Constitutional mismatch repair deficiency: a case on a commonly misinterpreted mutation in colon cancer.

It is estimated that 153,020 cases of CRC per year, with an increase in diagnoses in younger patients. We present a case of a female with an early presentation of Lynch Syndrome and CRC, who, on her third malignant presentation, was re-diagnosed as a constitutional mismatch repair deficiency.

Systematic review of the impact of heatwaves on health service demand in Australia.

OBJECTIVES: Heatwaves have been linked to increased levels of health service demand in Australia. This systematic literature review aimed to explore health service demand during Australian heatwaves for hospital admissions, emergency department presentations, ambulance call-outs, and risk of mortality. STUDY DESIGN: A systematic review to explore peer-reviewed heatwave literature published from 2000 to 2020. DATA SOURCES: Articles were reviewed from six databases (MEDLINE, Scopus, Web of Science, PsychINFO, ProQuest, Science Direct). Search terms included: heatwave, extreme heat, ambulance, emergency department, and hospital. Studies were included if they explored heat for a period of two or more consecutive days. Studies were excluded if they did not define a threshold for extreme heat or if they explored data only from workers compensation claims and major events. DATA SYNTHESIS: This review was prospectively registered with PROSPERO (# CRD42021227395 ). Forty-five papers were included in the final review following full-text screening. Following a quality assessment using the GRADE approach, data were extracted to a spreadsheet and compared. Significant increases in mortality, as well as hospital, emergency, and ambulance demand, were found across Australia during heatwave periods. Admissions for cardiovascular, renal, respiratory, mental and behavioural conditions exhibited increases during heatwaves. The most vulnerable groups during heatwaves were children (< 18 years) and the elderly (60+). CONCLUSIONS: Heatwaves in Australia will continue to increase in duration and frequency due to the effects of climate change. Health planning is essential at the community, state, and federal levels to mitigate the impacts of heatwaves on health and health service delivery especially for vulnerable populations. However, understanding the true impact of heatwaves on health service demand is complicated by differing definitions and methodology in the literature. The Excess Heat Factor (EHF) is the preferred approach to defining heatwaves given its consideration of local climate variability and acclimatisation. Future research should explore evidence-based and spatially relevant heatwave prevention programs. An enhanced understanding of heatwave health impacts including service demand will inform the development of such programs which are necessary to promote population and health system resilience.

Antibiotic Use on Goat Farms: An Investigation of Knowledge, Attitudes, and Behaviors of Missouri Goat Farmers.

Use of low dose, prophylactic antibiotics contributes to the emergence of antibiotic resistant bacteria. In one study, goat meat in Missouri was found to have a higher percentage of antibiotic residues at slaughter than the national average, so we attempted to identify factors related to goat production that may contribute to this issue. Using the knowledge, attitude, and behavior (KAB) model, we interviewed 11 Missouri goat farmers about factors affecting antibiotic use. Most of the farmers did not have specific protocols for managing illnesses and only relied on veterinarians for major health issues. Many felt veterinarians lacked knowledge about goat medicine so instead relied on other farmers' or their own experiences for treatment modalities. While most agreed that antibiotic resistance was a concern, only 4 of the 11 indicated that they only used antibiotics when prescribed by the veterinarian. Veterinarians should be relied on and valued for their medical expertise, but they are not always being utilized in this manner. Therefore, veterinary education should emphasize goat health management to a greater extent than it currently does, and soft skills to build collaborative relationships with farmers should be taught to promote preventative health measures and more judicious use of antibiotics.

Potential roles of Arnt2 in zebrafish larval development.

The aryl hydrocarbon receptor nuclear translocator (ARNT) is a basic helix-loop-helix-PAS heterodimeric transcription factor that dimerizes with other basic helix-loop-helix-PAS proteins to mediate biological responses. The function of ARNT2 is poorly understood. Here we provide an initial characterization of the zebrafish arnt2 null (arnt2(-/-)) mutant to identify functions of Arnt2 during development. Arnt2(-/-) mutant zebrafish develop normally until 120 hours postfertilization (hpf ) when morphological changes and functional deficits occur. The C-start escape response initiated by either touch or startle stimuli is absent in the mutants. Brain ventricle size is markedly increased at 120 hpf. Heart ventricles are enlarged, with decreased ventricle wall thickness. A cardiac arrhythmia, characterized by missing beats, is also observed in the mutants. This is associated with bradycardia in arnt2(-/-) larvae. Dilated liver sinusoids merge abnormally to form an extensive, labyrinth-like network of vascular channels. External appearance of arnt2(-/-) larvae at 120 hpf is indistinguishable from wild type except that the swim bladder is not inflated. The arnt2(-/-) mutants are not debilitated when phenotypic effects are first detected at 120 hpf that culminate in mortality, 4 days later around 216 hpf. Gross morphological assessment of the development of forebrain, midbrain, and hindbrain regions, neuromasts and Mauthner neurons, inner ear semicircular canals and otoliths, primary motor neurons, trigeminal ganglia, and trunk skeletal muscles, before or when the arnt2(-/-) phenotype was observed, failed to demonstrate a difference from wild type. The only effect in arnt2(-/-) larvae that occurred before 120 hpf was a decrease in expression of sim1, an Arnt2 dimerization partner, in the hypothalamus and ventral thalamus at 72 hpf. Further research is needed to determine if the primary functions of Arnt2 occur during the larval stage, when the phenotype is observed, or earlier in development.

