L-Menthol mouth rinse or ice slurry ingestion during the latter stages of exercise in the heat provide a novel stimulus to enhance performance despite elevation in mean body temperature.

PURPOSE: This study investigated the effects of L-menthol mouth rinse and ice slurry ingestion on time to exhaustion, when administered at the latter stages (~ 85%) of baseline exercise duration in the heat (35 °C). METHOD: Ten male participants performed four time to exhaustion (TTE) trials on a cycle ergometer at 70% Wmax. In a randomized crossover design, (1) placebo-flavored non-calorific mouth rinse, (2) L-menthol mouth rinse (0.01%), or (3) ice ingestion (1.25 g kg-1), was administered at 85% of participants' baseline TTE. Time to exhaustion, core and skin temperature, heart rate, rating of perceived effort, thermal comfort and thermal sensation were recorded. RESULTS: From the point of administration at 85% of baseline TTE, exercise time was extended by 1% (placebo, 15 s), 6% (L-menthol, 82 s) and 7% (ice, 108 s), relative to baseline performance (P = 0.036), with no difference between L-menthol and ice (P > 0.05). Core temperature, skin temperature, and heart rate increased with time but did not differ between conditions (P > 0.05). Thermal sensation did not differ significantly but demonstrated a large effect size (P = 0.080; [Formula: see text] = 0.260). CONCLUSION: These results indicate that both thermally cooling and non-thermally cooling oral stimuli have an equal and immediate behavioral, rather than physiological, influence on exhaustive exercise in the heat.

MYBPC1 mutations impair skeletal muscle function in zebrafish models of arthrogryposis.

Myosin-binding protein C1 (MYBPC1) is an abundant skeletal muscle protein that is expressed predominantly in slow-twitch muscle fibers. Human MYBPC1 mutations are associated with distal arthrogryposis type 1 and lethal congenital contracture syndrome type 4. As MYBPC1 function is incompletely understood, the mechanism by which human mutations result in contractures is unknown. Here, we demonstrate using antisense morpholino knockdown, that mybpc1 is required for embryonic motor activity and survival in a zebrafish model of arthrogryposis. Mybpc1 morphant embryos have severe body curvature, cardiac edema, impaired motor excitation and are delayed in hatching. Myofibril organization is selectively impaired in slow skeletal muscle and sarcomere numbers are greatly reduced in mybpc1 knockdown embryos, although electron microscopy reveals normal sarcomere structure. To evaluate the effects of human distal arthrogryposis mutations, mybpc1 mRNAs containing the corresponding human W236R and Y856H MYBPC1 mutations were injected into embryos. Dominant-negative effects of these mutations were suggested by the resultant mild bent body curvature, decreased motor activity, as well as impaired overall survival compared with overexpression of wild-type RNA. These results demonstrate a critical role for mybpc1 in slow skeletal muscle development and establish zebrafish as a tractable model of human distal arthrogryposis.

Kinesin family member 6 (kif6) is necessary for spine development in zebrafish.

BACKGROUND: Idiopathic scoliosis is a form of spinal deformity that affects 2-3% of children and results in curvature of the spine without structural defects of the vertebral units. The pathogenesis of idiopathic scoliosis remains poorly understood, in part due to the lack of a relevant animal model. RESULTS: We performed a forward mutagenesis screen in zebrafish to identify new models for idiopathic scoliosis. We isolated a recessive zebrafish mutant, called skolios, which develops isolated spinal curvature that arises independent of vertebral malformations. Using meiotic mapping and whole genome sequencing, we identified a nonsense mutation in kinesin family member 6 (kif6(gw326) ) unique to skolios mutants. Three additional kif6 frameshift alleles (gw327, gw328, gw329) were generated with transcription activator-like effector nucleases (TALENs). Zebrafish homozygous or compound heterozygous for kif6 frameshift mutations developed a scoliosis phenotype indistinguishable from skolios mutants, confirming that skolios is caused by the loss of kif6. Although kif6 may play a role in cilia, no evidence for cilia dysfunction was seen in kif6(gw326) mutants. CONCLUSIONS: Overall, these findings demonstrate a novel role for kif6 in spinal development and identify a new candidate gene for human idiopathic scoliosis.

Supporting the nation's transitioning veterans: Narrative review of practices and recommendations for psychotherapy and counseling of veterans separating from military service.

Each year, approximately 200,000 service members transition out of military service and return to civilian life. For many, the stresses of this military-to-civilian transition are vast and include instabilities in mental health, relationships, employment, education, and housing. Given their unique training, mental health professionals often find themselves on the front lines of efforts to support this population. However, to date, literature to guide work with this population has been scant and disorganized. This narrative review provides practitioners both within and outside the Veterans Health Administration with an overview of relevant literature in this area and offers concrete, practical recommendations for how to best support transitioning Veterans through psychotherapy and counseling. Three major themes are reviewed: (a) Engagement strategies, including clinical style, mitigation of privacy concerns, and consideration of broader psychosocial issues; (b) contextual considerations, including challenges of the "Thank You for Your Service" phenomenon, identity considerations, and circumstances of discharge; and (c) information about available services. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Bone strength and composition in spacefaring rodents: systematic review and meta-analysis.

