Correction: Self-collected and clinician-collected anal swabs show modest agreement for HPV genotyping.

[This corrects the article DOI: 10.1371/journal.pone.0250426.].

Self-collected and clinician-collected anal swabs show modest agreement for HPV genotyping.

BACKGROUND & AIM: Women with HIV/HPV coinfection and cervical lesions are at increased risk of developing HPV related anal cancer. Self-collection of anal swabs may facilitate HPV molecular testing in anal cancer screening, especially in high-risk groups, and yet it is not adequately studied. We evaluated level of agreement between self-collected anal swabs (SCAS) and clinician-collected anal swabs (CCAS) when used for HPV genotyping. We also described the anal HPV genotype distribution and HIV/HPV coinfection. METHODS: We performed a cross sectional study with participants from a visual-inspection-with-acetic-acid and cervicography (VIAC) clinic, in Harare, Zimbabwe. In a clinic setting, the women aged ≥18 years provided anal swabs in duplicate; first CCAS and then SCAS immediately after. HPV detection and genotyping were performed using next generation amplicon sequencing of a 450bp region of the HPV L1 gene. Level of agreement of HPV genotypes between CCAS and SCAS was calculated using the kappa statistic. McNemar tests were used to evaluate agreement in the proportion of genotypes detected by either method. RESULTS: Three-hundred women provided 600 samples for HPV genotyping. HPV genotypes were detected in 25% of SCAS and in 22% of CCAS. The most common genotypes with CCAS were HPV52, HPV62 and HPV70 and with SCAS were HPV62, HPV44, HPV52, HPV53 and HPV68. Total HPV genotypes detected in CCAS were more than those detected in SCAS, 32 versus 27. The agreement of HPV genotypes between the two methods was 0.55 in kappa value (k). The test of proportions using McNemar gave a Chi-square value of 0.75 (p = 0.39). Multiple HPV infections were detected in 28/75 and 29/67 women for CCAS and SCAS respectively. CONCLUSIONS: SCAS and CCAS anal swabs showed moderate agreement, with no statistically significant difference in the proportion of genotypes detected by either methods. Although the differences between the two methods were not statistically significant, CCAS detected more HPV genotypes than SCAS and more HPV infections were detected in SCAS than in CCAS. Our data suggest that self-collected anal swabs can be used as an alternative to clinician-collected anal swabs for HPV genotyping.

Model strategies to address barriers to cervical cancer treatment and palliative care among women in Zimbabwe: a public health approach.

BACKGROUND: Cervical cancer treatment and care remains limited in Zimbabwe despite the growing burden of the disease among women. This study was aimed at investigating strategies to address barriers in accessing treatment and care by women with cervical cancer in Harare, Zimbabwe. METHODS: A qualitative inquiry was conducted to generate evidence for this study. Eighty-four (84) participants were purposively selected for interviews and participation in focus group discussions. The participants were selected from cervical cancer patients, caregivers of cervical cancer patients, health workers involved in the care of cervical cancer patients as well as relevant policy makers in the Ministry of Health and Child Care. Participants were selected in such as a way as to ensure different of characteristics to obtain diverse perspectives about the issues under study. Discussion and interview guides were used as data collection tools and discussions/interviews were audio-recorded, transcribed and translated into English. Inductive thematic analysis was conducted using Dedoose software. RESULTS: Salient sub-themes that emerged in the study at the individual patient level were: provision of free or subsidized services, provision of transport to treating health facilities and provision of accommodation to patients undergoing treatment. At the societal level, the sub-themes were: strengthening of health education in communities and training of health workers and community engagement. Salient sub-themes from the national health system level were: establishment of more screening and treatment health facilities, increasing the capacities of existing facilities, decentralization of some services, building of multidisciplinary teams of health workers, development and rolling out of standardized guidelines and reformation of Acquired Immunodeficiency Virus (AIDS) levy into a fund that would finance priority disease areas. CONCLUSION: This study revealed some noteworthy strategies to improve access to cervical cancer treatment and care in low-income settings. Improved domestic investments in health systems and reforming health policies underpinned on strong political are recommended.

