Acceptability of short term neo-adjuvant androgen deprivation in patients with locally advanced prostate cancer

Purpose: To determine the acceptability of short term neo-adjuvant maximal androgen deprivation (MAD) to patients treated with external beam radiation for locally advanced prostate cancer. Methods: Between 1996 and 2000, 818 patients with locally advanced, but non-metastatic, prostate cancer were entered into a randomised clinical trial (TROG 96.01), which compared radiation treatment alone with the same radiation treatment and 3 or 6 months neo-adjuvant MAD with goserelin and flutamide. Relevant symptoms, and how troublesome they were to the patient, were scored using a self-assessment questionnaire. This was completed by the patient at registration, and at specified times during and after treatment. Patients taking flutamide had liver function tests checked at regular intervals. Results: All patients have completed at least 12 months follow-up after treatment. Nearly all patients completed planned treatment with goserelin, but 27% of patients in the 6-month MAD treatment arm, and 20% in the 3-month arm, had to stop flutamide early. This was mainly due to altered liver function (up to 17% patients) and bowel side effects (up to 8% patients). However, although flutamide resulted in more bowel symptoms for patients on MAD, there was significant reduction in some urinary symptoms on this treatment. Acute bowel and urinary side effects at the end of radiation treatment were similar in all treatment arms. Side effect severity was unrelated to radiation target volume size, which was reduced by MAD, but symptomatology prior to any treatment was a powerful predictor. Of the 36% of patients who were sexually active before any treatment, the majority became inactive whilst on MAD. However, sexual activity at 12 months after radiation treatment was similar in all treatment arms, indicating that the effects of short term MAD on sexual function are reversible. Conclusion: Despite temporary effects on sexual activity, and compliance difficulties with flutamide, short-term neo-adjuvant MAD was not perceived by patients to be a major inconvenience. If neo-adjuvant MAD in the way tested can be demonstrated to lead to improved biochemical control and/or survival, then patients would view these therapeutic gains as worthwhile. Compliance with short-term goserelin was excellent, confirming that LH-RH analogues have a potential role in more long-term adjuvant treatment. However, for more protracted androgen deprivation, survival advantages and deleterious effects need to be assessed in parallel, in order to determine the optimal duration of treatment. (C) 2003 Elsevier Ireland Ltd. All fights reserved.

Resistance training and reduction of treatment side effects in prostate cancer patients

Purpose: To examine the effect of progressive resistance training on muscle function, functional performance, balance, body composition, and muscle thickness in men receiving androgen deprivation for prostate cancer. Methods: Ten men aged 59-82 yr on androgen deprivation for localized prostate cancer undertook progressive resistance training for 20 wk at 6- to 12-repetition maximum (RM) for 12 upper- and lower-body exercises in a university exercise rehabilitation clinic. Outcome measures included muscle strength and muscle endurance for the upper and lower body, functional performance (repeated chair rise, usual and fast 6-m walk, 6-m backwards walk, stair climb, and 400-m walk time), and balance by sensory organization test. Body composition was measured by dual-energy x-ray absorptiometry and muscle thickness at four anatomical sites by B-mode ultrasound. Blood samples were assessed for prostate specific antigen (PSA), testosterone, growth hormone (GH), cortisol, and hemoglobin. Results: Muscle strength (chest press, 40.5%; seated row, 41.9%; leg press, 96.3%; P < 0.001) and muscle endurance (chest press, 114.9%; leg press, 167.1%; P < 0.001) increased significantly after training. Significant improvement (P < 0.05) occurred in the 6-m usual walk (14.1%), 6-m backwards walk (22.3%), chair rise (26.8%), stair climbing (10.4%), 400-m walk (7.4%), and balance (7.8%). Muscle thickness increased (P < 0.05) by 15.7% at the quadriceps site. Whole-body lean mass was preserved with no change in fat mass. There were no significant changes in PSA, testosterone, GH, cortisol, or hemoglobin. Conclusions: Progressive resistance exercise has beneficial effects on muscle strength, functional performance and balance in older men receiving androgen deprivation for prostate cancer and should be considered to preserve body composition and reduce treatment side effects.