Studying the effects of space travel on bone of experimental animals provides unique advantages, including the ability to perform post-mortem analysis and mechanical testing. To synthesize the available data to assess how much and how consistently bone strength and composition parameters are affected by spaceflight, we systematically identified studies reporting bone health in spacefaring animals from Medline, Embase, Web of Science, BIOSIS, and NASA Technical reports. Previously, we reported the effect of spaceflight on bone architecture and turnover in rodents and primates. For this study, we selected 28 articles reporting bone strength and composition in 60 rats and 60 mice from 17 space missions ranging from 7 to 33 days in duration. Whole bone mechanical indices were significantly decreased in spaceflight rodents, with the percent difference between spaceflight and ground control animals for maximum load of -15.24% [Confidence interval: -22.32, -8.17]. Bone mineral density and calcium content were significantly decreased in spaceflight rodents by -3.13% [-4.96, -1.29] and -1.75% [-2.97, -0.52] respectively. Thus, large deficits in bone architecture (6% loss in cortical area identified in a previous study) as well as changes in bone mass and tissue composition likely lead to bone strength reduction in spaceflight animals.

Partnered implementation of the veteran sponsorship initiative: protocol for a randomized hybrid type 2 effectiveness-implementation trial.

BACKGROUND: The USA is undergoing a suicide epidemic for its youngest Veterans (18-to-34-years-old) as their suicide rate has almost doubled since 2001. Veterans are at the highest risk during their first-year post-discharge, thus creating a "deadly gap." In response, the nation has developed strategies that emphasize a preventive, universal, and public health approach and embrace the value of community interventions. The three-step theory of suicide suggests that community interventions that reduce reintegration difficulties and promote connectedness for Veterans as they transition to civilian life have the greatest likelihood of reducing suicide. Recent research shows that the effectiveness of community interventions can be enhanced when augmented by volunteer and certified sponsors (1-on-1) who actively engage with Veterans, as part of the Veteran Sponsorship Initiative (VSI). METHOD/DESIGN: The purpose of this randomized hybrid type 2 effectiveness-implementation trial is to evaluate the implementation of the VSI in six cities in Texas in collaboration with the US Departments of Defense, Labor and Veterans Affairs, Texas government, and local stakeholders. Texas is an optimal location for this large-scale implementation as it has the second largest population of these young Veterans and is home to the largest US military installation, Fort Hood. The first aim is to determine the effectiveness of the VSI, as evidenced by measures of reintegration difficulties, health/psychological distress, VA healthcare utilization, connectedness, and suicidal risk. The second aim is to determine the feasibility and potential utility of a stakeholder-engaged plan for implementing the VSI in Texas with the intent of future expansion in more states. The evaluators will use a stepped wedge design with a sequential roll-out to participating cities over time. Participants (n=630) will be enrolled on military installations six months prior to discharge. Implementation efforts will draw upon a bundled implementation strategy that includes strategies such as ongoing training, implementation facilitation, and audit and feedback. Formative and summative evaluations will be guided by the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework and will include interviews with participants and periodic reflections with key stakeholders to longitudinally identify barriers and facilitators to implementation. DISCUSSION: This evaluation will have important implications for the national implementation of community interventions that address the epidemic of Veteran suicide. Aligned with the Evidence Act, it is the first large-scale implementation of an evidence-based practice that conducts a thorough assessment of TSMVs during the "deadly gap." TRIAL REGISTRATION: ClinicalTrials.gov ID number: NCT05224440 . Registered on 04 February 2022.

Bone health in spacefaring rodents and primates: systematic review and meta-analysis.

Animals in space exploration studies serve both as a model for human physiology and as a means to understand the physiological effects of microgravity. To quantify the microgravity-induced changes to bone health in animals, we systematically searched Medline, Embase, Web of Science, BIOSIS, and NASA Technical reports. We selected 40 papers focusing on the bone health of 95 rats, 61 mice, and 9 rhesus monkeys from 22 space missions. The percentage difference from ground control in rodents was -24.1% [Confidence interval: -43.4, -4.9] for trabecular bone volume fraction and -5.9% [-8.0, -3.8] for the cortical area. In primates, trabecular bone volume fraction was lower by -25.2% [-35.6, -14.7] in spaceflight animals compared to GC. Bone formation indices in rodent trabecular and cortical bone were significantly lower in microgravity. In contrast, osteoclast numbers were not affected in rats and were variably affected in mice. Thus, microgravity induces bone deficits in rodents and primates likely through the suppression of bone formation.

A gain of function mutation causing skeletal overgrowth in the rapunzel mutant.

