Safety and efficacy of the tumor-selective adenovirus enadenotucirev with or without paclitaxel in platinum-resistant ovarian cancer: a phase 1 clinical trial.

BACKGROUND: Treatment outcomes remain poor in recurrent platinum-resistant ovarian cancer. Enadenotucirev, a tumor-selective and blood stable adenoviral vector, has demonstrated a manageable safety profile in phase 1 studies in epithelial solid tumors. METHODS: We conducted a multicenter, open-label, phase 1 dose-escalation and dose-expansion study (OCTAVE) to assess enadenotucirev plus paclitaxel in patients with platinum-resistant epithelial ovarian cancer. During phase 1a, the maximum tolerated dose of intraperitoneally administered enadenotucirev monotherapy (three doses; days 1, 8 and 15) was assessed using a 3+3 dose-escalation model. Phase 1b included a dose-escalation and an intravenous dosing dose-expansion phase assessing enadenotucirev plus paclitaxel. For phase 1a/b, the primary objective was to determine the maximum tolerated dose of enadenotucirev (with paclitaxel in phase 1b). In the dose-expansion phase, the primary endpoint was progression-free survival (PFS). Additional endpoints included response rate and T-cell infiltration. RESULTS: Overall, 38 heavily pretreated patients were enrolled and treated. No dose-limiting toxicities were observed at any doses. However, frequent catheter complications led to the discontinuation of intraperitoneal dosing during phase 1b. Intravenous enadenotucirev (1×1012 viral particles; days 1, 3 and 5 every 28-days for two cycles) plus paclitaxel (80 mg/m2; days 9, 16 and 23 of each cycle) was thus selected for dose-expansion. Overall, 24/38 (63%) patients experienced at least 1 Grade ≥3 treatment-emergent adverse event (TEAE); most frequently neutropenia (21%). Six patients discontinued treatment due to TEAEs, including one patient due to a grade 2 treatment-emergent serious AE of catheter site infection (intraperitoneal enadenotucirev monotherapy). Among the 20 patients who received intravenous enadenotucirev plus paclitaxel, 4-month PFS rate was 64% (median 6.2 months), objective response rate was 10%, 35% of patients achieved stable disease and 65% of patients had a reduction in target lesion burden at ≥1 time point. Five out of six patients with matched pre-treatment and post-treatment biopsies treated with intravenous enadenotucirev plus paclitaxel had increased (mean 3.1-fold) infiltration of CD8 +T cells in post-treatment biopsies. CONCLUSIONS: Intravenously dosed enadenotucirev plus paclitaxel demonstrated manageable tolerability, an encouraging median PFS and increased tumor immune-cell infiltration in platinum-resistant ovarian cancer. TRIAL REGISTRATION NUMBER: NCT02028117.

Antenatal Exposure to UV-B Radiation and Preeclampsia: A Retrospective Cohort Study.

Background Risk of preeclampsia varies by month of delivery. We tested whether this seasonal patterning may be mediated through maternal vitamin D concentration using antenatal exposure to UV-B radiation as an instrumental variable. Methods and Results Scottish maternity records were linked to antenatal UV-B exposure derived from satellites between 2000 and 2010. Logistic regression analyses were used to explore the association between UV-B and preeclampsia, adjusting for the potential confounding effects of month of conception, child's sex, gestation, parity, and mean monthly temperature. Of the 522 896 eligible singleton deliveries, 8689 (1.66%) mothers developed preeclampsia. Total antenatal UV-B exposure ranged from 43.18 to 101.11 kJ/m2 and was associated with reduced risk of preeclampsia with evidence of a dose-response relationship (highest quintile of exposure: adjusted odds ratio, 0.57; 95% CI, 0.44-0.72; P<0.001). Associations were demonstrated for UV-B exposure in all 3 trimesters. Conclusions The seasonal patterning of preeclampsia may be mediated through low maternal vitamin D concentration in winter resulting from low UV-B radiation. Interventional studies are required to determine whether vitamin D supplements or UV-B-emitting light boxes can reduce the seasonal patterning of preeclampsia.

Effect of oxaliplatin plus 5-fluorouracil or capecitabine on circulating and imaging biomarkers in patients with metastatic colorectal cancer: a prospective biomarker study.

