Cardiovascular and Noncardiovascular Prescribing and Mortality After Takotsubo Comparison With Myocardial Infarction and General Population.

Background: Takotsubo syndrome is an increasingly common cardiac emergency with no known evidence-based treatment. Objectives: The purpose of this study was to investigate cardiovascular mortality and medication use after takotsubo syndrome. Methods: In a case-control study, all patients with takotsubo syndrome in Scotland between 2010 and 2017 (n = 620) were age, sex, and geographically matched to individuals in the general population (1:4, n = 2,480) and contemporaneous patients with acute myocardial infarction (1:1, n = 620). Electronic health record data linkage of mortality outcomes and drug prescribing were analyzed using Cox proportional hazard regression models. Results: Of the 3,720 study participants (mean age, 66 years; 91% women), 153 (25%) patients with takotsubo syndrome died over the median of 5.5 years follow-up. This exceeded mortality rates in the general population (N = 374 [15%]; HR: 1.78 [95% CI: 1.48-2.15], P < 0.0001), especially for cardiovascular (HR: 2.47 [95% CI: 1.81-3.39], P < 0.001) but also noncardiovascular (HR: 1.48 [95% CI: 1.16-1.87], P = 0.002) deaths. Mortality rates were lower for patients with takotsubo syndrome than those with myocardial infarction (31%, 195/620; HR: 0.76 [95% CI: 0.62-0.94], P = 0.012), which was attributable to lower rates of cardiovascular (HR: 0.61 [95% CI: 0.44-0.84], P = 0.002) but not non-cardiovascular (HR: 0.92 [95% CI: 0.69-1.23], P = 0.59) deaths. Despite comparable medications use, cardiovascular therapies were consistently associated with better survival in patients with myocardial infarction but not in those with takotsubo syndrome. Diuretic (P = 0.01), anti-inflammatory (P = 0.002), and psychotropic (P < 0.001) therapies were all associated with worse outcomes in patients with takotsubo syndrome. Conclusions: In patients with takotsubo syndrome, cardiovascular mortality is the leading cause of death, and this is not associated with cardiovascular therapy use.

Ruthenium-Catalyzed Chemo-Selective Carbene Insertion into C-H Bond of Styrene over Cyclopropanation: C-C Bond Formation.

The C-C bond formation reactions are important in organic synthesis. Heck reaction is known to arylate the terminal carbon of olefins; however, direct alkylation of the terminal carbon of olefin is limited. Herein, we report a novel ruthenium-catalyzed selective cross-coupling reaction of styrene and α-diazoesters to form a new C-C bond over cyclopropanation via the C-H insertion process for the first time. Using this novel methodology, a wide variety of substrates have been utilized and a variety of α-vinylated benzylic esters and densely functionalized olefins have been synthesized with good stereoselectivity under mild reaction conditions. The overall reaction process proceeds through the carbene insertion into styrene to form the desired products in good to excellent yields with proper stereoselectivity. The selective C-H inserted product, wide substrate scope, and excellent functional group tolerance are the best features of this work.

Impaired Cardiac and Skeletal Muscle Energetics Following Anthracycline Therapy for Breast Cancer.

