Stephen A Roberts

Effects of Testosterone on Muscle Strength, Physical Function, Body Composition, and Quality of Life in Intermediate-Frail and Frail Elderly Men: A Randomized, Double-Blind, Placebo-Controlled Study

CONTEXT Physical frailty is associated with reduced muscle strength, impaired physical function, and quality of life. Testosterone (T) increases muscle mass and strength in hypogonadal patients. It is unclear whether T has similar effects in intermediate-frail and frail elderly men with low to borderline-low T. OBJECTIVE Our objective was to determine the effects of 6 months T treatment in intermediate-frail and frail elderly men, on muscle mass and strength, physical function, and quality of life. DESIGN AND SETTING We conducted a randomized, double-blind, placebo-controlled, parallel-group, single-center study. PARTICIPANTS PARTICIPANTS were community-dwelling intermediate-frail and frail elderly men at least 65 yr of age with a total T at or below 12 nmol/liter or free T at or below 250 pmol/liter. METHODS Two hundred seventy-four participants were randomized to transdermal T (50 mg/d) or placebo gel for 6 months. Outcome measures included muscle strength, lean and fat mass, physical function, and self-reported quality of life. RESULTS Isometric knee extension peak torque improved in the T group (vs. placebo at 6 months), adjusted difference was 8.6 (95% confidence interval, 1.3-16.0; P = 0.02) Newton-meters. Lean body mass increased and fat mass decreased significantly in the T group by 1.08 +/- 1.8 and 0.9 +/- 1.6 kg, respectively. Physical function improved among older and frailer men. Somatic and sexual symptom scores decreased with T treatment; adjusted difference was -1.2 (-2.4 to -0.04) and -1.3 (-2.5 to -0.2), respectively. CONCLUSIONS T treatment in intermediate-frail and frail elderly men with low to borderline-low T for 6 months may prevent age-associated loss of lower limb muscle strength and improve body composition, quality of life, and physical function. Further investigations are warranted to extend these results.

The effect of age and menstrual cycle upon proliferative activity of the normal human breast.

The aim of this study was to determine the proliferative activity within the epithelial cells of the normal human breast in 122 patients (6 reduction mammoplasties and 116 fibroadenoma excisions) in relation to age and the phase of the menstrual cycle. Thirty three of the patients were on oral contraceptives and 33 were parous. Thin tissue slices were incubated with tritiated thymidine and processed for autoradiography. Other samples were fixed directly and prepared for histology. The labelling, mitotic and apoptotic indices (LI, MI and AI) were determined and all illustrated considerable variability. The labelling indices are significantly (P less than 0.05) influenced by both patient age and stage during the menstrual cycle and ranged from 0-11.5%. Maximum LI values were obtained on the 20.8th day of the cycle. A square root transformation of the data was used to reduce the skewness of the data to a more normal distribution. The square root of the LI declined by 0.22 per decade. The mitotic data showed similar significant (P less than 0.05) correlations against age and day of cycle with a peak on the 21.5th day of the cycle, a decline by 0.072 per decade and a range from 0-0.6%. The data for apoptotic cells were less clearly influenced by the stage of the menstrual cycle but showed a significant (P less than 0.5) decline with age. The AI in parous patients was significantly higher than that in non-parous patients. There was no significant effect of oral contraceptives on any of the parameters measured when age and stage of cycle were taken into account. The considerable variability in the data could not be fully accounted for by either technical factors, the age of the patients, or the day of the cycle. We conclude that proliferation is negatively related to age and is influenced by the menstrual cycle but that additional as yet unknown factors must account for a large part of the variability seen in the data.

Dose-Fractionation Sensitivity of Prostate Cancer Deduced From Radiotherapy Outcomes of 5,969 Patients in Seven International Institutional Datasets: α/β = 1.4 (0.9–2.2) Gy

