Neuroprotective mechanisms of creatine occur in the absence of mitochondrial creatine kinase

There is substantial evidence that creatine administration exerts neuroprotective effects both in vitro and in vivo. The precise mechanisms for these neuroprotective effects however are as yet unclear. We investigated whether creatine administration could exert neuroprotective effects in mice deficient in ubiquitous mitochondrial creatine kinase (UbMi-CK). UbMi-CK-deficient mice showed increased sensitivity to 1-methyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced dopamine depletion and loss of tyrosine hydroxylase (TH) stained neurons. Isolated mitochondria from these mice showed no alterations in calcium retention, oxygen utilization, membrane potential, or swelling in response to a calcium challenge. Creatine administration significantly increased brain concentrations of both creatine and PCr in the UbMi-CK knockout mice. Creatine administration to the UbMi-CK-deficient mice exerted significant neuroprotective effects against MPTP toxicity that were comparable in magnitude to those seen in wild-type mice. These results suggest that the neuroprotective effects of creatine are not mediated by an effect on UbMi-CK to inhibit the mitochondrial permeability transition, and are more likely to be mediated by maintenance of appropriate ATP/ADP and PCr/Cr levels.     

Olanzapine plus carbamazepine v. carbamazepine alone in treating manic episodes

BACKGROUND: Combinations of olanzapine and carbamazepine are often used in clinical practice in the management of mania. AIMS: To assess the efficacy and safety of olanzapine plus carbamazepine in mixed and manic bipolar episodes. METHOD: Randomised, double-blind, 6-week trial of olanzapine (10-30 mg/day) plus carbamazepine (400-1200 mg/day; n=58) v. placebo plus carbamazepine (n=60) followed by open-label, 20-week olanzapine (10-30 mg/day) plus carbamazepine (400-1200 mg/day, n=86), with change in manic symptoms as main outcome measure. Safety and pharmacokinetics were also evaluated. RESULTS: There were no significant differences (baseline to endpoint) in efficacy measures between treatment groups, but at 6 weeks triglyceride levels were significantly higher (P=0.008) and potentially clinically significant weight gain (>or=7%) occurred more frequently (24.6% v. 3.4%, P=0.002) in the combined olanzapine and carbamazepine group. Carbamazepine reduced olanzapine concentrations but olanzapine had no effect on carbamazepine concentrations. CONCLUSIONS: The combination of olanzapine and carbamazepine did not have superior efficacy to carbamazepine alone. The increases in weight and triglycerides observed during combination treatment are a matter of concern.     

Natural course and pathogenesis of transient focal neurologic symptoms during pregnancy

OBJECTIVES: To determine the pathogenesis and course of transient focal neurologic symptoms in pregnant women and to identify prognostic variables that will enable targeted workup. DESIGN: Case-control series. SETTING: Tertiary care university hospital. PATIENTS: Pregnant patients with acute transient focal neurologic symptoms. Women with histories of migraine, recurrent thromboembolism, or cerebrovascular disease were excluded. INTERVENTIONS: Diffusion-weighted imaging (DWI), perfusion-weighted imaging, fluid-attenuated inversion recovery (FLAIR) imaging, gradient-recalled echo imaging, and magnetic resonance venography (MRV) and angiography to determine the presence of brain ischemia and venous thrombosis. Patients underwent echocardiography, duplex ultrasonography, and a battery of hypercoagulability tests and were followed up a mean of 12 months after the event. RESULTS: Twenty-eight controls and 14 patients were enrolled from 23 773 pregnancies. Mean age was 31.2 (range, 24-41) years and mean gestational age at symptom onset was 28 (range, 17-44) weeks. No controls reported transient focal neurologic symptoms, migraine aura, or headache. Presenting symptoms included dysphasia (6 patients) and hemisensory (5) and hemimotor (7) syndrome. In 4 patients, these symptoms were preceded by scintillating scotoma; in 9 patients, focal symptoms were followed by a first-ever, throbbing, migraine-like headache. Only 1 patient had evidence of frank infarction on magnetic resonance imaging (MRI); 2 patients had single, small, hyperintense bright foci on FLAIR imaging without accompanying lesions on DWI, and 11 patients had normal MRI and MRV results. Echocardiography, carotid duplex ultrasonography, and hypercoagulability results were negative in all patients. None of the patients had ischemic events and 4 (29%) developed migraines with aura headaches during follow-up. CONCLUSIONS: Focal neurologic symptoms in healthy pregnant women are frequently preceded by aural visual phenomena and can usually be attributed to a first-ever migraine attack. Cerebral ischemia is less common than migraine and can be reliably diagnosed with MRI. Extensive evaluations to assess a putative hypercoagulable state and cardiocerebrovascular pathology may not be warranted in all such patients.     

