Wildfire Smoke Is Associated With an Increased Risk of Cardiorespiratory Emergency Department Visits in Alaska.

Alaskan wildfires have major ecological, social, and economic consequences, but associated health impacts remain unexplored. We estimated cardiorespiratory morbidity associated with wildfire smoke (WFS) fine particulate matter with a diameter less than 2.5 µm (PM2.5) in three major population centers (Anchorage, Fairbanks, and the Matanuska-Susitna Valley) during the 2015-2019 wildfire seasons. To estimate WFS PM2.5, we utilized data from ground-based monitors and satellite-based smoke plume estimates. We implemented time-stratified case-crossover analyses with single and distributed lag models to estimate the effect of WFS PM2.5 on cardiorespiratory emergency department (ED) visits. On the day of exposure to WFS PM2.5, there was an increased odds of asthma-related ED visits among 15-65 year olds (OR = 1.12, 95% CI = 1.08, 1.16), people >65 years (OR = 1.15, 95% CI = 1.01, 1.31), among Alaska Native people (OR = 1.16, 95% CI = 1.09, 1.23), and in Anchorage (OR = 1.10, 95% CI = 1.05, 1.15) and Fairbanks (OR = 1.12, 95% CI = 1.07, 1.17). There was an increased risk of heart failure related ED visits for Alaska Native people (Lag Day 5 OR = 1.13, 95% CI = 1.02, 1.25). We found evidence that rural populations may delay seeking care. As the frequency and magnitude of Alaskan wildfires continue to increase due to climate change, understanding the health impacts will be imperative. A nuanced understanding of the effects of WFS on specific demographic and geographic groups facilitates data-driven public health interventions and fire management protocols that address these adverse health effects.

Transoral robotic resection of oropharyngeal synovial sarcoma in a pediatric patient.

Localized synovial cell sarcomas are treated with surgical resection followed by chemo-radiation. Surgical resection of synovial sarcoma of the oropharynx and hypopharynx involves lip-splitting mandibulotomy resulting in treatment related morbidity. We report the successful use of Trans Oral Robotic Surgery for resection of localized synovial sarcoma of the lateral pharyngeal wall in a 15 year old patient. We were able to achieve negative surgical margins and avoid open surgery with its associated morbidity. At 2 years follow-up, patient is disease free, with no deficits in speech or swallowing functions and no cosmetic deformity.

Ammonia inhibits long-term potentiation via neurosteroid synthesis in hippocampal pyramidal neurons.

Neurosteroids are a class of endogenous steroids synthesized in the brain that are believed to be involved in the pathogenesis of neuropsychiatric disorders and memory impairment. Ammonia impairs long-term potentiation (LTP), a synaptic model of learning, in the hippocampus, a brain region involved in memory acquisition. Although mechanisms underlying ammonia-mediated LTP inhibition are not fully understood, we previously found that the activation of N-methyl-d-aspartate receptors (NMDARs) is important. Based on this, we hypothesize that metabolic stressors, including hyperammonemia, promote untimely NMDAR activation and result in neural adaptations that include the synthesis of allopregnanolone (alloP) and other GABA-potentiating neurosteroids that dampen neuronal activity and impair LTP and memory formation. Using an antibody against 5α-reduced neurosteroids, we found that 100 µM ammonia acutely enhanced neurosteroid immunostaining in pyramidal neurons in the CA1 region of rat hippocampal slices. The enhanced staining was blocked by finasteride, a selective inhibitor of 5α-reductase, a key enzyme required for alloP synthesis. Finasteride also overcame LTP inhibition by 100 µM ammonia, as did picrotoxin, an inhibitor of GABA-A receptors. These results indicate that GABA-enhancing neurosteroids, synthesized locally within pyramidal neurons, contribute significantly to ammonia-mediated synaptic dysfunction. These results suggest that the manipulation of neurosteroid synthesis could provide a strategy to improve cognitive function in individuals with hyperammonemia.

CEST-FISP: a novel technique for rapid chemical exchange saturation transfer MRI at 7 T.