PURPOSE There are reports of a high sensitivity of prostate cancer to radiotherapy dose fractionation, and this has prompted several trials of hypofractionation schedules. It remains unclear whether hypofractionation will provide a significant therapeutic benefit in the treatment of prostate cancer, and whether there are different fractionation sensitivities for different stages of disease. In order to address this, multiple primary datasets have been collected for analysis. METHODS AND MATERIALS Seven datasets were assembled from institutions worldwide. A total of 5969 patients were treated using external beams with or without androgen deprivation (AD). Standard fractionation (1.8-2.0 Gy per fraction) was used for 40% of the patients, and hypofractionation (2.5-6.7 Gy per fraction) for the remainder. The overall treatment time ranged from 1 to 8 weeks. Low-risk patients comprised 23% of the total, intermediate-risk 44%, and high-risk 33%. Direct analysis of the primary data for tumor control at 5 years was undertaken, using the Phoenix criterion of biochemical relapse-free survival, in order to calculate values in the linear-quadratic equation of k (natural log of the effective target cell number), α (dose-response slope using very low doses per fraction), and the ratio α/β that characterizes dose-fractionation sensitivity. RESULTS There was no significant difference between the α/β value for the three risk groups, and the value of α/β for the pooled data was 1.4 (95% CI = 0.9-2.2) Gy. Androgen deprivation improved the bNED outcome index by about 5% for all risk groups, but did not affect the α/β value. CONCLUSIONS The overall α/β value was consistently low, unaffected by AD deprivation, and lower than the appropriate values for late normal-tissue morbidity. Hence the fractionation sensitivity differential (tumor/normal tissue) favors the use of hypofractionated radiotherapy schedules for all risk groups, which is also very beneficial logistically in limited-resource settings.

Spermatogonial apoptosis has three morphologically recognizable phases and shows no circadian rhythm during normal spermatogenesis in the rat

Abstract. In this study we examined the possibility that regular or circadian fluctuations occur in the frequency of spontaneous spermatogonial apoptosis. Apoptosis of A2, A3 and A4 type spermatogonia occurring spontaneously in the normal rat testis was studied by light and electron microscopy. Normal and apoptotic A3 spermatogonia were quantified in 36 animals killed at two‐hourly intervals over a 24 h period. Three sequential phases of spermatogonial apoptosis were defined and quantified separately: (i) an early phase in which cells showed margination of nuclear chromatin, (ii) an intermediate phase in which phagocytosed apoptotic bodies were partly degraded and (iii) a late phase in which only debris of degraded apoptotic bodies was evident. Groups of spermatogonia linked by intercellular bridges underwent apoptosis synchronously. Normal and apoptotic A3 spermatogonia occurred at a mean frequency of 33.4 and 9.6 per 10 seminiferous tubule profiles respectively; there was a large variation in these frequencies between animals, but no peaks or circadian periodicity were detected. Progressive degradation of apoptotic bodies was evident, the average ratios of intermediate and late bodies to early bodies being 1.5 and 3.5, respectively. Absence of a circadian rhythm in these data does not exclude the possibility that initiation of apoptosis in susceptible spermatogonial clones is synchronous, and that affected clones undergo lag periods of differing duration before expressing morphological apoptosis.

Resolution of peanut allergy: case-control study

Abstract Objectives: To determine whether there are any differences between children who remain mildly or moderately allergic to peanut and children with similar histories but a negative reaction on challenge with peanut. Design: Case-controls matched for age and sex. Setting: Childrens day wards in two teaching hospitals. Intervention: Open food challenge with peanut. Subjects: 15 children with resolved peanut allergy (resolvers) and 15 with persistent allergy (persisters). Main outcome measure: Reaction on challenge with peanut, serum total and peanut specific IgE concentrations. Results: The groups had a similar median age at first reaction to peanut (11 months, range 5-38) and similar symptoms. Allergy to other foods was less common in resolvers (2/15) than persisters (9/15) (P=0.02). On skin prick testing with peanut all 13 resolvers tested but only 3/14 persisters had a weal of <6 mm (P<0.0001). Total and peanut specific IgE concentrations did not differ much between the groups. Conclusion: Appropriately trained clinicians must be prepared to challenge preschool children with peanut as some will be tolerant despite a history of reactions to peanut and a positive skin prick test with peanut. Preschool children whose apparent peanut allergy is refuted by food challenge show allergy to other foods less often than those in whom peanut allergy persists. The size of weal on skin prick testing to peanut predicts reactivity but not severity on peanut challenge. Key messages Peanut allergy rarely resolves in older children and adults Skin prick testing with peanut has a high negative predictive value, but some people with positive skin tests do not react to peanut challenge Some preschool children with a convincing history of reaction to peanut may become tolerant of peanut. Such children have fewer other manifestations of atopy than children whose peanut allergy persists Paediatricians must be prepared to undertake peanut challenges or refer children to units that will undertake such challenges

Circulating basal anti-Müllerian hormone levels as predictor of ovarian response in women undergoing ovarian stimulation for in vitro fertilization.

