Preparation and characterization of pH-independent sustained release tablet containing solid dispersion granules of a poorly water-soluble drug

Sustained release (SR) tablets containing solid dispersions (SD) granules of a poorly water-soluble drug were prepared to investigate the controlled pH-independent release of the drug. Losartan potassium (LST), an anti-hypertensive agent was chosen as a model drug because of its pH-dependent solubility and short elimination half-life. Poloxamer 188 was used as an SD carrier. A free-flowing SD granule was prepared by adsorbing the melt of the drug and poloxamer 188 onto the surface of an adsorbent, Aerosil 300 (fumed silicon dioxide), followed by direct compression with polyethylene oxide (PEO, 5 × 10(6)) to obtain an SD-loaded SR (SD-SR) matrix tablet. Differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) revealed partially amorphous structures of the drug in the SD granules. Scanning electron microscopy (SEM) and energy dispersive X-ray spectroscopy (EDS) images indicated adsorption of SD granules onto the surface of the adsorbent. The SD granules dissolved completely within 10 min, a dissolution rate much higher than that of pure LST. Moreover, pH-independent sustained release of LST from the SD-SR tablet was achieved for 2h in gastric fluid (pH 1.2) and for 10h in intestinal fluid (pH 6.8). A combination of SD techniques using surface adsorption and SR concepts is a promising approach to control the release rate of poorly water-soluble drugs in a pH-independent manner.     

Contextual memory and encoding strategies in young and older adults with and without depressive symptoms

Objectives: This study examines the role of depressive symptoms associated with age on contextual memory and how this association could impair the use of strategic instructions during encoding.

Method: Young and older controls and older adults with depressive symptoms performed memory recognition tests for item and context.

Results: Memory results indicated that mild depressive symptoms did not aggravate the age-related contextual memory pattern, but interfered with the magnitude of the memory enhancement provided by specific encoding instructions when compared with young adults. These between-group differences in the use of memory strategies were eliminated with the inclusion of the performance on Wisconsin Card Sorting Test as a covariate.

Conclusion: Mild depressive symptoms were associated with an impaired ability to use incidental memory strategies at encoding, suggesting the need for further investigation on the effects of non-clinical depressive symptomatology on cognitive decline in aging.     

NaHCO3- and NaCl-Type Hot Springs Enhance the Secretion of Inflammatory Cytokine Induced by Polyinosinic-Polycytidylic Acid in HaCaT Cells

BackgroundBackground: Hot springs have been traditionally used as an alternative treatment for a wide range of diseases, including rheumatoid arthritis, bronchial asthma, diabetes, hypertension, psoriasis and atopic dermatitis. However, the clinical effects and therapeutic mechanisms associated with hot springs remain poorly defined.ObjectiveThe purpose of this study was to demonstrate the different effects of hot springs on cellular viability and secretion of inflammatory cytokines on keratinocyte in two geographically representative types of hot springs: NaHCO₃-type and NaCl-type, which are the most common types in South Korea.MethodsWe performed WST-1, BrdU measurements, human inflammatory cytokine arrays and enzyme-linked immunosorbent assay in HaCaT cells stimulated with toll-like receptor 3 by polyinosinicpolycytidylic acid.ResultsThe interaction effects of cell viability and cell proliferation were not significantly different regardless of polyinosinic-polycytidylic acid stimulation and cultured hot springs type. Cytokine array and enzymelinked immunosorbent assay analysis showed increased expression of inflammatory cytokines such as interleukin6 and granulocyte-macrophage colony-stimulating factor by polyinosinic-polycytidylic acid stimulation, with expression levels differing according to hot springs hydrochemical composition. Cytokine reduction was not significant.ConclusionThe effects and mechanisms of hot springs treatment in keratinocytes were partially elucidated.     

Genetic, Biochemical, and Individual Responses of the Teleost Fish Carassius auratus to Uranium

Carassius auratus were exposed for 96 h to different concentrations of uranyl nitrate (corresponding to 0, 100, 450, and 2,025 μg U L⁻¹) and killed after different postexposure periods (0, 48, and 96 h) to assess uranium bioaccumulation, peroxisome proliferation (catalase [CAT]), lipid peroxidation (thiobarbituric acid reactive substances [TBARS]), and DNA integrity in erythrocytes (comet assay). In addition, feeding behaviour was recorded as a general response to toxicant exposure. Results provided evidence of uranium bioaccumulation in muscle of C. auratus after exposure to the highest concentrations (450 and 2,025 μg U L⁻¹). This tissue was able to depurate uranium to control levels 96 h after exposure ceased. However, no perturbations in feeding behaviour or cell damage were observed in the tested organisms, except for the apparent irreversible inhibition of CAT activity immediately after exposure in the highest concentration tested. Data on DNA integrity (comets) showed that waterborne uranium exposure was able to induce genotoxicity in C. auratus erythrocytes because fish exposed to all concentrations exhibited higher DNA damage than controls 96 h after exposure. No DNA damage repair was apparent throughout the postexposure period, which was contrary to a recovery scenario. This experiment provides evidence of uranium’s ability to induce physiologic impairment and genotoxicity in freshwater fish at environmentally relevant concentrations.     