Leading causes of death of women of reproductive age in the Republic of Georgia: findings from the National Reproductive Age Mortality Survey (2014).

PURPOSE: An understanding of women's health problems during the reproductive years, based on reliable cause-of-death data, is of critical importance to avoid premature female mortality. This study aimed to investigate mortality levels, cause-specific patterns, and trends in women of reproductive age in Georgia. MATERIALS AND METHODS: The National Reproductive Age Mortality Survey (2014) was conducted to identify all causes of death for women aged 15-49 years in 2012. The leading causes were compared with those in 2006, using directly age-standardized death rates (ASDRs). The accuracy of official cause-of-death data was assessed against verbal autopsy (VA) diagnoses, using kappa statistics, sensitivity, positive predictive value, and misclassification analyses. RESULTS: Of 913 eligible deaths, VAs were completed for 878 deaths. Noncommunicable diseases (NCDs) were the dominant causes of death (69.6% or 53.1/100,000), with cancer taking a major toll (45.2% or 34.5/100,000), followed by injuries (18.6% or 14.2/100,000). Breast cancer (12.5%), road injuries (9.1%), cervical cancer (6.5%), cerebrovascular diseases (5.2%), uterine cancer (4.1%), brain cancer (3.4%), suicide (3.1%), stomach cancer (3.0%), maternal disorders (2.6%), and liver cirrhosis (2.2%) contributed to the 10 leading specific causes of death, with the majority being substantially underreported in official statistics. This was primarily due to a significantly higher proportion (84%, p<0.05) of deaths routinely assigned ill-defined codes. Since 2006, statistically significant changes in ASDRs, with declines, were observed only for undetermined causes (40%, p<0.05) and ovarian cancer (54%, p<0.05); ovarian cancer and tuberculosis were replaced by stomach cancer and liver cirrhosis in the top 10 cause-of-death list. CONCLUSION: NCDs continue to be the major health threats for Georgian women of reproductive age. The VA method proved a feasible tool to yield essential cause-of-death information for this population. Further research is needed to inform national health promotion and disease prevention interventions to be focused on NCDs and reproductive health needs with an integrated approach.

Intra-host sequence variability in human papillomavirus.

Human papillomaviruses (HPVs) co-evolve slowly with the human host and each HPV genotype displays epithelial tropisms. We assessed the evolution of intra HPV genotype variants within samples, and their association to anogenital site, cervical cytology and HIV status. Variability in the L1 gene of 35 HPV genotypes was characterized phylogenetically using maximum likelihood, and portrayed by phenotype. Up to a thousand unique variants were identified within individual samples. In-depth analyses of the most prevalent genotypes, HPV16, HPV18 and HPV52, revealed that the high diversity was dominated by a few abundant variants. This suggests high intra-host mutation rates. Clades of HPV16, HPV18 and HPV52 were associated to anatomical site and HIV co-infection. Particularly, we observed that one HPV16 clade was specific to vaginal cells and one HPV52 clade was specific to anal cells. One major HPV52 clade, present in several samples, was strongly associated with cervical neoplasia. Overall, our data suggest that tissue tropism and HIV immunosuppression are strong shapers of HPV evolution.

Management of suspected primary Toxoplasma gondii infection in pregnant women in Norway: twenty years of experience of amniocentesis in a low-prevalence population.