OBJECTIVE To evaluate the clinical value of basal anti-Müllerian hormone (AMH) measurements compared with other available determinants, apart from chronologic age, in the prediction of ovarian response to gonadotrophin stimulation. DESIGN Prospective cohort study. SETTING Tertiary referral center for reproductive medicine and an IVF unit. PATIENT(S) Women undergoing their first cycle of controlled ovarian hyperstimulation (COH) for in vitro fertilization (IVF). MATERIALS AND METHODS Basal levels of FSH and AMH as well as antral follicle count (AFC) were measured in 165 subjects. All patients were followed prospectively and their cycle outcomes recorded. MAIN OUTCOME MEASURE(S) Predictive value of FSH, AMH, and AFC for extremes of ovarian response to stimulation. RESULT(S) Out of the 165 women, 134 were defined as normal responders, 15 as poor responders, and 16 as high responders. Subjects in the poor response group were significantly older then those in the other two groups. Anti-Müllerian hormone levels and AFC were markedly raised in the high responders and decreased in the poor responders. Compared with FSH and AFC, AMH performed better in the prediction of excessive response to ovarian stimulation-AMH area under receiver operating characteristic curve (ROC(AUC)) 0.81, FSH ROC(AUC) 0.66, AFC ROC(AUC) 0.69. For poor response, AMH (ROC(AUC) 0.88) was a significantly better predictor than FSH (ROC(AUC) 0.63) but not AFC (ROC(AUC) 0.81). AMH prediction of ovarian response was independent of age and PCOS. Anti-Müllerian hormone cutoffs of >3.75 ng/mL and <1.0 ng/mL would have modest sensitivity and specificity in predicting the extremes of response. CONCLUSION(S) Circulating AMH has the ability to predict excessive and poor response to stimulation with exogenous gonadotrophins. Overall, this biomarker is superior to basal FSH and AFC, and has the potential to be incorporated in to work-up protocols to predict patients ovarian response to treatment and to individualize strategies aiming at reducing the cancellation rate and the iatrogenic complications of COH.

Vitamin D status and muscle function in post-menarchal adolescent girls

CONTEXT There has been a resurgence of vitamin D deficiency among infants, toddlers, and adolescents in the United Kingdom. Myopathy is an important clinical symptom of vitamin D deficiency, yet it has not been widely studied. OBJECTIVE Our objective was to investigate the relationship of baseline serum 25 hydroxyvitamin D [25(OH)D] concentration and PTH with muscle power and force. DESIGN This was a cross-sectional study. SETTING The study was community based in a secondary school. PARTICIPANTS A total of 99 post-menarchal 12- to 14-yr-old females was included in the study. MAIN OUTCOME MEASURES Jumping mechanography to measure muscle power, velocity, jump height, and Esslinger Fitness Index from a two-legged counter movement jump and force from multiple one-legged hops was performed. Body height, weight, and serum concentrations of 25(OH)D, PTH, and calcium were measured. RESULTS Median serum 25(OH)D concentration was 21.3 nmol/liter (range 2.5-88.5) and PTH 3.7 pmol/liter (range 0.47-26.2). After correction for weight using a quadratic function, there was a positive relationship between 25(OH)D and jump velocity (P = 0.002), jump height (P = 0.005), power (P = 0.003), Esslinger Fitness Index (P = 0.003), and force (P = 0.05). There was a negative effect of PTH upon jump velocity (P = 0.04). CONCLUSION From these data we conclude that vitamin D was significantly associated with muscle power and force in adolescent girls.

Effects of soy-protein supplementation on epithelial proliferation in the histologically normal human breast.

