Synergic stimulation of serotonin 5-HT1A receptor and α2-adrenoceptors for neuropathic pain relief: Preclinical effects of 2-substituted imidazoline derivatives

Neuropathic pain affects millions of people causing disability and impairing quality of life. Commonly used analgesics are generally characterized by limited therapeutic outcomes. The serotonin 5-HT1A receptor and the α2 adrenergic receptors are involved in central nociceptive mechanisms with a pivotal role in the inhibitory descending pain pathway. Since their stimulation may modulate the nervous signaling altered by neuropathies, the purpose of the present research is the study of the combined activation of 5-HT1A and α2 receptors by rationally designed imidazoline ligands ((S)-(-)-1 and 2-5) in a rat model of neuropathic pain (chronic constriction injury - CCI). On day 14 after nerve damage, the acute administration per os (p.o.) of low doses of (S)-(-)-1 (0.1-1mg/kg) was able to significantly increase the pain threshold to mechanical noxious stimuli for more than 1h. (S)-(-)-1 efficacy was confirmed by the decrease of spontaneous pain evaluated as hind limb weight bearing alterations. The clinically-used compound gabapentin (100mg/kg p.o.) induced a pain relieving effect similar to (S)-(-)-1 administered at 100 fold lower dose. In the same model, the selected analogues, compounds 2-5 (1mg/kg p.o.) were effective 30min after administration. In particular, 5 fully reverted the CCI-induced hypersensitivity. The pain relieving activity of 5 was significantly prevented by the selective 5-HT1A receptor antagonist WAY 100635 (1mg/kg intraperitoneally, i.p.) and, at a lesser extent, by the α2 antagonist yohimbine (3mg/kg i.p.). A novel pharmacodynamic approach to the treatment of neuropathic pain is presented

Candida tropicalis fungaemia: incidence, risk factors and mortality in a general hospital

AbstractThe risk factors and clinical features of patients with Candida tropicalis fungaemia have not been fully defined. We performed a case–control study comparing 59 cases of C. tropicalis fungaemia with 177 episodes of fungaemia caused by other species of Candida in our hospital over a 24-year period (January 1985 to December 2008). Patients with C. tropicalis fungaemia were more likely to be older (median age, 67 vs. 56 years; p 0.01), to have cancer (45.5% vs. 31.6%, p 0.04), and to have the abdomen as the portal of entry (32.2% vs. 11.9%, p 0.001), and had a higher in-hospital mortality rate (61% vs. 44%, p 0.03). Multivariate analysis showed that the independent risk factors for C. tropicalis fungaemia were cancer (OR 4.5; 95% CI 1.05–3.83; p 0.03) and the abdomen as the portal of entry (OR 13.6; 95% CI 1.9–8.2; p <0.001). When survivors were compared with non-survivors, the risk factors associated with a poor outcome were neutropenia (19.4% vs. 0; p 0.03), corticosteroid treatment (36% vs. 13%; p 0.07), and septic shock (50% vs. 17.4%; p 0.01). The independent risk factors for mortality in the multivariate analysis were corticosteroid treatment (OR 8.2; 95% CI 0.9–27.7; p 0.04) and septic shock (OR 14.6; 95% CI 2.4–90.2; p 0.004), whereas urinary tract infection (OR 0.07; 95% CI 0.01–0.8; p 0.03) and catheter removal (OR 0.06; 95% CI 0.01–0.4; p 0.002) were protective factors. C. tropicalis is the fourth most common cause of fungaemia in our hospital. It is associated with underlying malignancy, the abdomen as the portal of entry, and poor outcome

Developement of real time diagnostics and feedback algorithms for JET in view of the next step

Real time control of many plasma parameters will be an essential aspect in the development of reliable high performance operation of Next Step Tokamaks. The main prerequisites for any feedback scheme are the precise real-time determination of the quantities to be controlled, requiring top quality and highly reliable diagnostics, and the availability of robust control algorithms. A new set of real time diagnostics was recently implemented on JET to prove the feasibility of determining, with high accuracy and time resolution, the most important plasma quantities. With regard to feedback algorithms, new model&#8211;based controllers were developed to allow a more robust control of several plasma parameters. Both diagnostics and algorithms were successfully used in several experiments, ranging from H-mode plasmas to configuration with ITBs. Since elaboration of computationally heavy measurements is often required, significant attention was devoted to non-algorithmic methods like Digital or Cellular Neural/Nonlinear Networks. The real time hardware and software adopted architectures are also described with particular attention to their relevance to ITER.Comment: 12th International Congress on Plasma Physics, 25-29 October 2004, Nice (France

