Deletion of Fibroblast growth factor 9 globally and in skeletal muscle results in enlarged tuberosities at sites of deltoid tendon attachments.

BACKGROUND: The growth of most bony tuberosities, like the deltoid tuberosity (DT), rely on the transmission of muscle forces at the tendon-bone attachment during skeletal growth. Tuberosities distribute muscle forces and provide mechanical leverage at attachment sites for joint stability and mobility. The genetic factors that regulate tuberosity growth remain largely unknown. In mouse embryos with global deletion of fibroblast growth factor 9 (Fgf9), the DT size is notably enlarged. In this study, we explored the tissue-specific regulation of DT size using both global and targeted deletion of Fgf9. RESULTS: We showed that cell hypertrophy and mineralization dynamics of the DT, as well as transcriptional signatures from skeletal muscle but not bone, were influenced by the global loss of Fgf9. Loss of Fgf9 during embryonic growth led to increased chondrocyte hypertrophy and reduced cell proliferation at the DT attachment site. This endured hypertrophy and limited proliferation may explain the abnormal mineralization patterns and locally dysregulated expression of markers of endochondral development in Fgf9null attachments. We then showed that targeted deletion of Fgf9 in skeletal muscle leads to postnatal enlargement of the DT. CONCLUSION: Taken together, we discovered that Fgf9 may play an influential role in muscle-bone cross-talk during embryonic and postnatal development.

The Brain Image Library: A Community-Contributed Microscopy Resource for Neuroscientists.

Advancements in microscopy techniques and computing technologies have enabled researchers to digitally reconstruct brains at micron scale. As a result, community efforts like the BRAIN Initiative Cell Census Network (BICCN) have generated thousands of whole-brain imaging datasets to trace neuronal circuitry and comprehensively map cell types. This data holds valuable information that extends beyond initial analyses, opening avenues for variation studies and robust classification of cell types in specific brain regions. However, the size and heterogeneity of these imaging data have historically made storage, sharing, and analysis difficult for individual investigators and impractical on a broad community scale. Here, we introduce the Brain Image Library (BIL), a public resource serving the neuroscience community that provides a persistent centralized repository for brain microscopy data. BIL currently holds thousands of brain datasets and provides an integrated analysis ecosystem, allowing for exploration, visualization, and data access without the need to download, thus encouraging scientific discovery and data reuse.

Idiopathic myelofibrosis in children: primary myelofibrosis, essential thrombocythemia, or transient process?

We report 3 pediatric cases of primary/idiopathic myelofibrosis (PMF/IMF). Two cases exhibited clinical courses not typically observed in adult patients in whom this process is much more common. One of these cases exhibited spontaneous clinical and bone marrow resolution, whereas the other case achieved near resolution of myelofibrosis in response to cytoreductive therapy alone. However, the third case of IMF that met diagnostic criteria for essential thrombocythemia with a JAK2V617F mutation had central venous thrombosis that resulted in blindness. PMF/IMF, a rare finding in children, does not seem to portend the same level of risk as seen in adults with the same process, thus less aggressive management may be appropriate. However, delayed diagnosis of mutation-associated PMF or essential thrombocythemia can lead to devastating consequences. We review the literature and discuss the complexities surrounding diagnosis, risk stratification, and management of pediatric PMF/IMF.

Comprehensive testing and rapid dissemination of local drug supply surveillance data in Rhode Island.

