Background: Erythropoietin (EPO) and its receptor play a major role in embryonic brain, are weakly expressed in normal postnatal/adult brain and up-regulated upon metabolic stress. EPO protects neurons from hypoxic/ ischemic injury. The objective of this trial is to study the safety and efficacy of recombinant human EPO (rhEPO) for treatment of ischemic stroke in man. Materials and Methods: The trial consisted of a safety part and an efficacy part. In the safety study, 13 patients received rhEPO intravenously (3.3 ϫ 10 4 IU/50 ml/30 min) once daily for the first 3 days after stroke. In the double-blind randomized proof-of-concept trial, 40 patients received either rhEPO or saline. Inclusion criteria were age Ͻ80 years, ischemic stroke within the middle cerebral artery territory confirmed by diffusion-weighted MRI, symptom onset Ͻ8 hr before drug administration, and deficits on stroke scales. The study endpoints were functional outcome at day 30 (Barthel Index, modified Rankin scale), NIH and Scandinavian stroke scales, evolution of

Rationale and objective:The present study tested the hypothesis that chronic interference by cannabis with endogenous cannabinoid systems during peripubertal development causes specific and persistent brain alterations in humans. As an index of cannabinoid action, visual scanning, along with other attentional functions, was chosen. Visual scanning undergoes a major maturation process around age 12-15 years and, in addition, the visual system is known to react specifically and sensitively to cannabinoids. Methods: From 250 individuals consuming cannabis regularly, 99 healthy pure cannabis users were selected. They were free of any other past or present drug abuse, or history of neuropsychiatric disease. After an interview, physical examination, analysis of routine laboratory parameters, plasma / urine analyses for drugs, and MMPI testing, users and respective controls were subjected to a computer-assisted attention test battery comprising visual scanning, alertness, divided attention, flexibility, and working memory. Results: Of the potential predictors of test performance within the user group, including present age, age of onset of cannabis use, degree of acute intoxication (THC+THCOH plasma levels), and cumulative toxicity (estimated total life dose), an early age of onset turned out to be the only predictor, predicting impaired reaction times exclusively in visual scanning. Early-onset users (onset before age 16; n = 48) showed a significant impairment in reaction times in this function, whereas late-onset users (onset after age 16; n = 51) did not differ from controls (n = 49). Conclusions: These data suggest that beginning cannabis use during early adolescence may lead to enduring effects on specific attentional functions in adulthood. Apparently, vulnerable periods during brain development exist that are subject to persistent alterations by interfering exogenous cannabinoids.

No abstract

In alcoholics, disturbances of the autonomic nervous system as well as of the hypothalamic-pituitary-adrenal axis (HPA) are known. However, these two systems have never been analyzed, under stimulated conditions, in parallel in the same patients. Moreover, studies using intravenous (i.v.) corticotropin releasing factor (CRF) to assess neuroendocrine function bypass the hypothalamic component of the HPA axis. Therefore, i.v. human (h) CRF (pituitary stimulation/exogenous CRF) and a multifaceted stress test (hypothalamic activation/endogenous CRF) were compared with respect to their effects on hemodynamics as well as plasma norepinephrine (NE), epinephrine (E), ACTH, and cortisol in abstinent alcoholics (n = 11) versus healthy men (n = 10). Each stimulus was tested twice, 12 weeks apart, in two separate experimental blocks (I and II). Alcoholics entered block 18 days after the last ethanol ingestion and were controlled for abstinence up to block II. hCRF caused a fall in mean arterial pressure (MAP), most pronounced in alcoholics, particularly in block II. In contrast, stress testing raised MAP in both groups and blocks. A sustained increase in ACTH, cortisol, and NE occurred after hCRF, although the ACTH response in alcoholics was blunted in both blocks. Stress testing elevated NE in both groups and blocks, while raising plasma ACTH and cortisol during block I only in controls. However, unlike the persistently blunted ACTH response to i.v. CRF, a normalization of the stress-induced ACTH output occurred in alcoholics after 12 weeks of abstinence. During block I, basal E levels were elevated in alcoholics whereas NE levels tended to be lower than in controls, resulting in a significantly decreased NE/E ratio that returned to near control values in block II. Neither CRF nor stress had any effect on circulating E in either group or block. To conclude: (1) Normalization of the ACTH response to stress, but not to i.v. CRF, after 12 weeks of abstinence, suggests that other ACTH secretagogues may be compensating for CRF dysfunction in alcoholics. (2) Despite the dramatically lowered plasma NE/E ratio in alcoholics, the NE response to stimuli was unaffected. (3) The exaggerated hypotensive reaction and blunted ACTH response to i.v. CRF may reveal a long-term dissociative dysregulation of CRF actions in alcoholics.