Variation in mortality rates in Australia: correlation with Indigenous status, remoteness and socio-economic deprivation

Background The aim of this study was to study ecological correlations between age-adjusted all-cause mortality rates in Australian statistical divisions and (1) the proportion of residents that self-identify as Indigenous, (2) remoteness, and (3) socio-economic deprivation. Methods All-cause mortality rates for 57 statistical divisions were calculated and directly standardized to the 1997 Australian population in 5-year age groups using Australian Bureau of Statistics (ABS) data. The proportion of residents who self-identified as Indigenous was obtained from the 1996 Census. Remoteness was measured using ARIA (Accessibility and Remoteness Index for Australia) values. Socioeconomic deprivation was measured using SEIFA (Socio-Economic index for Australia) values from the ABS. Results Age-standardized all-cause mortality varies twofold from 5.7 to 11.3 per 1000 across Australian statistical divisions. Strongest correlation was between Indigenous status and mortality (r = 0.69, p < 0.001). correlation between remoteness and mortality was modest (r = 0.39, p = 0.002) as was correlation between socio-economic deprivation and mortality (r = -0.42, p = 0.001). Excluding the three divisions with the highest mortality, a multiple regression model using the logarithm of the adjusted mortality rate as the dependent variable showed that the partial correlation (and hence proportion of the variance explained) for Indigenous status was 0.03 (9 per cent; p = 0.03), for SEIFA score was -0.17 (3 per cent; p = 0.22); and for remoteness was -0.22 (5 per cent; p = 0.13). Collectively, the three variables studied explain 13 per cent of the variability in mortality. Conclusions Ecological correlation exists between all-cause mortality, Indigenous status, remoteness and disadvantage across Australia. The strongest correlation is with indigenous status, and correlation with all three characteristics is weak when the three statistical divisions with the highest mortality rates are excluded. intervention targeted at these three statistical divisions could reduce much of the variability in mortality in Australia.

Intrinsic regional differences in androgen receptors and dihydrotestosterone metabolism in human preadipocytes

Androgens play an important role in regulating the central obesity that is a strong risk factor for cardiovascular disease and insulin resistance. This study confirms that androgen receptors are present in subcultured human preadipocytes, with androgen receptor gene expression and saturable specific dihydrotestosterone binding, dissociation constant 1.02 - 2.56 nM and maximal binding capacity 30.8 - 55.7 fmol/mg protein. There was an intrinsic regional difference in androgen receptor complement, with more androgen receptors in visceral than in subcutaneous preadipocytes. Dihydrotestosterone was metabolised by human preadipocytes, with more androstanediol produced by subcutaneous than visceral preadipocytes. While dihydrotestosterone metabolism was insufficient to explain the regional variation in androgen binding, both of these differences would reduce the androgen responsiveness of the subcutaneous preadipocytes compared with visceral preadipocytes. There were no gender differences in androgen binding or metabolism. While the direct effects of androgens on human PAS remain uncertain, these regional differences suggest that AR-mediated regulation of certain PA functions influences adipose tissue distribution.

Do increases in xylem sap pH and/or ABA concentration mediate stomatal closure following nitrate deprivation?