Molecular targets of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) within the zebrafish ovary: insights into TCDD-induced endocrine disruption and reproductive toxicity.

TCDD is a reproductive toxicant and endocrine disruptor, yet the mechanisms by which it causes these reproductive alterations are not fully understood. In order to provide additional insight into the molecular mechanisms that underlie TCDD's reproductive toxicity, we assessed TCDD-induced transcriptional changes in the ovary as they relate to previously described impacts on serum estradiol concentrations and altered follicular development in zebrafish. In silico computational approaches were used to correlate candidate regulatory motifs with observed changes in gene expression. Our data suggest that TCDD inhibits follicle maturation via attenuated gonadotropin responsiveness and/or depressed estradiol biosynthesis, and that interference of estrogen-regulated signal transduction may also contribute to TCDD's impacts on follicular development. TCDD may also alter ovarian function by disrupting various signaling pathways such as glucose and lipid metabolism, and regulation of transcription. Furthermore, events downstream from initial TCDD molecular-targets likely contribute to ovarian toxicity following chronic exposure to TCDD. Data presented here provide further insight into the mechanisms by which TCDD disrupts follicular development and reproduction in fish, and can be used to formulate new hypotheses regarding previously documented ovarian toxicity.

Developmental toxicity of low generation PAMAM dendrimers in zebrafish.

Biological molecules and intracellular structures operate at the nanoscale; therefore, development of nanomedicines shows great promise for the treatment of disease by using targeted drug delivery and gene therapies. PAMAM dendrimers, which are highly branched polymers with low polydispersity and high functionality, provide an ideal architecture for construction of effective drug carriers, gene transfer devices and imaging of biological systems. For example, dendrimers bioconjugated with selective ligands such as Arg-Gly-Asp (RGD) would theoretically target cells that contain integrin receptors and show potential for use as drug delivery devices. While RGD-conjugated dendrimers are generally considered not to be cytotoxic, there currently exists little information on the risks that such materials pose to human health. In an effort to compliment and extend the knowledge gleaned from cell culture assays, we have used the zebrafish embryo as a rapid, medium throughput, cost-effective whole-animal model to provide a more comprehensive and predictive developmental toxicity screen for nanomaterials such as PAMAM dendrimers. Using the zebrafish embryo, we have assessed the developmental toxicity of low generation (G3.5 and G4) PAMAM dendrimers, as well as RGD-conjugated forms for comparison. Our results demonstrate that G4 dendrimers, which have amino functional groups, are toxic and attenuate growth and development of zebrafish embryos at sublethal concentrations; however, G3.5 dendrimers, with carboxylic acid terminal functional groups, are not toxic to zebrafish embryos. Furthermore, RGD-conjugated G4 dendrimers are less potent in causing embryo toxicity than G4 dendrimers. RGD-conjugated G3.5 dendrimers do not elicit toxicity at the highest concentrations tested and warrant further study for use as a drug delivery device.

Structure and permeability of the egg capsule of the bonnethead shark, Sphyrna tiburo.

In the viviparous bonnethead shark, Sphyrna tiburo, a fluid-filled, acellular egg capsule surrounds fertilized eggs and developing embryos throughout gestation. Like other placental shark species, the capsule remains intact even at the placental implantation site. Although its intervention between the uterine and embryonic tissues of the placenta has long been thought to mediate physiological exchange, little information is available concerning even its basic structure or permeability to solutes. The 1 mum thick capsule wall consists of an inner layer of gelatinous material and an outer layer consisting of at least three laminae of orthogonally arranged fibrous material. These fibers are irregular and often branched. Permeability experiments showed that solutes less than 1,355 Da diffuse across the egg capsule whereas those greater than 6,000 Da do not pass through the membrane. Solute movement across the capsule is a concentration-dependent phenomenon indicating diffusion rather than active transport. Experimental data also suggest that there is an increase in the permeability of the egg capsule to low molecular weight materials during mid- and late gestation. These observations are discussed in relation to the function of the egg capsule as a mediator of maternal-embryonic interactions in matrotrophic sharks.

Actin-dependent motility of melanosomes from fish retinal pigment epithelial (RPE) cells investigated using in vitro motility assays.

Melanosomes (pigment granules) within retinal pigment epithelial (RPE) cells of fish and amphibians undergo massive migrations in response to light conditions to control light flux to the retina. Previous research has shown that melanosome motility within apical projections of dissociated fish RPE cells requires an intact actin cytoskeleton, but the mechanisms and motors involved in melanosome transport in RPE have not been identified. Two in vitro motility assays, the Nitella assay and the sliding filament assay, were used to characterize actin-dependent motor activity of RPE melanosomes. Melanosomes applied to dissected filets of the Characean alga, Nitella, moved along actin cables at a mean rate of 2 microm/min, similar to the rate of melanosome motility in dissociated, cultured RPE cells. Path lengths of motile melanosomes ranged from 9 to 37 microm. Melanosome motility in the sliding filament assay was much more variable, ranging from 0.4-33 microm/min; 70% of velocities ranged from 1-15 microm/min. Latex beads coated with skeletal muscle myosin II and added to Nitella filets moved in the same direction as RPE melanosomes, indicating that the motility is barbed-end directed. Immunoblotting using antibodies against myosin VIIa and rab27a revealed that both proteins are enriched on melanosome membranes, suggesting that they could play a role in melanosome transport within apical projections of fish RPE.