BACKGROUND: Anthracycline-related cardiac toxicity is a recognized consequence of cancer therapies. We assess resting cardiac and skeletal muscle energetics and myocyte, sarcomere, and mitochondrial integrity in patients with breast cancer receiving epirubicin. METHODS: In a prospective, mechanistic, observational, longitudinal study, we investigated chemotherapy-naive patients with breast cancer receiving epirubicin versus sex- and age-matched healthy controls. Resting energetic status of cardiac and skeletal muscle (phosphocreatine/gamma ATP and inorganic phosphate [Pi]/phosphocreatine, respectively) was assessed with 31P-magnetic resonance spectroscopy. Cardiac function and tissue characterization (magnetic resonance imaging and 2D-echocardiography), cardiac biomarkers (serum NT-pro-BNP and high-sensitivity troponin I), and structural assessments of skeletal muscle biopsies were obtained. All study assessments were performed before and after chemotherapy. RESULTS: Twenty-five female patients with breast cancer (median age, 53 years) received a mean epirubicin dose of 304 mg/m2, and 25 age/sex-matched controls were recruited. Despite comparable baseline cardiac and skeletal muscle energetics with the healthy controls, after chemotherapy, patients with breast cancer showed a reduction in cardiac phosphocreatine/gamma ATP ratio (2.0±0.7 versus 1.1±0.5; P=0.001) and an increase in skeletal muscle Pi/phosphocreatine ratio (0.1±0.1 versus 0.2±0.1; P=0.022). This occurred in the context of increases in left ventricular end-systolic and end-diastolic volumes (P=0.009 and P=0.008, respectively), T1 and T2 mapping (P=0.001 and P=0.028, respectively) but with preserved left ventricular ejection fraction, mass and global longitudinal strain, and no change in cardiac biomarkers. There was preservation of the mitochondrial copy number in skeletal muscle biopsies but a significant increase in areas of skeletal muscle degradation (P=0.001) in patients with breast cancer following chemotherapy. Patients with breast cancer demonstrated a reduction in skeletal muscle sarcomere number from the prechemotherapy stage compared with healthy controls (P=0.013). CONCLUSIONS: Contemporary doses of epirubicin for breast cancer treatment result in a significant reduction of cardiac and skeletal muscle high-energy 31P-metabolism alongside structural skeletal muscle changes. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04467411.

Bioremediation of polycyclic aromatic hydrocarbons: An updated microbiological review.

A class of organic priority pollutants known as PAHs is of critical public health and environmental concern due to its carcinogenic properties as well as its genotoxic, mutagenic, and cytotoxic properties. Research to eliminate PAHs from the environment has increased significantly due to awareness about their negative effects on the environment and human health. Various environmental factors, including nutrients, microorganisms present and their abundance, and the nature and chemical properties of the PAH affect the biodegradation of PAHs. A large spectrum of bacteria, fungi, and algae have ability to degrade PAHs with the biodegradation capacity of bacteria and fungi receiving the most attention. A considerable amount of research has been conducted in the last few decades on analyzing microbial communities for their genomic organization, enzymatic and biochemical properties capable of degrading PAH. While it is true that PAH degrading microorganisms offer potential for recovering damaged ecosystems in a cost-efficient way, new advances are needed to make these microbes more robust and successful at eliminating toxic chemicals. By optimizing some factors like adsorption, bioavailability and mass transfer of PAHs, microorganisms in their natural habitat could be greatly improved to biodegrade PAHs. This review aims to comprehensively discuss the latest findings and address the current wealth of knowledge in the microbial bioremediation of PAHs. Additionally, recent breakthroughs in PAH degradation are discussed in order to facilitate a broader understanding of the bioremediation of PAHs in the environment.

Structural and Functional Brain Changes in Acute Takotsubo Syndrome.

BACKGROUND: Takotsubo syndrome mimics an acute myocardial infarction, typically in the aftermath of mental or physical stress. OBJECTIVES: The mechanism by which emotional processing in the context of stress leads to significant cardiac injury is poorly understood, so a full exploration of brain structure and function in takotsubo syndrome patients merits investigation. METHODS: Twenty-five acute (<5 days) takotsubo patients and 25 control subjects were recruited into this observational cross-sectional study. Surface-based morphometry was carried out on magnetic resonance imaging (MRI) brain scans to extract cortical morphology based on volume, thickness, and surface area with the use of Freesurfer. Cortical morphology general linear models were corrected for age, sex, photoperiod, and total brain volume. Resting-state functional MRI and diffusion tensor tractography images were preprocessed and analyzed with the use of the Functional Magnetic Resonance Imaging of the Brain Diffusion Toolbox and Functional Connectivity Toolbox. RESULTS: There was significantly smaller total white matter and subcortical gray matter volumes in takotsubo (P < 0.001), with smaller total brain surface area but increased total cortical thickness (both P < 0.001). Individual gray matter regions (hippocampus and others) were significantly smaller in takotsubo (P < 0.001); only thalamus and insula were larger (P < 0.001). There was significant hyperfunctional and hypofunctional connectivity in multiple areas, including thalamus-amygdala-insula and basal ganglia (P < 0.05). All structural tractography connections were increased in takotsubo (P < 0.05). CONCLUSIONS: The authors showed smaller gray and white matter volumes driven by smaller cortical surface area, but increased cortical thickness and structural tractography connections with bidirectional changes in functional connectivity linked to emotion, language, reasoning, perception, and autonomic control. These are interventional targets in takotsubo patients' rehabilitation.