BACKGROUND: Primary infection with Toxoplasma gondii during pregnancy may pose a threat to the fetus. Women infected prior to conception are unlikely to transmit the parasite to the fetus. If maternal serology indicates a possible primary infection, amniocentesis for toxoplasma PCR analysis is performed and antiparasitic treatment given. However, discriminating between primary and latent infection is challenging and unnecessary amniocenteses may occur. Procedure-related fetal loss after amniocentesis is of concern. The aim of the present study was to determine whether amniocentesis is performed on the correct patients and whether the procedure is safe for this indication. METHODS: Retrospective study analysing data from all singleton pregnancies (n = 346) at Oslo University Hospital undergoing amniocentesis due to suspected maternal primary toxoplasma infection during 1993-2013. Maternal, neonatal and infant data were obtained from clinical hospital records, laboratory records and pregnancy charts. All serum samples were analysed at the Norwegian Institute of Public Health or at the Toxoplasma Reference Laboratory at Oslo University Hospital. The amniocenteses were performed at Oslo University Hospital by experienced personnel. Time of maternal infection was evaluated retrospectively based on serology results. RESULTS: 50% (173) of the women were infected before pregnancy, 23% (80) possibly in pregnancy and 27% (93) were certainly infected during pregnancy. Forty-nine (14%) women seroconverted, 42 (12%) had IgG antibody increase and 255 (74%) women had IgM positivity and low IgG avidity/high dye test titre. Fifteen offspring were infected with toxoplasma, one of them with negative PCR in the amniotic fluid. Median gestational age at amniocentesis was 16.7 gestational weeks (GWs) (Q1 = 15, Q3 = 22), with median sample volume 4 ml (Q1 = 3, Q3 = 7). Two miscarriages occurred 4 weeks after the procedure, both performed in GW 13. One of these had severe fetal toxoplasma infection. CONCLUSIONS: Half of our study population were infected before pregnancy. In order to reduce the unnecessary amniocenteses we advise confirmatory serology 3 weeks after a suspect result and suggest that the serology is interpreted by dedicated multidisciplinary staff. Amniocentesis is safe and useful as a diagnostic procedure in diagnosing congenital toxoplasma infection when performed after 15 GW.

Genotypic diversity of anogenital human papillomavirus in women attending cervical cancer screening in Harare, Zimbabwe.

Although anogenital cancers have been on a gradual rise in developing countries in the past few decades, they have been understudied. The objective was to investigate genotypic diversity of anogenital HPV amongst women reporting for routine cervical cancer screening in Harare in Zimbabwe. A cross-sectional study that enrolled 144 women ≥18 years from a cervical cancer-screening clinic was performed. Each woman provided a self-collected cervico-vaginal swab (VS) and a clinician-collected anal swab (CCAS). HIV testing was offered and cervical cytology was performed. Both VS and CCAS samples were HPV genotyped, using amplicon sequencing of the L1 gene region with Illumina technology. Mean age of the women was 39.9 (range 18-83 years, SD ± 11.0). HPV prevalence was 72% (104/144) in VS and 48% (69/144) in CCAS. The most common genotypes detected in both VS and CCAS were HPV18, HPV52, and HPV16. Sixty two percent of the subjects had multiple genotypic HPV infections. The odds of being HPV-positive among HIV-infected women were higher than in HIV-negative women in both the vagina and the anus (CCAS OR = 4.8; CI 2.4-9.8, P < 0.001) and (VS OR = 2.9; CI 1.3-6.4, P = 0.005). High HPV prevalence and diverse genotypes were detected in both the vagina and anus. Anal oncogenic HPV infection was common. HPV 52 was one of the most common oncogenic genotypes in both the vagina and anus. HIV co-infection played a significant role in the prevalence of HPV. These data have implications for design of primary and secondary programs for prevention of anogenital cancer in Zimbabwe.

Risk factors for severe postpartum hemorrhage: a case-control study.