Stomatal conductance (g(s)) of pepper (Capsicum annuum L.) plants decreased during the second photoperiod (day 2) after withholding nitrate (N). Stomatal closure of N-deprived plants was not associated with a decreased shoot water potential (Psi(shoot)); conversely Psi(shoot) was lower in N-supplied plants. N deprivation transiently (days 2 and 3) alkalized (0.2-0.3 pH units) xylem sap exuded from de-topped root systems under root pressure, and xylem sap expressed from excised shoots by pressurization. The ABA concentration of expressed sap increased 3-4-fold when measured on days 2 and 4. On day 2, leaves detached from N-deprived and N-supplied plants showed decreased transpiration rates when fed an alkaline (pH 7) artificial xylem (AX) solution, independent of the ABA concentration (10-100 nM) supplied. Thus changes in xylem sap composition following N deprivation can potentially close stomata. However, the lower transpiration rate of detached N-deprived leaves relative to N-supplied leaves shows that factors residing within N-deprived leaves also mediate stomatal closure, and that these factors assume greater importance as the duration of N deprivation increases.

Gender diagnosticity and androgen receptor gene CAG repeat sequence

The gender diagnosticity (GD) approach of Lippa (1995) was used to evaluate the relationship of within-sex differences in psychological masculinity-femininity to a genetic characteristic, the length of a repeated CAG sequence in the X-linked androgen receptor (AR) gene. Previously assessed adult samples in Australia and Sweden were used for this purpose. A weak relationship (correlations in the range .11 to .14) was obtained in both countries. Additional data from adolescent twins from Australia (12-, 14-, 16-year-olds) did not confirm such a relationship at those ages, especially for males. The fact that this sample consisted of twins permitted two kinds of within-pair comparisons: (1) Did the dizygotic twin who had the longer AR sequence have the higher GD score? (2) Was one twin's GD score more highly correlated with the other twin's AR score in MZ than in DZ pairs? The answer in both cases was negative. Clarification of these relationships will require large samples and measurements at additional ages.

Equine laminitis: glucose deprivation and MMP activation induce dermo-epidermal separation in vitro

Reasons for performing study: Acute laminitis is characterised by hoof lamellar dermal-epidermal separation at the basement membrane (BM) zone. Hoof lamellar explants cultured in vitro can also be made to separate at the basement membrane zone and investigating how this occurs may give insight into the poorly understood pathophysiology of laminitis. Objectives: To investigate why glucose deprivation and metalloproteinase (MMP) activation in cultured lamellar explants leads to dermo-epidermal separation. Methods: Explants, cultured without glucose or with the MMP activator p-amino-phenol-mercuric acetate (APMA), were subjected to tension and processed for transmission electron microscopy (TEM). Results: Without glucose, or with APMA, explants under tension separated at the dermo-epidermal junction. This in vitro separation occurred via 2 different ultrastructural processes. Lack of glucose reduced hemidesmosomes (HDs) numbers until they disappeared and the basal cell cytoskeleton collapsed. Anchoring filaments (AFs), connecting the basal cell plasmalemma to the BM, were unaffected although they failed under tension. APMA activation of constituent lamellar MMPs did not affect HDs but caused AFs to disappear, also leading to dermo-epidermal separation under tension. Conclusions: Natural laminitis may occur in situations where glucose uptake by lamellar basal cells is compromised (e.g. equine Cushing's disease, obesity, hyperlipaemia, ischaemia and septicaemia) or when lamellar MMPs are activated (alimentary carbohydrate overload). Potential relevance: Therapies designed to facilitate peripheral glucose uptake and inhibit lamellar MMP activation may prevent or ameliorate laminitis.

Influence of socioeconomic deprivation on the primary care burden and treatment of patients with a diagnosis of heart failure in general practice in Scotland: population based study