BACKGROUND: Patients with metastatic colorectal cancer are treated with cytotoxic chemotherapy supplemented by molecularly targeted therapies. There is a critical need to define biomarkers that can optimise the use of these therapies to maximise efficacy and avoid unnecessary toxicity. However, it is important to first define the changes in potential biomarkers following cytotoxic chemotherapy alone. This study reports the impact of standard cytotoxic chemotherapy across a range of circulating and imaging biomarkers. METHODS: A single-centre, prospective, biomarker-driven study. Eligible patients included those diagnosed with colorectal cancer with liver metastases that were planned to receive first line oxaliplatin plus 5-fluorouracil or capecitabine. Patients underwent paired blood sampling and magnetic resonance imaging (MRI), and biomarkers were associated with progression-free survival (PFS) and overall survival (OS). RESULTS: Twenty patients were recruited to the study. Data showed that chemotherapy significantly reduced the number of circulating tumour cells as well as the circulating concentrations of Ang1, Ang2, VEGF-A, VEGF-C and VEGF-D from pre-treatment to cycle 2 day 2. The changes in circulating concentrations were not associated with PFS or OS. On average, the MRI perfusion/permeability parameter, Ktrans, increased in response to cytotoxic chemotherapy from pre-treatment to cycle 2 day 2 and this increase was associated with worse OS (HR 1.099, 95%CI 1.01-1.20, p = 0.025). CONCLUSIONS: In patients diagnosed with colorectal cancer with liver metastases, treatment with standard chemotherapy changes cell- and protein-based biomarkers, although these changes are not associated with survival outcomes. In contrast, the imaging biomarker, Ktrans, offers promise to direct molecularly targeted therapies such as anti-angiogenic agents.

Objective and subjective reduction of cellulite volume using a localized vibrational massage device in a 24-week randomized intra-individual single-blind regression study.

Cellulite occurs in females and is a common condition of altered connective tissue matrix and increased adipogenicity with visible dimples and orange-peel appearance on the skins surface. Whilst advancements in methods continue to help our understanding, attempts to correct the appearance of cellulite topically have yielded limited success. Various kinds of non-invasive body contouring methods such as whole body vibration have been reported with demonstrable visible improvements in the cellulite condition. The aim of this study was to evaluate volume reduction and improvement of the visible appearance of cellulite as judged both objectively (AEVA-HE phase-shift 3-D fringe projection, macrophotography image grading) and subjectively (questionnaires) after application of a hand-held localized vibrational device over 24-weeks. The study was conducted on 40 healthy female volunteers who were instructed how to use the device on defined areas of cellulite of the outside and rear of the thighs (iliotibial band, and over biceps femoris region respectively). The initial 12 weeks of continuous massage application of the study were followed by a 12 week phase in which volunteers were split into 2 subgroups - one for assessment of regression effects and one for continuous application effects. AEVA (skin surface volume) measurements of cellulite-related dimples correlated with questionnaires and visual image evaluation scoring, in that in the iliotibial region cellulite was significantly reduced at 12 weeks. In the regression subgroup cellulite returned to initial values soon after cessation of treatment, whereas in the continuous application subgroup, cellulite remained diminished. The effect of this device to reduce cellulite as observed in this study proves that continuous use of vibrational massage is beneficial to mitigate visible signs of cellulite.

La cellulite se produit chez les femmes et est un état d'altération courant de la matrice du tissu conjonctif et d'une adipogenèse accrue se manifestant par l´apparition des fossettes visibles et un aspect de peau d'orange à la surface de la peau. Bien que les progrès des méthodes approfondissent notre compréhension, les tentatives de corrections de l'apparence de la cellulite par voie topique ont produit des résultats limités. Divers types de méthodes non invasives du body contouring, telle que la vibration entière de celui-ci, ont été rapportées, et ce, avec des améliorations visibles et démontrables de l'état de la cellulite.L'objectif de cette étude était d'évaluer la réduction du volume et l'amélioration de l'apparence visible de la cellulite, comme jugées à la fois objectivement (AEVA-HE phase-shift 3-D projection de franges, gradation d'images par macrophotographie) et subjectivement (questionnaires) après application localisée d'un appareil vibratoire manuel pendant 24 semaines. L'étude a été menée sur 40 femmes volontaires en bonne santé qui ont reçu des instructions à-propos de comment utiliser l'appareil sur des zones externes et bien définies de la cellulite et à l'arrière des cuisses (bande iliotibiale et sur la région du biceps fémoral respectivement). Les 12 premières semaines d'application de massage continue ont été suivies d'une phase de 12 semaines au cours de laquelle les volontaires ont été divisés en deux sous-groupes - un pour l'évaluation des effets de régression et un pour l'évaluation des effets de l'application continue.Les mesures AEVA (volume de la surface de la peau) des capitons liés à la cellulite corrélées avec les questionnaires et le score visuel d'évaluation d'images, dans laquelle, la cellulite dans la région iliotibiale, était significativement réduite à 12 semaines. Dans la régression du sous-groupe, la cellulite est revenue aux valeurs initiales peu après l'arrêt du traitement, tandis que dans le sous-groupe d'application continue, la cellulite est restée diminuée. L'effet de ce dispositif pour réduire la cellulite tel qu'observé dans cette étude prouve que l'utilisation continue du massage vibratoire est bénéfique pour mitiger les signes visibles de la cellulite.