Chemical exchange saturation transfer (CEST) and magnetization transfer techniques provide unique and potentially quantitative contrast mechanisms in multiple MRI applications. However, the in vivo implementation of these techniques has been limited by the relatively slow MRI acquisition techniques, especially on high-field MRI scanners. A new, rapid CEST-fast imaging with steady-state free precession technique was developed to provide sensitive CEST contrast in ∼20 sec. In this study at 7 T with in vitro bovine glycogen samples and initial in vivo results in a rat liver, the CEST-fast imaging with steady-state free precession technique was shown to provide equivalent CEST sensitivity in comparison to a conventional CEST-spin echo acquisition with a 50-fold reduction in acquisition time. The sensitivity of the CEST-fast imaging with steady-state free precession technique was also shown to be dependent on k-space encoding with centric k-space encoding providing a 30-40% increase in CEST sensitivity relative to linear encoding for 256 or more k-space lines. Overall, the CEST-fast imaging with steady-state free precession acquisition technique provides a rapid and sensitive imaging platform with the potential to provide quantitative CEST and magnetization transfer imaging data.

Measuring the quality of continuous epidural block for abdominal surgery.

BACKGROUND: In view of the wide variation in pain experience between patients, a clinical standard -- the time from the end of surgery to the first experience of pain -- was applied to 1359 consecutive patients in order to investigate whether the initial quality of epidural block has an effect on the overall quality of postoperative pain relief. METHODS: Clinical data were recorded in 58,118 out of 72,412 h in 1359 patients, and transferred to a database. Data collected included pain scores on a four-point verbal rating scale; nausea and vomiting; motor block; sedation scores; systolic blood pressure <100 and <90 mm Hg; ventilatory frequency <10 and <8 bpm; and hourly epidural infusion rate. RESULTS: As the time to first experience of pain increased from nil to >24 hours, the time from the first to last experience of pain shortened from 34 (19-50) h to 3 (1-12) h (p<0.001) and the proportion of patients receiving an epidural bolus decreased from 53 to 8% (p<0.001). Increases in the initial pain free time increased the proportion of patients with systolic BP<100 mmHg from 59 to 77%, (p<0.001) and increased the proportion of patients with respiratory rate <10 bpm from 13 to 26%, (p<0.001). CONCLUSION: Extending pain relief for more than 12 h beyond the end of abdominal surgery significantly improves the overall quality of postoperative pain relief, but is associated with an increase in side-effects.

Female receptivity phenotype of icebox mutants caused by a mutation in the L1-type cell adhesion molecule neuroglian.

Relatively little is known about the genes and brain structures that enable virgin female Drosophila to make the decision to mate or not. Classical genetic approaches have identified several mutant females that have a reluctance-to-mate phenotype, but most of these have additional behavioral defects. However, the icebox (ibx) mutation was previously reported to lower the sexual receptivity of females, without apparently affecting any other aspect of female behavior. We have shown that the ibx mutation maps to the 7F region of the Drosophila X chromosome to form a complex complementation group with both lethal and viable alleles of neuroglian (nrg). The L1-type cell adhesion molecule encoded by nrg consists of six immunoglobulin-like domains, five fibronectin-like domains, one transmembrane domain and one alternatively spliced intracellular domain. The ibx strain has a missense mutation causing a glycine-to-arginine change at amino acid 92 in the first immunoglobulin domain of nrg. Defects in the central brain of ibx mutants are similar to those observed in another nrg mutant, central brain deranged(1) (ceb(1)). However, both ceb(1) homozygous and ceb(1)/ibx heterozygous females are receptive. The expression of a transgene containing the non-neural isoform of nrg rescues both the receptivity and the brain structure phenotypes of ibx females.

Sexual health innovations in undergraduate medical education.

Recent national and global initiatives have drawn attention to the importance of sexual health to individuals' well-being. These initiatives advocate enhancement of efforts to address this under-represented topic in health professions curricula. University of Massachusetts Medical School (UMMS) has undertaken a comprehensive effort to develop an integrated curriculum in sexual health. The UMMS project draws upon the expertise of a multidisciplinary faculty of clinicians, basic scientists, a medical ethicist, and educators. This article describes the project's genesis and development at UMMS, and reports on three innovations in sexual health education implemented as part of this endeavor.

Liver enzyme activity and histological changes in the liver of silver foxes (Vulpes vulpes fulva) experimentally infected with opisthorchiid liver flukes. A contribution to the pathogenesis of opisthorchiidosis.