Mechanisms that regulate the growth and form of the vertebrate skeleton are largely unknown. The zebrafish mutant rapunzel has heterozygous defects in bone development, resulting in skeletal overgrowth, thus identification of the genetic lesion underlying rapunzel might provide insight into the molecular basis of skeletogenesis. In this report, we demonstrate that the rapunzel mutant results from a missense mutation in the previously uncharacterized rpz gene. This conclusion is supported by genetic mapping, identification of a missense mutation in rapunzel(c14) in a highly conserved region of the rpz gene, and suppression of the rapunzel homozygous embryonic phenotype with morpholino knockdown of rpz. In addition, rpz transcripts are identified in regions correlating with the homozygous embryonic phenotype (head, pectoral fin buds, somites and fin fold). This report provides the first gene identification for a mutation affecting segment number in the zebrafish fin and development of both the fin ray (dermal) and the axial skeleton.

Severe ceftriaxone-induced hemolysis complicated by diffuse cerebral ischemia in a child with sickle cell disease.

Ceftriaxone-induced hemolytic anemia is a rare and often fatal phenomenon. We report here the case of a 6-year-old female with sickle cell disease who survived a brisk and profound hemolytic reaction, resulting in hemoglobin of 0.4 g/dL, after ceftriaxone infusion. Ongoing hemolysis was abrogated with aggressive supportive care, but the patient suffered extensive neurologic sequelae as a result of the event. Serologic testing confirmed the presence of ceftriaxone antibodies.

Successful use of plasma exchange for profound hemolysis in a child with loxoscelism.

We describe a 6-year-old boy who presented with massive hemolysis, shock, disseminated intravascular coagulopathy, and acute renal failure after loxosceles envenomation. In this patient, plasma exchange therapy (PEX) successfully cleared the plasma from an initial hemolytic index of 2000 (equivalent to 2 g/dL hemoglobin, where optimetric laboratory evaluation is impossible) to an index of <50 (no detectable hemolysis). This allowed the PICU team to correct his coagulopathy, assess his degree of organ dysfunction, and provide routine laboratory assessments during continuous venovenous hemodiafiltration. After 9 single volume PEX sessions, his hemolysis and coagulopathy had resolved and his plasma had cleared sufficiently to permit routine laboratory assessments without difficulty. Multiorgan system support with an aggressive transfusion strategy, mechanical ventilation, inotropes, and continuous venovenous hemodiafiltration resulted in complete recovery. We conclude that in the presence of overwhelming hemolysis, plasma can become so icteric that optimetric laboratory evaluation is impossible. In this setting, PEX can be used to clear the plasma, restoring the ability to perform routine laboratory assessments.

A chemical screen to identify novel inhibitors of fin regeneration in zebrafish.

We performed a chemical screen to look for novel inhibitors of zebrafish caudal fin regeneration. In a pilot screen, 520 compounds were tested. Two compounds, budesonide and AGN192403, abrogated fin regeneration. One compound in particular, AGN192403, targets the imidazoline receptor, a pathway not previously linked to fin regeneration. In addition to inhibiting regeneration of the adult fin, AGN192403 also blocked regeneration of the larval fin fold. Finally, the inhibitory effect of AGN192403 on fin regeneration persisted after removal of the drug. These studies demonstrate that chemical screening is feasible in adult zebrafish and that it is a reasonable strategy to use for exploring the biology of regeneration.

A developmental transition in growth control during zebrafish caudal fin development.

A long-standing question in developmental biology is how do growing and developing animals achieve form and then maintain it. We have revealed a critical transition in growth control during zebrafish caudal fin development, wherein a switch from allometric to isometric growth occurs. This morphological transition led us to hypothesize additional physiological changes in growth control pathways. To test this, we fasted juvenile and adult zebrafish. Juvenile fins continued allometric growth until development of the mature bi-lobed shape was completed. In contrast, the isometric growth of mature adult fins arrested within days of initiating a fast. We explored the biochemical basis of this difference in physiology between the two phases by assessing the sensitivity to rapamycin, a drug that blocks a nutrient-sensing pathway. We show that the nutrition-independent, allometric growth phase is resistant to rapamycin at 10-fold higher concentrations than are effective at arresting growth in the nutrition-dependent, isometric growth phase. We thus link a morphological transition in growth control between allometric and isometric growth mechanisms to different physiological responses to nutritional state of the animal and finally to different pharmacological responses to a drug (rapamycin) that affects the nutrition-sensing mechanism described from yeast to human.

Saltatory control of isometric growth in the zebrafish caudal fin is disrupted in long fin and rapunzel mutants.

Zebrafish fins grow by sequentially adding new segments of bone to the distal end of each fin ray. In wild type zebrafish, segment addition is regulated such that an isometric relationship is maintained between fin length and body length over the lifespan of the growing fish. Using a novel, surrogate marker for fin growth in conjunction with cell proliferation assays, we demonstrate here that segment addition is not continuous, but rather proceeds by saltation. Saltation is a fundamental growth mechanism shared by disparate vertebrates, including humans. We further demonstrate that segment addition proceeds in conjunction with cyclic bursts of cell proliferation in the distal fin ray mesenchyme. In contrast, cells in the distal fin epidermis proliferate at a constant rate throughout the fin ray growth cycle. Finally, we show that two separate fin overgrowth mutants, long fin and rapunzel, bypass the stasis phase of the fin ray growth cycle to develop asymmetrical and symmetrical fin overgrowth, respectively.