Primitive Old World monkey from the earliest Miocene of Kenya and the evolution of cercopithecoid bilophodonty.

Old World monkeys (Cercopithecoidea) are a highly successful primate radiation, with more than 130 living species and the broadest geographic range of any extant group except humans. Although cercopithecoids are highly variable in habitat use, social behavior, and diet, a signature dental feature unites all of its extant members: bilophodonty (bi: two, loph: crest, dont: tooth), or the presence of two cross-lophs on the molars. This feature offers an adaptable Bauplan that, with small changes to its individual components, permits its members to process vastly different kinds of food. Old World monkeys diverged from apes perhaps 30 million years ago (Ma) according to molecular estimates, and the molar lophs are sometimes incompletely developed in fossil species, suggesting a mosaic origin for this key adaptation. However, critical aspects of the group's earliest evolution remain unknown because the cercopithecoid fossil record before ∼18 Ma consists of only two isolated teeth, one from Uganda and one from Tanzania. Here we describe a primitive Old World monkey from Nakwai, Kenya, dated at ∼22 Ma, that offers direct evidence for the initial key steps in the evolution of the cercopithecoid dentition. The simple dentition and absence of bilophodonty in the Nakwai monkey indicate that the initial radiation of Old World monkeys was first characterized by a reorganization of basic molar morphology, and a reliance on cusps rather than lophs suggests frugivorous diets and perhaps hard object feeding. Bilophodonty evolved later, likely in response to the inclusion of leaves in the diet.

Can biomarkers of extracellular matrix remodelling and wound healing be used to identify high risk patients infected with SARS-CoV-2?: lessons learned from pulmonary fibrosis.

Pulmonary fibrosis has been identified as a main factor leading to pulmonary dysfunction and poor quality of life in post-recovery Severe Acute Respiratory Syndrome (SARS) survivor's consequent to SARS-Cov-2 infection. Thus there is an urgent medical need for identification of readily available biomarkers that in patients with SARS-Cov-2 infection are able to; (1) identify patients in most need of medical care prior to admittance to an intensive care unit (ICU), and; (2) identify patients post-infection at risk of developing persistent fibrosis of lungs with subsequent impaired quality of life and increased morbidity and mortality. An intense amount of research have focused on wound healing and Extracellular Matrix (ECM) remodelling of the lungs related to lung function decline in pulmonary fibrosis (PF). A range of non-invasive serological biomarkers, reflecting tissue remodelling, and fibrosis have been shown to predict risk of acute exacerbations, lung function decline and mortality in PF and other interstitial lung diseases (Sand et al. in Respir Res 19:82, 2018). We suggest that lessons learned from such PF studies of the pathological processes leading to lung function decline could be used to better identify patients infected with SARS-Co-V2 at most risk of acute deterioration or persistent fibrotic damage of the lung and could consequently be used to guide treatment decisions.

A short-term transition from a high-fat diet to a normal-fat diet before pregnancy exacerbates female mouse offspring obesity.

BACKGROUND/OBJECTIVES: Recent findings have highlighted the detrimental influence of maternal overnutrition and obesity on fetal development and early life development. However, there are no evidence-based guidelines regarding the optimal strategy for dietary intervention before pregnancy. SUBJECTS/METHODS: We used a murine model to study whether switching from a high-fat (HF) diet to a normal-fat (NF) diet (H1N group) 1 week before pregnancy could lead to in utero reprogramming of female offspring obesity; comparator groups were offspring given a consistent maternal HF group or NF group until weaning. After weaning, all female offspring were given the HF diet for either 9 or 12 weeks before being killed humanely. RESULTS: H1N treatment did not result in maternal weight loss before pregnancy. NF offsprings were neither obese nor glucose intolerant during the entire experimental period. H1N offsprings were most obese after the 12-week postweaning HF diet and displayed glucose intolerance earlier than HF offsprings. Our mechanistic study showed reduced adipocyte insulin receptor substrate 1 (IRS1) and hepatic IRS2 expression and increased adipocyte p-Ser(636/639) and p-Ser(612) of H1N or HF offspring compared with that in the NF offspring. Among all groups, the H1N offspring had lowest level of IRS1 and the highest levels of p-Ser(636/639) and p-Ser(612) in gonadal adipocyte. In addition, the H1N offspring further reduced the expression of Glut4 and Glut2, vs those of the HF offspring, which was lower compared with the NF offspring. There were also enhanced expression of genes inhibiting glycogenesis and decreased hepatic glycogen in H1N vs HF or NF offspring. Furthermore, we showed extremely higher expression of lipogenesis and adipogenesis genes in gonadal adipocytes of H1N offspring compared with all other groups. CONCLUSIONS: Our results suggest that a transition from an HF diet to an NF diet shortly before pregnancy, without resulting in maternal weight loss, is not necessarily beneficial and may have deleterious effects on offspring.