BACKGROUND: The North American overdose crisis has continued at unprecedented rates with more than 100,000 overdose deaths estimated to have occurred in the United States in 2022. Regional variations in overdose rates signify differences in local drug supplies. State-level drug supply surveillance systems have been limited in their ability to document and communicate the rapidly changing drug supplies which can hinder harm reduction efforts at the community level. We sought to address by piloting a two-year, community-engaged local drug supply surveillance program in Rhode Island (RI). METHODS: The first set of samples (n = 125) were collected from May 2022 to January 2023 across RI and included used paraphernalia (e.g., cookers), refuse (e.g., baggies), and product. Samples were tested using comprehensive toxicology testing approaches via liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF-MS). Results were disseminated to participants and the broader public across platforms. RESULTS: Fentanyl was detected in 67.2% of all samples tested. 39.2% (n = 49) of samples were expected to be fentanyl. Xylazine was detected in 41.6% of all samples-always in combination with fentanyl-and no samples were expected to contain xylazine. In expected stimulant samples (n = 39), 10% contained fentanyl and/or analogues as major substances and 30.8% contained trace amounts of fentanyl and/or analogues. In expected stimulant samples, 15.4% contained xylazine with fentanyl. No opioids or benzodiazepines were detected in expected hallucinogen or dissociative samples (n = 7). In expected benzodiazepine samples (n = 8), no opioids were detected. CONCLUSIONS: Our results describe part of the local drug supply in Rhode Island, including a presence of NPS and adulterants (e.g., designer benzodiazepines, xylazine). Importantly, our findings underscore the feasibility of developing a community-driven drug supply surveillance database. Expanding drug supply surveillance initiatives is imperative for improving the health and safety of people who use drugs and informing public health approaches to addressing the overdose crisis.

Sexually dimorphic mechanisms of VGLUT-mediated protection from dopaminergic neurodegeneration.

Parkinson's disease (PD) targets some dopamine (DA) neurons more than others. Sex differences offer insights, with females more protected from DA neurodegeneration. The mammalian vesicular glutamate transporter VGLUT2 and Drosophila ortholog dVGLUT have been implicated as modulators of DA neuron resilience. However, the mechanisms by which VGLUT2/dVGLUT protects DA neurons remain unknown. We discovered DA neuron dVGLUT knockdown increased mitochondrial reactive oxygen species in a sexually dimorphic manner in response to depolarization or paraquat-induced stress, males being especially affected. DA neuron dVGLUT also reduced ATP biosynthetic burden during depolarization. RNA sequencing of VGLUT+ DA neurons in mice and flies identified candidate genes that we functionally screened to further dissect VGLUT-mediated DA neuron resilience across PD models. We discovered transcription factors modulating dVGLUT-dependent DA neuroprotection and identified dj-1ß as a regulator of sex-specific DA neuron dVGLUT expression. Overall, VGLUT protects DA neurons from PD-associated degeneration by maintaining mitochondrial health.

LiverClear: A versatile protocol for mouse liver tissue clearing.

Although there are numerous tissue clearing protocols, most are inadequate for clearing liver tissue. Here we present a flexible protocol for mouse liver tissue; we combine strategies from several previously published protocols for delipidation, decolorization, staining, and refractive index matching. LiverClear is sufficiently versatile to allow clearing of healthy and diseased mouse liver followed by immunofluorescence staining and imaging to visualize intact 3D structures such as bile ducts and hepatocyte canaliculi. We also adapted this protocol for clearing human livers. For complete details on the use and execution of this protocol, please refer to Molina et al. (2021).

Giant Coronary Artery Aneurysms.

We present the case of a patient with giant coronary artery aneurysm. He has underlying severe coronary atherosclerosis and concomitant aneurysms of the abdominal aorta and popliteal artery. Our patient was treated surgically in the past due to underlying severe atherosclerosis. Despite bypass, his coronary aneurysms continued to enlarge. There is a lack of randomized trials regarding management to guide the decision-making process. Our case describes the work-up and treatment of a patient with giant coronary artery aneurysm requiring urgent orthopedic surgery.

Anticoagulation in a Patient With Mechanical Prosthetic Valves and Calcific Uremic Arteriolopathy on Warfarin.