BACKGROUND: In high-income countries, the incidence of severe postpartum hemorrhage (PPH) has increased. This has important public health relevance because severe PPH is a leading cause of major maternal morbidity. However, few studies have identified risk factors for severe PPH within a contemporary obstetric cohort. METHODS: We performed a case-control study to identify risk factors for severe PPH among a cohort of women who delivered at one of three hospitals in Norway between 2008 and 2011. A case (severe PPH) was classified by an estimated blood loss ≥1500 mL or the need for blood transfusion for excessive postpartum bleeding. Using logistic regression, we applied a pragmatic strategy to identify independent risk factors for severe PPH. RESULTS: Among a total of 43,105 deliveries occurring between 2008 and 2011, we identified 1064 cases and 2059 random controls. The frequency of severe PPH was 2.5% (95% confidence interval (CI): 2.32-2.62). The most common etiologies for severe PPH were uterine atony (60%) and placental complications (36%). The strongest risk factors were a history of severe PPH (adjusted OR (aOR) = 8.97, 95% CI: 5.25-15.33), anticoagulant medication (aOR = 4.79, 95% CI: 2.72-8.41), anemia at booking (aOR = 4.27, 95% CI: 2.79-6.54), severe pre-eclampsia or HELLP syndrome (aOR = 3.03, 95% CI: 1.74-5.27), uterine fibromas (aOR = 2.71, 95% CI: 1.69-4.35), multiple pregnancy (aOR = 2.11, 95% CI: 1.39-3.22) and assisted reproductive technologies (aOR = 1.88, 95% CI: 1.33-2.65). CONCLUSIONS: Based on our findings, women with a history of severe PPH are at highest risk of severe PPH. As well as other established clinical risk factors for PPH, a history of severe PPH should be included as a risk factor in the development and validation of prediction models for PPH.

Inflammatory Markers and Plasma Lipids in HIV Patients: A Correlation Analysis Study.

BACKGROUND: Recent evidence suggests that HIV infection, even with treatment, increases the risk of coronary heart disease (CHD) and that both chronic inflammation and traditional risk factors play key roles in HIV-associated CHD. SUBJECTS AND METHODS: Patients (N=152), attending Harare HIV clinic, 26% of them male and 82% of them on antiretroviral therapy (ART), were studied. Inflammatory markers comprising of cytokines such as pro-inflammatory tumor necrosis factor-α, (TNF-α), anti-inflammatory interleukin 10, (IL-10) and highly sensitive C reactive protein (hsCRP) together with lipids were assayed using enzyme linked immunosorbent assay (ELISA), immuno-turbidimetric and enzymatic assays, respectively. Correlation analysis of inflammatory markers versus lipid profiles was carried out using bivariate regression analysis. RESULTS: Anti-inflammatory cytokine IL-10 and inflammatory hsCRP levels were elevated when measured in all the HIV positive patients, while TNF-α and lipid levels were within normal ranges. Pro-inflammatory TNF-α was significantly higher in ART-naive patients than ART-experienced patients, whereas the reverse was observed for anti-inflammatory IL-10 and anti-atherogenic HDL-C. Correlation analysis indicated a significant positive linear association between IL-10 and total cholesterol (TC) levels but no other correlations were found. CONCLUSION: High cytokine ratio (TNF-α/IL-10) indicates higher CHD risk in ART-naive patients compared to the ART-exposed. The CHD risk could be further strengthened by interplay between inflammatory markers and high prevalence of low HDL-C. Lack of correlation between pro-inflammatory markers (hsCRP and TNF-α) with lipid fractions and correlation between anti-inflammatory IL-10 with artherogenic TC were unexpected findings, necessitating further studies in future.

Inflammation-modulating cytokine profile and lipid interaction in HIV-related risk factors for cardiovascular diseases.

