Striatal Glutamate Release in L-DOPA-Induced Dyskinetic Animals.

Striatal Glutamate Release in l-DOPA-Induced Dyskinetic Animals.

Filed under: Drug and Alcohol Rehabilitation

PLoS One. 2013; 8(2): e55706
Nevalainen N, Lundblad M, Gerhardt GA, Strömberg I

l-DOPA-induced dyskinesia is a common side effect developed after chronic treatment with 3,4-dihydroxyphenyl-l-alanine (l-DOPA) in Parkinson’s disease. The biological mechanisms behind this side effect are not fully comprehended although involvement of dopaminergic, serotonergic, and glutamatergic systems has been suggested. The present study utilizes in vivo amperometry to investigate the impact from unilateral 6-hydroxydopamine lesions and l-DOPA (4 mg/kg, including benserazide 15 mg/kg) -induced dyskinetic behavior on striatal basal extracellular glutamate concentration and potassium-evoked glutamate release in urethane-anesthetized rats. Recordings were performed before and after local l-DOPA application in the striatum. In addition, effects from the 5-HT(1A) receptor agonist (2R)-(+)-8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OHDPAT; 1 mg/kg) was assessed on glutamate release and on dyskinetic behavior. The results revealed a bilateral ?30% reduction of basal extracellular glutamate concentration and attenuated potassium-evoked glutamate release after a unilateral dopamine-depletion in l-DOPA naïve animals. In dyskinetic subjects, basal glutamate concentration was comparable to normal controls, although potassium-evoked glutamate release was reduced to similar levels as in drug naïve dopamine-lesioned animals. Furthermore, acute striatal l-DOPA administration attenuated glutamate release in all groups, except in the dopamine-lesioned striatum of dyskinetic animals. Co-administration of 8-OHDPAT and l-DOPA decreased dyskinesia in dopamine-lesioned animals, but did not affect potassium-evoked glutamate release, which was seen in normal animals. These findings indicate altered glutamate transmission upon dopamine-depletion and dyskinesia.
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Mediterranean dietary pattern and risk of breast cancer.

Filed under: Drug and Alcohol Rehabilitation

PLoS One. 2013; 8(2): e55374
Couto E, Sandin S, Löf M, Ursin G, Adami HO, Weiderpass E

A Mediterranean diet has a recognized beneficial effect on health and longevity, with a protective influence on several cancers. However, its association with breast cancer risk remains unclear.We aimed to investigate whether adherence to a Mediterranean dietary pattern influences breast cancer risk.The Swedish Women’s Lifestyle and Health cohort study includes 49,258 women aged 30 to 49 years at recruitment in 1991-1992. Consumption of foods and beverages was measured at enrollment using a food frequency questionnaire. A Mediterranean diet score was constructed based on the consumption of alcohol, vegetables, fruits, legumes, cereals, fish, the ratio of unsaturated to saturated fat, and dairy and meat products. Relative risks (RR) for breast cancer and specific tumor characteristics (invasiveness, histological type, estrogen/progesterone receptor status, malignancy grade and stage) associated with this score were estimated using Cox regression controlling for potential confounders.1,278 incident breast cancers were diagnosed. Adherence to a Mediterranean dietary pattern was not statistically significantly associated with reduced risk of breast cancer overall, or with specific breast tumor characteristics. A RR (95% confidence interval) for breast cancer associated with a two-point increment in the Mediterranean diet score was 1.08 (1.00-1.15) in all women, and 1.10 (1.01-1.21) and 1.02 (0.91-1.15) in premenopausal and postmenopausal women, respectively. When alcohol was excluded from the Mediterranean diet score, results became not statistically significant.Adherence to a Mediterranean dietary pattern did not decrease breast cancer risk in this cohort of relatively young women.
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The Prolyl Isomerase Pin1 Acts Synergistically with CDK2 to Regulate the Basal Activity of Estrogen Receptor ? in Breast Cancer.

Filed under: Drug and Alcohol Rehabilitation

PLoS One. 2013; 8(2): e55355
Lucchetti C, Caligiuri I, Toffoli G, Giordano A, Rizzolio F

In hormone receptor-positive breast cancers, most tumors in the early stages of development depend on the activity of the estrogen receptor and its ligand, estradiol. Anti-estrogens, such as tamoxifen, have been used as the first line of therapy for over three decades due to the fact that they elicit cell cycle arrest. Unfortunately, after an initial period, most cells become resistant to hormonal therapy. Peptidylprolyl isomerase 1 (Pin1), a protein overexpressed in many tumor types including breast, has been demonstrated to modulate ERalpha activity and is involved in resistance to hormonal therapy. Here we show a new mechanism through which CDK2 drives an ERalpha-Pin1 interaction under hormone- and growth factor-free conditions. The PI3K/AKT pathway is necessary to activate CDK2, which phosphorylates ERalphaSer294, and mediates the binding between Pin1 and ERalpha. Site-directed mutagenesis demonstrated that ERalphaSer294 is essential for Pin1-ERalpha interaction and modulates ERalpha phosphorylation on Ser118 and Ser167, dimerization and activity. These results open up new drug treatment opportunities for breast cancer patients who are resistant to anti-estrogen therapy.
HubMed – drug


Incidence and risk factors for extensively drug-resistant tuberculosis in delhi region.

