Effects of caffeine on carotid sinus nerve chemosensory discharge in kittens and cats

Bairam, A., P. De Grandpré, C. Dauphin, and F. Marchal. Effects of caffeine on carotid sinus nervechemosensory discharge in kittens and cats. J. Appl.Physiol. 82(2): 413-418, 1997.Caffeine (C)decreases apneic episodes in premature infants and is thought tostimulate breathing mainly by a central mechanism. While the methylxanthines theophylline and aminophylline are known to alter thecarotid chemoreceptor activity, there are little data on C. The aim ofthe study was to examine the effects of C on the carotid sinus nervedischarge (CSND) in developing animals. Nine kittens 17-21 daysold and six adult cats that were anesthetized and artificially ventilated were studied. They received four consecutive doses of C,each of 10 mg/kg, administered at intervals of 20 min either asintravenous bolus injection (6 kittens, 3 cats) or continuous infusion(3 kittens, 3 cats). Bolus injections of C invariably induced a promptbut transient increase in the CSND from 4.1 ± 0.6 to 8.1 ± 1.0 (SE) impulses/s in kittens (P = 0.01)and from 3.9 ± 0.1 to 7.9 to 1.0 impulses/s in cats (after thefirst injection). This response was associated with a significantdecrease in arterial blood pressure. Continuous infusion of C did notinduce any early change in either CSND or blood pressure in kittens orcats. Fifteen minutes after C injection or infusion was begun, CSNDvalues in air, 8% O₂-balanceN₂, or 100%O₂ were not significantlydifferent from control. Haloperidol administered at theend of the experiment in four cats and four kittens significantlyincreased CSND and did not suppress the early response to C injection.It is concluded that caffeine administered by bolus in the kitteninduces a transient stimulation of the CSND that is associated with adecrease in the arterial blood pressure and is independent of thedopaminergic mechanisms in the carotid body. The lack of sustainedeffect implies the main mechanism to the ventilatory stimulation by Cmust be central.

     

Quinones bearing non-steroidal anti-inflammatory fragments as multitarget ligands for Alzheimer’s disease

The anti-amyloid properties shared by several quinones inspired the design of a new series of hybrids derived from the multi-target drug candidate memoquin (1). The hybrids consist of a central benzoquinone core and a fragment taken from non-steroidal anti-inflammatory drugs, connected through polyamine linkers. The new hybrids retain the potent anti-aggregating activity of the parent 1, while exhibiting micromolar AChE inhibitory activities. Remarkably, 2, 4, (R)-6 and (S)-6 were Aβ aggregation inhibitors even more potent than 1. The balanced amyloid/cholinesterase inhibitory profile is an added value that makes the present series of compounds promising leads against Alzheimer’s disease.     

Simultaneous binding of Guidance Cues NET1 and RGM blocks extracellular NEO1 signaling

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First observation of Lethocerus cordofanus (Hemiptera: Belostomatidae) preying on Afronycteris nana (Chiroptera: Vespertilionidae)

Giant water bugs (Hemiptera: Belostomatidae) are key predators in freshwater ecosystems and have been reported to feed on several species of vertebrates, including fishes, amphibians and reptiles. Here, we report the opportunistic predation of an adult female vesper bat (Afronycteris nana) by a giant water bug (Lethocerus cordofanus) in a temporary pond in a rice paddy in Guinea-Bissau, West Africa. To our best knowledge, this is the first instance of natural predation upon a mammal by a giant water bug to be documented in a scientific report.     

