Clinical and histological characteristics of HIV and hepatitis C virus-co-infected patients in Brazil: a case series study

Hepatitis C virus (HCV) is an important factor contributing to morbidity and mortality in patients co-infected with HIV and HCV. In addition, liver biopsy is an important tool in the clinical management of these patients. Although liver biopsy is controversial, it is recommended for all patients. Data regarding the clinical and histological characteristics of these patients are scarce not only in Brazil but in Latin America as a whole. With the goal of better understanding these characteristics and the benefit of liver biopsy indications in this disease setting, data collected from 234 patients followed from 1996 to 2004 at Casa da AIDS, S?o Paulo, were analyzed. The following variables were extracted from the patients' medical files at the time of liver biopsy: sex, age, hepatitis C infection risk factors, hepatitis C infection duration, ALT levels, CD4+ T cell counts, history of alcohol abuse, history of antiretroviral therapy, HCV genotype, and liver histological alterations. CONCLUSIONS: 1 - Hepatitis C virus 1 and 3 were the most frequently identified genotypes and were diagnosed in 72% and 25.5% of cases respectively; 2 - Structural liver alterations were found to be mild or absent in 48.2% (113/234) of the analyzed patients; 3 - Fifty-three patients (23%) had normal ALT levels and 4 - Significant liver architectural changes (F2-F3) were evident in 22.5% of the patients with normal ALT levels.     

SB 239063, a second-generation p38 mitogen-activated protein kinase inhibitor, reduces brain injury and neurological deficits in cerebral focal ischemia

The stress-activated mitogen-activated protein kinase (MAPK) p38 has been linked to the production of inflammatory cytokines/mediators/inflammation and death/apoptosis following cell stress. In these studies, a second-generation p38 MAPK inhibitor, SB 239063 (IC(50) = 44 nM), was found to exhibit improved kinase selectivity and increased cellular (3-fold) and in vivo (3- to 10-fold) activity over first-generation inhibitors. Oral SB 239063 inhibited lipopolysaccharide-induced plasma tumor necrosis factor production (IC(50) = 2.6 mg/kg) and reduced adjuvant-induced arthritis (51% at 10 mg/kg) in rats. SB 239063 reduced infarct volume (48%) and neurological deficits (42%) when administered orally (15 mg/kg, b.i.d.) before moderate stroke. Intravenous SB 239063 exhibited a clearance of 34 ml/min/kg, a volume of distribution of 3 l/kg, and a plasma half-life of 75 min. An i.v. dosing regimen that provided effective plasma concentrations of 0.38, 0.75, or 1.5 microg/ml (i.e., begun 15 min poststroke and continuing over the initial 6-h p38 activation period) was used. Significant and dose-proportional brain penetration of SB 239063 was demonstrated during these infusion periods. In both moderate and severe stroke, intravenous SB 239063 produced a maximum reduction of infarct size by 41 and 27% and neurological deficits by 35 and 33%, respectively. No effects of the drug were observed on cerebral perfusion, hemodynamics, or body temperature. Direct neuroprotective effects from oxygen and glucose deprivation were also demonstrated in organotypic cultures of rat brain tissue. This robust in vitro and in vivo SB 239063-induced neuroprotection emphasizes the potential role of MAPK pathways in ischemic stroke and also suggests that p38 inhibition warrants further study, including protection in other models of nervous system injury and neurodegeneration.     

Inhibition of p38 mitogen-activated protein kinase provides neuroprotection in cerebral focal ischemia

Mitogen-activated protein kinases (MAPKs) are involved in many cellular processes. The stress-activated MAPK, p38, has been linked to inflammatory cytokine production and cell death following cellular stress. Here, we demonstrate focal ischemic stroke-induced p38 enzyme activation (i.e., phosphorylation) in the brain. The second generation p38 MAPK inhibitor SB 239063 was identified to exhibit increased kinase selectivity and improved cellular and in vivo activity profiles, and thus was selected for evaluation in two rat models of permanent focal ischemic stroke. SB 239063 was administered orally pre- and post-stroke and intravenously post-stroke. Plasma concentration levels were achieved in excess of those that effectively inhibit p38 activity. In both moderate and severe stroke, SB 239063 reduced infarct size by 28-41%, and neurological deficits by 25-35%. In addition, neuroprotective plasma concentrations of SB 239063 that reduced p38 activity following stroke also reduced the stroke-induced expression of IL-1beta and TNFalpha (i.e., cytokines known to contribute to stroke-induced brain injury). SB 239063 also provided direct protection of cultured brain tissue to in vitro ischemia. This robust SB 239063-induced neuroprotection emphasizes a significant opportunity for targeting MAPK pathways in ischemic stroke injury, and also suggests that p38 inhibition be evaluated for protective effects in other experimental models of nervous system injury and neurodegeneration.     