Renin-Angiotensin and Endothelin Systems in Patients Post-Takotsubo Cardiomyopathy.

Background We investigate if renin-angiotensin and endothelin-1 response pathways follow the same pattern of recovery as left ventricular ejection fraction in patients with takotsubo cardiomyopathy. Methods and Results Ninety patients with takotsubo cardiomyopathy (n=30 in each of "acute," "convalescent" [3-5 months] and "recovered" [>1 year] groups) who were on minimal or no medication and were free of any significant cardiac/metabolic comorbidities, and 30 controls were studied. Serum concentrations of renin, angiotensin-converting enzyme, angiotensin II, big endothelin-1, endothelin-1 were measured using commercially available ELISA, and B-type natriuretic peptide was measured using an immunoassay. Mean left ventricular ejection fraction was <40% during the acute phase in all groups, but recovered to 63% in convalescent and 64% in the recovered groups, respectively. Serum renin concentrations remain persistently elevated after a episode of takotsubo cardiomyopathy (P=0.03 versus controls). Angiotensin converting enzyme levels are significantly depressed during the acute phase compared with convalescent (P=0.004), recovered takotsubo cardiomyopathy (P=0.02) or controls (P=0.03). Angiotensin II is increased in patients with takotsubo cardiomyopathy (P<0.001 versus controls) remaining persistently elevated in the chronically recovered group alone (P=0.03 versus controls). Big endothelin-1 levels are unchanged, but endothelin-1 is significantly lower after takotsubo cardiomyopathy compared with controls (P=0.03). Conclusions Despite "normalization" of the left ventricular ejection fraction, there is long-term maladaptive activation of renin-angiotensin system in patients with takotsubo cardiomyopathy. Registration URL: https://www.clinicaltrials.gov; Unique identifiers: NCT02897739, NCT02989454.

Takotsubo Syndrome: Pathophysiology, Emerging Concepts, and Clinical Implications.

Takotsubo syndrome is a condition characterized by acute transient left ventricular systolic dysfunction, which at presentation can be challenging to distinguish from acute myocardial infarction. Although previously thought to be a benign, self-limiting condition, recent studies have confirmed that patients with takotsubo syndrome have persistent subtle ongoing cardiac dysfunction, and many continue to have limiting symptoms despite restoration of left ventricular ejection fraction. Moreover, these patients have a substantial burden of morbidity and mortality, as well, with high rates of subsequent major adverse cardiovascular events that approach those of patients with acute coronary syndrome. The mechanisms behind this condition remain elusive. Despite substantial research, the medical community continues to have an incomplete understanding of its underlying pathogenesis and pathophysiology. Catecholamine-induced myocardial injury is the most established and well-known theory, but this does not explain all the clinical features and presentations of the condition, and numerous other pathways and abnormalities are emerging. Because of the poor understanding of its underlying pathophysiology, there is a lack of evidence-based interventions to treat the acute episode, to avoid recurrences, and to prevent major adverse cardiovascular events. This highlights the need for further research to gain a better understanding of the underlying pathophysiology to inform appropriate randomized controlled trials of interventions targeting the causative pathways. Only then can evidence-based management strategies be established to improve clinical outcomes of this potentially lethal condition.

Effect of housing and nutritional interventions during winter on wool attributes of Corriedale sheep.

