Kinetic and cross-linking studies indicate different receptors for endothelins and sarafotoxins in the ileum and cerebellum

AbstractKinetics of ligand/receptor interactions using ET-1, ET-3 and SRTX-b were studied and cross-linking experiments carried out in guinea pig ileum and rat cerebellar preparations. Dissociation studies indicate that the two regions are characterized by different receptor subtypes and different modes of ligand binding. Autoradiographic patterns obtained following cross-linking of ET-1 and ET-3 to the different issues support these conclusions

Indicators of the need for ICU admission following suicide bombing attacks

<p>Abstract</p> <p>Introduction</p> <p>Critical hospital resources, especially the demand for ICU beds, are usually limited following mass casualty incidents such as suicide bombing attacks (SBA). Our primary objective was to identify easily diagnosed external signs of injury that will serve as indicators of the need for ICU admission. Our secondary objective was to analyze under- and over-triage following suicidal bombing attacks.</p> <p>Methods</p> <p>A database was collected prospectively from patients who were admitted to Hadassah University Hospital Level I Trauma Centre, Jerusalem, Israel from August 2001-August 2005 following a SBA. One hundred and sixty four victims of 17 suicide bombing attacks were divided into two groups according to ICU and non-ICU admission.</p> <p>Results</p> <p>There were 86 patients in the ICU group (52.4%) and 78 patients in the non-ICU group (47.6%). Patients in the ICU group required significantly more operating room time compared with patients in the non-ICU group (59.3% vs. 25.6%, respectively, <it>p </it>= 0.0003). For the ICU group, median ICU stay was 4 days (IQR 2 to 8.25 days). On multivariable analysis only the presence of facial fractures (<it>p </it>= 0.014), peripheral vascular injury (<it>p </it>= 0.015), injury ≥ 4 body areas (<it>p </it>= 0.002) and skull fractures (<it>p </it>= 0.017) were found to be independent predictors of the need for ICU admission. Sixteen survivors (19.5%) in the ICU group were admitted to the ICU for one day only (ICU-LOS = 1) and were defined as over-triaged. Median ISS for this group was significantly lower compared with patients who were admitted to the ICU for > 1 day (ICU-LOS > 1). This group of over-triaged patients could not be distinguished from the other ICU patients based on external signs of trauma. None of the patients in the non-ICU group were subsequently transferred to the ICU.</p> <p>Conclusions</p> <p>Our results show that following SBA, injury to ≥ 4 areas, and certain types of injuries such as facial and skull fractures, and peripheral vascular injury, can serve as surrogates of severe trauma and the need for ICU admission. Over-triage rates following SBA can be limited by a concerted, focused plan implemented by dedicated personnel and by the liberal utilization of imaging studies.</p

Comparative skull analysis suggests species-specific captivity-related malformation in lions (Panthera leo)

Lion (Panthera leo) populations have dramatically decreased worldwide with a surviving population estimated at 32,000 across the African savannah. Lions have been kept in captivity for centuries and, although they reproduce well, high rates of stillbirths as well as morbidity and mortality of neonate and young lions are reported. Many of these cases are associated with bone malformations, including foramen magnum (FM) stenosis and thickened tentorium cerebelli. The precise causes of these malformations and whether they are unique to captive lions remain unclear. To test whether captivity is associated with FM stenosis, we evaluated 575 lion skulls of wild (N = 512) and captive (N = 63) origin. Tiger skulls (N = 276; 56 captive, 220 wild) were measured for comparison. While no differences were found between males and females or between subadults and adults in FM height (FMH), FMH of captive lions (17.36±3.20 mm) was significantly smaller and with greater variability when compared to that in wild lions (19.77±2.11 mm). There was no difference between wild (18.47±1.26 mm) and captive (18.56±1.64 mm) tigers in FMH. Birth origin (wild vs. captive) as a factor for FMH remained significant in lions even after controlling for age and sex. Whereas only 20/473 wild lions (4.2%) had FMH equal to or smaller than the 5th percentile of the wild population (16.60 mm), this was evident in 40.4% (23/57) of captive lion skulls. Similar comparison for tigers found no differences between the captive and wild populations. Lions with FMH equal to or smaller than the 5th percentile had wider skulls with smaller cranial volume. Cranial volume remained smaller in both male and female captive lions when controlled for skull size. These findings suggest species- and captivity-related predisposition for the pathology in lions.Scopu