Objectives To examine whether there are socioeconomic gradients in die incidence, prevalence, treatment, and follow up of patients with heart failure in primary care. Design Population based study. Setting 53 general practices (307741 patients) participating in the Scottish continuous morbidity recording project between 1 April 1999 and 31 March 2000. Participants 2186 adults with heart failure. Main outcome measures Comorbid diagnoses, frequency of visits to general practitioner, and prescribed drugs. Results 2186 patients with heart failure were seen (prevalence 7.1 per 1000 population, incidence 2.0 per 1000 population). The age and sex standardised incidence of heart failure increased with greater socioeconomic deprivation, from 1.8 per 1000 population in the most affluent stratum to 2.6 per 1000 population in the most deprived stratum (odds ratio 1.44, P=0.0003). On average, patients were seen 2.4 times yearly, but follow up rates were less frequent with increasing socioeconomic deprivation (from 2.6 yearly in the most affluent subgroup to 2.0 yearly in the most deprived subgroup, P=0.00009). Overall, 812 (80.6%) patients were prescribed diuretics, 396 (39.3%) angiotensin converting enzyme inhibitors, 216 (21.4%) beta blockers, 208 (20.7%) digoxin, and 86 (8.5%) spironolactone. The wide discrepancies in prescribing between different general practices disappeared after adjustment for patient age and sex. Prescribing patterns did not vary by deprivation categories on univariate or multivariate analyses. Conclusions Compared with affluent patients, socioeconomically deprived patients were 44% more likely to develop heart failure but 23% less likely to see their general practitioner on an ongoing basis. Prescribed treatment did not differ across socioeconomic gradients.

Polymorphic CAG repeat length in the androgen receptor gene and association with neurodegeneration in a heterozygous female carrier of Kennedy's disease

Kennedy's disease (spinobulbar muscular atrophy) is an X-linked form of motor neuron disease affecting adult males carrying a CAG trinucleotide repeat expansion within the androgen receptor gene. While expression of Kennedy's disease is thought to be confined to males carrying the causative mutation, subclinical manifestations have been reported in a few female carriers of the disease. The reasons that females are protected from the disease are not clear, especially given that all other diseases caused by CAG expansions display dominant expression. In the current study, we report the identification of a heterozygote female carrying the Kennedy's disease mutation who was clinically diagnosed with motor neuron disease. We describe analysis of CAG repeat number in this individual as well as 33 relatives within the pedigree, including two male carriers of the Kennedy's mutation. The female heterozygote carried one expanded allele of the androgen receptor gene with CAG repeats numbering in the Kennedy's disease range (44 CAGs), with the normal allele numbering in the upper-normal range (28 CAGs). The subject has two sons, one of whom carries the mutant allele of the gene and has been clinically diagnosed with Kennedy's disease, whilst the other son carries the second allele of the gene with CAGs numbering in the upper normal range and displays a normal phenotype. This coexistence of motor neuron disease and the presence of one expanded allele and one allele at the upper limit of the normal range may be a coincidence. However, we hypothesize that the expression of the Kennedy's disease mutation combined with a second allele with a large but normal CAG repeat sequence may have contributed to the motor neuron degeneration displayed in the heterozygote female and discuss the possible reasons for phenotypic expression in particular individuals.

Opposite effects of androgen receptor CAG repeat length on increased risk of left-handedness in males and females

Prenatal exposure to testosterone has been hypothesised to effect lateralization by influencing cell death in the foetal brain. Testosterone binds to the X chromosome linked androgen receptor, which contains a polymorphic polyglutamine CAG repeat, the length of which is positively correlated with testosterone levels in males, and negatively correlated in females. To determine whether the length of the androgen receptor mediates the effects of testosterone on laterality, we examined the association between the number of CAG repeats in the androgen receptor gene and handedness for writing. Association was tested by adding regression terms for the length of the androgen receptor alleles to a multi-factorial-threshold model of liability to left-handedness. In females we found the risk of left-handedness was greater in those with a greater number of repeats (p=0.04), this finding was replicated in a second independent sample of female twins (p=0.014). The length of the androgen receptor explained 6% of the total variance and 24% of the genetic variance in females. In males the risk of left-handedness was greater in those with fewer repeats (p=0.02), with variation in receptor length explaining 10% of the total variance and 24% of the genetic variance. Thus, consistent with Witelson's theory of testosterone action, in all three samples the likelihood of left handedness increased in those individuals with variants of the androgen receptor associated with lower testosterone levels.