The ozone-climate penalty: past, present, and future.

Climate change is expected to increase global mean temperatures leading to higher tropospheric ozone (O3) concentrations in already polluted regions, potentially eroding the benefits of expensive emission controls. The magnitude of the "O3-climate penalty" has generally decreased over the past three decades, which makes future predictions for climate impacts on air quality uncertain. Researchers attribute historical reductions in the O3-climate penalty to reductions in NOx emissions but have so far not extended this theory into a quantitative prediction for future effects. Here, we show that a three-dimensional air quality model can be used to map the behavior of the O3-climate penalty under varying NOx and VOC emissions in both NOx-limited and NOx-saturated conditions in Central and Southern California, respectively. Simulations suggest that the planned emissions control program for O3 precursors will not diminish the O3-climate penalty to zero as some observational studies might imply. The results further demonstrate that in a NOx-limited air basin, NOx control strategies alone are sufficient to both decrease the O3-climate penalty and mitigate O3 pollution, while in a NOx-saturated air basin, a modified emissions control plan that carefully chooses reductions in both NOx and VOC emissions may be necessary to eliminate the O3-climate penalty while simultaneously reducing base case O3 concentrations to desired levels. Additional modeling is needed to determine the behavior of the O3-climate penalty as NOx and VOC emissions evolve in other regions.

Rethinking primate origins again.

In 1974, Cartmill introduced the theory that the earliest primate adaptations were related to their being visually oriented predators active on slender branches. Given more recent data on primate-like marsupials, nocturnal prosimians, and early fossil primates, and the context in which these primates first appeared, this theory has been modified. We hypothesize that our earliest primate relatives were likely exploiting the products of co-evolving angiosperms, along with insects attracted to fruits and flowers, in the slender supports of the terminal branch milieu. This has been referred to as the primate/angiosperm co-evolution theory. Cartmill subsequently posited that: "If the first euprimates had grasping feet and blunt teeth adapted for eating fruit, but retained small divergent orbits…" then the angiosperm coevolution theory would have support. The recent discovery of Carpolestes simpsoni provides this support. In addition, new field data on small primate diets, and a new theory concerning the visual adaptations of primates, have provided further evidence supporting the angiosperm coevolution theory.

Quantitative trait locus analysis of contextual fear conditioning in mice.

Family, twin and adoption studies provide evidence for a substantial genetic component underlying individual differences in general intelligence, specific cognitive abilities and susceptibility to psychopathologies related to fear-inducing events. Contextual fear conditioning, which is highly conserved across species, can serve as a model for elucidating genes that regulate individual differences in learning and emotion. In fear conditioning, an initially neutral stimulus, such as a tone or a particular environment (context), elicits a fear response after it has been paired with an aversive stimulus, such as shock. Two neural circuits have been implicated in fear conditioning. The fear component is regulated by amygdaloid pathways, while the contextual component is, at least in part, dependent on the hippocampus. C57BL/6J (B6) and DBA/2J (D2) mice differ in several types of complex learning. including contextual fear conditioning. A quantitative trait locus (QTL) analysis of contextual fear conditioning was performed in a B6/D2 F2 intercross population. Two QTLs for contextual conditioning (lod score > 4.3) were identified on chromosomes 10 and 16. QTLs for conditioning to the auditory cue (lod score > 4.3) were localized to chromosomes 1 and 10. Suggestive QTLs (lod score = 2.8-4.1) for contextual conditioning were detected on chromosomes 1, 2 and 3.

