3, and 4 months of age. There is a paucity of data on the immunogenicity of this vaccine when it is administered concurrently with other vaccines in the primary immunization schedule of the United Kingdom. We immunized 55 term infants at 2, 3, and 4 months of age with the seven-valent pneumococcal conjugate vaccine (PCV7), the meningococcal group C conjugate (MCC) vaccine, and the diphtheria, tetanus, five-component acellular pertussis, inactivated polio, and Haemophilus influenzae type b (DTaP(5)/IPV/Hib-TT) vaccine. The immune responses to the H. influenzae type b (Hib), MCC, and tetanus vaccines were measured at 2, 5, and 12 months of age; and the immune responses to PCV7 were measured at 2 and 5 months and then either at 12 months or following a 4th dose of PCV7. There were increases in the geometric mean concentrations (GMCs) of all antigens postimmunization. Greater than or equal to 90% of the infants achieved putatively protective levels postimmunization for all vaccine antigens except pneumococcal serotype 6B and Hib. The GMCs of the PCV7 serotypes increased following a 4th dose, although one infant had not reached putative levels of protection against serotype 6B. In conclusion, when infants were vaccinated according to the schedule described above, they had lower postprimary immunization responses to Hib, meningococcus group C capsular polysaccharide, and pneumococcal serotype 6B than the responses demonstrated by use of the other schedules. Despite this finding, there was a good response following a 4th dose of PCV7.

Rates of very preterm birth in Europe and neonatal mortality rates.

OBJECTIVE: To estimate the influence of variation in the rate of very preterm delivery on the reported rate of neonatal death in 10 European regions. DESIGN: Comparison of 10 separate geographically defined European populations, from nine European countries, over a 1-year period (7 months in one region). PARTICIPANTS: All births that occurred between 22(+0) and 31(+6) weeks of gestation in 2003. MAIN OUTCOME MEASURE: Neonatal death rate adjusted for rate of delivery at this gestation. RESULTS: Rate of delivery of all births at 22(+0)-31(+6) weeks of gestation and live births only were calculated for each region. Two regions had significantly higher rates of very preterm delivery per 1000 births: Trent UK (16.8, 95% CI 15.7 to 17.9) and Northern UK (17.1, 95% CI 15.6 to 18.6); group mean 13.2 (95% CI 12.9 to 13.5). Four regions had rates significantly below the group average: Portugal North (10.7, 95% CI 9.6 to 11.8), Eastern and Central Netherlands (10.6, 95% CI 9.7 to 11.6), Eastern Denmark (11.2, 95% CI 10.1 to 12.4) and Lazio in Italy (11.0, 95% CI 10.1 to 11.9). Similar trends were seen in live birth data. Published rates of neonatal death for each region were then adjusted by applying (a) a standardised rate of very preterm delivery and (b) the existing death rate for babies born at this gestation in the individual region. This produced much greater homogeneity in terms of neonatal mortality. CONCLUSIONS: Variation in the rate of very preterm delivery has a major influence on reported neonatal death rates.

Investigating the variations in survival rates for very preterm infants in 10 European regions: the MOSAIC birth cohort.

OBJECTIVE: To investigate the variation in the survival rate and the mortality rates for very preterm infants across Europe. DESIGN: A prospective birth cohort of very preterm infants for 10 geographically defined European regions during 2003, followed to discharge home from hospital. PARTICIPANTS: All deliveries from 22 + 0 to 31 + 6 weeks' gestation. MAIN OUTCOME MEASURE: All outcomes of pregnancy by gestational age group, including termination of pregnancy for congenital anomalies and other reasons, antepartum stillbirth, intrapartum stillbirth, labour ward death, death after admission to a neonatal intensive care unit (NICU) and survival to discharge. RESULTS: Overall the proportion of this very preterm cohort who survived to discharge from neonatal care was 89.5%, varying from 93.2% to 74.8% across the regions. Less than 2% of infants <24 weeks' gestation and approximately half of the infants from 24 to 27 weeks' gestation survived to discharge home from the NICU. However large variations were seen in the timing of the deaths by region. Among all fetuses alive at onset of labour of 24-27 weeks' gestation, between 84.0% and 98.9% were born alive and between 64.6% and 97.8% were admitted to the NICU. For babies <24 weeks' gestation, between 0% and 79.6% of babies alive at onset of labour were admitted to neonatal intensive care. CONCLUSIONS: There are wide variations in the survival rates to discharge from neonatal intensive care for very preterm deliveries and in the timing of death across the MOSAIC regions. In order to directly compare international statistics for mortality in very preterm infants, data collection needs to be standardised. We believe that the standard point of comparison should be using all those infants alive at the onset of labour as the denominator for comparisons of mortality rates for very preterm infants analysing the cohort by gestational age band.

The impact of parasite dispersal on antagonistic host-parasite coevolution.

Coevolving populations of hosts and parasites are often subdivided into a set of patches connected by dispersal. Higher relative rates of parasite compared with host dispersal are expected to lead to parasite local adaptation. However, we know of no studies that have considered the implications of higher relative rates of parasite dispersal for other aspects of the coevolutionary process, such as the rate of coevolution and extent of evolutionary escalation of resistance and infectivity traits. We investigated the effect of phage dispersal on coevolution in experimental metapopulations of the bacterium Pseudomonas fluorescens SBW25 and its viral parasite, phage SBW25Phi2. Both the rate of coevolution and the breadth of evolved infectivity and resistance ranges peaked at intermediate rates of parasite dispersal. These results suggest that parasite dispersal can enhance the evolutionary potential of parasites through provision of novel genetic variation, but that high rates of parasite dispersal can impede the evolution of parasites by homogenizing genetic variation between patches, thereby constraining coevolution.