Calciphylaxis, or calcific uremic arteriolopathy (CUA), is a rare vascular calcific disease that is most often associated with renal dysfunction and warfarin, particularly end-stage renal disease (ESRD). This condition causes debilitatingly painful skin lesions, oftentimes plaques, throughout areas of cutaneous and subcutaneous adiposity. The progression of these lesions to black eschar with ulceration is the hallmark of CUA. In this report, we present the case of a Caucasian female with a past medical history of nephrogenic systemic fibrosis (NSF), ESRD, and mechanical aortic and mitral valves, anticoagulated with warfarin, who developed CUA. In the setting of mechanical prosthetic valves, vitamin K antagonists (VKA) and aspirin are the only evidence-based antithrombotic therapies. This case presents challenging decision-making when managing anticoagulant therapy in the absence of applicable guidelines.

Coronary Subclavian Steal Syndrome With Neurological Symptoms After Coronary Artery Bypass Grafting.

Coronary subclavian steal syndrome (CSSS) is a complication of coronary artery bypass graft surgery with the left internal mammary artery that results from left subclavian artery stenosis. A reversal of flow in the left internal mammary artery results in ischemia of the heart. We present the case of a 54-year-old man with CSSS with the rare symptom of dizziness. This indicates a potential component of undiagnosed vertebral steal syndrome as well.

Twinning: Coronary Artery Disease in Monozygotic Twins.

We present the case of a patient whose monozygotic twin brother suffered a fatal myocardial infarction at the age of 40. The patient presented with similar symptoms as his brother. Given the family history, ischemic evaluation was undertaken and revealed similar coronary anatomy and severe coronary artery disease (CAD). We review the current literature regarding genetic and environmental factors regarding coronary anatomy, locations of atherosclerotic lesions, and screening in twins.

First trimester mechanisms of gestational sac placental and foetal teratogenicity: a framework for birth cohort studies.

BACKGROUND: The function of the gestational sac (GS) and the placenta in the closely related processes of embryogenesis and teratogenicity in the first trimester has been minimally described. The prevailing assumption is that direct teratogenic effects are mediated by the critical extraembryonic organ, the placenta, which either blocks or transfers exposures to the foetus. Placental transfer is a dominant mechanism, but there are other paradigms by which the placenta can mediate teratogenic effects. Knowledge of these paradigms and first trimester human developmental biology can be useful to the epidemiologist in the conduct of biomarker-based studies of both maternal and child health. OBJECTIVE AND RATIONALE: Our aim is to provide a causal framework for modelling the teratogenic effects of first trimester exposures on child health outcomes mediated by the GS and placenta using biomarker data collected in the first trimester. We initially present first trimester human developmental biology for the sake of informing and strengthening epidemiologic approaches. We then propose analytic approaches of modelling placental mechanisms by way of causal diagrams using classical non-embryolethal teratogens (diethylstilboestrol [DES], folic acid deficiency and cytomegalovirus [CMV]) as illustrative examples. We extend this framework to two chronic exposures of particular current interest, phthalates and maternal adiposity. SEARCH METHODS: Information on teratogens was identified by a non-systematic, narrative review. For each teratogen, we included papers that answered the five following questions: (i) why were these exposures declared teratogens? (ii) is there a consensus on biologic mechanism? (iii) is there reported evidence of a placental mechanism? (iv) can we construct a theoretical model of a placental mechanism? and (v) can this knowledge inform future work on measurement and modelling of placental-foetal teratogenesis? We prioritized literature specific to human development, the organogenesis window in the first trimester and non-embryolethal mechanisms. OUTCOMES: As a result of our review of the literature on five exposures considered harmful in the first trimester, we developed four analytic strategies to address first trimester placental mechanisms in birth cohort studies: placental transfer and direct effects on the foetus (DES and maternal adiposity), indirect effects through targeted placental molecular pathways (DES and phthalates), pre-placental effects through disruptions in embryonic and extraembryonic tissue layer differentiation (folic acid deficiency), and multi-step mechanisms that involve maternal, placental and foetal immune function and inflammation (DES and CMV). WIDER IMPLICATIONS: The significance of this review is to offer a causal approach to classify the large number of potentially harmful exposures in pregnancy when the exposure occurs in the first trimester. Our review will facilitate future research by advancing knowledge of the first trimester mechanisms necessary for researchers to effectively associate environmental exposures with child health outcomes.