A high dietary intake of soy products (eg, as in Japan and Singapore) has been associated with a reduction in the incidence of breast cancer in premenopausal women. Phytoestrogens present in soybeans inhibit human breast cancer cell proliferation in vitro and breast cancer development in animal models, but no data exist on the effects of phytoestrogens on histologically normal human breasts. This study examines the effects of dietary soy supplementation on the proliferation rate of premenopausal, histologically normal breast epithelium and the expression of progesterone receptor. Women (n = 48) with benign or malignant breast disease were randomly assigned to receive their normal diet either alone or with a 60-g soy supplement (containing 45 mg isoflavones) taken daily for 14 d. Biopsy samples of normal breasts were labeled with [3H]thymidine to detect the number of cells in S phase and were immunocytochemically stained for the proliferation antigen Ki67. The phytoestrogens genistein, daidzein, equol, enterolactone, and enterodiol were measured in serum samples obtained before and after supplementation. Serum concentrations of the isoflavones genistein and daidzein increased in the soy group at 14 d. Results showed a strong correlation between Ki67 and the thymidine labeling index (r = 0.868, P < or = 0.001). The proliferation rate of breast lobular epithelium significantly increased after 14 d of soy supplementation when both the day of menstrual cycle and the age of patient were accounted for. Progesterone receptor expression increased significantly in the soy group. Short-term dietary soy stimulates breast proliferation; further studies are required to determine whether this is due to estrogen agonist activity and to examine the long-term effects of soy supplementation on the pituitary gland and breast.

Increased chromosomal radiosensitivity in breast cancer patients: a comparison of two assays

PURPOSE It has been shown previously that sensitivity to the induction of chromosome damage by ionizing radiation is, on average, higher in G2 or G0 lymphocytes of breast cancer patients than of normal healthy controls. The authors suggested that elevated chromosomal radiosensitivity may be a marker for breast cancer predisposition. To investigate whether the G0 micronucleus assay is a true surrogate for the more demanding G2 metaphase assay, both tests have now been performed on the same blood samples from 80 patients. METHODS For the G0 micronucleus assay, cells were exposed to 3.5 Gy 137Cs gamma-rays 6 h before mitogenic stimulation, treated with cytochalasin B at 24 h post-stimulation and harvested at 90 h. For the G2 assay, at 72 h after stimulation cells were given 0.5 Gy X-rays and harvested 90 min later. RESULTS Previous observations were confirmed, now with much larger numbers of donors, in that approximately 40% of breast cancer patients showed elevated sensitivity in the G2 assay (135 patients, 105 normals) and 25% in the G0 assay (130 patients, 68 normals). However, there was no correlation between G2 and G0 sensitivity for the 80 patients tested (r = -0.001, p = 0.99). Most of the sensitive patients were either G2 or G0 sensitive, with only 4% sensitive in both assays. CONCLUSIONS The results suggest that different mechanisms of chromosomal radiosensitivity operate in G2 and G0 cells and that, in general, each chromosomally radiosensitive patient is defective in only one such mechanism, possibly via mutation (or polymorphism) of a single gene. Such mutations may confer cancer predisposition, of low penetrance, in a substantial proportion of patients.

Uptake of first two doses of human papillomavirus vaccine by adolescent schoolgirls in Manchester: prospective cohort study

Objective To assess the feasibility and acceptability of delivering a human papillomavirus (HPV) vaccine to adolescent girls. Design Prospective cohort study. Setting 36 secondary schools in two primary care trusts in Greater Manchester, United Kingdom. Participants 2817 schoolgirls in year 8 (12 and 13 year olds). Intervention Delivery of the bivalent vaccine at 0, 1, and 6 months over one school year. Main outcome measures Vaccine uptake for doses 1 and 2 of a three dose schedule. Results Vaccine uptake was 70.6% (1989/2817) for the first dose and 68.5% (1930/2817) for the second dose. Uptake was significantly lower in schools with a higher proportion of ethnic minority girls (P<0.001 for trend) or higher proportion of girls entitled to free school meals (P=0.029 for trend). The main reason for parents’ refusal of vaccination was insufficient information about the vaccine and its long term safety. Maintaining the vaccine schedule was challenging as 16.3% (dose 1) and 23.6% (dose 2) of girls missed their vaccination day and had to be offered alternative appointments. No serious adverse events were reported. Conclusion Delivery of the first two doses of HPV vaccine to adolescent schoolgirls is encouraging, but the success of the vaccination programme depends on high coverage for the third dose.