Oral Versus Standard Antimicrobial Treatment for Pyogenic Native Vertebral Osteomyelitis: A Single-Center, Retrospective, Propensity Score-Balanced Analysis

Background: Interest in shorter antimicrobial regimens and oral treatment for osteoarticular infections is growing. The aim of this study is to assess whether there is an association between the administration of an entirely oral antibiotic therapy (OT) and the clinical outcome of native vertebral osteomyelitis (NVOs). Methods: We conducted a single-center, retrospective, observational study on consecutive patients with pyogenic NVOs over a 10-year period (2008-2018). We performed multivariate logistic regression analysis to identify risk factors for clinical failure, both in the whole population and in subgroups. The impact of OT versus standard treatment (intravenous induction followed by oral treatment whenever possible) was assessed in patients with a non-multidrug-resistant microorganism (MDRO) etiology, and the impact of a rifampin-containing regimen was assessed in patients affected by NVOs caused by staphylococci or of unknown etiology. Results: The study population included 249 patients, and 33 (13.3%) experienced clinical failure; the OT group consisted of 54 patients (21.7%). Multivariate regression analysis of the whole population selected Charlson comorbidity index (adjusted odds ratio [aOR], 1.291; 95% confidence interval [CI], 1.114-1.497; P =. 001) and MDRO etiology (aOR, 3.301; 95% CI, 1.368-7.964; P =. 008) as independent factors for clinical failure. Among patients affected by a non-MDRO NVO, OT was not associated with an increased risk of clinical failure (aOR, 0.487; 95% CI,. 133-1.782; P =. 271), even after adjustment for the propensity score of receiving OT. In the subgroup of patients with staphylococcal or unknown etiology, NVO rifampin was independently associated with favorable outcome (aOR, 0.315; 95% CI,. 105-.949; P =. 040). Conclusions: An entirely oral, highly bioavailable treatment, including rifampin, may be as effective as parenteral treatment in selected patients with NVOs

Control of positive end-expiratory pressure (PEEP) for small animal ventilators

<p>Abstract</p> <p>Background</p> <p>The positive end-expiratory pressure (PEEP) for the mechanical ventilation of small animals is frequently obtained with water seals or by using ventilators developed for human use. An alternative mechanism is the use of an on-off expiratory valve closing at the moment when the alveolar pressure is equal to the target PEEP. In this paper, a novel PEEP controller (PEEP-new) and the PEEP system of a commercial small-animal ventilator, both based on switching an on-off valve, are evaluated.</p> <p>Methods</p> <p>The proposed PEEP controller is a discrete integrator monitoring the error between the target PEEP and the airways opening pressure prior to the onset of an inspiratory cycle. In vitro as well as in vivo experiments with rats were carried out and the PEEP accuracy, settling time and under/overshoot were considered as a measure of performance.</p> <p>Results</p> <p>The commercial PEEP controller did not pass the tests since it ignores the airways resistive pressure drop, resulting in a PEEP 5 cmH₂O greater than the target in most conditions. The PEEP-new presented steady-state errors smaller than 0.5 cmH₂O, with settling times below 10 s and under/overshoot smaller than 2 cmH₂O.</p> <p>Conclusion</p> <p>The PEEP-new presented acceptable performance, considering accuracy and temporal response. This novel PEEP generator may prove useful in many applications for small animal ventilators.</p

Human Polyomaviruses in the Cerebrospinal Fluid of Neurological Patients.

BACKGROUND: Central nervous system (CNS) infections by human polyomaviruses (HPyVs), with the exception of JC (JCPyV), have been poorly studied. METHODS: In total, 234 cerebrospinal fluid (CSF) samples were collected from patients affected with neurological disorders. DNA was isolated and subjected to quantitative real-time PCR (Q-PCR) for the detection of six HPyVs: JCPyV, BKPyV, Merkel cell PyV (MCPyV), HPyV6, HPyV7, and HPyV9. Where possible, the molecular characterization of the viral strains was carried out by nested PCR and automated sequencing. RESULTS: JCPyV was detected in 3/234 (1.3%), BKPyV in 15/234 (6.4%), MCPyV in 22/234 (9.4%), and HPyV6 in 1/234 (0.4%) CSF samples. JCPyV was detected at the highest (p < 0.05) mean load (3.7 7 107 copies/mL), followed by BKPyV (1.9 7 106 copies/mL), MCPyV (1.9 7 105 copies/mL), and HPyV6 (3.3 7 104 copies/mL). The noncoding control regions (NCCRs) of the sequenced viral strains were rearranged. CONCLUSIONS: HPyVs other than JCPyV were found in the CSF of patients affected with different neurological diseases, probably as bystanders, rather than etiological agents of the disease. However, the fact that they can be latent in the CNS should be considered, especially in immunosuppressed patients

