Caspase activation and neuroprotection in caspase-3- deficient mice after in vivo cerebral ischemia and in vitro oxygen glucose deprivation

Caspase-3 is a major cell death effector protease in the adult and neonatal nervous system. We found a greater number and higher density of cells in the cortex of caspase-3(-/-) adult mice, consistent with a defect in developmental cell death. Caspase-3(-/-) mice were also more resistant to ischemic stress both in vivo and in vitro. After 2 h of ischemia and 48 h of reperfusion, cortical infarct volume was reduced by 55%, and the density of terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling-positive cells was decreased by 36% compared with wild type. When subjected to oxygen-glucose deprivation (2 h), cortical neurons cultured from mice deficient in caspase-3 expression were also more resistant to cell death by 59%. Mutant brains showed caspase-specific poly(ADP-ribose) polymerase cleavage product (85-kDa fragment) in vivo and in vitro, suggesting redundant mechanisms and persistence of caspase-mediated cell death. In the present study, we found that caspase-8 mediated poly(ADP-ribose) polymerase cleavage in caspase-3(-/-) neurons in vivo and in vitro. In addition, mutant neurons showed no evidence of compensatory activation by caspase-6 or caspase-7 after ischemia. Taken together, these data extend the pharmacological evidence supporting an important role for caspase-3 and caspase-8 as cell death mediators in mammalian cortex and indicate the potential advantages of targeting more than a single caspase family member to treat ischemic cell injury.     

Prolactin responses to phenylalanine and tyrosine in phenylketonuria.

In normal subjects, ingestion of tyrosine or phenylalanine stimulates prolactin (PRL) secretion. In patients with phenylketonuria (PKU), we found normal PRL responses to phenylalanine, demonstrating that conversion of phenylalanine to tyrosine is not necessary for PRL stimulation. PKU patients also showed greater PRL responses to tyrosine during dietary phenylalanine restriction than when consuming an unrestricted diet; this finding is consistent with inhibition by phenylalanine of tyrosine transport across the blood-brain barrier. Such competitive inhibition of a normal brain function may serve as a model for some of the neurotoxic effects of phenylalanine in PKU.     

Interleukin-10 promoter polymorphisms in rheumatoid arthritis and Felty's syndrome

OBJECTIVE: To examine whether promoter polymorphisms associated with variation in interleukin-10 (IL-10) production are relevant to the development of rheumatoid arthritis (RA) or Felty's syndrome (FS). METHODS: DNA was obtained from 44 FS patients, 117 RA patients and 295 controls. The promoter region between -533 and - 1120 was amplified by polymerase chain reaction, and polymorphisms detected by restriction enzyme digest or sequence-specific oligonucleotide probing. RESULTS: We found no significant difference in allele or haplotype frequencies between the groups. CONCLUSION: There is no association between FS or RA and these recently identified IL-10 promoter polymorphisms. Other genetic or environmental factors could explain the alterations in IL-10 levels seen in these conditions.      

Oral prostaglandin (PGE2) therapy for chronic viral hepatitis B and C

The cytoprotective effects of prostaglandins have been utilized in the prevention of hepatitis B virus reactivation after liver transplantation. This pilot study evaluated the effects of oral prostaglandin E₂ (PGE₂) in chronic viral hepatitis B and C. Twenty patients with chronic hepatitis B and 20 patients with chronic hepatitis C received 4mgday^–1 PGE₂ for 6 months. The lymphocyte antiviral enzyme 2',5'-oligoadenylate synthetase (2',5'-OAS) and peripheral blood monocyte procoagulant activity (PCA) were measured before, during and after the treatment. Three of 20 hepatitis B and five of 20 hepatitis C patients withdrew from the study. Eight of 17 hepatitis B patients responded: in seven of these eight patients, serum alanine aminotransferase (ALT) levels normalized; loss of viral replication was sustained in all eight patients; and seroconversion from hepatitis Be antigen (HBeAg) to hepatitis Be antibody (HBeAb) positivity occurred in seven patients over the 48-week duration of this study. In 14 of the 15 hepatitis C patients, hepatitis C virus (HCV) RNA remained detectable and the serum ALT levels remained elevated. 2',5'-OAS levels and PCA values did not correlate with other markers of response to PGE₂ therapy in either chronic hepatitis B or C. In summary, PGE₂ was associated with sustained loss of viral replication in 47% of chronic hepatitis B patients; no beneficial effects were apparent in chronic hepatitis C.     

