Increased length-dependent activation of human engineered heart tissue after chronic α1A-adrenergic agonist treatment: testing a novel heart failure therapy.

Chronic stimulation of cardiac α1A-adrenergic receptors (α1A-ARs) improves symptoms in multiple preclinical models of heart failure. However, the translational significance remains unclear. Human engineered heart tissues (EHTs) provide a means of quantifying the effects of chronic α1A-AR stimulation on human cardiomyocyte physiology. EHTs were created from thin slices of decellularized pig myocardium seeded with human induced pluripotent stem cell (iPSC)-derived cardiomyocytes and fibroblasts. With a paired experimental design, EHTs were cultured for 3 wk, mechanically tested, cultured again for 2 wk with α1A-AR agonist A61603 (10 nM) or vehicle control, and retested after drug washout for 24 h. Separate control experiments determined the effects of EHT age (3-5 wk) or repeat mechanical testing. We found that chronic A61603 treatment caused a 25% increase of length-dependent activation (LDA) of contraction compared with vehicle treatment (n = 7/group, P = 0.035). EHT force was not increased after chronic A61603 treatment. However, after vehicle treatment, EHT force was increased by 35% relative to baseline testing (n = 7/group, P = 0.022), suggesting EHT maturation. Control experiments suggested that increased EHT force resulted from repeat mechanical testing, not from EHT aging. RNA-seq analysis confirmed that the α1A-AR is expressed in human EHTs and found chronic A61603 treatment affected gene expression in biological pathways known to be activated by α1A-ARs, including the MAP kinase signaling pathway. In conclusion, increased LDA in human EHT after chronic A61603 treatment raises the possibility that chronic stimulation of the α1A-AR might be beneficial for increasing LDA in human myocardium and might be beneficial for treating human heart failure by restoring LDA.NEW & NOTEWORTHY Chronic stimulation of α1A-adrenergic receptors (α1A-ARs) is known to mediate therapeutic effects in animal heart failure models. To investigate the effects of chronic α1A-AR stimulation in human cardiomyocytes, we tested engineered heart tissue (EHT) created with iPSC-derived cardiomyocytes. RNA-seq analysis confirmed human EHT expressed α1A-ARs. Chronic (2 wk) α1A-AR stimulation with A61603 (10 nM) increased length-dependent activation (LDA) of contraction. Chronic α1A-AR stimulation might be beneficial for treating human heart failure by restoring LDA.

Dose-dependent expression of claudin-5 is a modifying factor in schizophrenia.

Schizophrenia is a neurodevelopmental disorder that affects up to 1% of the general population. Various genes show associations with schizophrenia and a very weak nominal association with the tight junction protein, claudin-5, has previously been identified. Claudin-5 is expressed in endothelial cells forming part of the blood-brain barrier (BBB). Furthermore, schizophrenia occurs in 30% of individuals with 22q11 deletion syndrome (22q11DS), a population who are haploinsufficient for the claudin-5 gene. Here, we show that a variant in the claudin-5 gene is weakly associated with schizophrenia in 22q11DS, leading to 75% less claudin-5 being expressed in endothelial cells. We also show that targeted adeno-associated virus-mediated suppression of claudin-5 in the mouse brain results in localized BBB disruption and behavioural changes. Using an inducible 'knockdown' mouse model, we further link claudin-5 suppression with psychosis through a distinct behavioural phenotype showing impairments in learning and memory, anxiety-like behaviour and sensorimotor gating. In addition, these animals develop seizures and die after 3-4 weeks of claudin-5 suppression, reinforcing the crucial role of claudin-5 in normal neurological function. Finally, we show that anti-psychotic medications dose-dependently increase claudin-5 expression in vitro and in vivo while aberrant, discontinuous expression of claudin-5 in the brains of schizophrenic patients post mortem was observed compared to age-matched controls. Together, these data suggest that BBB disruption may be a modifying factor in the development of schizophrenia and that drugs directly targeting the BBB may offer new therapeutic opportunities for treating this disorder.

Heparin versus placebo for acute coronary syndromes.