There are several factors that can directly or indirectly influence wool quality and quantity in sheep, the main elements being genetic and environmental factors. An experiment was conducted to assess the effect of different management/housing interventions during winter on wool quality and yield in Corriedale ewes. Forty healthy pregnant ewes were selected and divided into four groups (G1, G2, G3, G4) based on their body weight and parity. Throughout the study period, the groups G1 and G3 were reared inside the shed, while G2 and G4 were reared in an open shed with four-sided wire fencing and a roof shelter for direct rain/snow protection. The basic ration of all the four groups consisted of 1.25 kg roughage/head/day and 500 g concentrate/head/day. G3 and G4 were fed additional concentrate @ 100 g/head/day. Significant differences were observed in the crimp frequency, fibre diameter, fibre length and medullation percentage. G2 and G4 showed significantly (P < 0.05) higher fibre diameter but lower crimp frequency. Also, medullation percentage was significantly (P < 0.05) higher for G2. However, the studied rearing systems showed no significant differences for wool yield, staple length, scouring yield and burr content. The study concludes that the wool quality parameters observed in sheep, exposed to cold environment, meet most of the requirements of textile sector and thus can be reared in open houses without any adverse effects.

A systematic review of biomarkers in Takotsubo syndrome: A focus on better understanding the pathophysiology.

BACKGROUND: The diagnosis of Takotsubo syndrome is made based on clinical presentation, ECG, biomarker, imaging and coronary angiography. There is a lack of diagnostic biomarkers that can discriminate patients with Takotsubo syndrome from those with acute myocardial infarction (AMI) and provide clinical monitoring and prognostic information in the long-term. METHODS: A literature search of published Takotsubo syndrome biomarkers from PubMed was performed. All studies that included numerical biomarker data on Takotsubo syndrome was included. Exclusion criteria was any study without an AMI cohort for comparison in the acute phase biomarkers or due to the absence of numerical values. The results were tabulated in table form with results expressed as either mean ± SD or median (interquartile range). RESULTS: The literature search produced 14 relevant studies that met search criteria. The results showed; high sensitivity Troponin I (3.21 ± 4.4 vs 34.4 ± 37 ng/ml), BNP [972 (578.5-1671.0) pg/L vs 358 (50.5-688.0) pg/L in NSTEMI and vs 381 (106.0-934.0) pg/L in STEMI] and BNP/Troponin I ratio [642 (331.8-1226.5) vs 184.5 (50.5-372.3) pg/ug in NSTEMI and 7.5 (2.0-29.6) pg/ug in STEMI] patients. DISCUSSION: This study is limited by many studies being retrospective cohort studies. This data shows that acutely troponin is raised in Takotsubo syndrome but not enough to be discriminating from AMI. BNP level is significantly raised in Takotsubo syndrome compared to AMI. CONCLUSION: Current specificity of acute and chronic biomarkers for Takotsubo syndrome is lacking and further work is needed to address the gap in knowledge.

IL-33 ameliorates liver injury and inflammation in Poly I:C and Concanavalin-A induced acute hepatitis.

The IL-33/ST2 axis is known to be involved in liver pathologies and IL-33 is over-expressed in mouse hepatitis models. We aimed to investigate the proposed protective effect of IL-33 in murine fulminant hepatitis induced by a Toll like receptor 3 (TLR3) viral mimetic, Poly I:C or by Concanavalin-A (ConA). The Balb/C mice were administered intravenously with ConA (15 mg/kg) or Poly I:C (30 µg/mouse) to induce acute hepatitis along with vehicle control. The recombinant mouse IL-33 (rIL-33) was injected (0.2 µg/mouse) to mice 2 h prior to ConA or Poly I:C injection to check its hepato-protective effects. The gross lesions, level of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), histopathology (H&E staining) and levels of IFNγ and TNFα were measured by ELISA. The gross pathological liver injury induced by Poly I:C or ConA was reduced by rIL-33 administration in mice. The levels of AST and ALT were significantly (P ≤ 0.05) higher in mice challenged with Poly I:C or ConA in comparison to control mice. The rIL-33 pre-treated mice in both Poly I:C and ConA challenge groups showed significantly (P ≤ 0.05) lower levels of AST and ALT, and decreased liver injury (parenchymal and per-vascular necrotic areas) in histological liver sections. The soluble levels of TNFα and IFNγ were significantly (P ≤ 0.05) raised in Poly I:C or ConA challenged mice than control mice. The levels of TNFα and IFNγ were significantly reduced (P ≤ 0.05) in rIL-33 pre-treated mice. In conclusion, the exogenous IL-33 administration mitigated liver injury and inflammation (decreased levels of IFNγ and TNFα) in Poly I:C and ConA-induced acute hepatitis in mice.