An abstinence rate of >50% in this 9-year study strongly supports the concept of comprehensive, long-term outpatient treatment of alcoholics. Supervised, guided intake of AD, also over extended periods, can be used as a predominantly psychologically acting ingredient of successful alcoholism therapy.

The gestational history of 512 women with multiple sclerosis revealed that the risk of MS-onset, exacerbation, or progression was two to three times as high during the 6 months after childbirth as during pregnancy. Using a progression-index as a measure of prognosis (disability divided by duration), the speed of deterioration was comparable for women who became pregnant and those who did not. An apparent but insignificant trend toward better prognosis for women with pregnancies after MS-onset was most likely due to their younger age at onset. The natural course of pregnancy and childbirth was comparable among women pregnant before and during the disease. There was no evidence of an increased frequency of congenital malformations in the offsprings.

In perifused pancreatic islets, the fluorescence of reduced pyridine nucleotides (NAD(P)H) was measured continuously. Elevation of glucose concentration in the medium from 0-5 mM to 20 mlVl led to an increase in l~AD(P)H-fluorescence beginning 10-20 sec after change of medium. Perifusion with calcium-free media had no influence on this effect. It was, however, partially or completely blocked by 2-deoxy D-glucose, D-glucosamine, or D-mannoheptulose. D-mannose, but not D-fructose and L-lactate, enhanced ~qAD(P)I-I-fluorescence from pancreatic islets. Pyruvate caused but a small fluorescence increase. From these observations it is concluded that D-glucose leads to the increase of NAD(P)I-i-fluorescence by mediation of the phosphoglyceraldehyde dehydrogenase reaction.

Besides its other effects, MMT (methadone maintenance treatment) reduces the high mortality of intravenous heroin addicts to about 30% of controls. On the other hand, deaths of patients and non-patients have been attributed to methadone. Here, we will report on the major reasons for deaths attributed to methadone and discuss suggestions for their prevention. 69% of deaths attributed to methadone occurred in subjects not on MMT at the time of their death. 51% of deaths attributed to methadone in subjects in MMT occurred during the dose-finding period of MMT. Further apparent risk situations are methadone intake in addition to that received for MMT, discharge from prison and intravenous injection of methadone. Intake of methadone in non-patients is almost entirely due to abuse of diverted take-home methadone. Not giving methadone as take-home should reduce methadone deaths most effectively. Replacing take-home methadone by substances acting longer than one day, such as LAAM (levacetylmethadol) or buprenorphine, should also be effective. Restriction of take-home prescriptions to substances with a slow onset of action, such as LAAM, or to partial agonists with an extended safety margin such as buprenorphine should be partly effective. Meticulous evaluation of substance history, slow dose increases and strict supervision of the patient by experienced personal should prevent methadone overdose during the dose-finding period. Discharge from prison closely corresponds to this situation; informing addicts shortly before discharge and psychosocial help during the first months out of prison may reduce this risk. Naloxone as an adjunct to oral agonist preparations should effectively prevent high-risk intravenous injection, for example of methadone syrup. This has been the case with tilidine plus naloxone in Germany. Reducing deaths attributable to methadone increases the net benefit of MMT. Also, reducing deaths attributable to methadone avoids decreases in the public acceptance of MMT.