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Weather forecasts are fundamentally uncertain, so predicting the range of probable weather scenarios is crucial for important decisions, from warning the public about hazardous weather to planning renewable energy use. Traditionally, weather forecasts have been based on numerical weather prediction (NWP) 1 , which relies on physics-based simulations of the atmosphere. Recent advances in machine learning (ML)-based weather prediction (MLWP) have produced ML-based models with less forecast error than single NWP simulations 2,3 . However, these advances have focused primarily on single, deterministic forecasts that fail to represent uncertainty and estimate risk. Overall, MLWP has remained less accurate and reliable than state-of-the-art NWP ensemble forecasts. Here we introduce GenCast, a probabilistic weather model with greater skill and speed than the top operational medium-range weather forecast in the world, ENS, the ensemble forecast of the European Centre for Medium-Range Weather Forecasts 4 . GenCast is an ML weather prediction method, trained on decades of reanalysis data. GenCast generates an ensemble of stochastic 15-day global forecasts, at 12-h steps and 0.25° latitude-longitude resolution, for more than 80 surface and atmospheric variables, in 8 min. It has greater skill than ENS on 97.2% of 1,320 targets we evaluated and better predicts extreme weather, tropical cyclone tracks and wind power production. This work helps open the next chapter in operational weather forecasting, in which crucial weather-dependent decisions are made more accurately and efficiently., Competing Interests: Competing interests: I.P., A.S.-G., F.A., T.R.A., A.E.K., D.M., T.E., J.S., S.M., P.B., R.L. and M.W. are employees of Alphabet and own Alphabet stock. Provisional patent 63/614,461 was filed covering the algorithm described in this paper, listing the authors I.P., M.W., A.S.-G., F.A., R.L. and P.B. as inventors. The authors declare no other competing interests related to the paper., (© 2024. The Author(s).)

Subjective well-being (SWB) describes an individual's life evaluation. Direct elicitation methods for SWB via rating scales do not force individuals to trade-off among life domains, whilst best-worst scaling (BWS) approaches only provide relative measures. This paper instead offers a dual-response BWS task, where respondents nominate areas of most and least importance and satisfaction with respect to 11 SWB domains, whilst also eliciting anchoring points to obtain an absolute measure of domain satisfaction. Combining domain satisfaction and importance produces a robust measure of individual SWB, but statistically unique relative to other life satisfaction measures utilizing single- and multi-item ratings, including global satisfaction and those aggregated over SWB domains, as well as eudemonia. Surveying 2500 Australians reveals anchored-BWS improves discrimination amongst domains in terms of importance and satisfaction, illustrating its value as a diagnostic tool for SWB measurement to focus services, policy, and initiatives in areas to most impact wellbeing. This includes highlighting a major discrepancy between health satisfaction and importance, whilst also reporting that SWB is significantly lower for Indigenous, unemployed, middle-aged, males and lower income groups., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Key Points: We present the largest cohort of structured histopathology reports on primary ciliary dyskinesia-related chronic rhinosinusitis (PCD-CRS). Despite endoscopic differences, PCD-CRS and cystic fibrosis-related chronic rhinosinusitis (CF-CRS) had similar structured histopathology reports. Compared to healthy patients and those with idiopathic chronic rhinosinusitis without nasal polyps, patients with PCD-CRS had an increased neutrophil count., (© 2023 ARS‐AAOA, LLC.)

The development of COVID-19 vaccines is occurring at unprecedented speeds, but require high coverage rates to be successful. This research examines individuals' psychological beliefs that may act as enablers and barriers to vaccination intentions. Using the health beliefs model as a guide to our conceptual framework, we explore factors influencing vaccine hesitancy and health beliefs regarding risks and severity of the disease, along with individual variables such as income, age, religion, altruism, and collectivism. A questionnaire using newly created measures for various antecedents provided 4303 usable responses from Australia, Canada, England, New Zealand, and the United States. A factor analytic and structural equation model indicates that trust in vaccine approval, the perceived effectiveness of the vaccine for protecting others, and conspiracy beliefs are the most significant drivers of intentions to vaccinate. Older people, those seeking employment, and those who have received a recent influenza vaccine are more likely to be vaccinated against COVID-19. The findings have implications for improving communication strategies targeting individuals about the merits of vaccination, particularly focusing on younger individuals and expanded message framing to include altruistic considerations, and to improve government transparency regarding the effectiveness and side effects of vaccines., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021. Published by Elsevier Ltd.)

