NOS isoform-specific regulation of basal but not exercise-induced mitochondrial biogenesis in mouse skeletal muscle

Nitric oxide is a potential regulator of mitochondrial biogenesis. Therefore, we investigated if mice deficient in endothelial nitric oxide synthase (eNOS-/-) or neuronal NOS (nNOS-/-) have attenuated activation of skeletal muscle mitochondrial biogenesis in response to exercise. eNOS-/-, nNOS-/- and C57Bl6 (CON) mice (16.3 ± 0.2 weeks old) either remained in their cages (basal) or ran on a treadmill (16 m min-1, 5 grade) for 60 min (n = 8 per group) and were killed 6 h after exercise. Other eNOS-/-, nNOS-/- and CON mice exercise trained for 9 days (60 min per day) and were killed 24 h after the last bout of exercise training. eNOS-/- mice had significantly higher nNOS protein and nNOS-/- mice had significantly higher eNOS protein in the EDL, but not the soleus. The basal mitochondrial biogenesis markers NRF1, NRF2α and mtTFA mRNA were significantly (P< 0.05) higher in the soleus and EDL of nNOS-/- mice whilst basal citrate synthase activity was higher in the soleus and basal PGC-1α mRNA higher in the EDL. Also, eNOS-/- mice had significantly higher basal citrate synthase activity in the soleus but not the EDL. Acute exercise increased (P< 0.05) PGC-1α mRNA in soleus and EDL and NRF2α mRNA in the EDL to a similar extent in all genotypes. In addition, short-term exercise training significantly increased cytochrome c protein in all genotypes (P< 0.05) in the EDL. In conclusion, eNOS and nNOS are differentially involved in the basal regulation of mitochondrial biogenesis in skeletal muscle but are not critical for exercise-induced increases in mitochondrial biogenesis in skeletal muscle.

Effect of nitric oxide synthase inhibition on mitochondrial biogenesis in rat skeletal muscle

The purpose of this study was to determine whether nitric oxide synthase (NOS) inhibition decreased basal and exercise-induced skeletal muscle mitochondrial biogenesis. Male Sprague-Dawley rats were assigned to one of four treatment groups: NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME, ingested for 2 days in drinking water, 1 mg/ml) followed by acute exercise, no L-NAME ingestion and acute exercise, rest plus L-NAME, and rest without L-NAME. The exercised rats ran on a treadmill for 53 ± 2 min and were then killed 4 h later. NOS inhibition significantly (P < 0.05; main effect) decreased basal peroxisome proliferator-activated receptor-{gamma} coactivator 1beta (PGC-1beta) mRNA levels and tended (P = 0.08) to decrease mtTFA mRNA levels in the soleus, but not the extensor digitorum longus (EDL) muscle. This coincided with significantly reduced basal levels of cytochrome c oxidase (COX) I and COX IV mRNA, COX IV protein and COX enzyme activity following NOS inhibition in the soleus, but not the EDL muscle. NOS inhibition had no effect on citrate synthase or beta-hydroxyacyl CoA dehydrogenase activity, or cytochrome c protein abundance in the soleus or EDL. NOS inhibition did not reduce the exercise-induced increase in peroxisome proliferator-activated receptor-{gamma} coactivator 1{alpha} (PGC-1{alpha}) mRNA in the soleus or EDL. In conclusion, inhibition of NOS appears to decrease some aspects of the mitochondrial respiratory chain in the soleus under basal conditions, but does not attenuate exercise-induced mitochondrial biogenesis in the soleus or in the EDL.

Attrition from an internet-based psychological intervention for erectile dysfunction : who is likely to drop out?

The current study evaluated the dropout rate from an internet-based treatment program for erectile dysfunction (ED), and determined reasons for attrition from this program. Only 12 of 40 treatment group men and 19 of 20 control group men completed the post-test measures. Reasons for the men being excluded or dropping out of the study are discussed. These reasons included medical conditions that contributed to their ED, the man's partner not being interested in participating in the program, a lack of motivation from the man, or the time commitment being too demanding.