Extraskeletal Calcifications in Hutchinson-Gilford Progeria Syndrome.

PURPOSE: Children with Hutchinson-Gilford progeria syndrome (HGPS), a rare premature aging disease, exhibit extraskeletal calcifications detected by radiographic analysis and on physical examination. The aim of this study was to describe the natural history and pathophysiology of these abnormal calcifications in HGPS, and to determine whether medications and/or supplements tested in clinical trials alter their development. METHODS: Children from two successive clinical trials administering 1) lonafarnib (n = 26) and 2) lonafarnib + pravastatin + zoledronic acid (n = 37) were studied at baseline (pre-therapy), one year on therapy, and at end-of-therapy (3.3-4.3 years after the baseline visit). Calcium supplementation (oral calcium carbonate) was administered during the first year of the second trial and was subsequently discontinued. Information on calcifications was obtained from physical examinations, radiographs, and serum and urinary biochemical measures. The mineral content of two skin-derived calcifications was determined by x-ray diffraction. RESULTS: Extraskeletal calcifications were detected radiographically in 12/39 (31%) patients at baseline. The odds of exhibiting calcifications increased with age (p = 0.045). The odds were unaffected by receipt of lonafarnib, pravastatin, and zoledronate therapies. However, administration of calcium carbonate supplementation, in conjunction with all three therapeutic agents, significantly increased the odds of developing calcifications (p = 0.009), with the odds plateauing after the supplement's discontinuation. Composition analysis of calcinosis cutis showed hydroxyapatite similar to bone. Although serum calcium, phosphorus, and parathyroid hormone (PTH) were within normal limits at baseline and on-therapy, PTH increased significantly after lonafarnib initiation (p < 0.001). Both the urinary calcium/creatinine ratio and tubular reabsorption of phosphate (TRP) were elevated at baseline in 22/39 (56%) and 31/37 (84%) evaluable patients, respectively, with no significant changes while on-therapy. The mean calcium × phosphorus product (Ca × Pi) was within normal limits, but plasma magnesium decreased over both clinical trials. Fibroblast growth factor 23 (FGF23) was lower compared to age-matched controls (p = 0.03). CONCLUSIONS: Extraskeletal calcifications increased with age in children with HGPS and were composed of hydroxyapatite. The urinary calcium/creatinine ratio and TRP were elevated for age while FGF23 was decreased. Magnesium decreased and PTH increased after lonafarnib therapy which may alter the ability to mobilize calcium. These findings demonstrate that children with HGPS with normal renal function and an unremarkable Ca × Pi develop extraskeletal calcifications by an unidentified mechanism that may involve decreased plasma magnesium and FGF23. Calcium carbonate accelerated their development and is, therefore, not recommended for routine supplementation in these children.

The role of spousal relationships in fibromyalgia patients' quality of life.

Fibromyalgia (FM) is a chronic pain syndrome that includes debilitating symptoms such as widespread pain and tenderness, fatigue, and poor physical functioning. Research has shown FM patients' choice of coping style and relationship quality with their spouse can impact their mental quality of life (QoL), but no known study has examined the protective nature of relationship quality and coping behaviors on both patient physical and mental QoL in the context of chronic pain. We examined 204 patients with FM on the (a) roles of coping styles and relationship quality on patient quality of life, and (b) moderating effect of relationship quality on the association between negative coping style and patient QoL. A series of multiple regressions found patients' coping styles were not significantly associated with physical QoL, but were significantly associated with mental QoL. Patients' relationship quality with their spouse was significantly associated with mental QoL, but not physical QoL and no significant interactions with negative coping style were found. Our results emphasize the importance of coping styles and relationship quality between patients and their spouses in the context of chronic pain. Clinicians can incorporate the patient's relationship as part of a more holistic approach to care and improving outcomes.