HIV infection and antiretroviral therapy (ART) are associated with changes in plasma levels of lipoproteins, thus posing the risk of cardiovascular complications in infected individuals. The alteration in plasma lipoprotein levels results from dysregulation of inflammation-modulating cytokines that control lipid metabolism. Little is understood regarding the relationship between the cytokines and serum lipid levels, which have been reported to be altered in adults receiving ART. The objective of this study was to describe the profiles of inflammation-modulating cytokines and their relationship to lipids as cardiovascular disease (CVD) risk factors in HIV infection. This observational cross-sectional study measured plasma levels of interleukin (IL)-10, tumor necrosis factor-alpha (TNF)-α, IL-4, total cholesterol (TC), and high-density lipoprotein cholesterol (HDL-c) in HIV-infected and uninfected adults. A total of 219 HIV-infected participants were enrolled from an HIV treatment center; of them, 187 were receiving ART and 32 were ART naïve, while 65 were HIV-uninfected blood donors. HIV-infected individuals had higher levels of IL-10 (HIV-infected ART-naïve [P=0.0024] and ART-receiving [P=0.033]) than their uninfected counterparts. ART-naïve subjects had significantly higher plasma levels of IL-10 than ART-receiving subjects (P=0.0014). No significant difference was observed in plasma levels of IL-4 and TNF-α across the three groups. Regarding plasma lipoproteins, HDL-c levels were reduced in HIV ART-naïve (P=0.002) and ART-receiving (P=0.015) subjects compared to HIV-uninfected subjects. Similarly, TC levels were lower in the HIV-infected than in the HIV-uninfected group regardless of whether the patients were undergoing ART or not (P<0.001). IL-10 levels correlated with TC levels in the HIV-uninfected group but not in the HIV-infected groups. Levels of HDL-c were reduced, while IL-10 plasma concentrations were elevated in HIV-infected individuals. A correlation observed in HIV-uninfected individuals between anti-inflammatory cytokine IL-10 and TC was lost in HIV-infected individuals. Clinical significance of these differences needs to be ascertained with respect to HIV-related CVD risk.

Lower Urinary and Serum Progesterone-Induced Blocking Factor in Women with Preterm Birth.

The aim of the study was to compare urine and serum concentrations of PIBF at 24-28 gestational weeks in women with preterm birth, with those of women who delivered at term and to evaluate the impact of PIBF on the outcome of pregnancy. Case-control study was performed in period from 1.6.2010-31.7.2013. Biological samples (urine and serum) were collected from 126 pregnant women. All biological samples were obtained at 24-28 gestation weeks. We measured PIBF concentration and compared women who delivered preterm and those who delivered at term. Thirteen of 126 pregnant women (10.3%) who were included in the study delivered preterm. Among women that actually delivered preterm, median concentrations of PIBF were significantly lower (12.3ng/ml; 101.3ng/ml) than in women who delivered at term (77.0ng/ml; 412.7ng/ml). The serum and urine 24-28 gestational weeks PIBF in those who delivered preterm were generally low from 24 to 37 gestational weeks, while the serum and urine PIBF concentration reached a peak in those delivering between 37-38 gestational weeks, even significantly different from those delivering at 39 to 40 and after 40 gestational weeks. Preterm birth may be predictable at 24-28 gestational week by lower than normal pregnancy PIBF values and measurement of PIBF concentration in biological fluids at that time may be of importance in clinical practice.

Higher risk for adverse obstetric outcomes among immigrants of African and Asian descent: a comparison study at a low-risk maternity hospital in Norway.

BACKGROUND: Immigrants have higher risks for some adverse obstetric outcomes, and 40 percent of women giving birth at the low-risk maternity ward in Baerum Hospital, Norway, are immigrants. This study compared obstetric outcomes between immigrants and ethnic Norwegians giving birth in a low-risk setting. METHODS: This was a population-based study linking the Medical Birth Registry of Norway to Statistics Norway. The study included the first registered birth during the study period to immigrant and ethnic Norwegian women at Baerum Hospital from 2006 to 2010. The main outcome measures were onset of labor, operative vaginal delivery, cesarean delivery, episiotomy, postpartum bleeding > 500 mL, epidural analgesia, labor dystocia, gestational age, meconium-stained liquor, 5-minute Apgar score, birthweight, and transfer to a neonatal intensive care unit. RESULTS: A total of 11,540 women originating from 141 countries were divided into seven groups. Compared with Norwegians, women from East, Southeast, and Central Asia had increased risk for operative vaginal delivery, postpartum bleeding, and low Apgar score. The African women had increased risk for postterm birth, meconium-stained liquor, episiotomy, operative vaginal delivery, emergency cesarean delivery, postpartum bleeding, low Apgar score, and low birthweight. Women from South and Western Asia had increased risk for low birthweight. CONCLUSION: Obstetric outcomes of immigrants differ significantly from those of Norwegians, even in a low-risk maternity unit. Thus, immigrant women would benefit from more targeted care during pregnancy and childbirth, even in low-risk settings.