Mitochondrial DNA diversity of the Asian moon scallop, Amusium pleuronectes (Pectinidae), in Thailand

Sequence variation of the mitochondrial DNA 16S rRNA region of the Asian moon scallop, Amusium pleuronectes, was surveyed in seven populations along the coast of Thailand. A total of 16 unique haplotypes were detected among 174 individuals with a total 27 variable sites out of 534 bp sequenced. The mitochondrial haplotypes grouped into two distinct arrays (estimated to differ by about 2.62% to 2.99% nucleotide divergence) that characterized samples collected from the Gulf of Thailand versus the Andaman Sea. Low levels of intrapopulation variation were observed, while in contrast, significant divergence was observed between populations from the Gulf of Thailand and Andaman Sea. Results of AMOVA reveal a high F ST value (0.765) and showed that the majority of the total genetic variance (76.03%) occurred among groups (i.e., Andaman Sea and the Gulf of Thailand) and little among populations within the group (0.52%) and within populations (23.45%). The genetic differentiation between the populations recorded in the present study is similar to that observed in a variety of marine species in the Indo-Pacific. The implications of the findings for management of A. pleuronectes genetic resources in Thailand are discussed.

Phylogenetic relationships among nine scallop species (Bivalvia : Pectinidae) inferred from nucleotide sequences of one mitochondrial and three nuclear gene regions

Current knowledge of the evolutionary relationships among scallop species (Mollusca: Bivalvia: Pectinidae) in the Indo-Pacific region is rather scanty. To enhance the understanding of the relationships within this group, phylogenies of nine species of scallops with the majority from coastal regions of Thailand, were reconstructed by maximum parsimony, maximum likelihood, and Bayesian methods using sequences of the 16S rRNA of the mitochondrial genome, and a fragment containing the ITS1, 5.8S and ITS2 genes of the nuclear DNA. The trees that resulted from the three methods of analysis were topologically identical, however, gained different levels of support at some nodes. Nine species were clustered into two major clades, corresponding to two subfamilies (Pectininae and Chlamydinae) of the three currently recognized subfamilies within Pectinidae. Overall, the relationships reported herein are mostly in accordance with the previous molecular studies that used sequences of the mtDNA cytochrome oxidase subunit I, and the classification system based on microsculpture of shell features and morphological characteristics of juveniles. Levels of divergences were different among genes (i.e., the 5.8S gene showed the lowest levels of nucleotide divergence at all levels, whereas the 16S rRNA showed the highest level of variation within species, and ITS2 gene revealed the highest level of divergence at higher levels).

The impact of erectile dysfunction on female partners : a qualitative investigation

Sexual dysfunction research has primarily focused on understanding and treating problems of erectile dysfunction (ED) in men. Research has paid little attention to the impact of ED on women. The current study reports on an investigation of women's perception of their partners' ED, what they had tried to do about the problem and the impact of ED on them and their relationship. In-depth interviews were conducted with 51 women who were currently in a heterosexual relationship with a man with ED. The findings provide detailed information on women's experience of their partners' ED. They also demonstrate the need for educational resources on sexual difficulties for both the lay public and their medical practitioners. In the clinical situation, the study demonstrated the value of involving the female partner in the treatment process in improving a couple's sexual satisfaction.

Investigating women's preference for sildenafil or tadalafil use by their partners with erectile dysfunction : the partners' preference study.

Introduction: Several preference studies comparing a short-acting with a longer-acting phosphodiesterase type 5 inhibitor have been conducted in men. Most men in those studies preferred tadalafil rather than sildenafil, and recent post hoc analysis of one study described several factors associated with men’s treatment preference. No prospective studies have investigated the woman partners’ preferences.

Aim: To investigate the treatment preference of women who were partners of men using oral medications for erectile dysfunction (ED) in a single-center open-label crossover study.

Methods: One hundred heterosexual couples in stable relationships, with male partners having ED based on the erectile function subscale of the International Index of Erectile Function, were randomly assigned to receive sildenafil or  tadalafil for a 12-week phase, followed by another 12-week period using the alternate drug. Male and female participants completed sexual event diaries during both study phases, and the female participants were interviewed at  baseline, midpoint, and end of study.