Taurine-like GABA aminotransferase inhibitors prevent rabbit brain slices against oxygen–glucose deprivation-induced damage

The activation of the GABAergic system has been shown to protect brain tissues against the damage that occurs after cerebral ischaemia. On the other hand, the taurine analogues (±)Piperidine-3-sulphonic- (PSA), 2-aminoethane phosphonic- (AEP), 2-(N-acetylamino) cyclohexane sulfonic-acids (ATAHS) and 2-aminobenzene sulfonate-acids (ANSA) have been reported to block GABA metabolism by inhibiting rabbit brain GABA aminotransferase and to increase GABA content in rabbit brain slices. The present investigation explored the neuroprotection provided by GABA, Vigabatrin (VIGA) and taurine analogues in the course of oxygen–glucose deprivation and reperfusion induced damage of rabbit brain slices. Tissue damage was assessed by measuring the release of glutamate and lactate dehydrogenase (LDH) during reperfusion and by determining final tissue water gain, measured as the index of cell swelling. GABA (30–300?μM) and VIGA (30–300?μM) significantly antagonised LDH and glutamate release, as well as tissue water gain caused by oxygen–glucose deprivation and reperfusion. Lower (1–10?μM) or higher concentrations (up to 3,000?μM) were ineffective. ANSA, PSA and ATAHS significantly reduced glutamate and LDH release and tissue water gain in a range of concentrations between 30 and 300?μM. Lower (0–10?μM) or higher (up to 3,000?μM) concentrations were ineffective. Both mechanisms suggest hormetic (“U-shaped”) effects. These results indicate that the GABAergic system activation performed directly by GABA or indirectly through GABA aminotransferase inhibition is a promising approach for protecting the brain against ischemia and reperfusion-induced damage.     

Phosphorylation of atrial natriuretic factor R1 receptor by serine/threonine protein kinases: evidences for receptor regulation

The 130 kDa atrial natriuretic factor receptor (ANF-R₁) purified from bovine adrenal zona glomerulosa is phosphorylated in vitro by serine/threonine protein kinases such as cAMP-, cGMP-dependent and protein kinase C. This phosphorylation is independent of the presence of ANF (99–126) and there is no detectable intrinsic kinase activity associated with the ANF-R₁ receptor or with its activated form. In bovine adrenal zona glomerulosa cells, TPA (phorbol ester) induces a marked inhibition of the ANF-stimulated cGMP accumulation as well as of the membrane ANF-sensitive guanylate cyclase catalytic activity without any change in the binding capacity or affinity for ¹²⁵I-ANF. However, we have demonstrated a significant ³²P incorporation in the ANF-R₁ receptor of the TPA-treated cells. The effect of TPA on the zona glomerulosa ANF-R₁ receptors was abolished by calphostin C, a specific protein kinase C inhibitor. Altered ANF actions due to blunted response of guanylate cyclase to ANF could be a consequence of the ANF receptor phosphorylation by excessive activity of protein kinase C and might be involved in the pathogenesis of hypertension.Abbreviations ANF Atrial Natriuretic Factor - ANF-R₁ Atrial Natriuretic Factor Receptor, subtype 1 - ATP Adenosine Triphosphate - CaCl₂ Calcium Chloride - cAMP Adenosine cyclic 3,5-Monophosphate acid - cGMP Guanosine cyclic 35-Monophosphate acid - EDC 1-Ethyl-3-[3-Dimethylaminopropyl] Carbodiimide - EDTA Ethylenediaminetetraacetic Acid - GTP Guanosine Triphosphate - IBMX 3-isobutyl-1-methylxanthine - kDa Kilodaltons - MgCl₂ Magnesium Chloride - MgAC Magnesium Acetate - NaCl Sodium Chloride - PAGE Polyacrylamide Gel Electrophoresis - PKA cAMP-dependent protein kinase - PKG cGMP-dependent Protein Kinase - PKC Calcium/Phospholipid-dependent Protein Kinase - RIA Radioimmunoassay - SDS Sodium Dodecyl Sulfate - SHR Spontaneously Hypertensive Rat - Tris HCl Tris (Hydroxymethyl) aminomethane Hydrochloride - TPA 12-O-Tetradecanoyl-Phorbol-13-Acetate     

'Tissue' transglutaminase ablation reduces neuronal death and prolongs survival in a mouse model of Huntington's disease

By crossing Huntington's disease (HD) R6/1 transgenic mice with 'tissue' transglutaminase (TG2) knock-out mice, we have demonstrated that this multifunctional enzyme plays an important role in the neuronal death characterising this disorder in vivo. In fact, a large reduction in cell death is observed in R6/1, TG2(-/-) compared with R6/1 transgenic mice. In addition, we have shown that the formation of neuronal intranuclear inclusions (NII) is potentiated in absence of the 'tissue' transglutaminase. These phenomena are paralleled by a significant improvement both in motor performances and survival of R6/1, TG2(-/-) versus R6/1 mice. Taken together these findings suggest an important role for tissue transglutaminase in the regulation of neuronal cell death occurring in Huntington's disease.     