The impact of COVID-19 across health services, including treatment services for people who use drugs, is emerging but likely to have a high impact. Treatment services for people who use drugs provide essential treatment services including opiate agonist treatment and needle syringe programmes alongside other important treatment programmes across all substance types including withdrawal and counselling services. Drug and alcohol hospital consultation-liaison clinicians support emergency departments and other services provided in hospital settings in efficiently managing patients who use drugs and present with other health problems.COVID-19 will impact on staff availability for work due to illness. Patients may require home isolation and quarantine periods. Ensuring ongoing supply of opiate treatment during these periods will require significant changes to how treatment is provided. The use of monthly depot buprenorphine as well as moving from a framework of supervised dosing will be required for patients on sublingual buprenorphine and methadone. Ensuring ready access to take-home naloxone for patients is crucial to reduce overdose risks. Delivery of methadone and buprenorphine to the homes of people with confirmed COVID-19 infections is likely to need to occur to support home isolation.People who use drugs are likely to be more vulnerable during the COVID-19 epidemic, due to poorer health literacy and stigma and discrimination towards this group. People who use drugs may prioritise drug use above other health concerns. Adequate supply of clean injecting equipment is important to prevent outbreaks of blood-borne viruses. Opiate users may misinterpret SARS-CoV2 symptoms as opiate withdrawal and manage this by using opioids. Ensuring people who use drugs have access to drug treatment as well as access to screening and testing for SARS-CoV2 where this is indicated is important.

Background: Vast volumes of data, coded through hierarchical terminologies (e.g., International Classification of Diseases, Tenth Revision-Clinical Modification [ICD10-CM], Medical Subject Headings [MeSH]), are generated routinely in electronic health record systems and medical literature databases. Although graphic representations can help to augment human understanding of such data sets, a graph with hundreds or thousands of nodes challenges human comprehension. To improve comprehension, new tools are needed to extract the overviews of such data sets. We aim to develop a visual interactive analytic tool for filtering and summarizing large health data sets coded with hierarchical terminologies (VIADS) as an online, and publicly accessible tool. The ultimate goals are to filter, summarize the health data sets, extract insights, compare and highlight the differences between various health data sets by using VIADS. The results generated from VIADS can be utilized as data-driven evidence to facilitate clinicians, clinical researchers, and health care administrators to make more informed clinical, research, and administrative decisions. We utilized the following tools and the development environments to develop VIADS: Django, Python, JavaScript, Vis.js, Graph.js, JQuery, Plotly, Chart.js, Unittest, R, and MySQL., Results: VIADS was developed successfully and the beta version is accessible publicly. In this paper, we introduce the architecture design, development, and functionalities of VIADS. VIADS includes six modules: user account management module, data sets validation module, data analytic module, data visualization module, terminology module, dashboard. Currently, VIADS supports health data sets coded by ICD-9, ICD-10, and MeSH. We also present the visualization improvement provided by VIADS in regard to interactive features (e.g., zoom in and out, customization of graph layout, expanded information of nodes, 3D plots) and efficient screen space usage., Conclusions: VIADS meets the design objectives and can be used to filter, summarize, compare, highlight and visualize large health data sets that coded by hierarchical terminologies, such as ICD-9, ICD-10 and MeSH. Our further usability and utility studies will provide more details about how the end users are using VIADS to facilitate their clinical, research or health administrative decision making.

Phenomenon : Preclerkship medical education has undergone extensive reform, and the clerkship years are growing targets for curricular innovation. As institutions implement new preclerkship curricula to better prepare medical students to practice medicine in the context of modern healthcare systems, the perspective of clerkship leaders regarding clerkship student roles and potential for change will facilitate redefining these roles so that preclerkship educational innovations can continue into clerkships. Approach : In this qualitative exploratory study, authors conducted semistructured interviews with clerkship and site directors for eight core clerkships from April to May 2016. Questions addressed how clerkship leaders perceive current student roles and the potential for change. Through iterative consensus building, authors identified themes describing current ideal clerkship student roles applicable to future roles. Findings : Twenty-three of 24 (96%) directors participated. Findings fell into four themes: factors influencing the clerkship role, clerkship student role archetypes, workplace authenticity and value, and potential for change. Student, supervisor, and context factors determine the clerkship student role. Three role archetypes emerged: the apprentice (an assistant completing concrete patient care tasks), the academic (a researcher bringing literature back to the team), and the communicator (an interdisciplinary and patient liaison). Each archetype was considered authentic and valuable. Positive attitudes toward preclerkship curricular changes were associated with openness to evolution of the clerkship students' role. These emerging roles mapped to the archetypes. Insights : Clerkship leaders perceive that student, supervisor, and context factors result in varying emphasis on role archetypes, which in turn lead to different types of learning. Medical educators can use the archetypes to articulate how expanded student roles align learning with clinical needs, particularly as they relate to health systems science and inquiry.