Regular exercise improves the well-being of parents of children with cancer.

AIM: Parents of children with cancer describe impaired physical and social functioning, sleep disturbance and poor mental health. Exercise-related interventions impact positively on these quality of life domains, but have not been examined in this population. The aim of this longitudinal pilot study was to explore the feasibility of a 12-week pedometer-monitored walking intervention among parents of children with cancer, assessing adherence to a set activity target of 70,000 steps per week, and to explore the benefits of physical activity on mental and physical health. METHODS: Parents were provided with a pedometer and requested to achieve a daily step count of 10,000 steps per day for 12 weeks. Mood, well-being and psychological distress were examined using validated questionnaires (Profile of Mood States 2nd edition [POMS-2], Distress Thermometer for Parents [DT-P] and Depression Anxiety Stress Scales [DASS-42]) at baseline, midpoint (6 weeks) and endpoint (12 weeks) to identify changes in these domains with increased activity. RESULTS: Fifteen parents were recruited. The majority increased their counts during the first 4 weeks of the study and maintained this to week 8 (n = 12). Time-dependent improvements were identified in the following psychometric test outcomes at week 12: DT-P score (likelihood ratio test [LRT] P = 0.02), POMS-2 total mood disturbance (LRT P = 0.03), fatigue inertia (LRT P = 0.009), tension anxiety (LRT P = 0.007) and vigour activity (LRT P = 0.001). CONCLUSIONS: Mental health benefits of a pedometer-based exercise intervention for parents of children with cancer were identified. Such programs should be included in a holistic approach to improve the psychological outcomes of parents whose children are receiving treatment for cancer.

Bilateral parietal contributions to spatial language.

It is commonly held that language is largely lateralized to the left hemisphere in most individuals, whereas spatial processing is associated with right hemisphere regions. In recent years, a number of neuroimaging studies have yielded conflicting results regarding the role of language and spatial processing areas in processing language about space (e.g., Carpenter, Just, Keller, Eddy, & Thulborn, 1999; Damasio et al., 2001). In the present study, we used sparse scanning event-related functional magnetic resonance imaging (fMRI) to investigate the neural correlates of spatial language, that is; language used to communicate the spatial relationship of one object to another. During scanning, participants listened to sentences about object relationships that were either spatial or non-spatial in nature (color or size relationships). Sentences describing spatial relationships elicited more activation in the superior parietal lobule and precuneus bilaterally in comparison to sentences describing size or color relationships. Activation of the precuneus suggests that spatial sentences elicit spatial-mental imagery, while the activation of the SPL suggests sentences containing spatial language involve integration of two distinct sets of information - linguistic and spatial.

Three doses of vitamin D, bone mineral density, and geometry in older women during modest weight control in a 1-year randomized controlled trial.

The effects of higher than recommended vitamin D doses on bone mineral density (BMD) and quality are not known. In this study, higher intakes, in postmenopausal women undergoing weight control over 1 year, had no effect on areal or volumetric BMD but prevented the deterioration in cortical bone geometry. INTRODUCTION: Studies examining how bone responds to a standard dose of vitamin D supplementation have been inconsistent. In addition, the effects of higher doses on BMD and quality are not known. Postmenopausal women undergoing weight control to improve health outcomes are particularly at risk for bone loss and might benefit from supplemental vitamin D intake above the recommended allowance. METHODS: This 1-year-long, randomized, double-blind controlled study addresses whether vitamin D supplementation, in healthy overweight/obese older women, affects BMD and bone structural parameters. In addition, bone turnover and serum total, free, and bioavailable 25-hydroxyvitamin D (25OHD) responses to one of three daily levels of vitamin D3 (600, 2000, 4000 IU) with 1.2 Ca g/day during weight control were examined. RESULTS: Fifty-eight women (age, 58 ± 6 years; body mass index, 30.2 ± 3.8 kg/m2, serum 25OHD, 27.3 ± 4.4 ng/mL) were randomized to treatment. After 1 year, serum 25OHD concentrations increased to 26.5 ± 4.4, 35.9 ± 4.5, and 41.5 ± 6.9 ng/mL, in groups 600, 2000, and 4000 IU, respectively, and differed between groups (p < 0.01). Weight change was similar between groups (-3.0 ± 4.1 %). Cortical (Ct) thickness of the tibia changed by -1.5 ± 5.1 %, +0.6 ± 3.2 %, and +2.0 ± 4.5 % in groups 600, 2000, and 4000 IU, respectively, and each group was significantly different from each other (p < 0.05). CONCLUSION: The decline in Ct thickness was prevented with higher vitamin D3 supplementation, but there were no other significant changes due to treatment over 1 year. Whether these findings translate to changes in biomechanical properties leading to reduced fracture risk should be addressed in future studies.