Onychomycosis in patients with chronic leg ulcer and toenail abnormalities

Nails have a limited number of reactive patterns to disease. Accordingly, toenail changes of different etiologies may mimic onychomycosis.

OBJECTIVE

To determine the prevalence of toenail onychomycosis among patients with leg ulcer and toenail abnormalities attending a dermatology clinic.

METHODS

A cross-sectional study was conducted through the analysis of clinical records and results of mycological examination.

RESULTS

A total of 81 patients were included, with a median age of 76.0 years. Most ulcers were of venous etiology, followed by those of mixed and arterial pathogenesis. The mycological evaluation confirmed the diagnosis of onychomycosis in 27.2% of the patients. The etiologic agent was a dermatophyte in 59.1% of isolates in nail samples, while Trichophyton interdigitale was the most frequent fungal species (40.9%).

CONCLUSIONS

Most toenail abnormalities in patients with chronic leg ulcer were not onychomycosis. This study highlights the importance of systematic mycological examination in these patients, in order to avoid overtreatment with systemic antifungals, unnecessary costs and side effects.     

Bleeding in carriers of hemophilia

A wide range of factor VIII and IX levels is observed in heterozygous carriers of hemophilia as well as in noncarriers. In female carriers, extreme lyonization may lead to low clotting factor levels. We studied the effect of heterozygous hemophilia carriership on the occurrence of bleeding symptoms. A postal survey was performed among most of the women who were tested for carriership of hemophilia in the Netherlands before 2001. The questionnaire included items on personal characteristics, characteristics of hemophilia in the affected family members, and carrier testing and history of bleeding problems such as bleeding after tooth extraction, bleeding after tonsillectomy, and other operations. Information on clotting factor levels was obtained from the hospital charts. Logistic regression was used to assess the relation of carrier status and clotting factor levels with the occurrence of hemorrhagic events. In 2004, 766 questionnaires were sent, and 546 women responded (80%). Of these, 274 were carriers of hemophilia A or B. The median clotting factor level of carriers was 0.60 IU/mL (range, 0.05-2.19 IU/mL) compared with 1.02 IU/mL (range, 0.45-3.28 IU/mL) in noncarriers. Clotting factor levels from 0.60 to 0.05 IU/mL were increasingly associated with prolonged bleeding from small wounds and prolonged bleeding after tooth extraction, tonsillectomy, and operations. Carriers of hemophilia bleed more than other women, especially after medical interventions. Our findings suggest that not only clotting factor levels at the extreme of the distribution, resembling mild hemophilia, but also mildly reduced clotting factor levels between 0.41 and 0.60 IU/mL are associated with bleeding.     

ER-localized bestrophin 1 activates Ca2+-dependent ion channels TMEM16A and SK4 possibly by acting as a counterion channel

Bestrophins form Ca²⁺-activated Cl^? channels and regulate intracellular Ca²⁺ signaling. We demonstrate that bestrophin 1 is localized in the endoplasmic reticulum (ER), where it interacts with stromal interacting molecule 1, the ER-Ca²⁺ sensor. Intracellular Ca²⁺ transients elicited by stimulation of purinergic P2Y₂ receptors in HEK293 cells were augmented by hBest1. The p21-activated protein kinase Pak2 was found to phosphorylate hBest1, thereby enhancing Ca²⁺ signaling and activation of Ca²⁺-dependent Cl^? (TMEM16A) and K⁺ (SK4) channels. Lack of bestrophin 1 expression in respiratory epithelial cells of mBest1 knockout mice caused expansion of ER cisterns and induced Ca²⁺ deposits. hBest1 is, therefore, important for Ca²⁺ handling of the ER store and may resemble the long-suspected counterion channel to balance transient membrane potentials occurring through inositol triphosphate (IP₃)-induced Ca²⁺ release and store refill. Thus, bestrophin 1 regulates compartmentalized Ca²⁺ signaling that plays an essential role in Best macular dystrophy, inflammatory diseases such as cystic fibrosis, as well as proliferation.     