Background: Single nucleotide polymorphisms (SNPs) located within the human genome have been shown to have utility as markers of identity in the differentiation of DNA from individual contributors. Massively parallel DNA sequencing (MPS) technologies and human genome SNP databases allow for the design of suites of identity-linked target regions, amenable to sequencing in a multiplexed and massively parallel manner. Therefore, tools are needed for leveraging the genotypic information found within SNP databases for the discovery of genomic targets that can be evaluated on MPS platforms., Results: The SNP island target identification algorithm (TIA) was developed as a user-tunable system to leverage SNP information within databases. Using data within the 1000 Genomes Project SNP database, human genome regions were identified that contain globally ubiquitous identity-linked SNPs and that were responsive to targeted resequencing on MPS platforms. Algorithmic filters were used to exclude target regions that did not conform to user-tunable SNP island target characteristics. To validate the accuracy of TIA for discovering these identity-linked SNP islands within the human genome, SNP island target regions were amplified from 70 contributor genomic DNA samples using the polymerase chain reaction. Multiplexed amplicons were sequenced using the Illumina MiSeq platform, and the resulting sequences were analyzed for SNP variations. 166 putative identity-linked SNPs were targeted in the identified genomic regions. Of the 309 SNPs that provided discerning power across individual SNP profiles, 74 previously undefined SNPs were identified during evaluation of targets from individual genomes. Overall, DNA samples of 70 individuals were uniquely identified using a subset of the suite of identity-linked SNP islands., Conclusions: TIA offers a tunable genome search tool for the discovery of targeted genomic regions that are scalable in the population frequency and numbers of SNPs contained within the SNP island regions. It also allows the definition of sequence length and sequence variability of the target region as well as the less variable flanking regions for tailoring to MPS platforms. As shown in this study, TIA can be used to discover identity-linked SNP islands within the human genome, useful for differentiating individuals by targeted resequencing on MPS technologies.

Ghrelin plays a major physiological role in the control of food intake, and inverse agonists of the ghrelin receptor (GHS-R1a) are widely considered to offer utility as antiobesity agents by lowering the set-point for hunger between meals. We identified an acylurea series of ghrelin modulators from high throughput screening and optimized binding affinity through structure-activity relationship studies. Furthermore, we identified specific substructural changes, which switched partial agonist activity to inverse agonist activity, and optimized physicochemical and DMPK properties to afford the non-CNS penetrant inverse agonist 22 (AZ-GHS-22) and the CNS penetrant inverse agonist 38 (AZ-GHS-38). Free feeding efficacy experiments showed that CNS exposure was necessary to obtain reduced food intake in mice, and it was demonstrated using GHS-R1a null and wild-type mice that this effect operates through a mechanism involving GHS-R1a.

Foreign-born workers have high rates of occupational mortality and morbidity, despite downward trends for the U.S. workforce overall. They have limited access to health care services. Medical interpreters (MIs) facilitate care of acutely injured, low-English-proficiency (LEP) patients, including those sustaining occupational injuries. Our goal was to assess the potential for MIs to serve as advocates of LEP patients injured at work and to deliver preventive messages. We conducted interviews and a focus group of MIs regarding their attitudes toward foreign-born workers, knowledge of occupational health, and perceived roles. They were familiar with occupational injuries and sympathetic toward foreign-born workers, and they described their roles as conduits, cultural brokers, and advocates for hospitals, providers, and patients. More detailed and representative data would require a larger investigation. However, the time-sensitive nature of policy-making at this point mandates that occupational health stakeholders participate in the national dialogue on standards, training, and licensure for MIs to promote improved access and quality of health care for LEP patients who have been injured at work.

An increased focus on hypertension prevention and control, especially in high-risk populations, may have a substantial impact on cardiovascular health outcomes. A continuing medical education (CME) program trained primary care providers in evidence-based guidelines for hypertension prevention and control. This study evaluated its effectiveness in reducing patients' blood pressure for the sessions occurring from 2003 to 2007. Using the Hypertension Initiative Database, 8183 patients of CME providers (CME patients) were paired with controls and changes in blood pressure, provider visits, prescription months, and the proportion of patients with blood pressure <140/90 mm Hg before and after the intervention date were estimated. In the 2-year period before training and the 2-year period afterwards, CME patients' systolic blood pressure decreased by 1.99 mm Hg and diastolic blood pressure decreased by 1.49 mm Hg. The CME patients displayed an increase in provider visits but no statistically significant change in prescription months. Restricting the analysis to the subsample of patients with uncontrolled hypertension (>140/90 mm Hg), the changes in blood pressure were similar in magnitude to those in the entire population. The CME program, by promoting evidence-based practice, improves patients' blood pressure and could serve as a positive model for future hypertension interventions., (© 2011 Wiley Periodicals, Inc.)

