The proteome of higher plant mitochondria.

Plant mitochondria perform a wide range of functions in the plant cell ranging from providing energy and metabolic intermediates, via coenzyme biosynthesis and their own biogenesis to retrograde signaling and programmed cell death. To perform these functions, they contain a proteome of >2000 different proteins expressed in some cells under some conditions. The vast majority of these proteins are imported, in many cases by a dedicated protein import machinery. Recent proteomic studies have identified about 1000 different proteins in both Arabidopsis and potato mitochondria, but even for energy-related proteins, the most well-studied functional protein group in mitochondria, <75% of the proteins are recognized as mitochondrial by even one of six of the most widely used prediction algorithms. The mitochondrial proteomes contain proteins representing a wide range of different functions. Some protein groups, like energy-related proteins, membrane transporters, and de novo fatty acid synthesis, appear to be well covered by the proteome, while others like RNA metabolism appear to be poorly covered possibly because of low abundance. The proteomic studies have improved our understanding of basic mitochondrial functions, have led to the discovery of new mitochondrial metabolic pathways and are helping us towards appreciating the dynamic role of the mitochondria in the responses of the plant cell to biotic and abiotic stress.

A double-blind, placebo-controlled study of oral nalmefene for alcohol dependence.

BACKGROUND: Nalmefene is a newer opioid antagonist that is structurally similar to naltrexone but with a number of potential pharmacological advantages for the treatment of alcohol dependence, including no dose-dependent association with toxic effects to the liver, greater oral bioavailability, longer duration of antagonist action, and more competitive binding with opioid receptor subtypes that are thought to reinforce drinking. METHODS: A double-blind, placebo-controlled trial was conducted to evaluate the safety and efficacy of 2 doses of oral nalmefene for alcohol dependence. The 105 outpatient volunteers were abstinent for a mean of 2 weeks prior to random assignment to the placebo or 20- or 80-mg/d dose nalmefene groups for 12 weeks. Cognitive behavioral therapy was provided weekly during treatment. Self-reported drinking or abstinence was confirmed by determinations of breath alcohol concentration and by collateral informant reports. RESULTS: Outcomes did not differ between the 20- and 80-mg dose nalmefene groups. Significantly fewer patients treated with nalmefene than patients given placebo relapsed to heavy drinking through 12 weeks of treatment (P<.02), with a significant treatment effect at the first weekly study visit (P<.02). The odds ratio of relapsing to heavy drinking was 2.4 times greater with placebo compared with nalmefene (95% confidence interval, 1.05-5.59). Patients treated with nalmefene also had fewer subsequent relapses (P<.03) than patients given placebo. CONCLUSIONS: Treatment with nalmefene was effective in preventing relapse to heavy drinking relative to placebo in alcohol-dependent outpatients and was accompanied by acceptable side effects.

A double-blind, placebo-controlled pilot study to evaluate the efficacy and safety of oral nalmefene HCl for alcohol dependence.

A dozen studies have been published showing that opiate antagonists suppress alcohol drinking in animals, and two independent placebo-controlled, double-blind clinical trials of naltrexone found this agent was associated with decreased alcohol craving and consumption in alcohol-dependent patients. Nalmefene is a newer opiate antagonist that has a number of potential advantages over naltrexone in the treatment of alcoholism, including no dose-dependent association with liver toxicity and more effective binding to central opiate receptors. Consequently, a double-blind pilot study was conducted to gather preliminary data on the safety and efficacy of nalmefene for reducing alcohol consumption in alcohol-dependent subjects. Twenty-one alcohol-dependent subjects meeting admission criteria were randomly assigned to 12 weeks of double-blind treatment with 40 mg nalmefene, 10 mg nalmefene, or placebo, resulting in 7 patients/treatment group. Nalmefene was well tolerated, with no serious adverse drug reactions. The 40 mg group had a significantly lower rate of relapse (p < or = 0.05), and a greater increase in the number of abstinent days/week (p < or = 0.09), than the other treatment groups. A significant decrease in the number of drinks/drinking day was noted for both nalmefene groups (p < or = 0.04), but not for placebo. These results were supported by parallel decreases in ALT. These pilot data provide preliminary support for the hypotheses that nalmefene can be safely given to alcoholics, and that nalmefene may have a role in reducing alcohol consumption and preventing relapse, particularly at the 40 mg level. A full-scale study is underway to confirm these preliminary findings.

Changes in transaminases over the course of a 12-week, double-blind nalmefene trial in a 38-year-old female subject.

A 38-year-old female was drinking 30 drinks/week before entering a 12-week, double-blind study of nalmefene for the treatment of alcohol dependence. Liver function tests (LFTs) were within normal limits at baseline and week 4, but on week 8, the ALT showed a 7-fold increase, and the AST showed a 4-fold increase from baseline. A decision was made to continue study medication based on the patient's positive response to this therapy (i.e., achieving complete abstinence) and no known dose-dependent association with liver toxicity in over 1300 patients treated with nalmefene for other indications. LFTs were repeated serially to assess the trend of the LFT values. The patient achieved total abstinence over the course of the study period and at the 3-month posttreatment follow-up was continuing to maintain these gains from the study program, and her LFTs had returned to normal. A gradual return to normal in ALT and AST, while treatment with nalmefene continued, does not support the role of nalmefene as an hepatotoxin. Relapse to drinking was excluded because of normal values for the gamma-glutamyltransferase, and verification of sobriety by self-report, significant other, and breathalyzer. A virology panel ruled out the presence of viral hepatitis. Dietary intake before the elevation in LFTs contained elements that have established association with hepatocellular changes. The routine prescription of serial LFTs in alcoholism pharmacotherapy trials may be expected to reveal clinically nonsignificant elevations that could potentially be related to exogenous factors, such as dietary composition and should not be reflexively attributed to medication under investigation and/or drinking.