Ovulation Induction for the General Gynecologist.

The practice of ovulation induction often falls to the reproductive endocrinology and infertility specialist. However, attitudes toward the evaluation and treatment of infertility has shifted among general obstetrician-gynecologists (OB-GYN). This review discusses the underlying scientific basis of anovulation and clinical guidelines regarding the use of different medications for the purpose of promoting follicular recruitment and ovulation for the general OB-GYN.

B Lymphoblastic Leukemia With a Novel t(11;15) (q23;q15) and Unique Burkittoid Morphologic and Immunophenotypic Findings in a 9-Year-Old Boy.

B lymphoblastic leukemia is a B progenitor cell neoplasm with a range of immature immunophenotypes and several associated cytogenetic lesions. In contrast, Burkitt leukemia/lymphoma is a mature B lymphocyte neoplasm with a characteristic germinal center immunophenotype and MYC rearrangement. With modern immunophenotyping and cytogenetic methods, the distinction between these 2 entities is seldom ambiguous. Herein, we report a case of a 9-year-old white boy with circulating leukemic cells that demonstrate morphologic overlap between Burkitt leukemia and B lymphoblastic leukemia. Flow cytometry and immunohistochemical stains demonstrated expression of sets of markers with overlap between immature and mature immunophenotypes. While the leukemic cells tested positive for terminal deoxynucleotidyl transferase (TdT), they expressed CD20, BCL6 (in a subset), and lambda-restricted surface light chain. Molecular studies confirmed a true clonal light chain rearrangement, whereas fluorescent in situ hybridization (FISH) results were negative for MYC rearrangement. Metaphase cytogenetics identified a novel gene rearrangement, t(11;15)(q23;q15), that does not involve the MLL gene. This unique cytogenetic abnormality involves the loss of INO80, an adenosine triphosphatase (ATPase) with DNA binding ability. This cytogenetic abnormality may represent a unique feature of this overlap entity of B lymphoblastic lymphoma that expresses markers of maturity and demonstrates Burkitt-like morphology.

The ambiguous boundary between EBV-related hemophagocytic lymphohistiocytosis and systemic EBV-driven T cell lymphoproliferative disorder.

Epstein Barr virus (EBV)-related hemophagocytic lymphohistiocytosis (EBV-HLH) is a form of acquired, infection-related HLH which typically represents a fulminant presentation of an acute EBV infection of CD8+ T cells with 30-50% mortality rate. Systemic EBV-positive lymphoproliferative disease of childhood (SE-LPD) is a rare T cell lymphoproliferative disorder predominantly arising in the setting of acute EBV infection, often presenting with HLH. Since both entities have been associated with clonal T cell populations, the discrimination between these diseases is often ambiguous. We report a unique case of a 21 years old female who presented with clinical and laboratory findings of florid HLH in the setting of markedly elevated EBV titers (>1 million) and an aberrant T cell population shown to be clonal by flow cytometry, karyotype, and molecular studies. This case raises the differential of EBV-HLH versus SE-LPD. Review of the literature identified 74 cases of reported EBV-HLH and 21 cases of SE-LPD with associated HLH in 25 studies. Of those cases with available outcome data, 62 of 92 cases (67%) were fatal. Of 60 cases in which molecular clonality was demonstrated, 37 (62%) were fatal, while all 14 cases (100%) demonstrating karyotypic abnormalities were fatal. Given the karyotypic findings in this sentinel case, a diagnosis of SE-LPD was rendered. The overlapping clinical and pathologic findings suggest that EBV-HLH and SE-LPD are a biologic continuum, rather than discrete entities. The most clinically useful marker of mortality was an abnormal karyotype rather than other standards of clonality assessment.