Identification of two sublineages of genotype G2 rotavirus among diarrheic children in Parauapebas,Southern Pará State,Brazil

On a world scale, group A human rotaviruses are the most common cause of severe acute gastroenteritis during infancy and childhood, including five (G1, G2, G3, G4, and G9) epidemiologically important genotypes. Among these, G2 denotes a different genogroup which appears to have a cyclic pattern of occurrence and yet little information is available about its genetic variability. The aim of this report was to characterize the emergence of G2 genotype in Paraupebas, Southern Pará State, Brazil, some of which detected after introduction of rotavirus vaccine. A total of 241 fecal specimens from young children with acute gastroenteritis were collected from the “Yutaka Takeda Hospital,” a Municipality Hospital, and at the Parauapebas' Health Unit, Pará, from January to September 2006 and during March to November 2008. All samples were tested for rotavirus using immunochromatography, polyacrylamide gel electrophoresis (PAGE), and RT‐PCR, yielding an overall positivity of 12.45% (30/241). Rotavirus G2P[4] was identified in 27 of 30 samples (90%), followed by G1P[8] (2/30, 6.67%) and G9P[8] (1/30, 3.33%). Phylogenetic analysis was performed in 15 of the G2 strains, all of which grouped into lineage II. Four of these strains clustered into sublineage II‐a (year 2006) and 11 into one possible new sublineage named II‐c (year 2008, except SAL‐1920‐C). The recent re‐emergence of G2 genotype associated with lineage II in Brazil warrants the continuous monitoring of circulating rotavirus strains following the nationwide universal use of rotavirus vaccine. J. Med. Virol. 82:712–719, 2010. © 2010 Wiley‐Liss, Inc.     

Effects of genital prolapse surgery on sexuality

OBJECTIVE: A prospective study was performed to evaluate the effects of genital prolapse surgery on sexuality. Additionally we investigated which variables are risk factors for persistence or development of sexual problems after surgery. METHODS: All 82 patients participating in a randomized trial comparing vaginal and abdominal surgical correction of descensus uteri, were asked to complete the Questionnaire for screening Sexual Dysfunctions (QSD) before and at six months and one year after surgery. RESULTS: Sixty-two patients completed the questionnaire. General satisfaction about sexuality was significantly improved after surgery. Of 41 patients who were sexually active both before surgery and at one year after surgery, 28 (68.3%) patients reported sexual problems before surgery. In 13 (46.4%) of these patients, all sexual problems disappeared. Of the 13 patients without sexual problems before surgery, two patients reported de novo sexual problems. The relative risk on disappearance of sexual problems in patients with large cystocele was 1.5 (95% confidence interval 1.1-2.1) times higher than the risk in patients without large cystocele. CONCLUSION: Satisfaction about sexuality increases and the prevalence of sexual problems decreases in patients undergoing surgical correction of descensus uteri.     

Membrane sweeping and prevention of post-term pregnancy in low-risk pregnancies: a randomised controlled trial

OBJECTIVE: To evaluate the effectiveness of membrane sweeping at 41 weeks for the prevention of post-term pregnancy. DESIGN: A multicentre randomised controlled trial. SETTING: Fifty-one primary care midwifery practices in the Netherlands. POPULATION: A total of 742 low-risk pregnant women at 41 weeks of gestation. METHODS: Participants were randomly assigned to serial sweeping of the membranes (every 48 hours until labour commenced up to 42 weeks of gestation) or no intervention. MAIN OUTCOME MEASURES: Post-term pregnancy (>or=42 weeks). Subgroup analyses were performed on nulliparous and parous women. Secondary outcomes included adverse effects. RESULTS: Serial sweeping of the membranes at 41 weeks decreased the risk of post-term pregnancy (87/375 [23%] versus 149/367 [41%]; relative risk [RR] 0.57, 95% CI 0.46-0.71; number needed to treat [NNT] 6 [95% CI 4-9]). Benefits were also seen in both subgroups (nulliparous: 57/198 [29%] versus 89/192 [46%]; RR 0.62 [95% CI 0.48-0.81]; NNT 6 [95% CI 4-12] and parous: 30/177 [17%] versus 60/175 [34%]; RR 0.49 [95% CI 0.34-0.73]; NNT 6 [95% CI 4-6]). Adverse effects were similar in both the groups except for uncomplicated bleeding, which was reported more frequently in the sweeping group. Other obstetric outcomes and indicators of neonatal morbidity were similar in both groups. There were two perinatal deaths in each group. CONCLUSIONS: Membrane sweeping at 41 weeks can substantially reduce the proportion of women with post-term pregnancy.