Frequency of Betapapillomavirus infections among HIV infected and uninfected Black Zimbabweans with cutaneous lesions.

Human papillomavirus (HPV) types from the Betapapillomavirus (ß-HPV) genus are plentiful in non-melanoma skin cancers and warts among Caucasians, but there is paucity of information among black Africans. To determine the frequency of ß-HPV genotypes in cutaneous infections among Black Zimbabweans, a cross-sectional study was carried out in which blood samples and skin biopsies were collected from patients infected and uninfected with HIV attending a referral hospital. We included 144 participants (72 infected and 72 uninfected with HIV) with clinically apparent cutaneous warts (n = 34), suspected non-melanoma skin cancers (n = 98) and Kaposi sarcoma (KS) (n = 18). The skin biopsies were analyzed for HPV DNA presence and type. ß-HPV DNA was identified among 70% (101/144) and was significantly higher among patients infected with HIV, 79% (57/72) compared to the HIV uninfected 61% (44/72) [OR = 2.42, 95% CI (1.09-5.47), P = 0.018]. All patients with warts, 89% of those with KS and 58% of those with non-melanoma skin cancers were HPV DNA positive and ß-HPV type 14 was identified in nearly half of the study participants 49.3% (71/144). Single HPV infections were observed in 33.7% (34/101) of the participants that were HPV DNA positive, 66.3% (67/101) had multiple HPV types. There was no significant difference between patients infected and uninfected with HIV in terms of multiple HPV infections. The distribution of different HPV types did not reveal any association with age and gender but there was an association between HPV 14 and HIV immune status. ß-HPVs are not uncommon among the Black Zimbabweans with skin lesions.

Presence of Betapapillomavirus in Kaposi sarcoma lesions.

Human herpes virus 8 (HHV 8) is recognized as the necessary cause of Kaposi sarcoma (KS) and in the recent past the human papillomavirus (HPV) has been linked to the development of cutaneous basal cell and squamous cell carcinomas. In a cross sectional study investigating Beta-HPV infections in skin lesions, an unexpected occurrence of HPV DNA was found in KS lesions of HIV infected individuals. Of the 18 KS cases included in the study 16 (89%) had HPV DNA detected. The most common Betapapillomavirus types were HPV14 [15 cases (83.3%)], HPV12 [8 cases (44.4%)], and HPV24 [7 cases (39%)]. Multiple Beta-HPV types were detected in 10 (62.5%) of the participants with HPV DNA positive lesions; of these 7 had a CD4+ count below 350 cells/µl and 3 had CD4+ counts above 350 cells/µl. The presence of Beta-HPV DNA in KS lesions is a newly described phenomenon. Further studies to elucidate the role of Beta-HPV in KS need to be conducted as it is possible that HHV 8 may not be the solitary viral carcinogen in KS tumorigenesis.

Dydrogesterone supplementation in women with threatened preterm delivery--the impact on cytokine profile, hormone profile, and progesterone-induced blocking factor.

Progesterone is indispensable in creating a suitable endometrial environment for implantation, and also for the maintenance of pregnancy. Successful pregnancy depends on an appropriate maternal immune response to the fetus. A protein called progesterone-induced blocking factor (PIBF) acts by inducing Th2-dominant cytokine production to mediate the immunological effects of progesterone. The aim of this prospective study was to compare serum concentrations of progesterone (P), estradiol (E2), anti-inflammatory (IL-10) and pro-inflammatory (IL-6, TNFα, IFNγ) cytokines, and serum PIBF concentrations in women with threatened preterm delivery who were given progesterone supplementation (study group) with those of women with threatened preterm delivery who were not given progesterone supplementation (control group). After dydrogesterone treatment of patients in the study group, serum PIBF as well as progesterone concentrations significantly increased. Women in this group had significantly higher serum levels of IL-10 than controls. The length of gestation was significantly higher in the group of women who were given progesterone supplementation. Our data suggest that dydrogesterone treatment of women at risk of preterm delivery results in increased PIBF production and IL-10 concentrations, and lower concentrations of IFNγ.