Door-to-balloon time for primary percutaneous coronary intervention: how does Northern West Virginia compare?

BACKGROUND: The National Registry of Myocardial Infarction reported that only 4% of patients transferred for primary percutaneous coronary intervention (PCI) achieved the recommendation of a door-to-balloon time of < 90 min. OBJECTIVES: To see if the American College of Cardiologists/American Heart Association (ACC/AHA) guideline of < 90 min door-to-balloon time for primary PCI is being met in a rural area of West Virginia, and compare to the national average. METHODS: A chart review of all cases of emergent primary PCI for ST-segment elevation myocardial infarction (STEMI) performed in the northern panhandle of West Virginia. RESULTS: The northern panhandle of West Virginia has seven hospitals, of which only one has the capability to perform primary PCI. Two hundred two patients underwent emergent PCI for STEMI from January 1, 2009-September 11, 2010. For each patient, the initial presenting time, arrival time to the PCI hospital, and start of PCI time were recorded. Eight patients were eliminated from the study for not having an initial presenting time. Of the remaining 194 patients, 89 were transferred for primary PCI. Forty-nine patients met the ACC/AHA recommendation of < 90 min door-to-balloon time. The average door-to-balloon time for patients transferred for primary PCI was 104.9 min (Standard Deviation [STD]. 58.2219, 95% confidence interval 92.85-117.04). CONCLUSION: Fifty-five percent of patients transferred for primary PCI in the northern panhandle of West Virginia met the recommended guidelines. This is an improvement on the national average of 4%.

Popular extreme sea level metrics can better communicate impacts.

Estimates of changes in the frequency or height of contemporary extreme sea levels (ESLs) under various climate change scenarios are often used by climate and sea level scientists to help communicate the physical basis for societal concern regarding sea level rise. Changes in ESLs (i.e., the hazard) are often represented using various metrics and indicators that, when anchored to salient impacts on human systems and the natural environment, provide useful information to policy makers, stakeholders, and the general public. While changes in hazards are often anchored to impacts at local scales, aggregate global summary metrics generally lack the context of local exposure and vulnerability that facilitates translating hazards into impacts. Contextualizing changes in hazards is also needed when communicating the timing of when projected ESL frequencies cross critical thresholds, such as the year in which ESLs higher than the design height benchmark of protective infrastructure (e.g., the 100-year water level) are expected to occur within the lifetime of that infrastructure. We present specific examples demonstrating the need for such contextualization using a simple flood exposure model, local sea level rise projections, and population exposure estimates for 414 global cities. We suggest regional and global climate assessment reports integrate global, regional, and local perspectives on coastal risk to address hazard, vulnerability and exposure simultaneously. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10584-021-03288-6.

Case of ischemic colitis in a young adolescent associated with triphasic hormonal contraceptive therapy: a case report and review of the literature.

There has been speculation that third generation hormonal contraceptives may be less prone to inducing clotting than the earlier generation products. We present a case of colonic ischemia in a young adolescent receiving pharmacotherapy with a third-generation hormonal contraceptive. Ischemic colitis is an uncommon adverse effect in young adolescents associated with hormonal contraception, especially the third generation agents. We believe this case to be the second-youngest patient reported with ischemic colitis due to this therapy. Clinical vigilance is recommended for women presenting with abdominal pain, with or without hematochezia, who are receiving hormonal contraceptive therapy. Since their introduction in the early 1960's, the combination hormonal contraceptives have been utilized by millions of women for both contraceptive and non-contraceptive purposes. Although a variety of adverse effects can be experienced by individuals taking these agents, it has been demonstrated that these agents are associated with an increased risk of venous and arterial thromboses. Publications more consistently report on the cardiovascular-, pulmonary-, peripheral vascular-, or cerebrovascular-based thrombotic events associated with these agents. During the past several decades changes have been incorporated in the dose and types of compounds included in the combination hormonal contraceptive products in an attempt to reduce the risk of coagulation and other adverse effects. Less common and less frequently publicized are the gastrointestinal-based thrombotic events that result in ischemia and presents as severe abdominal pain, with or without hematochezia. We report an uncommon case of reversible colonic ischemia in who we believe to be the second-youngest adolescent female reported in the literature (youngest aged 16 years) to have this diagnosis associated with the use of a newer, third-generation oral combination hormonal contraceptive (Naranjo scale of 7; Probable).