Effectiveness of nitric oxide agents in preventing the early onset of pre-eclampsia and possible modification of metabolic factors in high-risk pregnancies:

Objectives: To determine the effectiveness of nitric oxide agents in modifying the metabolic factors of pre-eclampsia and its effectiveness in preventing the onset of pre-eclampsia in high-risk pregnancies. Introduction: Pre-eclampsia is a major cause of maternal death during the prenatal and neonatal periods. Nitric oxide is a vasodilator and platelet aggregation inhibitor responsible for the vascular adaptation of the placenta. Although various studies have established that nitric oxide is effective in preventing complications from pre-eclampsia, there is limited evidence to show that administering nitric oxide agents to the high-risk women before 20 weeks’ gestation will prevent the onset of pre-eclampsia. Inclusion criteria: This review will consider randomized controlled trials that compare nitric oxide donors and precursors with a placebo or no intervention on pregnant women (18 to 44 years) with ≤ 20-week gestational age that are at high risk of pre-eclampsia. The primary outcome of interest will be the onset of pre-eclampsia. Secondary outcomes include increased systolic and diastolic blood pressure, elevated asymmetric dimethylarginine levels, decreased endothelial nitric oxide synthase activity, reduced maternal placental vasculature, and abnormal Doppler ultrasound waveforms. Methods: Data sources will be drawn up from MEDLINE, CINAHL, ProQuest (Health and Medicine) and Web of Science from inception till current date. No language restrictions will be applied in the search strategy. Selected studies will be assessed against the JBI critical appraisal checklist, and the certainty of evidence and strength of recommendations from findings will also be ascertained. Systematic review registration number: CRD4201809929

The urgent need to develop novel strategies for the diagnosis and treatment of snakebites

Snakebite envenoming (SBE) is a priority neglected tropical disease, which kills over one hundred thousand people per year. However, many millions of survivors also suffer through disabilities and long-term health consequences. The only treatment, antivenom, has a number of major associated problems, not least, adverse reactions and limited availability. This emphasises the necessity for urgent improvements to the management of this disease. Administration of antivenom is too frequently based on symptomatology, which results in wasting crucial time. The majority of SBE-affected regions rely on broad-spectrum polyvalent antivenoms that have a low content of case-specific efficacious immunoglobulins. Research into small molecular therapeutics such as varespladib/methyl-varespladib (PLA2 inhibitors) and batimastat/marimastat (metalloprotease inhibitors) suggest that such adjunctive treatments could be hugely beneficial to victims. Progress into toxin-specific monoclonal antibodies as well as alternative binding scaffolds such as aptamers hold much promise for future treatment strategies. SBE is not implicit during snakebite, due to venom metering. Thus, the delay between bite and symptom presentation is critical and when symptoms appear it may often already be too late. The development of reliable diagnostical tools could therefore initiate a paradigm shift in the treatment of SBE. While the complete eradication of SBE is an impossibility, mitigation is in the pipeline, and new treatments are emerging

The cytochemical localization of adenylate cyclase activity in mucous and serous cells of the salivary gland