Concerns for decreased foetal movements in uncomplicated pregnancies--increased risk of foetal growth restriction and stillbirth among women being overweight, advanced age or smoking.

INTRODUCTION: We aimed to determine whether the clinical characteristics of women in uncomplicated pregnancies presenting with decreased foetal movements (DFMs) would help target subgroups of women at the highest risk. Furthermore, we also aimed whether DFMs in complicated pregnancies identified the additional needs for intensified management. METHODS: Singleton third trimester pregnancies (n=2374) presenting with DFMs from June 2004 through October 2005 were prospectively registered in 14 delivery units in Norway. Among pregnancies that were uncomplicated until registration for DFMs, cases with good outcomes (birth weight between 10th and 90th percentile, term delivery and live-born child) were compared with cases with adverse outcomes. RESULTS: In uncomplicated pregnancies, maternal overweight, advanced age and smoking identified subgroups of cases at increased risk of foetal growth restriction and stillbirth. DFMs of longer duration, in particular the perceived absence of movements, identified cases at increased risk of stillbirth, irrespective of other maternal characteristics. When women with complicated pregnancies reported DFMs, additional indications for follow-up were found in 1/3 of cases. CONCLUSIONS: Maternal overweight, advanced age, smoking and the duration of DFMs are the characteristics that help in identifying pregnancies that should be targeted for intensified management. Time matters and knowledge-based information are needed to improve foetal health.

Effects of hormone therapy on depressive symptoms and cognitive functions in women with Alzheimer disease: a 12 month randomized, double-blind, placebo-controlled study of low-dose estradiol and norethisterone.

OBJECTIVE: To elucidate the effects of low-dose 17beta-estradiol and norethisterone (hormone therapy [HT]) versus placebo in women with Alzheimer Disease (AD) on cognition, depressive symptoms, and activities of daily living. DESIGN: A 12-month randomized, double-blind, placebo-controlled study, stratified by apolipoprotein E (ApoE) genotype (with versus without the epsilon4 allele), duration of education (< or =9 versus >9 years), and age (< or =75 versus >75 years) performed during 2000-2004. SETTING: Ambulatory memory clinic in a general hospital. PARTICIPANTS: Sixty-five female outpatients aged 65-89 years who met criteria for probable AD according to Diagnostic and Statistical Manual of Mental Disorders, fourth edition and International Classification of Diseases, tenth edition. Ten patients were excluded, resulting in 55 participants who had at least one posttreatment efficacy evaluation. INTERVENTION: Randomly assigned to receive either 1-mg estradiol and 0.5-mg norethisterone or placebo once daily. MEASUREMENTS: Cognitive variables were the Dementia Rating Scale, tests from Consortium to Establish a Registry for AD, Global Deterioration Scale (GDS) and Barthel Index. RESULTS: When only treatment effects were compared by analysis of variance, there were nonsignificant differences between treatment groups for all efficacy variables. A linear model analysis, including stratifying factors in addition to treatment in the model, revealed a significant main effect on mood. The depressive symptoms were lower in the HT group than in the placebo group. Those treated with HT without the ApoE epsilon4 allele had better mood, Word Learning Memory score, and GDS score. Those in the HT group with a higher level of education obtained a better GDS score. Adverse events did not differ between the groups. CONCLUSION: HT interacts with ApoE genotype in women with AD. Women without an ApoE epsilon4 allele may get better mood and cognition with HT. HT may reduce depressive mood and give less cognitive decline.

Nicotine affects the expression of brain-derived neurotrophic factor mRNA and protein in the hippocampus of hypoxic newborn piglets.