Outcomes and Cost-Effectiveness of Integrating HIV and Nutrition Service Delivery: Pilots in Malawi and Mozambique.

This paper provides the first estimates of impact and cost-effectiveness for integrated HIV and nutrition service delivery in sub-Saharan Africa. HIV and undernutrition are synergistic co-epidemics impacting millions of children throughout the region. To alleviate this co-epidemic, UNICEF supported small-scale pilot programs in Malawi and Mozambique that integrated HIV and nutrition service delivery. We use trends from integration sites and comparison sites to estimate the number of lives saved, infections averted and/or undernutrition cases cured due to programmatic activities, and to estimate cost-effectiveness. Results suggest that Malawi's program had a cost-effectiveness of $11-29/DALY, while Mozambique's was $16-59/DALY. Some components were more effective than others ($1-4/DALY for Malawi's Male motivators vs. $179/DALY for Mozambique's One stop shops). These results suggest that integrating HIV and nutrition programming leads to a positive impact on health outcomes and should motivate additional work to evaluate impact and determine cost-effectiveness using an appropriate research design.

Standardized Mixed-Meal Tolerance and Arginine Stimulation Tests Provide Reproducible and Complementary Measures of ß-Cell Function: Results From the Foundation for the National Institutes of Health Biomarkers Consortium Investigative Series.

OBJECTIVE: Standardized, reproducible, and feasible quantification of ß-cell function (BCF) is necessary for the evaluation of interventions to improve insulin secretion and important for comparison across studies. We therefore characterized the responses to, and reproducibility of, standardized methods of in vivo BCF across different glucose tolerance states. RESEARCH DESIGN AND METHODS: Participants classified as having normal glucose tolerance (NGT; n = 23), prediabetes (PDM; n = 17), and type 2 diabetes mellitus (T2DM; n = 22) underwent two standardized mixed-meal tolerance tests (MMTT) and two standardized arginine stimulation tests (AST) in a test-retest paradigm and one frequently sampled intravenous glucose tolerance test (FSIGT). RESULTS: From the MMTT, insulin secretion in T2DM was >86% lower compared with NGT or PDM (P < 0.001). Insulin sensitivity (Si) decreased from NGT to PDM (∼50%) to T2DM (93% lower [P < 0.001]). In the AST, insulin secretory response to arginine at basal glucose and during hyperglycemia was lower in T2DM compared with NGT and PDM (>58%; all P < 0.001). FSIGT showed decreases in both insulin secretion and Si across populations (P < 0.001), although Si did not differ significantly between PDM and T2DM populations. Reproducibility was generally good for the MMTT, with intraclass correlation coefficients (ICCs) ranging from ∼0.3 to ∼0.8 depending on population and variable. Reproducibility for the AST was very good, with ICC values >0.8 across all variables and populations. CONCLUSIONS: Standardized MMTT and AST provide reproducible and complementary measures of BCF with characteristics favorable for longitudinal interventional trials use.

Antiangiogenic therapy in oncology: current status and future directions.

Angiogenesis, the formation of new blood vessels from pre-existing vessels, has been validated as a target in several tumour types through randomised trials, incorporating vascular endothelial growth factor (VEGF) pathway inhibitors into the therapeutic armoury. Although some tumours such as renal cell carcinoma, ovarian and cervical cancers, and pancreatic neuroendocrine tumours are sensitive to these drugs, others such as prostate cancer, pancreatic adenocarcinoma, and melanoma are resistant. Even when drugs have yielded significant results, improvements in progression-free survival, and, in some cases, overall survival, are modest. Thus, a crucial issue in development of these drugs is the search for predictive biomarkers-tests that predict which patients will, and will not, benefit before initiation of therapy. Development of biomarkers is important because of the need to balance efficacy, toxicity, and cost. Novel combinations of these drugs with other antiangiogenics or other classes of drugs are being developed, and the appreciation that these drugs have immunomodulatory and other modes of action will lead to combination regimens that capitalise on these newly understood mechanisms.