Effect of routine intensive care interactions on metabolic rate

The alterations in metabolic (oxygen consumption [VO2] and carbon dioxide production [VCO2]) and hemodynamic (heart rate and blood pressure) parameters caused by various common intensive care activities were examined in a group of 23 mechanically-ventilated critically-ill patients. The observed variations in metabolic rate can be classified into four categories as follows: (a) the lowest energy expenditure, which was associated with sleeping in the majority (83 percent) of instances; (b) resting, which was defined as a state where the patient was lying motionless with eyes open and responding to surrounding events, where VO2 and VCO2 averaged 9.1 +/- 7.5(SD) percent and 7.5 +/- 7.3 percent, respectively, above the lowest values; (c) a variety of routine daily care activities (eg, bathing, performing a physical examination) that although not particularly painful, caused arousal from the resting state. During these situations, VO2 and VCO2 averaged about 20 percent above lowest values; and (d) chest physical therapy, which was associated with metabolic increases of 35 percent above lowest values as well as increases in both heart rate and blood pressure. This study demonstrates that routine daily ICU activities can significantly alter metabolic rate, and thus, it is important to couple such measurements with astute observations of the patients' activity state. In addition, we have defined an activity state--resting--that can be used in the calculation of energy expenditure as well as for intrapatient and interpatient comparisons.     

Effects of electroacupuncture on gastric mucosal blood flow and transmucosal potential difference in stress rats

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Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial

OBJECTIVE: Tumor necrosis factor (TNF) is an important proinflammatory cytokine that mediates inflammatory synovitis and articular matrix degradation in rheumatoid arthritis (RA). We investigated the ability of adalimumab, a human anti-TNF monoclonal antibody, to inhibit the progression of structural joint damage, reduce the signs and symptoms, and improve physical function in patients with active RA receiving concomitant treatment with methotrexate (MTX). METHODS: In this multicenter, 52-week, double-blind, placebo-controlled study, 619 patients with active RA who had an inadequate response to MTX were randomized to receive adalimumab 40 mg subcutaneously every other week (n = 207), adalimumab 20 mg subcutaneously every week (n = 212), or placebo (n = 200) plus concomitant MTX. The primary efficacy end points were radiographic progression at week 52 (total Sharp score by a modified method [TSS]), clinical response at week 24 (improvements of at least 20% in the American College of Rheumatology core criteria [ACR20]), and physical function at week 52 (disability index of the Health Assessment Questionnaire [HAQ]). RESULTS: At week 52, there was statistically significantly less radiographic progression, as measured by the change in TSS, in the patients receiving adalimumab either 40 mg every other week (mean +/- SD change 0.1 +/- 4.8) or 20 mg weekly (0.8 +/- 4.9) as compared with that in the placebo group (2.7 +/- 6.8) (P < or = 0.001 for each comparison). In addition, there were statistically significant changes in the components of the TSS. At week 24, ACR20 responses were achieved by 63% and 61% of patients in the adalimumab 40 mg every other week and 20 mg weekly groups, respectively, versus 30% of patients in the placebo group (P < or = 0.001 for each comparison). At week 52, ACR20 responses were achieved by 59% and 55% of patients taking adalimumab 40 mg every other week and 20 mg weekly, respectively, versus 24% of patients taking placebo (P < or = 0.001 for each comparison). At week 52, physical function as measured by the HAQ demonstrated statistically significant improvement with adalimumab 40 mg every other week and 20 mg weekly compared with placebo (mean change in HAQ score -0.59 and -0.61, respectively, versus -0.25; P < or = 0.001 for each comparison). A total of 467 patients (75.4%) completed 52 weeks of treatment. Adalimumab was generally well tolerated. Discontinuations occurred in 22.0% of adalimumab-treated patients and in 30.0% of placebo-treated patients. The rate of adverse events (both serious and nonserious) was comparable in the adalimumab and placebo groups, although the proportion of patients reporting serious infections was higher in patients receiving adalimumab (3.8%) than in those receiving placebo (0.5%) (P < or = 0.02), and was highest in the patients receiving 40 mg every other week. CONCLUSION: In this 52-week trial, adalimumab was more effective than placebo at inhibiting the progression of structural joint damage, reducing the signs and symptoms, and improving physical function in patients with active RA who had demonstrated an incomplete response to MTX.     

Analysis of fasting antroduodenal manometry in children

Antroduodenal manometry has been used to determine the pathophysiology associated with signs and symptoms of gastrointestinal motility disorders. The diagnostic value of antroduodenal manomentry has been limited by the paucity of data from normal children. In this study, we compared antroduodenal manometry findings from 95 patients with symptoms suggesting a gastrointestinal motility disorder to 20 control children. Phase III of the migrating motor complex (MMC) was less frequent in patients (P<0.05), especially in those who required total parenteral nutrition (P<0.001), than in controls. Abnormal migration of phase III and short intervals between phase IIIs were more frequent in patients than in controls (P<0.01 andP<0.05, respectively). During phase II, persistent low-amplitude contractions and sustained tonic-phasic contraction were found only in parenteral-nutrition-dependent children. Short or prolonged duration of phase III, absence of phase I following phase III, tonic contractions during phase III, low amplitude of phase III contractions in a single recording site and clusters of contractions or prolonged propagating contractions during phase II were not more frequent in patients than in controls. We conclude that there are five manometric features having a clear association with pediatric gastrointestinal motility disorders: (1) absence of phase III of the MMC, (2) abnormal migration of phase III, (3) short intervals between phase III episodes, (4) persistent low-amplitude contractions, and (5) sustained tonic-phasic contractions.