CCN2/connective tissue growth factor is essential for pericyte adhesion and endothelial basement membrane formation during angiogenesis

CCN2/Connective Tissue Growth Factor (CTGF) is a matricellular protein that regulates cell adhesion, migration, and survival. CCN2 is best known for its ability to promote fibrosis by mediating the ability of transforming growth factor β (TGFβ) to induce excess extracellular matrix production. In addition to its role in pathological processes, CCN2 is required for chondrogenesis. CCN2 is also highly expressed during development in endothelial cells, suggesting a role in angiogenesis. The potential role of CCN2 in angiogenesis is unclear, however, as both pro- and anti-angiogenic effects have been reported. Here, through analysis of Ccn2-deficient mice, we show that CCN2 is required for stable association and retention of pericytes by endothelial cells. PDGF signaling and the establishment of the endothelial basement membrane are required for pericytes recruitment and retention. CCN2 induced PDGF-B expression in endothelial cells, and potentiated PDGF-B-mediated Akt signaling in mural (vascular smooth muscle/pericyte) cells. In addition, CCN2 induced the production of endothelial basement membrane components in vitro, and was required for their expression in vivo. Overall, these results highlight CCN2 as an essential mediator of vascular remodeling by regulating endothelial-pericyte interactions. Although most studies of CCN2 function have focused on effects of CCN2 overexpression on the interstitial extracellular matrix, the results presented here show that CCN2 is required for the normal production of vascular basement membranes.     

Risk factors and outcomes of candidemia caused by biofilm-forming isolates in a tertiary care hospital

Background

Very few data exist on risk factors for developing biofilm-forming Candida bloodstream infection (CBSI) or on variables associated with the outcome of patients treated for this infection.

Methods and Findings

We identified 207 patients with CBSI, from whom 84 biofilm-forming and 123 non biofilm-forming Candida isolates were recovered. A case-case-control study to identify risk factors and a cohort study to analyze outcomes were conducted. In addition, two sub-groups of case patients were analyzed after matching for age, sex, APACHE III score, and receipt of adequate antifungal therapy. Independent predictors of biofilm-forming CBSI were presence of central venous catheter (odds ratio [OR], 6.44; 95% confidence interval [95% CI], 3.21–12.92) or urinary catheter (OR, 2.40; 95% CI, 1.18–4.91), use of total parenteral nutrition (OR, 5.21; 95% CI, 2.59–10.48), and diabetes mellitus (OR, 4.47; 95% CI, 2.03–9.83). Hospital mortality, post-CBSI hospital length of stay (LOS) (calculated only among survivors), and costs of antifungal therapy were significantly greater among patients infected by biofilm-forming isolates than those infected by non-biofilm-forming isolates. Among biofilm-forming CBSI patients receiving adequate antifungal therapy, those treated with highly active anti-biofilm (HAAB) agents (e.g., caspofungin) had significantly shorter post-CBSI hospital LOS than those treated with non-HAAB antifungal agents (e.g., fluconazole); this difference was confirmed when this analysis was conducted only among survivors. After matching, all the outcomes were still favorable for patients with non-biofilm-forming CBSI. Furthermore, the biofilm-forming CBSI was significantly associated with a matched excess risk for hospital death of 1.77 compared to non-biofilm-forming CBSI.

Conclusions

Our data show that biofilm growth by Candida has an adverse impact on clinical and economic outcomes of CBSI. Of note, better outcomes were seen for those CBSI patients who received HAAB antifungal therapy.