Fetuin A is down-regulated in rats during heterotopic ossification after Achilles tenotomy

We investigated the role of fetuin A during heterotopic ossification (HO) in rats following Achilles tenotomy. We performed a right midpoint Achilles tenotomy on 24 rats. At 5 and 10 h after surgery, we investigated the formation of ectopic bone using X-ray and histological examination. We evaluated the mRNA level of fetuin A using real-time PCR. Presence of fetuin A in the Achilles tendon was assessed by immunohistochemical staining. We also measured the serum concentration of fetuin A using enzyme linked immunosorbent assay (ELISA). The expression of fetuin A was significantly decreased in both the liver and Achilles tendon during HO. ELISA showed a small amount of fetuin A in blood throughout the development of HO. Immunohistochemical staining showed that fetuin A was abundant in the ectopic bone. Fetuin A appears to be involved in the formation of ectopic bone induced by Achilles tenotomy, and a deficiency of fetuin A plays a role in the development of HO.     

N-Ethylmaleimide-modified subfragment-1 and heavy meromyosin inhibit reactivated contraction in motile models of retinal cones

The mechanism of contraction in motile models of teleost retinal cones has been examined by using N-ethylmaleimide (NEM)-modified myosin fragments (NEM-S-1 and NEM-heavy meromyosin [HMM]) to prevent access of native myosin to actin filaments during reactivation of contraction. In the diurnal light/dark cycle, retinal cones of green sunfish (Lepomis cyanellus) and bluegill (lepomis macrochirus) exhibit length changes of more than 90 mum. The motile myoid region of the cone contracts from 100 mum in the dark to 6 mum in the light. Motile models for cone contraction have been obtained by lysis of dark-adapted retinas with the non-ionic detergent, Brij-58. These cone motile models undergo Ca(++)-and ATP-dependent reactivated contraction, with morphology and rate comparable to those observed in vivo (Burnside, B.,B. Smith, M. Nagata, and K. Porrello, 1982, J. Cell Biol., 92:198-206). The cone myoids contain longitudinally oriented actin filaments which bind myosin subfragment-1 (S-1) to form characteristic “arrowhead” complexes which dissociate in the presence of MgATP (Burnside, B., 1978, J. Cell Biol., 78:227-246). Modification of S-1 or HMM with the sulfhydryl reagent, NEM, produces new species, NEM-S-1 or NEM-HMM, which still bind actin but which fail to detach in the presence of MgATP (Meeusen, R.L., and W.Z. Cande, 1979, J. Cell Biol., 82:57-65). We have used NEM-S-1 and NEM-HMM to test whether cone contraction depends on an actomyosin force- generating system. We find that reactivated contraction of cone models is inhibited by NEM-S-1 and NEM-HMM but not by the unmodified species, S-1 and HMM. Thus, reactivated cone contraction exhibits NEM-S-1 and NEM-HMM sensitivity as well as Ca(++)- and ATP- dependence. These observations are consistent with and actimyosin-mediated mechanism for force production during cone contraction.     

Fine-tuning of Voltage Sensitivity of the Kv1.2 Potassium Channel by Interhelix Loop Dynamics

Many proteins function by changing conformation in response to ligand binding or changes in other factors in their environment. Any change in the sequence of a protein, for example during evolution, which alters the relative free energies of the different functional conformations changes the conditions under which the protein will function. Voltage-gated ion channels are membrane proteins that open and close an ion-selective pore in response to changes in transmembrane voltage. The charged S4 transmembrane helix transduces changes in transmembrane voltage into a change in protein internal energy by interacting with the rest of the channel protein through a combination of non-covalent interactions between adjacent helices and covalent interactions along the peptide backbone. However, the structural basis for the wide variation in the V₅₀ value between different voltage-gated potassium channels is not well defined. To test the role of the loop linking the S3 helix and the S4 helix in voltage sensitivity, we have constructed a set of mutants of the rat K_v1.2 channel that vary solely in the length and composition of the extracellular loop that connects S4 to S3. We evaluated the effect of these different loop substitutions on the voltage sensitivity of the channel and compared these experimental results with molecular dynamics simulations of the loop structures. Here, we show that this loop has a significant role in setting the precise V₅₀ of activation in K_v1 family channels.     

Fatal septicemic shock associated with Strongyloides stercoralis infection in a patient with angioimmunoblastic T-cell lymphoma: a case report and literature review

IntroductionStrongyloides stercoralis infection can persist in the host for several decades, and patients with cancer and other clinical conditions who are exposed to immunosuppressive therapy are at risk of developing hyperinfection.Case reportThis is a case of angioimmunoblastic T-cell lymphoma (AITL) in a patient with lymphadenopathy and bulky neck mass. Severe sepsis and episodes of diarrhea were observed upon the first cycle of cyclophosphamide, doxorubicin, oncovin (vincristine) and prednisone (CHOP) regime chemotherapy preceded by high dose of dexamethasone. There was Klebsiella pneumoniae bacteremia and moderate eosinophilia. Rhabditiform S. stercoralis larvae were observed in the stool, and this was confirmed by real-time PCR. Strongyloides-specific IgG and IgG4 were also positive. The patient was treated with oral albendazole (400 mg/day) for 3 days and intravenous tazocin (4.5gm/6 hours) for 5 days; however he succumbed following multi-organ failure.ConclusionThis is likely a case of Strongyloides hyperinfection with secondary bacteremia.     