BACKGROUND: Acute coronary syndromes (ACS) represent a spectrum of disease including unstable angina (UA) and non-ST segment myocardial infarction (NSTEMI). Despite treatment with aspirin, beta-blockers and nitroglycerin, UA/NSTEMI is still associated with significant morbidity and mortality. Although emerging evidence suggests that low molecular weight heparin (LMWH) is more efficacious compared to unfractionated heparin (UFH), there is limited data to support the role of heparins as a drug class in the treatment of ACS. OBJECTIVES: To determine the effect of heparins (UFH and LMWH) compared with placebo for the treatment of patients with ACS. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials on The Cochrane Library (issue 4, 2002), MEDLINE (1966 to May 2002), EMBASE (1980 to May 2002) and CINAHL (1982 to May 2002). Authors of included studies and pharmaceutical industry representatives were contacted to determine if unpublished studies which met the inclusion criteria were available. SELECTION CRITERIA: Randomized controlled trials of parenteral UFH or LMWH versus placebo in people with ACS (UA or NSTEMI). DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed quality of studies. Data were extracted independently by two reviewers. Study authors were contacted to verify and clarify missing data. MAIN RESULTS: Eight studies (3118 participants) were included in this review. We found no evidence for difference in overall mortality between the groups treated with heparin and placebo (RR = 0.84, 95% CI 0.36 to 1.98). Heparins reduced the occurrence of MI (RR = 0.40, 95% CI 0.25 to 0.63, NNT = 33). An increase in the incidence of minor bleeds (RR = 6.80, 95% CI 1.23 to 37.49, NNH = 17). AUTHORS' CONCLUSIONS: Compared to placebo, patients treated with heparins had similar risk of mortality, revascularization, recurrent angina, major bleeding and thrombocytopenia. However, those treated with heparins had decreased risk of MI and a higher incidence of minor bleeding.

Loss of translational control in yeast compromised for the major mRNA decay pathway.

The cytoplasmic fate of mRNAs is dictated by the relative activities of the intimately connected mRNA decay and translation initiation pathways. In this study, we have found that yeast strains compromised for stages downstream of deadenylation in the major mRNA decay pathway are incapable of inhibiting global translation initiation in response to stress. In the past, the paradigm of the eIF2alpha kinase-dependent amino acid starvation pathway in yeast has been used to evaluate this highly conserved stress response in all eukaryotic cells. Using a similar approach we have found that even though the mRNA decay mutants maintain high levels of general translation, they exhibit many of the hallmarks of amino acid starvation, including increased eIF2alpha phosphorylation and activated GCN4 mRNA translation. Therefore, these mutants appear translationally oblivious to decreased ternary complex abundance, and we propose that this is due to higher rates of mRNA recruitment to the 40S ribosomal subunit.

Emergency department patients' opinions of screening for intimate partner violence among women.

BACKGROUND: Universal screening for intimate partner violence (IPV) in the emergency department (ED) has been advocated by many medical institutions. Policies implemented for IPV screening have met with numerous obstacles. One such obstacle is the perception by emergency personnel that patients might be offended by such screening if they presented to the ED for problems unrelated to trauma. OBJECTIVES: To assess opinions of adult ED patients regarding a policy of universal IPV screening for women presenting to the ED. METHODS: This study was conducted in EDs in Halifax, Nova Scotia, and St John's, Newfoundland. Patients were questioned as to whether it was appropriate for all women to be asked if they had experienced violent or threatening behaviour from someone close to them. Patients in significant pain or in extremis were not approached. RESULTS: The data consist of a convenience sample of 514 adult ED patients, aged 16-95 years. Two (0.4%) were excluded from the analysis. Of 512 analysed, 442 (86.0%) answered "yes" to the question, 53 (10.3%) answered "no", 17 (3.3%) had no opinion. There were no significant differences between the proportion of "yes" and "no" answers in the male and female groups. CONCLUSION: Universal screening for IPV of adult female patients presenting to the ED was supported by most patients. Patient objections should not be seen as a reason to withhold questioning on this issue.

Experimentally induced caseous lymphadenitis in goats.

Caseous lymphadenitis was experimentally induced in goats by inoculating 1 x 10(6) Corynebacterium pseudotuberculosis by 3 routes: subcutaneous, intradermal, and submucosal. The incubation period for the development of abscesses in the present study ranged from 41 to 147 days, the average being 95.2 days. The shedding period for C pseudotuberculosis from opened abscesses ranged from 9 to 37 days, with an average of 20.3 days. The infection spread to mediastinal lymph nodes in 1 goat and to lumbar lymph nodes in 5 goats. None of the goats had abscesses in the mesenteric lymph nodes. Corynebacterium pseudotuberculosis was recovered from all the abscessed lymph nodes but not from the feces or nasal secretions.

Serum proteins of normal goats and goats with caseous lymphadenitis.

Values for total serum proteins and relative percentages of albumin, alpha 1-globulin, alpha 2-globulin, beta-globulin, and gamma-globulin were determined for the goat. These normal values were compared with those obtained for goats infected with Corynebacterium pseudotuberculosis. Goats chronically infected with C pseudotuberculosis show significantly higher total serum protein values than normal goats, apparently due to increased gamma-globulins. This higher protein value is also associated with a decrease in serum alpha 2- and beta-globulins.