Blood samples from silver foxes experimentally infected with Opisthorchis felineus and Metorchis bilis, respectively, were examined for the activity of liver enzymes. The average activities of aspartate aminotransferase (AST), glutamate dehydrogenase (GLDH), alkaline phosphatase and alanine aminotransferase in uninfected control animals were 20, 1.8, 57 and 44 units/l, respectively. The liver enzymes in infected foxes reacted differently, depending on dose, species of flukes and individual peculiarities. The highest individual deviation of infected from control animals was registered in the case of GLDH, reaching increases of up to 200-fold. In contrast, AST showed the lowest deviation from control values (less than 10-fold). By the end of the study period, enzyme activities had declined. The prepatent periods for M. bilis and O. felineus in foxes were 2 weeks and 4 weeks, respectively. High egg per gram values were established at the beginning of the patent period. At necropsy, chronic inflammatory reactions were found in the bile ducts and in the wall of the gall bladder. The number of flukes at the end of the study was low.

Indirect ELISA for the detection of antibodies against Opisthorchis felineus (Rivolta, 1884) and Metorchis bilis (Braun, 1790) in foxes.

Serological investigations focused on the detection of specific opisthorchiid liver fluke antibodies in silver foxes (Vulpes vulpes fulva). Animals were experimentally infected with Opisthorchis felineus (nos. 1 and 2) and Metorchis bilis (nos. 3-8) by feeding fish with a counted number of metacercariae. Four foxes remained as non-infected negative controls (nos. 9-12). For the indirect ELISA, an excretory-secretory antigen was produced by in vitro cultivation of O. felineus and M. bilis adults isolated from livers of experimentally infected hamsters. Immunoglobulin G (IgG) seroconversion against homologous antigen took place between weeks 2 and 6 postinfection (p.i.) and foxes remained seropositive up to the end of the trial at week 41 p.i. In contrast, IgG titres against heterologous antigen remained significantly lower and stayed near the cut-off. All infected animals excreted opisthorchiid eggs, starting between weeks 2 and 4 p.i. The number of liver flukes found at necropsy was relatively low, except in one fox that was sacrificed at the week 11 p.i. These results suggest that the ELISA is a suitable tool for the detection of specific O. felineus and M. bilis antibodies in the fox.

Phenotypic analysis of conditionally immortalized cells isolated from the BPK model of ARPKD.

To study the pathophysiology of autosomal recessive polycystic kidney disease (ARPKD), we sought to develop conditionally immortalized control and cystic murine collecting tubule (CT) cell lines. CT cells were isolated from intercross breedings between BPK mice (bpk(+/-)), a murine model of ARPKD, and the Immorto mice (H-2K(b)-ts-A58(+/+)). Second-generation outbred offspring (BPK x Immorto) homozygous for the BPK mutation (bpk(-/-); Im(+/+/-); cystic BPK/H-2K(b)-ts-A58), were phenotypically indistinguishable from inbred cystic BPK animals (bpk(-/-)). Cystic BPK/H-2K(b)-ts-A58 mice developed biliary ductal ectasia and massively enlarged kidneys, leading to renal failure and death by postnatal day 24. Principal cells (PC) were isolated from outbred cystic and noncystic BPK/H-2K(b)-ts-A58 littermates at specific developmental stages. Epithelial monolayers were under nonpermissive conditions for markers of epithelial cell polarity and PC function. Cystic and noncystic cells displayed several properties characteristic of PCs in vivo, including amiloride-sensitive sodium transport and aquaporin 2 expression. Cystic cells exhibited apical epidermal growth factor receptor (EGFR) mislocalization but normal expression of ZO-1 and E-cadherin. Hence, these cell lines retain the requisite characteristics of PCs, and cystic BPK/H-2K(b)-ts-A58 PCs retained the abnormal EGFR membrane expression characteristic of ARPKD. These cell lines represent important new reagents for studying the pathogenesis of ARPKD.

A novel inhibitor of tumor necrosis factor-alpha converting enzyme ameliorates polycystic kidney disease.