An option to increase the productivity of saline land is to graze sheep on salt-tolerant plants, which, during the summer/autumn period, can contain 20% to 25% of their dry matter as salt. This study assessed the impact of coping with high dietary salt loads on the reproductive performance of grazing ewes. From the time of artificial insemination until parturition, 2-year-old maiden Merino ewes were fed either a high-salt diet (NaCl 13% of dry matter) or control diet (NaCl 0.5% of dry matter). Pregnancy rates, lamb birth weights, milk composition and the plasma concentrations of hormones related to salt and water balance, and energy metabolism were measured. Leptin and insulin concentrations were lower (1.4 ± 0.09 v. 1.5 ± 0.12 ng/ml; (P < 0.05) and 7.2 ± 0.55 v. 8.2 ± 0.83 ng/ml; P < 0.02) in response to high-salt ingestion as was aldosterone concentration (27 ± 2.7 v. 49 ± 5.4 pg/ml; P < 0.05), presumably to achieve salt and water homeostasis. Arginine vasopressin concentration was not significantly affected by the diets, but plasma concentration of T3 differed during gestation (P < 0.02), resulting in lower concentrations in the high-salt group in the first third of gestation (1.2 ± 0.18 v. 1.3 ± 0.14 pmol/ml) and higher concentrations in the final third of gestation (0.8 ± 0.16 v. 0.6 ± 0.06 pmol/ml). T4 concentration was lower in ewes ingesting high salt for the first two-thirds of pregnancy (162 ± 8.6 v. 212 ± 13 ng/ml; P < 0.001). No substantial effects of high salt ingestion on pregnancy rates, lamb birth weights or milk composition were detected.

The carcass and eating quality of sheep grazing a saltbush dominant saline pasture system or on a 'control' dry pasture, stubble plot both supplemented with barley for 14 weeks was investigated (Experiment 1, 50 (2×25) 6 month merino lamb wethers and Experiment 2, 50 (2×25) 18 month old merino hogget wethers). Treatment had no significant effect on eating quality attributes (P>0.05). Saltbush grazed sheep in both experiments had a significantly (P<0.01) lower carcass fat and significantly higher lean (P<0.01) content than the control grazed sheep. This is a positive finding as fat denudation is a significant cost to processors. The long term consumption of saltbush and barley prior to slaughter did increase muscle fluid content (P<0.05) but did not result in a decreased carcass weight loss at slaughter due to confounding changes in body composition. Grazing saltbush resulted in increased urine weight (P<0.001) and decreased urine concentration (P<0.05) at slaughter indicating an improved hydration status at slaughter. However both experiments demonstrated sub-optimal liveweight gains indicating that saltbush with a barley supplement can still be effectively used as a maintenance ration without compromising carcass and eating quality.

Forage halophytes such as saltbush (Atriplex spp.) are widely used to revegetate Australian saline land and can provide a medium-quality fodder source. An animal house experiment was conducted to investigate differences in the carcass and eating quality of sheep ingesting saltbush from saline land in combination with a barley supplement. Twenty-six merino hoggets (two groups of 13) were fed either a 60 : 40 dried saltbush (Atriplex nummularia): barley (S + B) ration or a 33 : 25 : 42 lupins : barley : oaten hay ration (C) for 10 weeks prior to commercial slaughter. After 10 weeks, all sheep were commercially slaughtered and a single loin (from 12th rib to chump) collected from each animal for taste-panel analysis. Carcass weight, total tissue depth over the 12th rib 110 mm from the midline (GR fat depth), ultimate pH and colour were determined and X-ray bone densitometry used to estimate the fat content of the carcass. Blood samples were taken to assess the hormonal response to ingesting these diets and fatty acid profiles of the subcutaneous and intramuscular fat were determined. Both groups grew at the same rate (62 g/day) and had similar hot carcass weights (P > 0.01) (17.2 ± 0.3 kg for S + B and 17.9 ± 0.3 kg for C). However, these live weights may not be high enough to be commercially viable such that saltbush and barley may only be suitable as a maintenance feed. The S + B-fed sheep had a significantly (P = 0.055) lower fat and higher lean content (P < 0.05) than the C group. This is a positive finding as fat denudation is a significant cost to processors and farmers can produce sheep that are depositing less fat or more lean per unit of live-weight gain. The decreased fat and increased lean content were attributed to the higher protein : energy ratio available for production and lower circulating insulin and higher growth hormone of the S + B-fed sheep. The lower body-fat content and lower metabolisable energy and digestible organic matter intake did correlate with the sheep fed the S + B diet, having a significantly lower percentage of unsaturated fat and equal levels of saturated fat than the C treatment. Diet had no effect on the ultimate pH or colour of the meat. Treatment had no significant effect on any of the eating-quality attributes (P > 0.1). The drying of the saltbush, the shorter length of the experimental period and the low carcass fat content were believed to have contributed to this result. Further field experiments are needed to clarify the benefits to carcass and eating quality of ingesting saltbush.

The rat orphan receptor UHR-1 and its human orthologue, GPR10, were first isolated in 1995. The ligand for this receptor, prolactin-releasing peptide (PrRP), was identified in 1998 by reverse pharmacology and has subsequently been implicated in a number of physiological processes. As supported by its localization and regulation in the hypothalamus and brainstem, we have shown previously that PrRP is involved in energy homeostasis. Here we describe a naturally occurring polymorphism in the UHR-1 gene that results in an ATG to ATA change at the putative translational initiation site. The presence of the polymorphism abolished the binding of 125I PrRP in rat brain slices but did not affect the ability of PrRP to reduce fast-induced food intake. Together this data suggest that PrRP may be exerting its feeding effects through a receptor other than UHR-1.