Main Outcome Measures: Primary outcome data were the women’s final  interviews during which they were asked which drug they preferred and their reasons for that preference.

Results: A total of 79.2% of the women preferred their partners’ use of tadalafil, while 15.6% preferred sildenafil. Preference was not affected by age or treatment order randomization. Women preferring tadalafil reported feeling more relaxed, experiencing less pressure, and enjoying a more natural or spontaneous sexual experience as reasons for their choice. Mean number of tablets used, events recorded, events per week, and days between events were not significantly different during each study phase.

Conclusion: Women’s preferences were similar to men when using these two drugs. While the women’s reasons for preferring tadalafil emphasized relaxed, satisfying, longer-lasting sexual experiences, those preferring sildenafil focused on satisfaction and drug effectiveness for their partner.

What can prevalence studies tell us about female sexual difficulty and dysfunction?

Introduction. Many recent studies have investigated the prevalence of female sexual difficulty/dysfunction.
Aim. Investigate female sexual difficulty/dysfunction using data from prevalence studies.
Methods. We reviewed published prevalence studies excluding those that had not included each category of sexual difficulty (desire, arousal, orgasm, and pain), were based on convenience sampling, or had a response rate <50% or a sample size <100.
Main Outcome Measures. For each study we used the prevalence of any sexual difficulty as the denominator and calculated the proportion of women reporting each type of difficulty. For each category of sexual difficulty we used the prevalence of that difficulty lasting 1 month or more as the denominator and calculated the proportion of difficulties lasting several months or more and 6 months or more.
Results. Only 11 of 1,248 studies identified met our inclusion criteria. These studies used different measures of sexual dysfunction, so generating a simple summary prevalence was not possible. However, we observed consistent patterns in the published data. Among women with any sexual difficulty, on average, 64% (range 16–75%) experienced desire difficulty, 35% (range 16– 48%) experienced orgasm difficulty, 31% (range 12–64%) experienced arousal difficulty, and 26% (range 7–58%) experienced sexual pain. Of the sexual difficulties that occurred for 1 month or more in the previous year, 62–89% persisted for at least several months and 25–28% persisted for 6 months or more. Two studies investigated distress. Only a proportion of women with sexual difficulty were distressed by it (21–67%).
Conclusions. Desire difficulty is the most common sexual difficulty experienced by women. While the majority of difficulties last for less than 6 months, up to a third persist for 6 months or more. Sexual difficulties do not always cause distress. Consequently, prevalence estimates will vary depending on the time frame specified by researchers and whether distress is included in these estimates.

Risk factors for female sexual dysfunction in the general population : exploring factors associated with low sexual function and sexual distress

Introduction. No previous population-based studies have used validated instruments to measure female sexual dysfunction (FSD) in Australian women across a broad age range.
Aim. To estimate prevalence and explore factors associated with the  components of FSD.
Main Outcome Measures. Sexual Function Questionnaire measured low sexual function. Female Sexual Distress Scale measured sexual distress.
Methods. Multivariate analysis of postal survey data from a random sample of 356 women aged 20–70 years.
Results. Low desire was more likely to occur in women in relationships for 20–29 years (odds ratio 3.7, 95% confidence intervals 1.1–12.8) and less likely in women reporting greater satisfaction with their partner as a lover (0.3, 0.1–0.9) or who placed greater importance on sex (0.1, 0.03–0.3). Low genital arousal was more likely among women who were perimenopausal (4.4, 1.2–15.7), postmenopausal (5.3, 1.6–17.7), or depressed (2.5, 1.1–5.3), and was less likely in women taking hormone therapy (0.2, 0.04–0.7), more educated (0.5, 0.3–0.96), in their 30s (0.2, 0.1–0.7) or 40s (0.2, 0.1–0.7), or placed greater importance on sex (0.2, 0.05–0.5). Low orgasmic function was less likely in women who were in their 30s (0.3, 0.1–0.8) or who placed greater importance on sex (0.3, 0.1–0.7). Sexual distress was positively associated with depression (3.1, 1.2–7.8) and was inversely associated with better communication of sexual needs (0.2, 0.05–0.5). Results were adjusted for other covariates including age, psychological, socioeconomic, physiological, and relationship factors.
Conclusions. Relationship factors were more important to low desire than age or menopause, whereas physiological and psychological factors were more important to low genital arousal and low orgasmic function than relationship factors. Sexual distress was associated with both psychological and relationship factors.