Successful laparoscope-assisted orchiectomy in three cryptorchid sheep.

Three adult Corriedale cryptorchid sheep were subjected to laparoscope-assisted orchiectomy of the retained testicles. One (n = 2) or both (n = 1) the testicles were missing in their scrotal sac and inguinal regions. Ultrasonography was used to locate the retained testicles and their distance from the abdominal surface. The animals were restrained in dorsal recumbency and Trendlenburg posture under lumbosacral epidural anaesthesia using 2% lignocaine hydrochloride. Two laparoscopic ports were created in the caudal abdomen adjacent to the retained testicles. They were identified by their ovoid shape, white glistening surface (Tunica albuginea) and typical vasculature. Laparoscope-assisted exteriorization of the testicles after enlarging the ports, ligation of their blood supply and resection of the spermatic cord was performed successfully. The scrotal testes in two rams were then subjected to routine Burdizzoo castration. The laparoscopic port sites healed without complications and all the animals continued to do well subsequently. From this case report, it is concluded that in sheep the laparoscopy; a minimally invasive procedure can confirm abdominal retention of testicle/s and may also be used for their retrieval in a single sitting. Although total laparoscopic procedure is expected to reduce the incision size further but requires advanced laparoscopic instruments and expertise.

Idebenone improves quality of ram sperm by mitigating oxidative stress during cryopreservation.

The present study was designed to test the effect of different levels of idebenone, a potent antioxidant on the quality of ram semen at post thaw. Eighteen (18) ejaculates were collected and extended with tris extender supplemented with no antioxidant (CON), with 2 µM idebenone (Id2), 5 µM idebenone (Id5), 7.5 µM idebenone (Id7.5) and 10 µM idebenone (Id10). The sperm quality was determined in terms of percent sperm motility, live sperm percentage, percent hypoosmotic swelling test (HOST) positive spermatozoa and percent intact acrosome (PIA). Moreover, malondialdehyde (MDA) level, an end product of lipid peroxidation (LPO) was also measured at post thaw both in seminal plasma and sperm cell. At post thaw, the percent sperm motility was significantly higher (p < 0.05) for Id10 as compared to Id2, Id5, Id7.5 and control. The live sperm percentage was non-significantly (p > 0.05) higher for Id10 as compared to control, Id5 and Id7.5 but significantly higher than Id2. The percent HOST positive spermatozoa was significantly higher (p < 0.05) for Id10 than control, Id2 and Id5. The MDA level in seminal plasma was significantly lower (p < 0.05) for Id10 than control and Id2. The MDA level in spermatozoa did show similar trend as in seminal plasma. Further, all the sperm parameters at all idebenone levels declined significantly from pre freeze to post thaw. In conclusion, idebenone at 10 µM level improved post thaw sperm quality by mitigating peroxidative stress, hence could be considered as a promising antioxidant additive for cryopreservation of ram semen.

Risk factors for sudden cardiac death to determine high risk patients in specific patient populations that may benefit from a wearable defibrillator.