Considerations for understanding protein measurements: Identification of formation, degradation and more pathological relevant epitopes.

OBJECTIVES: There is a need for precision medicine and an unspoken promise of an optimal approach for identification of the right patients for value-based medicine based on big data. However, there may be a misconception that measurement of proteins is more valuable than measurement of fewer selected biomarkers. In population-based research, variation may be somewhat eliminated by quantity. However, this fascination of numbers may limit the attention to and understanding of the single. This review highlights that protein measurements (with collagens as examples) may mean different things depending on the targeted epitope - formation or degradation of tissues, and even signaling potential of proteins. DESIGN AND METHODS: PubMed was searched for collagen, neo-epitope, biomarkers. RESULTS: Ample examples of assays with specific epitopes, either pathological such as HbA1c, or domain specific such as pro-peptides, which total protein arrays would not have identified were evident. CONCLUSIONS: We suggest that big data may be considered as the funnel of data points, in which most important parameters will be selected. If the technical precision is low or the biological accuracy is limited, and we include suboptimal quality of biomarkers, disguised as big data, we may not be able to fulfill the promise of helping patients searching for the optimal treatment. Alternatively, if the technical precision of the total protein quantification is high, but we miss the functional domains with the most considerable biological meaning, we miss the most important and valuable information of a given protein. This review highlights that measurements of the same protein in different ways may provide completely different meanings. We need to understand the pathological importance of each epitope quantified to maximize protein measurements.

Lysine deacetylases are produced in pancreatic beta cells and are differentially regulated by proinflammatory cytokines.

AIMS/HYPOTHESIS: Cytokine-induced beta cell toxicity is abrogated by non-selective inhibitors of lysine deacetylases (KDACs). The KDAC family consists of 11 members, namely histone deacetylases HDAC1 to HDAC11, but it is not known which KDAC members play a role in cytokine-mediated beta cell death. The aim of the present study was to examine the KDAC gene expression profile of the beta cell and to investigate whether KDAC expression is regulated by cytokines. In addition, the protective effect of the non-selective KDAC inhibitor ITF2357 and interdependent regulation of four selected KDACs were investigated. METHODS: The beta cell line INS-1 and intact rat and human islets were exposed to cytokines with or without ITF2357. Expression of mRNA was assessed by real-time PCR and selected targets validated at the protein level by immunoblotting. Effects on cytokine-induced toxicity were investigated by in vitro assays. RESULTS: Hdac1 to Hdac11 were expressed and differentially regulated by cytokines in INS-1 cells and rat islets. HDAC1, -2, -6 and -11 were found to be expressed and regulated by cytokines in human islets. ITF2357 protected against cytokine-induced beta cell apoptosis and counteracted cytokine-induced attenuation of basal insulin secretion. In addition, cytokine-induced regulation of Hdac2 and Hdac6, but not Hdac1 and Hdac11, was reduced by KDAC inhibition. CONCLUSIONS/INTERPRETATION: All classical KDAC genes are expressed by beta cells and differentially regulated by cytokines. Based on the relative expression levels and degree of regulation by cytokines, we propose that HDAC1, -2, -6 and -11 are of particular importance for beta cell function. These observations may help in the design of specific KDAC inhibitors to prevent beta cell destruction in situ and in islet grafts.

Oligocene mammals from Ethiopia and faunal exchange between Afro-Arabia and Eurasia.

Afro-Arabian mammalian communities underwent a marked transition near the Oligocene/Miocene boundary at approximately 24 million years (Myr) ago. Although it is well documented that the endemic paenungulate taxa were replaced by migrants from the Northern Hemisphere, the timing and evolutionary dynamics of this transition have long been a mystery because faunas from about 32 to 24 Myr ago are largely unknown. Here we report a late Oligocene fossil assemblage from Ethiopia, which constrains the migration to postdate 27 Myr ago, and yields new insight into the indigenous faunal dynamics that preceded this event. The fauna is composed of large paenungulate herbivores and reveals not only which earlier taxa persisted into the late Oligocene epoch but also demonstrates that one group, the Proboscidea, underwent a marked diversification. When Eurasian immigrants entered Afro-Arabia, a pattern of winners and losers among the endemics emerged: less diverse taxa such as arsinoitheres became extinct, moderately species-rich groups such as hyracoids continued into the Miocene with reduced diversity, whereas the proboscideans successfully carried their adaptive radiation out of Afro-Arabia and across the world.