Purpose: This investigation determines the drug delivery capacity of Lipospheres, which are drug-containing solid-filled vesicles made of triglyceride with a phospholipid outer covering, to release local anesthetic in vitro and to produce sustained peripheral nerve block in vivo., Methods: The local anesthetic, bupivacaine, was loaded into Lipospheres in several dosage forms, characterized, and measured for in vitro release. In rats, Lipospheres were administered into a large space between muscle layers surrounding the sciatic nerve to assess sensory and motor block in vivo., Results: The particle size of Lipospheres was determined to be between 5 and 15 microm, with over 90% surface phospholopid. Lipospheres released bupivacaine over two days under ideal sink conditions. Liposphere nerve application produced dose-dependent and reversible block. Indeed, sustained local anesthetic block (SLAB) was observed for 1-3 days in various in vivo tests: a) Hind paw withdrawal latency to noxious heat was increased over 50% for 96 hr period after application of 3.6% or 5.6% bupivacaine-Lipospheres. The 3.6% and 5.6% doses were estimated to release bupivacaine at 200 and 311 microg drug/ hr, respectively, based on release spanning 72 hr. Application of 1.6% bupivacaine-Lipospheres increased withdraw latency 25-250% but for only a 24 hr duration; b) Similarly, vocalization threshold to hind paw stimulation was increased 25-50% for 72 hr following application of 3.6% bupivacaine-Lipospheres; c) Finally, sensory blockade outlasted or equaled corresponding motor block duration for all Liposphere drug dosages., Conclusions: Liposphere delivery of local anesthetic drugs may be well suited for site-specific pharmacotherapy of neural tissue to produce SLAB. Dose-dependent effects in duration of action may include lipophilic tissue storage.

Full-length cytosolic phospholipase A2 (cPLA2) was cloned from U937 cells and polymorphonuclear leukocytes (PMNLs) while a naturally occurring variant of cPLA2, which lacks residues Val473-Ala749 but has a C-terminal extension of ILMNLSEYMLWMSKVKRFM (DcPLA2) was cloned from PMNLs and mononuclear leukocytes. We were unable to clone DcPLA2 from U937 cells. When cPLA2 and DcPLA2 were expressed in insect cells, both proteins were detected in cell lysates by SDS/PAGE as single bands of apparent molecular masses 100 kDa and 57 kDa, respectively. Full-length cPLA2 was phosphorylated stoichiometrically by p42 mitogen-activated protein (MAP) kinase in vitro at a similar rate to other physiological substrates of this protein kinase and the major site of phosphorylation was identified by amino acid sequencing as Ser505. [32P]Ser(P)505 in cPLA2 was only dephosphorylated at a slow rate by mammalian tissue homogenates. Protein phosphatases 2A, 2B and 2C all contributed significantly to the overall dephosphorylation of cPLA2. The phosphorylation of cPLA2 by p42 MAP kinase correlated with an approximately 1.5-fold increase in specific enzyme activity which was reversed by dephosphorylation.

In this baseline study, the authors analyze in detail many of the factors that influenced the research career intentions of the 1994 U.S. graduates of MD-only programs. Studies of the research interests of the nation's medical school graduates are important because MD-PhD programs do not produce sufficient numbers of physician-scientists, and the remainder must come from the regular population of medical graduates. Data on school characteristics and medical students' demographics, research career intentions, and educational experiences were derived from the AAMC's Institutional Profile System (IPS), Student Application and Information Management System (SAIMS), Matriculating Student Questionnaire (MSQ), and Medical School Graduation Questionnaire (GQ). The 1994 GQ was used as the index instrument to make the correlations reported in this article. A number of findings emerged concerning the 1994 graduates. A greater percentage of these students who began medical school with strong research career intentions and maintained these intentions had entered private medical schools. The lower rate of research interest amongst the students enrolled in public medical schools was compounded by the significantly greater loss of earlier research intentions of those in public schools compared with those in private schools.(ABSTRACT TRUNCATED AT 250 WORDS)

Polyanhydride polymer matrices have been used successfully for sustained release of a number of drugs in vitro and in vivo. Dibucaine free base, dibucaine HCl, and bupivacaine HCl were incorporated into polymer matrices with copolymer 1,3-bis(p-carboxyphenoxy)propane-sebacic acid anhydride (1:4). Drug release was measured in vitro following incubation of the drug-polymer matrices in phosphate buffered solution, pH 7.4, at 37 degrees C, to approximate in vivo conditions. Local anesthetics were released in a sustained manner yielding 90% cumulative drug release over periods ranging from 3 to 14 days. The kinetics of release varied with both the choice of local anesthetic and the method of drug incorporation into the matrix (hot melt versus compression molding). Polymer local anesthetic matrix devices (PLAM), loaded by hot melt incorporation with 20% bupivacaine, were implanted in vivo adjacent to the sciatic nerve in three rats. Reversible neural blockade was observed for 4 days in all animals. Polymer implants without local anesthetic showed no neural blockade. This technology could lead to methods of prolonged blockade of peripheral nerves or of sympathetic ganglia, which may be utilized for the management of postoperative pain, sympathetically maintained pain, or certain forms of chronic pain.