BACKGROUND: There is a high risk for sudden cardiac death (SCD) in certain patient groups that would not meet criteria for implantable cardioverter defibrillator (ICD) therapy. In conditions such as hypertrophic cardiomyopathy (HCM) there are clear risk scores that help define patients who are high risk for SCD and would benefit from ICD therapy. There are however many areas of uncertainty such as certain patients post myocardial infarction (MI). These patients are high risk for SCD but there is no clear tool for risk stratifying such patients. AIM: To assess risk factors for sudden cardiac death in major cardiac disorders and to help select patients who might benefit from Wearable cardiac defibrillators (WCD). METHODS: A literature search was performed looking for risk factors for SCD in patients post-MI, patients with left ventricular systolic dysfunction (LVSD), HCM, long QT syndrome (LQTS). There were 41 studies included and risk factors and the relative risks for SCD were compiled in table form. RESULTS: We extracted data on relative risk for SCD of specific variables such as age, gender, ejection fraction. The greatest risk factors for SCD in post MI patients was the presence of diabetes [Hazard ratio (HR) 1.90-3.80], in patient with LVSD was ventricular tachycardia (Relative risk 3.50), in LQTS was a prolonged QTc (HR 36.53) and in patients with HCM was LVH greater than 20 mm (HR 3.10). A proportion of patients currently not suitable for ICD might benefit from a WCD. CONCLUSION: There is a very high risk of SCD post MI, in patients with LVSD, HCM and LQTS even in those who do not meet criteria for ICD implantation. These patients may be candidates for a WCD. The development of more sensitive risk calculators to predict SCD is necessary in these patients to help guide treatment.

Retraction : Live birth of a Pashmina goat kid after transfer of handmade cloned embryos.

This article released online on March 5, 2019 as advance publication was withdrawn from consideration for publication in Journal of Reproduction and Development at author's request.

Live birth of a Pashmina goat kid after transfer of handmade cloned embryos.

The present study aimed to establish a zona free (handmade cloning) embryo production system for Pashmina goat embryos. Abattoir derived oocytes were matured in vitro; after maturation, oocytes were enucleated and fused with somatic cells derived from an adult Pashmina goat tissue. The reconstructs were activated using a calcium ionophore-DMAP procedure. The embryos were distributed into two experimental groups. In Experiment 1, the embryos were cultured in one of the following four culture media (i) G1.G2 media (ii) Modified synthetic oviduct fluid (mSOF) (iii) Research vitro cleave media (RVCL) and (iv) Embryo development media (EDM), and were cultured for 7 days. The cleavage rates in G1.G2, RVCL, and mSOF were higher than those in EDM (86.8, 82.4, 77.3, and 68.8%, respectively). Blastocyst rates were higher in RVCL than those in mSOF, EDM, and G1.G2 (15.0, 10.5, 4.9, and 2.2%, respectively). In experiment 2, the embryos were cultured in five different culture systems: (i) Flat surface (FS), (ii) Well in drop (WID), (iii) Well of well (WOW), (iv) Micro drop, and (v) Hanging drop, for 7 days. The cleavage rates in FS and WID were higher than those in WOW, Micro drop, and Hanging drop (84.3, 81.2, 73.6, 73.5, and 70.3%, respectively). The blastocyst rates were higher in WID than those in WOW, Micro drop, Hanging drop, and FS systems (21.6, 13.7, 11.5, 10.9, and 3.9%, respectively). The embryos produced in experiment 2 were transferred to synchronized recipients. Of the three pregnancies established on day 40, one resulted in the delivery of a healthy Pashmina kid.

Crosstalk of liver immune cells and cell death mechanisms in different murine models of liver injury and its clinical relevance.

BACKGROUND: Liver inflammation or hepatitis is a result of pluripotent interactions of cell death molecules, cytokines, chemokines and the resident immune cells collectively called as microenvironment. The interplay of these inflammatory mediators and switching of immune responses during hepatotoxic, viral, drug-induced and immune cell-mediated hepatitis decide the fate of liver pathology. The present review aimed to describe the mechanisms of liver injury, its relevance to human liver pathology and insights for the future therapeutic interventions. DATA SOURCES: The data of mouse hepatic models and relevant human liver diseases presented in this review are systematically collected from PubMed, ScienceDirect and the Web of Science databases published in English. RESULTS: The hepatotoxic liver injury in mice induced by the metabolites of CCl4, acetaminophen or alcohol represent necrotic cell death with activation of cytochrome pathway, formation of reactive oxygen species (ROS) and mitochondrial damage. The Fas or TNF-alpha induced apoptotic liver injury was dependent on activation of caspases, release of cytochrome c and apoptosome formation. The ConA-hepatitis demonstrated the involvement of TRAIL-dependent necrotic/necroptotic cell death with activation of RIPK1/3. The alpha-GalCer-induced liver injury was mediated by TNF-alpha. The LPS-induced hepatitis involved TNF-alpha, Fas/FasL, and perforin/granzyme cell death pathways. The MHV3 or Poly(I:C) induced liver injury was mediated by natural killer cells and TNF-alpha signaling. The necrotic ischemia-reperfusion liver injury was mediated by hypoxia, ROS, and pro-inflammatory cytokines; however, necroptotic cell death was found in partial hepatectomy. The crucial role of immune cells and cell death mediators in viral hepatitis (HBV, HCV), drug-induced liver injury, non-alcoholic fatty liver disease and alcoholic liver disease in human were discussed. CONCLUSIONS: The mouse animal models of hepatitis provide a parallel approach for the study of human liver pathology. Blocking or stimulating the pathways associated with liver cell death could unveil the novel therapeutic strategies in the management of liver diseases.