Immunologic abnormalities in chronic fatigue syndrome.

The chronic fatigue syndrome (CFS), formerly known as chronic Epstein-Barr virus syndrome, is a clinical state of some complexity and uncertain etiology. In order to characterize in a comprehensive manner the status of laboratory markers associated with cellular immune function in patients with this syndrome, 30 patients with clinically defined CFS were studied. All of the subjects were found to have multiple abnormalities in these markers. The most consistent immunological abnormality detected among these patients, when compared with normal controls, was low natural killer (NK) cell cytotoxicity. The number of NK cells, as defined by reactivity with monoclonal antibody NKH.1 (CD56), was elevated, but the killing of K562 tumor cells per CD56 cell was significantly diminished. Lymphoproliferative responses after stimulation with phytohemagglutinin and pokeweed mitogen were decreased in most patients when compared with those in normal controls, as was the production of gamma interferon following mitogen stimulation. Lymphocyte phenotypic marker analysis of peripheral blood lymphocytes showed that there were significant differences between patients with CFS and controls. There was an increase in the percentage of suppressor-cytotoxic T lymphocytes, CD8, and a proportionally larger increase in the number of CD8 cells expressing the class II activation marker. Most patients had an elevated number of CD2 cells which expressed the activation marker CDw26. The numbers of CD4 cells and the helper subset of CD4+CD29+ cells in patients with CFS were not different from those in controls. There was, however, a significant decrease in the suppressor inducer subset of CD4+ CD45RA+ cells. The number of B cells, CD20 and CD21, were elevated, as were the numbers of a subset of B cells which coexpressed CD20 and CD5. The patterns of immune marker abnormalities observed was compatible with a chronic viral reactivation syndrome.

[Different prevalence of some indices of cardiac and vascular impairment in normal weight and obese patients with essential arterial hypertension]. / Differente prevalenza di alcuni indici di compromissione cardiaca e vascolare in pazienti normopeso e obesi affetti da ipertensione arteriosa essenziale.

Certain physiopathological features that differentiate essential arterial hypertension in normal weight and obese patients are recalled. The results of a retrospective study carried out in 293 hypertensive patients admitted to the Clinic in recent years are reported with a view to evaluating the prevalence of certain parameters (ischaemic cardiopathy, left ventricular hypertrophy, renal, vasculo-cerebral and retinal impairment) in patients subdivided into two groups: normal weight and obese. The study showed in the first group a higher prevalence of signs of ischaemic cardiopathy; in the second a higher prevalence of left ventricular hypertrophy. This difference is accentuated in the subgroup of smokers as regards ischaemic cardiopathy and in non-smokers as regards left ventricular hypertrophy. The possible explanations for this different behaviour are discussed.

[Behavior of the turnover of I131-fibrinogen in various diseases of the connective tissue]. / Comportamento del turnover del I131-fibrinogeno in alcune malattie del connettivo.

It is generally admitted that alteration to the blood coagulation system, particularly the creation of fibrin from fibrinogen may play a pathogenetic role in the complex mechanism that characterises rheumatic diseases of the connective tissue. A study was therefore conducted to see whether accelerated fibrinogen turnover could be demonstrated in such patients. To this end the clearance of fibrinogen marked with I131 was assessed in 25 patients in various stages of connectivitis and 10 controls was measured. The results showed a distinct acceleration in fibrinogen turnover only in patients with highly active rheumatoid arthritis. In contrast patients with rheumatoid arthritis in the regressive phase or with stable progressive systemic sclerosis showed values similar to the control subjects. Finally the possible explanations for this behaviour are examined and the clinical interest of the technique employed is assessed.

[Treatment of chronic cerebrovascular insufficiency and chronic obliterating arteriopathy of the lower extremities with buflomedil hydrochloride]. / Trattamento dell'insufficienza cerebro-vascolare cronica e dell'arteriopatia obliterante cronica degli arti inferiori con buflomedil cloridrato.

Research has been carried out into the effects of a new vasoactive substance, buflomedil hydrochloride, on two groups of patients suffering from cerebrovascular insufficiency and obliterating arteriopathy at the lower extremities. Ten clinical parameters were assessed in the first group of patients (insomnia, headache, vertigo, tinnitus, asthenia, shaking, changes in reflexes, anorexia, memory disturbances, problems of concentration and character disturbances); in the second group, the muscular flow of the gastrocnemius as measured by the muscular clearance of NaI131 at rest, during standard exercise conditions, during ten minutes following exercise and in the post-ischaemic phase. The results can be considered satisfactory in both groups, especially after prolonged treatment and in the early stage of the disease. Drug tolerance was very good.