Background: Prolonged nerve blockade is potentially useful in the management of many acute and chronic pain problems. Aside from infusions via an indwelling catheter, most currently available nondestructive techniques for prolonging local anesthetic action cannot provide more than 1-2 days of blockade. Bioerodible polymer matrixes have been used to deliver a variety of drugs in patients and animals for periods lasting weeks to years. Previously, dibucaine and bupivacaine were incorporated into copolymers of 1,3 bis(p-carboxyphenoxy) propane-sebacic acid anhydride (1:4), and demonstrated sustained release in vitro following incubation of the drug-polymer matrixes in phosphate-buffered solution (pH 7.4, 37 degrees C)., Methods: In the present study, cylindrical pellets made from polymer matrixes incorporated with bupivacaine-HCl were implanted surgically along the sciatic nerves of rats. Neural block was assessed by direct observation of motor skills and by leg-withdrawal latency to a hot surface. Biochemical and histologic examinations were performed 2 weeks after implantation., Results: Sensory and motor blockade was produced for periods ranging from 2 to 6 days. Contralateral control legs receiving polymer implants without drug showed no block. Blockade was reversible, and animals appeared to recover sensory and motor function normally. Biochemical indexes of nerve and muscle function were indistinguishable from contralateral controls., Conclusions: This biodegradable polymer system provides a promising new alternative for the delivery of local anesthetics to peripheral nerves to produce prolonged blockade for the management of acute and chronic pain.

This article presents two implant cases where a periapical radiolucency developed, with a sinus tract, while the implants were still submerged. A corrective surgical treatment for these unique lesions is detailed, and the possible etiologies are discussed.

To increase sensitivity and to improve normalization of RNA levels in Northern blot analysis, a comparatively inexpensive optical scanner was utilized for digitizing photonegatives of ethidium bromide stained gels and autoradiograms. The optical scanner captures the image with a maximum resolution of 300 dots per inch by assigning one of 256 gray levels (8-bit) to each dot in the image. With the use of the public domain NIH Image program (requires a Macintosh II and an 8-bit video card), gel or autoradiogram bands in the digitized image are selected and their average gray scale density measured. We found that the digitized image of a photonegative of a TAE (Tris-acetate/EDTA) agarose gel, loaded incrementally with 50-1500 ng total RNA, produced a linear response over a 4-fold range down to 100 ng (R2 greater than 0.950). In utilizing "quantification" gels like this, RNA samples that are too dilute or too small for traditional spectrophotometric techniques can be normalized and loaded uniformly onto subsequent Northern gels. Results from autoradiogram scans demonstrate highly linear gray scale responses over a 4-fold range of total RNA (R2 greater than 0.950) that are reproducible with different blots and probe types (e.g., riboprobe, cDNA and oligonucleotide). In addition, we describe a normalization technique using a 30-mer oligonucleotide probe for rat 28S ribosomal RNA as a measure of total RNA loaded per gel lane. Altogether, this scanning, ribosomal RNA normalization system allows the measurement of relative changes between 20% and 400% using standard autoradiographic methods.

Neonatal capsaicin treatment (50 mg/kg SC in two-day-old rats) increased thermal pain thresholds in both sexes when measured at different ages, decreased the responsiveness of adult females to specific noxious stimulation, and differentially decreased the magnitude of vaginocervical stimulation (VS)-produced analgesia in nociceptive tests. When adult, "capsaicin" females (n = 37) were significantly greater than controls (n = 24) in vocalization threshold (VT) to electrical tail shock (55.4%) and in paw lick (PL) latency to a hot plate (75.9%). In contrast, neither tail flick (TF) latency nor the leg withdrawal reflex (LWR) to mechanical pressure of the ipsilateral hind paw was affected by neonatal capsaicin. In response to VS, the controls showed a significant increase in thermal (TF, 279%; PL, 411%), mechanical pressure (LWR, 100%) and electrical (VT, 86.8%) pain thresholds. The "capsaicin" females response to VS was significantly less than controls in TF (26.1%), PL (26.0%), and LWR (54.1%) measures, and surprisingly, during VS their VT was significantly decreased below baseline levels 12.2% +/- 4.3. These results suggest that neonatal capsaicin treatment differentially attenuates the analgesia-producing component of VS, while sparing a nociception-inducing component of this stimulus. That is, after neonatal capsaicin treatment, the ability of VS to produce analgesia is reduced; moreover, VS lowers the VT, suggesting that it actually becomes a noxious stimulus in and of itself.