Filed under: Drug and Alcohol Rehabilitation

PLoS One. 2013; 8(2): e55299
Porwal C, Kaushik A, Makkar N, Banavaliker JN, Hanif M, Singla R, Bhatnagar AK, Behera D, Pande JN, Singh UB

India with a major burden of multidrug-resistant tuberculosis (MDR-TB) does not have national level data on this hazardous disease. Since 2006, emergence of extensively drug-resistant TB (XDR-TB) is considered a serious threat to global TB control. This study highlights the demographic and clinical risk factors associated with XDR-TB in Delhi.The study was conducted during April 2007 to May 2010. Six hundred eleven MDR-TB suspects were enrolled from four tertiary care hospitals, treating TB patients in Delhi and the demographic details recorded. Sputum samples were cultured using rapid, automated liquid culture system (MGIT 960). Drug susceptibility testing (DST) for Rifampicin (RIF) and Isoniazid (INH) was performed for all positive M. tuberculosis (M.tb) cultures. All MDR-TB isolates were tested for sensitivity to second-line drugs [Amikacin (AMK), Capreomycin (CAP), Ofloxacin (OFX), Ethionamide (ETA)].Of 611, 483 patients were infected with MDR M. tuberculosis (M.tb) strains. Eighteen MDR-TB isolates (3.7%) were XDR M.tb strains. Family history of TB (p 0.045), socioeconomic status (p 0.013), concomitant illness (p 0.001) and previous intake of 2(nd) line injectable drugs (p 0.001) were significantly associated with occurrence of XDR-TB. Only two of the patients enrolled were HIV seropositive, but had a negative culture for M. tuberculosis. 56/483 isolates were pre-XDR M. tuberculosis, though the occurrence of pre-XDR-TB did not show any significant demographical associations.The actual incidence and prevalence rate of XDR-TB in India is not available, although some scattered data is available. This study raises a concern about existence of XDR-TB in India, though small, signaling a need to strengthen the TB control program for early diagnosis of both tuberculosis and drug resistance in order to break the chains of transmission.
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To Study the Clinical, Biochemical and Radiological Features of Acute Pancreatitis in HIV and AIDS.

Filed under: Drug and Alcohol Rehabilitation

J Clin Med Res. 2013 Feb; 5(1): 12-7
Raza S, Chaudhry NA, Brown JD, Aghaie S, Rezai D, Khan A, Tan Pde L, Berger BJ

Pancreatitis complicating HIV infection, even in the Highly Active Antiretroviral Therapy (HAART) era, remains a management challenge. We felt there is a need to discern patterns in the biochemical markers, radiological studies, co-infections, length of stay (LOS) in patients with HIV or AIDS AND pancreatitis.This is a retrospective study conducted from June, 2008 to August, 2010 on patients admitted with acute pancreatitis to our hospital. We extracted and compared the following parameters: biochemical markers, HBV markers (surface antigen, core antibody and surface antibody), HCV antibody, radiological studies, and length of stay (LOS). The Balthazar Grade score was used to assess radiological severity of disease. We stratified the cohort into comparison subsets according to CD4 count.Ninety-four admissions met the criteria for HIV or AIDS AND pancreatitis; 67 unique patients comprised the cohort. Median age was 48 years (range, 23 to 60 years). Thirty seven (55%) were male, 30 (45%), female. Two third (n = 51) (76%) were African American. Known risk factors included a history of pancreatitis, 17 (25%); cholecystitis, 13 (19%); alcohol abuse, 25 (37%); Intravenous drug abuse, 18 (27%). Only 36 (38%) admissions were on HAART regimen. Biochemical features on admission were: WBC, 6,100/mm(3) (900 – 25,700); amylase, 152 U/L (30 – 1,344); lipase, 702.5 U/L (30 – 5,766), triglyceride, 65 mg/dL (57 – 400); glucose, 94 mg/dL (60 – 1,670); lactate, 2.3 mmol/L (1.09 – 5.49); AST, 61.5 U/L (9 – 1,950); LDH, 762 U/L (394 – 5,500); bicarbonate 19.5 mEq/L (3.3 – 82.7). Interestingly, 62% patients had normal pancreas on CT scan on admission. Of 67 individuals, hepatitis profile was available in 43, 21 (49%) were positive for HCV, 11 (26%) had markers for HBV. Four of 11 patients (36) with CD4 < 50 had evidence of persistent HBV (+core, -surface ab). Patients with CD4 < 200 have a median time for hospital course of 8 days (range 4 - 61 days) compare to 3 days in patients with CD4 > 200. P = 0.03 via t-test comparison. One patient with CD4 < 50 died due to acute pancreatitis.Pancreatitis remains a major cause of morbidity in HIV-infected individuals. This study has provided detailed features in the HAART therapy era about the clinical, biochemical and radiological features of pancreatitis. Half of our patients were positive for HCV; additionally, 36% with CD4 < 50 had persistent HBV. As opposed to earlier studies, we did not find a female predominance. Patients with CD4 < 200 had a 2.67-fold increase length of stay. Future studies are needed for a closer look on viral cofactors which might precipitate episodes of acute pancreatitis. HubMed – drug


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