Insomnia and exacerbation of anxiety associated with high-EPA fish oil supplements after successful treatment of depression.

A 54-year-old male consulted his general practitioner for increasing general anxiety and mild panic attacks despite effective treatment for recurrent major depressive disorder, which included a fish oil supplement enriched in eicosapentaenoic acid (EPA). The patient would awaken suddenly at night with shortness of breath and overwhelming worry. During the daytime, he felt a general, nonspecific anxiety and frequently experienced sympathetic activation upon confronting routine challenges. He also experienced dyspnea-induced feelings of panic. He reported that he stopped taking the fish oil supplements after several more months of symptoms, and his anxiety and insomnia then largely disappeared. Several weeks later, he resumed consumption of high-EPA fish oil at the prior dosage for 2 days. On both nights, the patient reported nighttime awakening similar to the previous episodes, followed by daytime agitation. Since halting the fish oil supplements, the anxiety and insomnia have not returned and his depression remains in remission.

Enhanced function of immuno-isolated islets in diabetes therapy by co-encapsulation with an anti-inflammatory drug.

Immuno-isolation of islets has the potential to enable the replacement of pancreatic function in diabetic patients. However, host response to the encapsulated islets frequently leads to fibrotic overgrowth with subsequent impairment of the transplanted grafts. Here, we identified and incorporated anti-inflammatory agents into islet-containing microcapsules to address this challenge. In vivo subcutaneous screening of 16 small molecule anti-inflammatory drugs was performed to identify promising compounds that could minimize the formation of fibrotic cell layers. Using parallel non-invasive fluorescent and bioluminescent imaging, we identified dexamethasone and curcumin as the most effective drugs in inhibiting the activities of inflammatory proteases and reactive oxygen species in the host response to subcutaneously injected biomaterials. Next, we demonstrated that co-encapsulating curcumin with pancreatic rat islets in alginate microcapsules reduced fibrotic overgrowth and improved glycemic control in a mouse model of chemically-induced type I diabetes. These results showed that localized administration of anti-inflammatory drug can improve the longevity of encapsulated islets and may facilitate the translation of this technology toward a long-term cure for type I diabetes.

Complex histopathologic response in rat kidney to oral ß-myrcene: an unusual dose-related nephrosis and low-dose alpha2u-globulin nephropathy.

Oral gavage studies with ß-myrcene in male F344 rats showed a complex renal pathology comprising both alpha2u-globulin (α2u-g) nephropathy, an unusual nephrosis involving the outer stripe of outer medulla (OSOM), and an increased incidence of renal tubule tumors by 2 years. In the 90-day and 2-year studies, respectively, α2u-g nephropathy and linear papillary mineralization were observed in males at the two lower doses but were absent from the high dose. Nephrosis was characterized by dilation of the S3 tubules, nuclear enlargement (including karyomegaly), and luminal pyknotic cells, all in the outermost OSOM. Nephrosis was minimal at the higher doses in the 90-day study, but progressed to a severe grade in males dosed with 1,000 mg/kg for 2 years. Renal tubule tumors developed in treated groups with incidences up to 30% in the 250 and 500 mg/kg male dose groups. Tumors at the lower doses in males may have been associated with α2u-g nephropathy, while those at higher doses in both sexes may have been due to the nephrosis. Because ß-myrcene induced a complex spectrum of renal pathology, the α2u-g nephropathy mechanism cannot be the sole mechanism of carcinogenesis in these rats.

Skeletal health in adult patients with classic galactosemia.