GABAergic neurotransmission has been implicated in the control of the steroid-dependent behavior, lordosis. GABA has dual effects on lordosis: it facilitates lordosis through actions in the medial hypothalamus (mHYP) and it inhibits lordosis through actions in the preoptic area (POA). In the present study, gonadally intact and ovariectomized female rats were behaviorally tested with a sexually active male. Brains were removed from sexually receptive female either 1 or 24 h after behavioral testing. There was a significant difference in endogenous GABA concentration in HYP and POA between receptive, postreceptive and ovariectomized nonreceptive females. Specifically, GABA levels in postreceptive females were higher in the HYP (20%) and lower in the POA (21%) in comparison to receptive females (p less than 0.05). There was also a significant change in binding parameters of 3H-muscimol in the HYP and POA of receptive females as compared to 24 h postreceptive and ovariectomized rats. Attempts to modulate 3H-GABA release from hypothalamic tissue slices by estrogen or progesterone in ovariectomized rats yielded no effect on this parameter.

Dental implants have become an accepted form of dental care, with reported functional 5-year success rates of 90% and higher. These impressive statistics include, but do not identify, the problems that may have been created by clinical ineptitude. Diagnostic acumen and preventive measures at each stage of the implant treatment can avoid many problems. Also, appropriate measures of timely recognition, rescue, and repair can often restore ailing implants and their prosthetic appliances to full function.

Two groups of 1-month-old pre-ruminant lambs of similar mean liveweights were fed identical liquid milk-replacer diets except that the zinc contents were either 5 micrograms (deficient diet) or 32 micrograms per gram of dry matter (control diet). These diets were fed for 4 weeks, after which all the lambs received the control diet for 2 weeks. In the lambs fed the deficient diet plasma zinc concentration decreased markedly during the first 2 weeks and skin lesions developed around their mouths. Autophagic vacuoles also developed in most follicle bulbs along with a variety of defects in the wool fibres and progressive inhibition of wool growth. Food intake and liveweight increase were not significantly depressed until the third and fourth weeks of feeding the deficient diet. During this period the wool was shed from the zinc-deficient lambs as a result of the fibres being degraded and distorted within thickened outer root sheaths in the distal (upper) parts of the follicles. In addition, the epidermis of the wool-bearing skin became slightly acanthotic and hyperkeratotic, although not parakeratotic. When the deficient lambs were fed the control diet for 2 weeks, their food intake, liveweight gain and plasma zinc concentration increased to almost those of the control lambs, but their rate of wool growth was still low and the epidermis had not returned to normal. Compared with previous studies the findings of this study suggest that pre-ruminant lambs may be more susceptible to the effects of zinc deficiency than ruminant lambs.

The effect of maternal metabolic state on the response to dietary zinc deficiency was assessed with the pregnant rat as a model. Sprague-Dawley rats were fed from mating to term: 1) a zinc-adequate (100 micrograms/g) control diet ad libitum, or 2) a zinc-deficient diet (0.7 micrograms/g) ad libitum, or 3) a control diet at reduced intake, or 4) a zinc-deficient diet at reduced intake, or 5) a zinc-deficient diet ad libitum plus additional zinc-deficient diet, fed by intubation, to maintain total intake at approximately 14 g/day. Dams receiving the zinc-deficient diet deposited more zinc (240-330%) into the products of conception than was consumed, showing that tissue catabolism is a substantial source of zinc. In rats fed the control diet ad libitum only 3% of the zinc consumed was deposited into the products of conception. Litters from dams fed the deficient diet at restricted levels (resulting in greater tissue catabolism) had fewer malformations and resorptions than litters from dams fed the zinc-deficient diet ad libitum. Maintenance of total intake of the zinc-deficient diet at 14 g/day by intubation resulted in a pronounced drop in voluntary intake. By day 18 of pregnancy voluntary intake had almost ceased, following day 18 the rats became severely distressed if any zinc-deficient diet was force-fed. Rats fed the zinc-deficient diet ad libitum also displayed a dramatic fall in voluntary intake after day 18 of gestation. These data show that the reduction in food intake during zinc deficiency is not due to gustatory influences alone and that metabolic state, defined as the balance between anabolism and catabolism, is a critical factor in determining the availability of zinc to the litter during zinc deficiency.

Earlier studies have shown that diets that increase tissue catabolism reduce the teratogenic effects of zinc deficiency. The hypothesis that zinc may be released from body tissues when the metabolic state is altered was further tested. Nonpregnant Sprague-Dawley females were injected with 65Zn; after equilibration, the two major pools of zinc, bone and muscle had different specific activities, muscle being much higher. Females were mated and fed diets adequate in zinc and calcium, deficient in zinc alone or deficient in both zinc and calcium. Calculations using weight loss, zinc content of maternal bone and muscle and total zinc content of the fetus at term indicated that most of the zinc in the fetus at term in both the zinc-deficient and zinc-calcium-deficient groups came from breakdown of maternal muscle in the last 3 d of pregnancy. The relatively small amount of additional zinc released from bone in the zinc-calcium-deficient rats early in pregnancy was sufficient to prevent abnormal organogenesis. Specific activity of zinc in the zinc-deficient and zinc-calcium-deficient fetuses was equal and high, indicating that most zinc in these fetuses came from maternal tissues and from the same maternal sources in both groups. In contrast, specific activity of zinc in the fetuses from rats fed adequate zinc and calcium was less than 30% of that in either of the deficient groups; this is consistent with the hypothesis that most zinc accrued by these fetuses came directly from the diet.