A Flood Damage Allowance Framework for Coastal Protection With Deep Uncertainty in Sea Level Rise.

Deep uncertainty describes situations when there is either ignorance or disagreement over (1) models used to describe key system processes and (2) probability distributions used to characterize the uncertainty of key variables and parameters. Future projections of Antarctic ice sheet (AIS) mass loss remain characterized by deep uncertainty. This complicates decisions on long-lived coastal protection projects when determining what margin of safety to implement. If the chosen margin of safety does not properly account for uncertainties in sea level rise, the effectiveness of flood protection could decrease over time, potentially putting lives and properties at a greater risk. To address this issue, we develop a flood damage allowance framework for calculating the height of a flood protection strategy needed to ensure that a given level of financial risk is maintained. The damage allowance framework considers decision maker preferences such as planning horizons, protection strategies, and subjective views of AIS stability. We use Manhattan-with the population and built environment fixed in time-to illustrate how our framework could be used to calculate a range of damage allowances based on multiple plausible scenarios of AIS melt. Under high greenhouse gas emissions, we find that results are sensitive to the selection of the upper limit of AIS contributions to sea level rise. Design metrics that specify financial risk targets, such as expected flood damage, allow for the calculation of avoided flood damages (i.e., benefits) that can be combined with estimates of construction cost and then integrated into existing financial decision-making approaches (e.g., benefit-cost analysis).

Antarctic Ice Sheet and emission scenario controls on 21st-century extreme sea-level changes.

Uncertainties in Representative Concentration Pathway (RCP) scenarios and Antarctic Ice Sheet (AIS) melt propagate into uncertainties in projected mean sea-level (MSL) changes and extreme sea-level (ESL) events. Here we quantify the impact of RCP scenarios and AIS contributions on 21st-century ESL changes at tide-gauge sites across the globe using extreme-value statistics. We find that even under RCP2.6, almost half of the sites could be exposed annually to a present-day 100-year ESL event by 2050. Most tropical sites face large increases in ESL events earlier and for scenarios with smaller MSL changes than extratropical sites. Strong emission reductions lower the probability of large ESL changes but due to AIS uncertainties, cannot fully eliminate the probability that large increases in frequencies of ESL events will occur. Under RCP8.5 and rapid AIS mass loss, many tropical sites, including low-lying islands face a MSL rise by 2100 that exceeds the present-day 100-year event level.

Paleoenvironment of the earliest hominoids: new evidence from the oligocene avifauna of egypt.

Analysis of fossil birds from the Oligocene Jebel Qatrani Formation in the Fayum depression of Egypt, site of the oldest known hominoid primates, allows precise paleoenvironmental reconstruction of the climatic and biotic conditions that influenced some of the earliest stages of hominoid evolution. Unlike the fossil mammals of the Fayum, which belong largely to extinct groups, most of the birds are referable to living families, with some being close to modern genera. The avifauna consists mainly of aquatic species, with such forms as jacanas (Jacanidae) and shoebilled storks (Balaenicipitidae) indicating expanses of freshwater with dense floating vegetation. An avifauna closely analogous to that of the Fayum is found today only in a limited area of Uganda, north and west of Lake Victoria, a region of swampland bordered by forest and grasslands that presents marked faunal similarities to the environment inferred for the Egyptian Oligocene.

Diurnality, nocturnality, and the evolution of primate visual systems.