The present study was undertaken to localize adenylate cyclase activity in salivary glands by cytochemical means. For the study, serous parotid glands and mixed sublingual glands of the rat were used. Pieces of the fixed glands were incubated with adenosine triphosphate (ATP) or adenylyl-imidodi-phosphate (AMP-PNP) as substrate: inorganic pyrophosphate or PNP liberated upon the action of adenylate cyclase on the substrates is precipitated by lead ions at their sites of production. In both glands, the reaction product was detected along the myoepithelial cell membranes in contact with secretory cells, indicating that a high level of adenylate cyclase activity occurs in association with these cell membranes. The association with a high level of the enzyme activity might be related to the contractile nature of myoepithelial cells which are supposed to aid secretory cells in discharging secretion products. A high level of adenylate cyclase activity was also detected associated with serous secretory cells (acinar cells of the parotid gland and demilune cells of the sublingual gland), but not with mucous secretory cells. In serous cells, deposits of reaction product were localized along the extracellular space of the apical cell membrane bordering the lumen. This is the portion of the cell membrane which fuses with the granule membranes during secretion. Since the granule membranes are not associated with a detectable level of adenylate cyclase activity, it appears that the enzyme activity becomes activated or associated with the granule membranes as they become part of the cell membrane by fusion. The association with a high level of adenylate cyclase activity appears to be related to the ability of the membrane to fuse with other membranes. It is likely, since the luminal membrane of mucous cells which does not fuse with mucous granule membranes during secretion is not associated with a detectable enzyme activity.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/38201/1/400040206_ftp.pd

Amylase mRNA synthesis and ageing in rat parotid glands following isoproterenol-stimulated secretion

In the parotid, as well as in other exocrine glands, secretory protein synthesis declines with age. However, whether this decline in the steady-state rate of protein synthesis reflects the reduced digestive activity of the animal or actual cellular alterations that affect synthesis is unknown. Here the ability to synthesize amylase and its mRNA during the period of enhanced protein synthesis following secretion induced by isoproterenol was compared in acinar cells of 2-and 24-month-old rats. In unstimulated glands, rates of synthesis of total protein and amylase, as well as amounts of amylase mRNA, were significantly less in the older rats than in their younger counterparts. After stimulation with isoproterenol, which induced the secretion of about 50% of stored proteins, rates of synthesis of total protein, as well as amylase, were increased by about 2.5 x the unstimulated rates in both age groups. However, the amount of amylase mRNA did not increase in parallel with the increase in the rate of amylase protein synthesis in both young and old rats. The molecular size of the mRNA was the same in stimulated and unstimulated glands of both age groups. Thus, it appears that parotid acinar cells from old rats can be stimulated to synthesize secretory proteins at an increased rate. It remains to be determined what causes the reduced rate of protein synthesis in unstimulated glands in old rats.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30081/1/0000452.pd

Preclinical evaluation of the efficacy of antivenoms for snakebite envenoming: State-of-the-art and challenges ahead

Animal-derived antivenoms constitute the mainstay in the therapy of snakebite envenoming. The efficacy of antivenoms to neutralize toxicity of medically-relevant snake venoms has to be demonstrated through meticulous preclinical testing before their introduction into the clinical setting. The gold standard in the preclinical assessment and quality control of antivenoms is the neutralization of venom-induced lethality. In addition, depending on the pathophysiological profile of snake venoms, the neutralization of other toxic activities has to be evaluated, such as hemorrhagic, myotoxic, edema-forming, dermonecrotic, in vitro coagulant, and defibrinogenating effects. There is a need to develop laboratory assays to evaluate neutralization of other relevant venom activities. The concept of the 3Rs (Replacement, Reduction, and Refinement) in Toxinology is of utmost importance, and some advances have been performed in their implementation. A significant leap forward in the study of the immunological reactivity of antivenoms against venoms has been the development of “antivenomics”, which brings the analytical power of mass spectrometry to the evaluation of antivenoms. International partnerships are required to assess the preclinical efficacy of antivenoms against snake venoms in different regions of the world in order to have a detailed knowledge on the neutralizing profile of these immunotherapeuticsMinisterio de Economía y Competitividad/[BFU2013-42833-P]//EspañaUCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Instituto Clodomiro Picado (ICP)UCR::Vicerrectoría de Docencia::Salud::Facultad de Microbiologí