Safety and efficacy of fentanyl administered by patient controlled analgesia in children with cancer pain

Background Pain is the most common discomfort experienced by children with cancer and occurs in almost 89% of patients in an advanced stage of the disease. It is most often not adequately treated because of inexperience and unfounded fears of analgesic treatment. In adults, patient controlled analgesia (PCA) is widely administered, while in children with moderate to severe cancer pain its use is still under evaluation for safety and efficacy. Goals of work To evaluate the efficacy and safety of fentanyl administered by PCA in children with cancer pain. Materials and methods Eighteen children (range 6 to 15 years) with moderate to severe pain were enrolled and treated with fentanyl by PCA plus background infusion (BI) (BI of 1 μg/kg/h with booster doses of 1 μg/kg by intravenous route). To evaluate efficacy and safety of the analgesic treatment, different subjective and objective parameters were monitored at 4-h intervals. In addition, patients’ satisfaction was assessed by a questionnaire at the end of the treatment. Main results All children experienced a good degree of analgesia and did not require any other analgesic drug during the treatment. Both subjective and objective parameters improved after starting pain-relieving treatment and no major side effects occurred. The questionnaire administered to the children showed a high grade of satisfaction. Conclusions PCA plus BI with fentanyl administered by intravenous route is a safe and efficacious method for analgesia in children with moderate to severe cancer pain. Our policy of fentanyl-treatment did not show any major side effects.     

老年糖尿病患者强化糖尿病教育的效果与评价

目的:观察强化糖尿病教育对老年2型糖尿病患者血糖控制的影响,并对教育的方法模式及患者的顺应性作出评价。方法:①随机选取老年2型糖尿病患者156例,均为2004-03/07青岛大学医学院附属医院门诊就诊患者,年龄(64.7±6.6)岁,病程(10.54±7.06)年。②入选患者在原有糖尿病治疗方案的基础上进行强化糖尿病教育:入选后半年之内每月进行一次糖尿病教育,半年后每3个月一次教育,教育以糖尿病有关知识专题集体讲座为主,辅以答疑。专人负责电话通知患者教育讲座的具体的时间、地点和内容。每次讲座时监测空腹血糖、餐后2h血糖,入选时、教育后第6,12个月测定糖化血红蛋白;同时记录患者接受教育频率,计算依从率。③采用随机区组设计的方差分析(广义线性模型)分析数据完整的患者的空腹血糖、餐后2h血糖及糖化血红蛋白随时间变化情况(入选时、第6,12个月时)。结果:①依从率:入选时156例,第2次教育时为125例,依从率74.8%,随着时间的延长,接受强化教育的患者逐渐减少,至第6个月时依从率28.1%,至1年时仅有33例接受教育,依从率为21.2%。②完成全程教育的33例患者的资料:教育第6,12个月时的空腹血糖、餐后2h血糖较入选时下降[空腹血糖:(7.9±2.1),(7.8±1.4),(9.7±2.1)mmol/L,F=31.05,P<0.01;餐后2h血糖:(12.0±4.0),(12.2±3.3),(17.8±3.8)mmol/L,F=56.61,P<0.01];糖化血红蛋白在教育第6,12个月也较入选时下降,但无统计学意义[(7.0±1.1)%,(6.9±1.1)%,(7.6±1.7)%,F=2.97,P=0.06]。结论:强化糖尿病教育可使老年2型糖尿病患者血糖有效持续稳定地控制,但患者接受强化教育的依从性差。     

Domperidone: a peripherally acting dopamine2-receptor antagonist

OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and safety of domperidone in the treatment of gastrointestinal motility disorders and emesis. DATA SOURCES: MEDLINE and Excerpta Medica online databases were searched to identify published reports. STUDY SELECTION: Domperidone has been marketed worldwide outside the US since 1978, and extensive clinical data for this drug are available. This review focuses on the clinical experience from controlled studies of domperidone in the treatment of motility disorders, particularly diabetic gastroparesis. Also, case reports are used in summarizing safety. The control comparator groups included placebo or other prokinetic drugs (metoclopramide and cisapride). Controlled clinical trials of domperidone's efficacy and safety as an antiemetic are also briefly examined. Although a variety of domperidone dosage forms have been marketed, data generated from trials using the 10-mg tablet are highlighted because this is the only dosage form available in Canada and is under investigation in the US. DATA EXTRACTION: Because symptoms do not correlate with objective measures of gastrointestinal motility and they are the primary reason that patients with motility disorders seek treatment, the primary outcome extracted from the clinical studies was symptomatic response to treatment. Safety and efficacy between domperidone and placebo, metoclopramide, or cisapride were compared. DATA SYNTHESIS: Domperidone, a peripheral dopamine2-receptor antagonist, regulates the motility of gastric and small intestinal smooth muscle and has been shown to have some effects on the motor function of the esophagus. It also has antiemetic activity as a result of blockade of dopamine receptors in the chemoreceptor trigger zone. In controlled clinical trials, domperidone provided better relief of symptoms (anorexia, nausea, vomiting, abdominal pain, early satiety, bloating, distension) than placebo in patients with symptoms of diabetic gastropathy; symptomatic improvement was similar with domperidone and metoclopramide or cisapride. Domperidone also provided short-term relief of symptoms in patients with dyspepsia or gastroesophageal reflux, prevented nausea and vomiting associated with emetogenic chemotherapy, and prevented the gastrointestinal and emetic adverse effects of antiparkinsonian drugs. Because very little domperidone crosses the blood-brain barrier, reports of central nervous system adverse effects, such as dystonic reactions, are rare. CONCLUSIONS: Domperidone is a unique gastrokinetic and antiemetic drug. Because of its favorable safety profile, domperidone appears to be an attractive alternative to metoclopramide. In the management of diabetic gastropathy, domperidone's antiemetic activity distinguishes it from cisapride.     