Much of the recent research on the evolution of primate visual systems has assumed that a minimum number of shifts have occurred in circadian activity patterns over the course of primate evolution. The evolutionary origins of key higher taxonomic groups have been interpreted by some researchers as a consequence of a rare shift from nocturnality to diurnality (e.g., Anthropoidea) or from diurnality to nocturnality (e.g., Tarsiidae). Interpreting the evolution of primate visual systems with an ecological approach without parsimony constraints suggests that the evolutionary transitions in activity pattern are more common than what would be allowed by parsimony models, and that such transitions are probably less important in the origin of higher level taxa. The analysis of 17 communities of primates distributed widely around the world and through geological time shows that primate communities consistently contain both nocturnal and diurnal forms, regardless of the taxonomic sources of the communities. This suggests that primates in a community will adapt their circadian pattern to fill empty diurnal or nocturnal niches. Several evolutionary transitions from one pattern to the other within narrow taxonomic groups are solidly documented, and these cases probably represent a small fraction of such transitions throughout the Cenozoic. One or more switches have been documented among platyrrhine monkeys, Malagasy prosimians, Eocene omomyids, Eocene adapoids, and early African anthropoids, with inconclusive but suggestive data within tarsiids. The interpretation of living and extinct primates as fitting into one of two diarhythmic categories is itself problematic, because many extant primates show significant behavioral activity both nocturnally and diurnally. Parsimony models routinely interpret ancestral primates to have been nocturnal, but analyses of morphological and genetic data indicate that they may have been diurnal, or that early primate radiations were likely to have generated both nocturnal and diurnal forms, especially given the unusual annual light regimes faced by Early Tertiary primates living outside today's latitudinal tropics. We review the essential morphology and physiology of the primate visual system to look for features that might constrain evolutionary switches, and we find that the pattern of variation within and among primate groups in eye size, corneal size, retinal morphology, and opsin distribution are all consistent with the idea that there is considerable evolutionary flexibility in the visual system. These results suggest that primate lineages may evolve from diurnal to nocturnal, and vice versa, more readily and more rapidly than has been suggested by the use of strict parsimony models. This has implications for interpreting the fossil record and reconstructing key evolutionary events in primate evolution.

Estimating economic damage from climate change in the United States.

Estimates of climate change damage are central to the design of climate policies. Here, we develop a flexible architecture for computing damages that integrates climate science, econometric analyses, and process models. We use this approach to construct spatially explicit, probabilistic, and empirically derived estimates of economic damage in the United States from climate change. The combined value of market and nonmarket damage across analyzed sectors-agriculture, crime, coastal storms, energy, human mortality, and labor-increases quadratically in global mean temperature, costing roughly 1.2% of gross domestic product per +1°C on average. Importantly, risk is distributed unequally across locations, generating a large transfer of value northward and westward that increases economic inequality. By the late 21st century, the poorest third of counties are projected to experience damages between 2 and 20% of county income (90% chance) under business-as-usual emissions (Representative Concentration Pathway 8.5).

Daily melatonin administration at middle age suppresses male rat visceral fat, plasma leptin, and plasma insulin to youthful levels.

Human and rat pineal melatonin secretion decline with aging, whereas visceral fat and plasma insulin levels increase. Melatonin modulates fat metabolism in some mammalian species, so these aging-associated melatonin, fat and insulin changes could be functionally related. Accordingly, we investigated the effects of daily melatonin supplementation to male Sprague-Dawley rats, starting at middle age (10 months) and continuing into old age (22 months). Melatonin was added to the drinking water (92% of which was consumed at night) at a dosage (4 microg/ml) previously reported to attenuate the aging-associated decrease in survival rate in male rats, as well as at a 10-fold lower dosage. The higher dosage produced nocturnal plasma melatonin levels in middle-aged rats which were 15-fold higher than in young (4 months) rats; nocturnal plasma melatonin levels in middle-aged rats receiving the lower dosage were not significantly different from young or middle-aged controls. Relative (% of body wt) retroperitoneal and epididymal fat, as well as plasma insulin and leptin levels, were all significantly increased at middle age when compared to young rats. All were restored within 10 weeks to youthful (4 month) levels in response to both dosages of melatonin. Continued treatment until old age maintained suppression of visceral (retroperitoneal + epididymal) fat levels. Plasma corticosterone and total thyroxine (T4) levels were not significantly altered by aging or melatonin treatment. Plasma testosterone, insulin-like growth factor I (IGF-I) and total triiodothyronine (T3) decreased by middle age; these aging-associated decreases were not significantly altered by melatonin treatment. Thus, visceral fat, insulin and leptin responses to melatonin administration may be independent of marked changes in gonadal, thyroid, adrenal or somatotropin regulation. Since increased visceral fat is associated with increased insulin resistance, diabetes, and cardiovascular disease, these results suggest that appropriate melatonin supplementation may potentially provide prophylaxis or therapy for some prominent pathologies associated with aging.