Modeling response rates in surveys of female sexual difficulty and dysfunction

INTRODUCTION: Studies that address sensitive topics, such as female sexual difficulty and dysfunction, often achieve poor response rates that can bias  results. Factors that affect response rates to studies in this area are not well characterized.
AIM: To model the response rate in studies investigating the prevalence of female sexual difficulty and dysfunction.
METHODS: Databases were searched for English-language, prevalence studies using the search terms: sexual difficulties/dysfunction, woman/women/female, prevalence, and cross-sectional. Studies that did not report response rates or were clinic-based were excluded. A multiple linear regression model was constructed.
MAIN OUTCOME MEASURES: Published response rates.
RESULTS: A total of 1,380 publications were identified, and 54 of these met our inclusion criteria. Our model explained 58% of the variance in response rates of studies investigating the prevalence of difficulty with desire, arousal, orgasm, or sexual pain (R(2) = 0.581, P = 0.027). This model was based on study design variables, study year, location, and the reported prevalence of each type of sexual difficulty. More recent studies (beta = -1.05, P = 0.037) and studies that only included women over 50 years of age (beta = -31.11, P = 0.007) had lower response rates. The use of face-to-face interviews was associated with a higher response rate (beta = 20.51, P = 0.036). Studies that did not include questions regarding desire difficulties achieved higher response rates than those that did include questions on desire difficulty (beta = 23.70, P = 0.034).
CONCLUSION: Response rates in prevalence studies addressing female sexual difficulty and dysfunction are frequently low and have decreased by an average of just over 1% per anum since the late 60s. Participation may improve by conducting interviews in person. Studies that investigate a broad range of ages may be less representative of older women, due to a poorer response in older age groups. Lower response rates in studies that investigate desire difficulty suggest that sexual desire is a particularly sensitive topic.

The impact of study design on prevalence estimates of female sexual dysfunction

Introduction, objectives Despite increasing research, the true prevalence of Female Sexual Dysfunction (FSD) remains a contentious issue. Previous research suggests that aspects of study design affect the reported prevalence of FSD. We compare commonly used instruments for assessing FSD. Methods A random sample of 240 Australian women aged 20-70 participated in this population based, cross-sectional study. A questionnaire mailed to women across Australia included four instruments for assessing FSD. The Sexual Function Questionnaire combined with the Female Sexual Distress Scale (SFQ-FSDS) was employed as a standard, validated instrument. Alternative instruments were the SFQ alone and two modified versions of a set of questions originally developed by Laumann et al. Results When assessed by the SFQ-FSDS, prevalence estimates (and 95% confidence intervals) of Hypoactive Sexual Desire Disorder, Female Sexual Arousal Disorder (genital subtype), Female Orgasmic Disorder, and Dysparunia were 16%(11-20%), 8%(4-11%), 9%(6-13%), 2%(0.1-3%) respectively. The prevalence estimates of these same disorders obtained using alternative instruments were 32-55%, 17-35%, 17-33% and 3-25% respectively. The sensitivity of alternative instruments varied widely (0 to 1.0). Specificities ranged from 0.51 to 0.99. Positive predictive values ranged from 0 to 0.57. Negative predictive values were all above 0.90. Changing the time span for recalling sexual experiences in an instrument altered the prevalence estimates, sensitivity and specificity. 32% of women with low desire, 31% with low genital arousal, 36% with orgasm difficulty and 57% with sexual pain were sexually distressed. Conclusion Over a third of women who were classified as suffering FSD by alternative instruments did not have FSD when assessed by SFQ-FSDS. Alternative instruments produced substantially higher prevalence estimates of FSD and identified different groups of women. Consequently, the instruments researchers choose to assess FSD may affect both the prevalence estimates and risk factors they report.