Indole alkaloids produced by a marine fungus isolate of Penicillium janthinellum Biourge

Three new indole alkaloids, shearinines D, E, and F (1-3), together with the known shearinine A (4) were isolated from the marine-derived strain of the fungus Penicillium janthinellum Biourge. The chemical structures of 1-4 were established by 2D NMR and HREIMS data. Shearinines A, D, and E induce apoptosis in human leukemia HL-60 cells, and shearinine E also inhibits EGF-induced malignant transformation of JB6 P+ Cl 41 cells in a soft agar.     

Isolation and structures of erylosides from the Caribbean sponge Erylus formosus

Nine new triterpene glycosides, erylosides F1-F4 (1-4), M (5), N (6), O (7), P (8), and Q (9), along with previously known erylosides F (10) and H (11) were isolated from the sponge Erylus formosus collected from the Mexican Gulf (Puerto Morelos, Mexico). Structures of 1-4 were determined as the corresponding biosides having aglycons related to penasterol with additional oxidation patterns in their side chains. Erylosides 5-9 contain new variants of carbohydrate chains with three (5, 6), four (7), and six (8, 9) sugar units, respectively. Erylosides 5, 7, 8, and 6, 9 contain 14-carboxy-24-methylenelanost-8(9)-en-3beta-ol and penasterol as aglycons, respectively. In contrast with its epimer 2, the compound 3 induced the early apoptosis of Ehrlich carcinoma cells at a concentration of 100 microg/mL, while 1 and 10 activated the Ca2+ influx into mouse spleenocytes (130% of the control) at the same doses.     

Health care in the CIS countries

The study analyses the technical efficiency of community hospitals in Ukraine during 1997–2001. Hospital cost amount to two-thirds of Ukrainian spending on health care. Data are available on the number of beds, physicians and nurses employed, surgical procedures performed, and admissions and patient days. We employ data envelopment analysis to calculate the efficiency of hospitals and to assess productivity changes over time. The scores calculated with an output-oriented model assuming constant returns to scale range from 150% to 110%. Average relative inefficiency of the hospitals is initially above 30% and later drops to 15% or below. The average productivity change is positive but below 1%; a Malmquist index decomposition reveals that negative technological progress is overcompensated by positive catching-up.     

Relationship between DNA strand breaks and inhibition of poly(ADP-ribosylation): enhancement of carcinogen-induced transformation

Inhibition of poly(ADP-Rib) by benzamide (BA) or 3-aminobenzamide(3AB) for a limited period (i.e., when ADP-ribosylation is elevated)during and shortly following X-ray or MNNG-induced DNA damageof BALB/3T3 cells significantly (3- to 30-fold) enhanced transformationfrequency by these agents. Individual Type III foci isolatedfrom benzamide, X-ray, or X-ray plus benzamide treated cultureswere established and characterized for growth in soft agar andfor tumor induction in nude mice. DNA isolated from representativetransformed lines established as a result of BA, X-ray or X-rayand BA treatments was transfected onto NIH/3T3 cells. Transformationefficiencies ranging from 0.17 to 0.28 foci/ µg of DNAwere observed suggesting the possibility that dominant transforminggene(s) were responsible for the oncogenic phenotype of radiationand benzamide transformed DNA.     

Transplacental and transgeneration carcinogenic effect of 7,12-dimethylbenz[a]anthracene: relationship with ras oncogene activation.

Transgeneration transmission of the carcinogenic action of 7,12-dimethylbenz[a]anthracene (DMBA) was studied in two generations of mice using transplacental DMBA initiation followed by postnatal skin tumor promotion with 12-O-tetradecanoylphorbol-13-acetate (TPA) in the first generation (F0) and only promotion in the second generation (F1). Local application of TPA resulted in increased skin tumor yield in both the in utero DMBA-exposed mice and their progeny (P = 0.0002 and P = 0.0941 respectively compared to control). Similarly, lung tumor incidence was increased in the two generations of mice (P less than 0.0001 and P = 0.0080 respectively). The results suggest transgeneration transfer of the effect of DMBA. A to T mutation at the second base of codon 61 of the Ha-ras oncogene was found in skin tumors of DMBA-exposed mice, but not in tumors induced by TPA without initiation. Analysis of Ki-ras codon 61 in seven lung tumors from DMBA-treated mice revealed three types of mutation: two cases with CA[C or G or T], one case with CCA and one case with CTA (the remaining cases having only the wild type). Six of these mice also had skin tumors, which contained A to T mutation at the second base of codon 61 of the Ha-ras gene in five cases. Thus mutations of different ras genes were found in skin and lung tumors from the same animals. In the progeny (F1) of DMBA-exposed F0 mice, only skin tumor samples were available for oncogene analysis and none contained the Ha-ras mutation. The results confirm our previous finding that initiation of skin and lung tumorigenesis can be transmitted transgenerationally. On the other hand, our data from a limited number of skin tumors suggests that ras gene mutation may not be critically involved in this transmission.