Apoptosis rate and transcriptional response of pancreatic islets exposed to the PPAR gamma agonist Pioglitazone

To explore the molecular pathways underlying thiazolidinediones effects on pancreatic islets in conditions mimicking normo- and hyperglycemia, apoptosis rate and transcriptional response to Pioglitazone at both physiological and supraphysiological glucose concentrations were evaluated. Adult rat islets were cultured at physiological (5.6 mM) and supraphysiological (23 mM) glucose concentrations in presence of 10 μM Pioglitazone or vehicle. RNA expression profiling was evaluated with the PancChip 13k cDNA microarray after 24-h, and expression results for some selected genes were validated by qRT-PCR. The effects of Pioglitazone were investigated regarding apoptosis rate after 24-, 48- and 72-h. At 5.6 mM glucose, 101 genes were modulated by Pioglitazone, while 1,235 genes were affected at 23 mM glucose. Gene networks related to lipid metabolism were identified as altered by Pioglitazone at both glucose concentrations. At 23 mM glucose, cell cycle and cell death pathways were significantly regulated as well. At 5.6 mM glucose, Pioglitazone elicited a transient reduction in islets apoptosis rate while at 23 mM, Bcl2 expression was reduced and apoptosis rate was increased by Pioglitazone. Our data demonstrate that the effect of Pioglitazone on gene expression profile and apoptosis rate depends on the glucose concentration. The modulation of genes related to cell death and the increased apoptosis rate observed at supraphysiological glucose concentration raise concerns about Pioglitazone’s direct effects in conditions of hyperglycemia and reinforce the necessity of additional studies designed to evaluate TZDs effects on the preservation of β-cell function in situations where glucotoxicity might be more relevant than lipotoxicity.This work was supported by grants from NIDDK (UO1 DK 56947; P30 DK 19525) and from FAPESP (04/018165, 04/014670 and 04/107974). The authors are grateful to Takeda Chemicals Industries (Japan) for supplying pioglitazone hydrochloride pure substance.This work was supported by grants from NIDDK (UO1 DK 56947; P30 DK 19525) and from FAPESP (04/01816-5, 04/01467-0 and 04/10797-4). The authors are grateful to Takeda Chemicals Industries (Japan) for supplying pioglitazone hydrochloride pure substance

Baixos níveis de glicemia e outras complicações durante suplementação de hormônio do crescimento na sepse

O perfil glicêmico esperado em pacientes pós-operatórios sépticos recebendo nutrição enteral de elevado teor calórico é de valores sanguíneos no limite superior do normal ou mesmo hiperglicemia moderada.A adição de hormônio do crescimento (GH) como agente anabólico deveria reforçar ainda mais esta tendência.Num paciente com câncer submetido a gastrectomia parcial e linfadenectomia, que se complicou no pós operatório com abscesso subfrênico e sepse prolongada, administrou-se conjuntamente dieta de sonda (38,3 kcal/kg/dia) e GH (0,17 UI/kg/dia).Antes da introdução de GH as taxas glicêmicas situavam-se nos limites inferiores do normal, e esta tendência persistiu durante a maior parte do período terapêutico.Duas complicações adicionais, nominalmente parada cardíaca e edema periférico, foram documentadas nesta mesma etapa.Conclui-se que a sepse é o mais provável mecanismo de redução da glicemia neste caso, e que o emprego de dieta enteral e de GH não conseguiu prevenir tal efeito.É questionável se a parada cardíaca foi devida ao suplemento hormonal, mas o edema periférico é um secundarismo bem conhecido deste agente em estudos clínicos.Blood glucose levels in the high normal range or even moderate hyperglycemia is the expected profile in septic postoperative patients receiving high-calorie enteral alimentation. The addition of growth hormone as an anabolic agent should additionally reinforce this tendency. In a cancer patient undergoing partial gastrectomy with lymphadenectomy and suffering from postoperative subphrenic abscess and prolonged sepsis, tube feeding (38.3 kcal/kg/day) and growth hormone (0.17 IU/kg/day) were simultaneously administered for 25 days. Blood glucose levels were in the lower limits of the normal range before growth hormone introduction, and continued with a similar tendency during most of the therapeutic period. Two additional complications, namely heart arrest and peripheral edema, were documented during the same period. It is concluded that sepsis was the most likely mechanism for low glucose values, and that high-calorie enteral diet and growth hormone supplementation did not prevent that result. It is uncertain whether heart arrest was due to the drug, but its association with peripheral edema is well documented in clinical series