BACKGROUND: Transforming growth factor-alpha (TGF-alpha) expression is abnormal in polycystic kidney disease. We previously demonstrated that blockade of the epidermal growth factor receptor (EGFR), the receptor for TGF-alpha, significantly slowed disease progression in the bpk murine model of autosomal-recessive kidney disease (ARPKD). In the present study, kidney TGF-alpha expression in this model is characterized, and the therapeutic potential of inhibiting TGF-alpha in ARPKD is examined using a novel inhibitor of tumor necrosis factor-alpha converting enzyme (TACE), the metalloproteinase that cleaves membrane-bound TGF-alpha to release the secreted ligand. METHODS: Immunohistochemistry (IH) and Western analysis were performed on kidneys from cystic bpk mice and noncystic littermates at postnatal days 7, 14, and 21. Bpk mice and normal controls were treated with WTACE2, a competitive inhibitor of TACE, from day 7 until day 21, and the effects on kidney histology and renal function were assessed. RESULTS: Increased TGF-alpha expression by IH was demonstrated in the proximal tubules (PT) at postnatal day 7 and collecting tubules (CT) by day 21. A parallel increase in kidney TGF-alpha expression was demonstrated by Western analysis. Treatment of cystic bpk mice with WTACE2 resulted in a 43% reduction in kidney weight to body weight ratio (11.2 vs. 19.7%), improved cystic index (3.2 vs. 4.8), reduced cystic CT to PT ratio (1.2 vs. 8), and a greater than 30% reduction in BUN and serum creatinine. CONCLUSIONS: These findings support the pathophysiological role of the TGF-alpha/EGFR axis in murine ARPKD and demonstrate that inhibition of TGF-alpha secretion has therapeutic potential in PKD.

Technical knockout, a Drosophila model of mitochondrial deafness.

Mutations in mtDNA-encoded components of the mitochondrial translational apparatus are associated with diverse pathological states in humans, notably sensorineural deafness. To develop animal models of such disorders, we have manipulated the nuclear gene for mitochondrial ribosomal protein S12 in Drosophila (technical knockout, tko). The prototypic mutant tko(25t) exhibits developmental delay, bang sensitivity, impaired male courtship, and defective response to sound. On the basis of a transgenic reversion test, these phenotypes are attributable to a single substitution (L85H) at a conserved residue of the tko protein. The mutant is hypersensitive to doxycyclin, an antibiotic that selectively inhibits mitochondrial protein synthesis, and mutant larvae have greatly diminished activities of mitochondrial redox enzymes and decreased levels of mitochondrial small-subunit rRNA. A second mutation in the tko gene, Q116K, which is predicted to impair the accuracy of mitochondrial translation, results in the completely different phenotype of recessive female sterility, based on three independent transgenic insertions. We infer that the tko(25t) mutant provides a model of mitochondrial hearing impairment resulting from a quantitative deficiency of mitochondrial translational capacity.

Promoter characterization and genomic organization of the human breast cancer resistance protein (ATP-binding cassette transporter G2) gene.

The breast cancer resistance protein (BCRP) gene, formally known as ATP-binding cassette transporter G2 (ABCG2) gene, encodes an ABC half transporter that causes resistance to certain cancer chemotherapeutic drugs when transfected and expressed in drug sensitive cancer cells. Here we report the organization of the BCRP gene, and the initial characterization of the BCRP promoter. We identified the genomic sequence of BCRP and its promoter by screening a human genomic lambda phage library, as well as a BAC library, and by searching the human genome database. The BCRP gene spans over 66 kb and consists of 16 exons and 15 introns. The exons range in size from 60 to 532 bp. The translational start site is found in the second exon. The first exon contains the majority of the 5' UTR. Promoter activity was characterized by a luciferase reporter assay using transient transfection of the human breast cancer cell line MCF7, and the human choriocarcinoma cell lines JAR, BeWo and JEG-3, which we find to have high endogenous expression of BCRP. The BCRP gene is transcribed by a TATA-less promoter with several putative Sp1 sites, which are downstream from a putative CpG island. The sequence 312 bp directly upstream from the BCRP transcriptional start site conferred basal promoter activity. The 5' region upstream of the basal promoter is characterized by both positive and negative regulatory domains.

Can progression of autosomal dominant or autosomal recessive polycystic kidney disease be prevented?