Brain-derived neurotrophic factor (BDNF) is highly expressed in the developing brain. It has anti-apoptotic abilities, and protects the neonatal brain. In experimental settings in adult animals, pre-treatment with nicotine has shown increased BDNF levels, indicating a possible contribution to nicotine's anti-apoptotic effect. Apoptosis contributes to the development of brain damage in perinatal asphyxia. We examined the effects of nicotine on apoptosis-inducing factor (AIF), caspase-3 and BDNF in the hippocampus of a neonatal piglet model of global hypoxia. Forty-one anesthetized newborn piglets were randomized to one of four groups receiving different infusions after hypoxia (1) nicotine 130 microg/kg/h, 2) 260 microg/kg/h, 3) adrenaline, and 4) saline, all 2.6 mL/kg/h. Four hours after hypoxia they were euthanized. The left hemisphere/hippocampus was examined by histopathology and immunohistochemistry; the right hippocampus was analyzed using real time PCR. There was a significantly higher expression of BDNF mRNA and protein in the animals treated with nicotine 130 microg/kg/h vs. the saline treated group (mRNA P=0.038; protein P=0.009). There were no differences regarding AIF or caspase-3. We conclude that nicotine (130 microg/kg/h), infused over 1 h after global hypoxia in neonatal piglets, increases levels of both BDNF mRNA and protein in the hippocampus. This might imply neuroprotective effects of nicotine in asphyxiated neonates.

Nicotine in a small-to-moderate dose does not cause a significant increase in plasma catecholamine levels in newborn piglets.

BACKGROUND: Nicotine has a wide range of effects. Several studies are being undertaken investigating the positive effects on inflammation and apoptosis. Recently, nicotine has been investigated in a piglet model of perinatal asphyxia, where the question has been raised whether nicotine's effect on the sympathetic nervous system can explain some of the positive effects. OBJECTIVES: We hypothesized that nicotine in small-to-moderate doses would not cause a significant increase in plasma catecholamine levels, whereas a higher dose would give a significant effect, confirming the believed dose-dependent matter in which nicotine exerts its effect on the sympathetic nervous system. METHODS: Seventeen anesthetized newborn piglets were randomized to one of three doses of nicotine (130, 260 or 1,000 microg/kg/h) that was given intravenously for 1 h. Blood samples for catecholamine analyzes were drawn at baseline and at the end of the infusion. Catecholamines were determined using HPLC. RESULTS: No significant increase in catecholamines was detected in the animals treated with the small or moderate nicotine doses, whereas the higher dose gave a significant increase in adrenaline (p = 0.019). CONCLUSION: Nicotine in small-to-moderate doses does not cause significant increase in plasma catecholamines, thus indicating that the positive effects of nicotine in studies using these doses most likely cannot be explained by the systemic release of catecholamines.

Resuscitation with 21 or 100% oxygen in hypoxic nicotine-pretreated newborn piglets: possible neuroprotective effects of nicotine.

BACKGROUND: Perinatal asphyxia is a major concern in perinatal medicine. Resuscitation and ways to prevent and minimize adverse outcomes after perinatal asphyxia are subject to extensive research. OBJECTIVES: In this study we hypothesized that, prior to hypoxia, intravenously administered nicotine might have an effect on how newborn piglets tolerate hypoxia, with regard to the time and degree of damage inflicted, due to its suggested neuroprotective abilities, and further that resuscitation with 21 compared with 100% oxygen in nicotine-pretreated animals would cause less cerebral damage. METHODS: Thirty anesthetized newborn piglets were randomized to either hypoxia or control groups, and pretreatment with either saline or nicotine. In addition, the nicotine/hypoxia group was randomized to resuscitation with either 21 or 100% oxygen for 15 min following hypoxia. RESULTS: We found significantly more necrosis in the striatum and cortex combined (p = 0.036), and in the striatum alone (p = 0.026), in the animals pretreated with nicotine and resuscitated with 100% when compared to 21% oxygen. There was no significant difference in the cerebellum. We also found significantly increased tolerance to hypoxia as measured by the time interval that the animals endured hypoxia: 103.8 +/- 28.2 min in the nicotine-pretreated animals vs. 66.5 +/- 19.5 min in the saline-pretreated animals (p = 0.035). CONCLUSION: Nicotine enhances newborn piglets' ability to endure hypoxia, and resuscitation with 21% oxygen inflicts less necrosis than 100% oxygen. The potential neuroprotective effects of nicotine in the newborn brain should be further investigated.