Potential Therapeutic Aspects of Alarmin Cytokine Interleukin 33 or Its Inhibitors in Various Diseases.

PURPOSE: The purpose of this review was to examine the comprehensively accumulated data regarding potential therapeutic aspects of exogenous administration of interleukin 33 (IL-33) or its antagonists in allergic, cancerous, infectious, and inflammatory diseases. METHODS: A selected review was undertaken of publications that examined the protective and exacerbating effects of IL-33 or its inhibitors in different diseases. Mechanisms of action are summarized to examine the putative role of IL-33 in various diseases. FINDINGS: IL-33 promoted antibacterial, antiviral, anti-inflammatory, and vaccine adjuvant functions. However, in TH2-biased respiratory, allergic, parasitic, and inflammatory conditions, IL-33 exhibited disease-sensitizing effects. The alarmin cytokine IL-33 induced protective effects in diseases via recruitment of regulatory T cells; antiviral CD8(+) cells, natural killer cells, γδ T cells, and nuocytes; antibacterial and antifungal neutrophils or macrophages; vaccine-associated B/T cells; and inhibition of nuclear factor-κB-mediated gene transcription. In contrast, IL-33 exacerbated the disease process by increasing TH2 cytokines, IgE and eosinophilic immune responses, and inhibition of leukocyte recruitment in various diseases. IMPLICATIONS: The protective or exacerbated aspects of use of IL-33 or its inhibitors are dependent on the type of infection or inflammatory condition, duration of disease (acute or chronic), organ involved, cytokine microenvironment, dose or kinetics of IL-33, and genetic predisposition. The alarmin cytokine IL-33 acts at cellular, molecular, and transcriptional levels to mediate pluripotent functions in various diseases and has potential therapeutic value to mitigate the disease process.

Streptozotocin Induced Acute Clinical Effects in Rabbits (Oryctolagus cuniculus).

BACKGROUND & OBJECTIVES: Streptozotocin (STZ) is used for induction of Type-1 diabetes mellitus in animal models. Its beta-cytotoxic action results in sudden release of insulin leading to severe hypoglycaemia and even mortality. However, its sensitivity varies with species. Present investigation was aimed at studying STZ induced acute clinical effects in rabbits. METHODS: Streptozotocin @ 65 mg/kg b.w. was administered to thirteen New Zealand White rabbits, 1-1.5 kg body weight, as single intravenous dose in 1mL citrate buffer, pH 4.6. Blood glucose levels were recorded before drug administration and then at 20 min, 1h, and hourly up to 9 hours post-treatment followed by intravenous and oral glucose therapy. Clinical signs were noted. RESULTS: STZ caused immediate hyperglycaemia up to 4 hours, and then progressively severe hypoglycaemia up to 9 hours. Hypoglycaemia caused characteristic behavioural alterations including lethargy, dullness, sitting quietly but appearing alert, followed by aesthesia and then muscular weakness with characteristic postural changes starting from drooping of head and torticollis, Rabbits recovered following glucose therapy. Marked individual variations in response vis-a-vis onset and severity of glycaemic changes were observed. CONCLUSION: STZ induced a characteristic multiphasic immediate response in rabbits similar to one reported in other rodents. Behavioural changes were characteristic of hypoglycaemia warranting early management in order to avoid fatalities.