Diversity among health care leaders in Canada: a cross-sectional study of perceived gender and race

Background:Diverse health care leadership teams may improve health care experiences and outcomes for patients. We sought to explore the race and gender of hospital and health ministry executives in Canada and compare their diversity with that of the populations they serve.Methods:This cross-sectional study included leaders of Canada’s largest hospitals and all provincial and territorial health ministries. We included individuals listed on institutional websites as part of the leadership team if a name and photo were available. Six reviewers coded and analyzed the perceived race and gender of leaders, in duplicate. We compared the proportion of racialized health care leaders with the race demographics of the general population from the 2016 Canadian Census.Results:We included 3056 leaders from 135 institutions, with reviewer concordance on gender for 3022 leaders and on race for 2946 leaders. Reviewers perceived 37 (47.4%) of 78 health ministry leaders as women, and fewer than 5 (< 7%) of 80 as racialized. In Alberta, Saskatchewan, Prince Edward Island and Nova Scotia, provinces with a centralized hospital executive team, reviewers coded 36 (50.0%) of 72 leaders as women and 5 (7.1%) of 70 as racialized. In British Columbia, New Brunswick and Newfoundland and Labrador, provinces with hospital leadership by region, reviewers perceived 120 (56.1%) of 214 leaders as women and 24 (11.5%) of 209 as racialized. In Manitoba, Ontario and Quebec, where leadership teams exist at each hospital, reviewers perceived 1326 (49.9%) of 2658 leaders as women and 243 (9.2%) of 2633 as racialized. We calculated the representation gap between racialized executives and the racialized population as 14.5% for British Columbia, 27.5% for Manitoba, 20.7% for Ontario, 12.4% for Quebec, 7.6% for New Brunswick, 7.3% for Prince Edward Island and 11.6% for Newfoundland and Labrador.Interpretation:In a study of more than 3000 health care leaders in Canada, gender parity was present, but racialized executives were substantially under-represented. This work should prompt health care institutions to increase racial diversity in leadership.

Race and gender-based disparities in health care leadership^1–4 may negatively affect the health of marginalized patients.^5,6 Diverse leadership is an integral step in establishing equitable health care institutions that serve the needs of all community members.⁷ Many barriers prevent racialized people, women and gender nonbinary individuals from attaining leadership positions, including reduced access to networking opportunities, ^8–10 discrimination from patients and colleagues^2,11–13 and an institutional culture that views white, male leaders as most effective. ^14,15 The intersectional effects of discrimination may intensify these barriers for racialized women and nonbinary people.^16,17 Fundamentally, diversity and inclusion in our institutions is important on the basis of basic human rights for all people.¹⁸Health care leadership in Europe and the United States is thought to lack gender and racial diversity.^19–22 The degree to which these imbalances exist across Canadian health care institutions is not clear. Despite past evidence that men hold a disproportionate number of health care leadership positions in Canada,^23,24 a recent study noted gender parity among leaders of provincial and territorial ministries of health.²⁵ Among university faculty^26,27 and administration, ²⁸ racialized individuals appear to be under-represented, suggesting that a similar trend may exist in health care leadership.Race and gender can be studied in many ways.²⁹ Perceived race is a measure of “the race that others believe you to be,” and these assessments “influence how people are treated and form the basis of racial discrimination including nondeliberate actions that nonetheless lead to socioeconomic inequities.”²⁹ Similarly, perceived gender refers to an observer’s assumptions about a person’s gender, which can lead to differential and unfair treatment. ³⁰ Assessing perceived race and gender provides crucial insights into the ways in which social inequalities are informed and produced.²⁹ In this study, we sought to identify the perceived race and gender of hospital executive leaders in Canada and of nonelected leaders of the provincial and territorial health ministries. Furthermore, we wanted to analyze how the perceived racial composition of health care leadership compares with the racial composition of the population in the geographic areas that these leaders serve.     

Human umbilical cord perivascular cells (HUCPVC): A mesenchymal cell source for dermal wound healing

Human bone marrow mesenchymal stem cells (hBM-MSC) have recently been employed in the clinical treatment of challenging skin defects. We have described an MSC population that can be easily harvested from human umbilical cord perivascular tissue, human umbilical cord perivascular cells (HUCPVC), which exhibit a higher proliferative rate and frequency than hBM-MSC. Our objective was to establish whether HUCPVC could promote healing of full thickness murine skin defects, and thus find utility as a cell source for dermal repair. To this end, bilateral full thickness defects were created on the dorsum of Balb/c nude mice. Fibrin was used as a delivery vehicle for 1 x 106 PKH-67 labeled HUCPVC with contralateral controls receiving fibrin only. Epifluorescent and brightfield microscopic evaluation of the wound site was carried out at 3 and 7 days while mechanical testing of wounds was carried out at 3, 7, and 10 days. Our results show that by 3 days, marked contraction of the wound was observed in the fibrin controls whilst the HUCPVC samples exhibited neither collapse nor contraction of the defect, and the dermal repair tissue was considerably thicker and more organized. By 7 days, complete re-epithelialization of the HUCPVC wounds was observed whilst in the controls re-epithelialization was limited to the wound margins. Wound strength was significantly increased in the HUCPVC treatment group by 3 and 7 days but no statistical difference was seen at 10 days. We conclude that HUCPVCs accelerate early wound healing in full thickness skin defects and thus represent a putative source of human MSCs for use in dermal tissue engineering.     

Synthesis of the non-peptidic snail toxin 6-bromo-2-mercaptotryptamine dimer (BrMT)2, its lower and higher thio homologs and their ability to modulate potassium ion channels

The first synthesis of the non-peptidic snail toxin 6-bromo-2-mercaptotryptamine dimer (BrMT)₂ is described, along with the preparation of its lower and higher thio homologs. The synthetic (BrMT)₂ and its derivatives reported herein are all capable of slowing the activation of the K_v1.1 potassium ion channel. Only the monosulfide variant shows significant slowing of the deactivation process. This synthetic strategy can now be applied to creating a more extensive set of compounds that vary in the length of the linker connecting the two monomers, the substituents on the indole ring core, and terminal amine.