Two experiments were carried out in Western Australia to investigate the effect of zinc supplementation, on the reproductive performance of grazing Merino ewes. We found that supplemental zinc, when provided prior to mating and throughout pregnancy, increased the number of lambs produced by 14% (P<0.05) in both experiments.An intermediate zinc treatment, when supplementation was begun later in pregnancy gave a 9% (P<0.01) increase in the number of lambs in one experiment and no increase in the second. Lamb birth weights were increased by zinc supplementation in Experiment 1 and in Experiment 2, 12-20-week-old lambs from zinc supplemented ewes were 2.1 kg heavier than those from nonsupplemented controls. Plasma zince levels decreased significantly during pregnancy and lactation, but were increased at some sampling dates by 20-25% by zinc supplementation.

An experiment was conducted to determine the effects of autogenic and "opposite autogenic" verbal formulae upon electrodermal activity. In a between-subjects design, 15 unpracticed volunteers listened to and followed tape recorded imagery suggestions for relaxation and quietude, heaviness and warmth in the extremities, warmth in the central area of the body, coolness of the forehead, and calmness and regularity of breathing and circulation; 15 additional volunteers were exposed to opposite suggestions. Frequency of spontaneous GSRs, cumulative peak amplitude of spontaneous GSRs, and basal skin resistance levels were measured during 2 min epochs before and after the suggestions. Directionally appropriate changes occurred in all three electrodermal measures; these changes were significant for the two GSR measures and approached significance for the BSR measure. The autogenic suggestions produced greater and more reliable visceral effects than did the "opposite autogenic" suggestions.

Phencyclidine (PCP), haloperidol, and naloxone were administered alone and in combination to rats responding under a fixed-interval schedule for water presentation. Lower doses of PCP (0.25-2.0 mg/kg) and naloxone (0.001-0.1 mg/kg) produced increases while higher doses produced dose-dependent decreases in response rate. Haloperidol (0.0625-0.5 mg/kg) produced a monotonic dose-dependent decrease in responding. When a dose of naloxone (8.0 mg/kg) that did not alter responding was administered prior to the PCP, the PCP dose-response curve was shifted to 6.5-fold lower doses of PCP. When a dose of haloperidol (0.0625 mg/kg) that did not alter responding was administered prior to the PCP, the PCP dose-response curve was shifted to 1.5-fold higher dose of PCP. These observations are discussed in relation to current views of the mechanism of PCP action.

Several alternative fatty acid substrates have been employed to characterise the kinetics of rat basophilic leukaemia cell (RBL-1) 5-lipoxygenase. Using arachidonic acid (AA) as substrate, enzymes rates declined at high substrate concentrations (greater than 25 microM) and were associated with pronounced lag phases. The concentrations of AA at which apparent substrate inhibition and lag phases were observed were comparable with those at which AA induced emulsion formation in aqueous media. No evidence for substrate inhibition or lag phases was observed using eicosapentaenoic acid (EPA), a more soluble substrate which did not induce emulsion formation at concentrations up to 100 microM. Reactions catalysed by RBL-1 5-lipoxygenase terminated before exhaustion of substrate. AA and EPA induced time-dependent enzyme inactivation at concentrations 100-fold lower than their apparent Km values for the enzyme. The ability of several fatty acids to induce time-dependent inactivation was directly proportional to their substrate potency. We conclude that apparent substrate inhibition is a consequence of a change from monomeric to micellar substrate which has a lower affinity for the enzyme and that premature termination of the enzyme reactions is a consequence of product-induced enzyme inactivation.

The utilization and distribution of copper during dietary copper deficiency was studied in the pregnant rat, and the effects of maternal copper deficiency on fetal development were compared with those of maternal zinc deficiency. Sprague-Dawley rats were fed from mating to term (per gram diet): 1) a control diet (10 micrograms copper, 100 micrograms zinc) or 2) a copper-deficient diet (0.7 micrograms copper, 100 micrograms zinc) or 3) a zinc-deficient diet (10 micrograms copper; 0.7 micrograms zinc). Dams fed the copper-deficient diet deposited only 15.5% of the dietary copper consumed during pregnancy into the products of conception (fetuses, uterus and placentas); in comparison dams fed the zinc-deficient diet deposited more zinc into their litters than was consumed (240%). Copper concentration in the fetuses of copper-deficient dams was 30% of that of controls, but the size and number of live fetuses was unaffected. The zinc concentration of the zinc-deficient fetuses was 78% of that of the controls, and both the size and number of live fetuses were considerably lower than normal. Accumulation of copper in the products of conception may be accounted for by dietary copper intake, whereas accumulation of zinc in fetuses of zinc-deficient females is dependent in part on catabolism of maternal tissues.