Importance of assessing family dysfunction in conjunction with standardised measures when treating substance abuse

In this thesis, the link between substance abuse and family dysfunction is examined, and an argument is made for the assessment of family dysfunction when treating clients with substance abuse issues. Family dysfunction has been associated with a broad range of problems in children (e.g., low self esteem, increased risk of child abuse) through to adolescence and adulthood (e.g., increased risk of mental disorders such as depressive disorders, substance abuse disorders, and personality disorders) (Kaplan & Sadock, 1998). It is not the purpose of this thesis to suggest that family dysfunction causes substance abuse but rather to highlight that family dysfunction can in some cases place the individual at greater risk of substance abuse. Therefore, in order to understand the reasons why substance abuse developed and how it is maintained in the present requires the assessment of family dysfunction. Further, the importance of assessing the role and impact that family dysfunction may have had on the client, may help to better understand the nature and extent of substance abuse so that relevant and appropriate treatment goals for change may be set, progress monitored, and risk of relapse reduced. Chapter 1 provides a brief introduction to this thesis, and Chapter 2 is a review of the literature on the impact of family dysfunction including poor parental attachment and supervision, neglect, physical and sexual abuse, in adolescence and adulthood. Four case studies are presented to illustrate how family dysfunction and substance abuse may be related, thus highlighting the importance of assessing family dysfunction when treating substance abuse clients. All of the case studies include an individual with a substance abuse disorder (namely heroin) but they are diverse in terms of the types and extent of family dysfunction. The final chapter discusses the case studies in relation to the literature reviewed. Lastly, it gives consideration to the implication of a history of family dysfunction, and how it may impact negatively on treatment and therefore prognosis.

Elevated intracardiac angiotensin II leads to cardiac hypertrophy and mechanical dysfunction in normotensive mice

Introduction
Angiotensin II (Ang II) is known to induce cardiac growth and modulate myocardial contractility. It has been reported that elevated levels of endogenous Ang II contribute to the development of cardiac hypertrophy in hypertensives. However, the long-term functional effects of cardiac exposure to Ang II in normotensives is unclear.

A recently developed transgenic mouse (TG1306/1R), in which cardiac-specific overproduction of Ang II produces primary hypertrophy, provides a new experimental model for investigation of this phenotype. The aim of the present study was to use this model to investigate whether there is a functional deficit in primary hypertrophy that may predispose to cardiac failure and sudden death. We hypothesised that primary cardiac hypertrophy is associated with mechanical dysfunction in the basal state.

Methods
Normotensive heterozygous TG1306/1R mice harbouring multiple copies of a cardiac-specific rat angiotensinogen gene were studied at age 30—40 weeks and compared with age-matched wild-type littermates. Left ventricular function was measured ex vivo in bicarbonate buffer-perfused, Langendorffmounted hearts ( at a perfusion pressure of 80 mmHg, 37°C) using a fluid-filled PVC balloon interfaced to a pressure transducer and digital data acquisition system.

Results
There was no difference in the mean (±SEM) intrinsic heart rate of TG1306/1R and wild-type control mice (357.4±11.8 vs. 367.5±20.9 bpm, n=9 & 7). Under standardised end-diastolic pressure conditions, TG1306/1R hearts exhibited a significant reduction in peak developed pressure (132.2±9.4 vs. 161.5±3.1 mmHg, n=9 & 7, p<0.05) and maximum rate of pressure development (3566.7±323.7 vs. 4486.3±109.4 mmHg, n=9 & 7, p<0.05). TG1306/1R mice show a significant correlation between incidence of arrhythmia and increasing heart size (Spearman's correlation coefficient 0.61).

Conclusion
These data demonstrate that chronic in vivo exposure to elevated levels of intra-cardiac Ang II is associated with significant contractile abnormalities evident in the ex vivo intact heart. Our findings suggest that endogenous overproduction of cardiac Ang II, independent of changes in blood pressure, is sufficient to induce ventricular remodelling that culminates in impaired cardiac function which may precede failure.