Data from animal and human studies suggest that the rate of progression of renal insufficiency can be retarded with careful control of blood pressure, institution of a low-protein diet, and the use of lipid-lowering agents. These therapeutic interventions become important when managing patients with renal insufficiency secondary to autosomal dominant polycystic kidney disease (PKD) and autosomal recessive polycystic kidney disease, in which end-stage renal disease is present in nearly 17,000 individuals per year. Several dietary and pharmacologic intervention strategies including blood pressure control, dietary modification, and the use of antioxidants as well as lipid-lowering agents have been studied in humans and animals with PKD in an effort to slow the rate of renal progression. This article reviews the current understanding of the effectiveness of these conventional therapies, as well as novel therapies that specifically target the mediators of cyst formation in PKD using tyrosine kinase inhibitors and gene therapy in an effort to identify potential strategies for retarding cyst formation and parenchymal injury in PKD. Current pharmacologic and dietary strategies fail to show any consistent benefits in preserving renal function and reducing renal injury in human PKD. The therapeutic potential for exciting new gene therapies and pharmacologic agents designed to target the pathophysiologic pathways involved in cyst formation are promising. Randomized, controlled trials in children and adults with early PKD are necessary to evaluate the effectiveness of these therapeutic interventions.

PBK/TOPK is a novel mitotic kinase which is upregulated in Burkitt's lymphoma and other highly proliferative malignant cells.

PBK/TOPK is a recently cloned serine/threonine kinase which is phosphorylated during mitosis. Earlier work indicated that this kinase is upregulated in a Burkitt's lymphoma cell line (GA-10). To determine whether PBK/TOPK is upregulated in other mitotically active neoplastic cell lines and tissues, Northern analysis was performed on a panel of malignant cell lines and on clinical samples from patients with leukemia or lymphoma. While PBK/TOPK mRNA was not detectable in normal peripheral blood cells and was weakly expressed in hyperplastic tonsillar B-cells, significantly higher levels of mRNA were detected in 8 Burkitt's lymphoma cell lines, 10 other neoplastic cell lines, and 2 clinical samples-one derived from a patient with ALL and a second derived from a patient with relapsed myeloma. In addition, Northern analysis of fetal tissues showed upregulated expression of PBK/TOPK in fetal kidney, lung, spleen, brain, and testis. These data suggest that PBK/TOPK expression is increased in highly proliferative malignant cells and during normal fetal development.

The utility of laboratory screening in medically III patients with psychiatric symptoms.

The presence of psychiatric illness in general hospital medical inpatients can complicate a patient's clinical course. Currently, there is no standard laboratory work-up recommended for this patient population. To begin to assess the utility of a routine panel of tests, the results of serum vitamin B12 (cobalamin) levels, folate levels, thyroid stimulating hormone levels, and syphilis serology of 349 patients were reviewed. These patients had been admitted to the hospital for nonpsychiatric conditions but either had preexisting psychiatric disturbances or developed a mood spectrum disorder or cognitive spectrum disorder during their hospitalization. The incidence of vitamin B12 and folate deficiencies in these patients was found to be higher than has been reported for the general population. Thus, routine screening for these vitamin deficiencies may be indicated because of their prevalence in this patient population.

Localization of the mouse kidney disease (kd) gene to a YAC/BAC contig on Chromosome 10.

Mice that are homozygous for the kidney disease (kd) gene on Chromosome (Chr) 10 spontaneously develop a progressive and fatal interstitial nephritis. The disease phenotype is similar to that of the human disease, juvenile nephronophthisis. Using a backcross and intercross breeding strategy and analysis of over 900 resultant progeny, this genetic locus has now been mapped to a minimal co-segregating region of approximately two megabases between D10Mit 193 and D10Mit 38. The location assigned to kd by this study is over 3 cM from the current Mouse Genome Database location. The entire interval has been cloned in yeast artificial chromosome (YAC) and bacterial artificial chromosome (BAC) clones. Recombinant analysis has permitted assignment of 13 Mit microsatellite markers to positions near or within the region. Two new markers have been identified by using single-strand conformation polymorphism (SSCP) analysis of sequenced BAC ends. Several BAC end sequences align with human BAC clones from Chr 6q2 that contain NR2E1. Snx3, and Ros1. Three murine genes, CD24a, fyn, and ColX reported to map in or near the kd region as defined by this study have been evaluated. Though not definitely excluded, they appear to be unlikely candidates.