Utility of blood cultures in the management of adults with community acquired pneumonia discharged from the emergency department.

STUDY OBJECTIVE: To assess the clinical value of blood cultures (BCs) in the management of adult patients discharged from the emergency department (ED) with a diagnosis of community acquired pneumonia (CAP). METHODS: The courses of antibiotic regimens and outcomes of patients with positive BC results were examined to assess their influence on BCs. RESULTS: BCs were obtained from 289 outpatients. Six clinically significant organisms were identified (a yield of 2.1%). Outpatients with CAP who had blood cultures performed had a 0.69% (2 of 289) chance of having a change of treatment directed by the results of the culture. CONCLUSION: BCs have little utility in the ambulatory management of CAP.

Patients with community acquired pneumonia discharged from the emergency department according to a clinical practice guideline.

OBJECTIVES: To assess the safety of discharging patients with community acquired pneumonia (CAP) according to a clinical practice guideline. METHODS: A systematic retrospective review of medical records of 867 adult patients discharged from an emergency department (ED) with CAP between 3 January 1999 and 3 January 2001. Readmission or death rates within 30 days of discharge were evaluated, using data from all local hospitals and from the provincial coroner. RESULTS: Of 685 patients with pneumonia severity index (PSI) scores of <91, 13 (1.9%) were readmitted and five (0.76%) died within 30 days of the ED visit. Thirty day readmission and death rates for patients with PSI >90 were 7.14% (13 of 182) and 9.34% (17 of 182), respectively. CONCLUSION: Adult patients with CAP discharged from the ED according to the recommendations of a clinical practice guideline based on the PSI have low readmission and death rates, and are generally safely managed as outpatients.

An unusual epizootic of actinobacillosis in dairy heifers.

Actinobacillosis developed in a group of 52 Holstein-Friesian replacement heifers. They were confined to 4 pens in a barn. Cervical abscesses were first observed by the owner in 1 heifer a month after the heifers were fed chopped haylage that was particularly dry, tough, and stemmy. During the weeks that followed, morbidity reached 73% in heifers given the feed. Calves up to 4 months old were not given the haylage and did not develop the disease. Standard bacteriologic methods were used to identify Actinobacillus lignieresii from exudate of abscesses. A biopsy of superficial granulomatous tissue of the lips revealed fibers thought to be of plant origin. Affected cattle recovered in 3 to 6 months. The lesions of 3 cattle given sodium iodide intravenously and of 4 given streptomycin regressed sooner than those given penicillin or no treatment.

Relationship between serum immunoglobulin values and incidence of respiratory disease in calves.

Severe respiratory disease, with high morbidity and high mortality, occurred in 2 groups of bull calves (14 to 64 days old) raised in th same facility. Necropsy findings included lesions of acute or chronic bronchopneumonia. Serum immunoglobulin G (IgG) values were determined for all calves at 3 to 6 days of age. Calves that died of respiratory disease had an average IgG value of 1,267 mg/100 ml, whereas calves that lived had an average IgG value of 2,698 mg/100 ml. Calves with low serum IgG values had higher morbidity, had to be treated earlier in life, and had to be treated more frequently per day, when compared with calves that had high serum IgG values.

Rib fractures following minor trauma in older patients: a not-so-benign injury.

Two older adults presented to the emergency department with rib fractures following minor trauma. Both were discharged on oral analgesics and died within 2 days. Rib fractures more often lead to adverse outcomes in older adults. Emergency physicians should consider admitting any such patient who presents with two or more rib fractures.

Immunization against experimental murine salmonellosis with liposome-associated O-antigen.

Partially delipidated Salmonella typhimurium (O-1,4,5,12) lipopolysaccharide was incorporated into small multilamellar liposomes composed of either naturally occurring or synthetic phospholipids. Vaccination of mice with the liposome-lipopolysaccharide complexes induced a cellular response specific for O-1,4,5,12 determinants, as determined by the development of a delayed-type hypersensitivity reaction. The liposome-lipopolysaccharide vaccines were significantly more effective, compared with other nonviable vaccines tested, in protecting mice against a lethal intravenous challenge infection with virulent S. typhimurium. Protection afforded by the liposome-lipopolysaccharide vaccines was comparable to that conferred by a live S. typhimurium vaccine. Results suggest that liposome-induced modulation of the host immune response in favor of cell-mediated immunity may be more efficacious in preventing diseases in which cell-mediated immunity is of prime importance.