Endogenous opioid inhibition and facilitation of gonadotropin-releasing hormone release from the median eminence in vitro: potential role of catecholamines.

The intrahypothalamic site(s) of endogenous opioid regulation of GnRH secretion remains to be resolved. Accordingly, we used an in vitro acute incubation system to evaluate GnRH, dopamine (DA), and norepinephrine (NE) release from adult male rat median eminences (MEs) in response to the opiate receptor agonist morphine (MOR) and the opiate receptor antagonist naloxone (NAL). MOR (2 mM) stimulated basal and K+-induced GnRH release from isolated MEs, but 0.25, 5, or 100 microM MOR was without significant effect. NAL (1 mg/ml; 2.8 mM) increased basal GnRH release, but 0.01 mg NAL/ml suppressed basal GnRH release, and neither 0.001 nor 0.1 mg NAL/ml had an appreciable effect. NAL did not significantly alter K+-induced GnRH release. In a separate experiment, 1 mg NAL/ml stimulated but 0.01 mg NAL/ml inhibited basal release of DA and NE from the ME. NAL (1 ng/ml) also decreased K+-induced DA and NE release. The rates of basal and K+-induced DA and NE release were highly correlated with GnRH release during corresponding 0, 0.01, and 1.0 mg/ml NAL treatments in the preceding experiment (r = 0.98 and 0.93, respectively). Thus, 2 mM MOR stimulated but different NAL dosages either stimulated or inhibited GnRH release from isolated MEs, suggesting complex opioid regulation at the level of the GnRH neurosecretory terminals. The precise correlation between GnRH and DA/NE release suggests that the catecholamine terminals close to both GnRH- and endorphin-containing terminals in the ME may mediate this opioid regulation.

Daily melatonin administration to middle-aged male rats suppresses body weight, intraabdominal adiposity, and plasma leptin and insulin independent of food intake and total body fat.

Pineal melatonin secretion declines with aging, whereas visceral fat, plasma insulin, and plasma leptin tend to increase. We have previously demonstrated that daily melatonin administration at middle age suppressed male rat intraabdominal visceral fat, plasma leptin, and plasma insulin to youthful levels; the current study was designed to begin investigating mechanisms that mediate these responses. Melatonin (0.4 microg/ml) or vehicle was administered in the drinking water of 10-month-old male Sprague Dawley rats (18/treatment) for 12 weeks. Half (9/treatment) were then killed, and the other half were submitted to cross-over treatment for an additional 12 weeks. Twelve weeks of melatonin treatment decreased (P<0.05) body weight (BW; by 7% relative to controls), relative intraabdominal adiposity (by 16%), plasma leptin (by 33%), and plasma insulin (by 25%) while increasing (P<0.05) locomotor activity (by 19%), core body temperature (by 0.5 C), and morning plasma corticosterone (by 154%), restoring each of these parameters toward more youthful levels. Food intake and total body fat were not changed by melatonin treatment. Melatonin-treated rats that were then crossed over to control treatment for a further 12 weeks gained BW, whereas control rats that were crossed to melatonin treatment lost BW, but food intake did not change in either group. Feed efficiency (grams of BW change per g cumulative food intake), a measure of metabolic function, was negative in melatonin-treated rats and positive in control rats before cross-over (P<0.001); this relationship was reversed after cross-over (P<0.001). Thus, melatonin treatment in middle age decreased BW, intraabdominal adiposity, plasma insulin, and plasma leptin, without altering food intake or total adiposity. These results suggest that the decrease in endogenous melatonin with aging may alter metabolism and physical activity, resulting in increased BW, visceral adiposity, and associated detrimental metabolic consequences.