The angiotensin type 1 receptor antagonist, eprosartan, attenuates the progression of renal disease in spontaneously hypertensive stroke-prone rats with accelerated hypertension

The effects of the angiotensin type 1 (AT(1)) receptor antagonist, eprosartan, were studied in a model of severe, chronic hypertension. Treatment of male spontaneously hypertensive stroke prone rats (SHR-SP) fed a high-fat, high-salt diet with eprosartan (60 mg/kg/day i.p.) for 12 weeks resulted in a lowering of blood pressure (250 +/- 9 versus 284 +/- 8 mm Hg), renal expression of transforming growth factor-beta mRNA (1.5 +/- 0.2 versus 5.4 +/- 1.4) and the matrix components: plasminogen activator inhibitor-1 (5.2 +/- 1.4 versus 31.4 +/- 10.7), fibronectin (2.2 +/- 0.6 versus 8.2 +/- 2.2), collagen I-alpha 1 (5.6 +/- 2.0 versus 23.8 +/- 7.3), and collagen III (2.7 +/- 0.9 versus 7.6 +/- 2.1). Data were corrected for rpL32 mRNA expression and expressed relative to Wistar Kyoto (WKY) rats [=1.0]. Expression of fibronectin protein was also lowered by eprosartan (0.8 +/- 0.1 versus 1.9 +/- 0.5), relative to WKY rats. Eprosartan provided significant renoprotection to SHR-SP rats as measured by decreased proteinuria (22 +/- 2 versus 127 +/- 13 mg/day) and histological evidence of active renal damage (5 +/- 2 versus 195 +/- 6) and renal fibrosis (5.9 +/- 0.7 versus 16.4 +/- 1.9) in vehicle- versus eprosartan-treated rats, respectively. Our results demonstrated that AT(1) receptor blockade with eprosartan can reduce blood pressure and preserve renal structure and function in this model of severe, chronic hypertension. These effects were accompanied by a decreased renal expression of transforming growth factor-beta1, plasminogen activator inhibitor-1, and several other extracellular matrix proteins compared with vehicle-treated SHR-SP.     

Plasma chitotriosidase in health and pathology

Chitotriosidase (Chit), a member of the mammalian chitinase family, structurally homologous to chitinases from other species, is synthesized and secreted by specifically activated macrophages. After discovery of a striking increase of plasma Chit activity in serum from Gaucher's disease type I patients, an increasing number of inherited and acquired conditions sharing macrophage activation have been associated with increased Chit activity. In addition to lipid storage disorders, where Chit activity has longer been used as a marker of disease activity and therapeutic response, elevation of plasma Chit may occur in hematological disorders with storage of erythrocyte membrane breakdown products as thalassemia and different systemic infectious diseases sustained by fungi and other pathogens. Recently, increased Chit activity was demonstrated in CNS from patients with different neurological disorders. After a wide range of unwanted stimuli such as those occurring in stroke, multiple sclerosis, and Alzheimer's disease, resident cells like microglia and a few other cell types promptly activate a complex immune cascade which then might be monitored also by measuring Chit activity. The increased activity of Chit, wherever it is documented, represents one ancestral response of innate immunity which may have a wide range of clinical applications.     

beta-hexosaminidase, alpha-D-mannosidase, and beta-mannosidase expression in serum from patients with carbohydrate-deficient glycoprotein syndrome type I

The activity of beta-hexosaminidase, determined with 4-methylumbelliferyl-beta-N-acetylglucopyranoside substrate, and of beta-D-mannosidase was significantly higher in the serum of patients with carbohydrate-deficient glycoprotein (CDG) syndrome type IA (phosphomannomutase deficiency) than in controls. No significant differences were observed in the activity of beta-hexosaminidase, determined using 4-methylumbelliferyl-beta-N-acetylglucopyranoside-6-sulphate as substrate, and the activity of alpha-D-mannosidase. Using DEAE-cellulose chromatography, a greater amount of hexosaminidase B than hexosaminidase A was detected in CDG serum. In CDG serum, hexosaminidase A was eluted in a more basic position in the salt gradient. An isoenzyme of alpha-D-mannosidase and beta-D-mannosidase was identified in control and CDG sera. alpha-D-Mannosidase isoenzyme was eluted in a slightly more basic position in CDG serum than in control serum, whereas beta-D-mannosidase isoenzyme was eluted in the same position.