SUMMARY: This study evaluated bone health in adults with galactosemia. Associations between bone mineral density (BMD) and nutritional and biochemical variables were explored. Calcium level predicted hip and spine BMD, and gonadotropin levels were inversely associated with spinal BMD in women. These results afford insights into management strategies for these patients. INTRODUCTION: Bone loss is a complication of galactosemia. Dietary restriction, primary ovarian insufficiency in women, and disease-related alterations of bone metabolism may contribute. This study examined relationships between clinical factors and BMD in patients with galactosemia. METHODS: This cross-sectional sample included 33 adults (16 women) with classic galactosemia, mean age 32.0 ± 11.8 years. BMD was measured by dual-energy X-ray absorptiometry, and was correlated with age, height, weight, fractures, nutritional factors, hormonal status, and bone biomarkers. RESULTS: There was a significant difference in hip BMD between women and men (0.799 vs. 0.896 g/cm(2), p = 0.014). The percentage of subjects with BMD-Z <-2.0 was also greater for women than men [33 vs. 18 % (spine), 27 vs. 6 % (hip)], and more women reported sustaining fractures. Bivariate analyses yielded correlations between BMI and BMD-Z [at the hip in women (r = 0.58, p < 0.05) and spine in men (r = 0.53, p < 0.05)]. In women, weight was also correlated with BMD-Z (r = 0.57, p < 0.05 at hip), and C-telopeptides (r = -0.59 at spine and -0.63 hip, p < 0.05) and osteocalcin (r = -0.71 at spine and -0.72 hip, p < 0.05) were inversely correlated with BMD-Z. In final regression models, higher gonadotropin levels were associated with lower spinal BMD in women (p = 0.017); serum calcium was a significant predictor of hip (p = 0.014) and spine (p = 0.013) BMD in both sexes. CONCLUSIONS: Bone density in adults with galactosemia is low, indicating the potential for increased fracture risk, the etiology of which appears to be multifactorial.

Transurethral resection biopsy as part of a saturation biopsy protocol: a cohort study and review of the literature.

OBJECTIVE: To evaluate the prostate cancer (CaP) detection rate and morbidity of performing a transurethral resection biopsy of the prostate (TURBP) at the same time as a saturation biopsy (SBx). PATIENTS: A total of 102 men with previous negative transrectal ultrasound (TRUS) biopsies underwent a SBx under formal anaesthesia. Fifty-four [54 (52.9%)] had a combined SBx and TURBP (Group 1) and 48 (47.1%) had a SBx only (Group 2). RESULTS: The CaP detection rate in Group 1 was 38.9% (21/54), which was significantly higher than the detection rate of 27.1% (13/48) in Group 2 (P = 0.005). CaP was detected via TURBP in 12 patients (22.2%) from Group 1, including 8 (14.8%) patients who had CaP solely in their TURBP chips. According to the D'Amico classification, 66.6% (14/21) of the cancers in Group 1 were intermediate (n = 4) or high risk (n = 10). Of the 8 'TURBP only' cancers, 75% (6/8) were intermediate (n = 2) or high risk (n = 4). Seven of these eight patients went on to have a radical prostatectomy (RP) but only 2 (28.6%) were found to have a pure anterior/transition zone (TZ) tumor. The postoperative urinary retention and emergency admission rates for Groups 1 and 2 were 29.6% (16/54) vs. 16.6% (8/48) (P = 0.095) and 11.1% (6/54) vs. 5.5% (2/48) (n = 0.17). There was no difference in terms of hematuria (P = 0.54), urinary tract infection (UTI) (P = 0.22), or sepsis (P = 0.21), and patients in Group 1 spent an average of 0.5 days longer in hospital (1.9 vs. 1.4; P = 0.008). CONCLUSIONS: TURBP in association with SBx increases the detection of clinically important CaP. However, this does have to be balanced against the small increased incidence of urinary retention, emergency re-admission, and longer hospital stay.

Culturally-Competent Treatments for Asian Americans: The Relevance of Mindfulness and Acceptance-Based Psychotherapies.

The development of effective treatments for Asian Americans is important because treatment disparities continue to exist for this population. Because of their theoretical grounding in East Asian philosophies, mindfulness and acceptance-based psychotherapies appear to constitute promising ways to provide culturally responsive mental health care to Asian Americans. However, in practice these approaches often reflect conceptions of mental health that are more consistent with Western world views. We review points of intersection and divergence between Western-based mindfulness and acceptance psychotherapies and Asian American cultural values. We then propose a culturally syntonic approach that accentuates certain components of mindfulness and acceptance psychotherapies and adapts other components of these approaches to be more consistent with Asian American cultural values.

Renal histopathology in toxicity and carcinogenicity studies with tert-butyl alcohol administered in drinking water to F344 rats: a pathology working group review and re-evaluation.

An independent Pathology Working Group (PWG) re-evaluated the kidney changes in National Toxicology Program (NTP) toxicology/carcinogenicity studies of tert-butyl alcohol (TBA) in F344/N rats to determine possible mode(s) of action underlying renal tubule tumors in male rats at 2-years. In the 13-week study, the PWG confirmed that the normal pattern of round hyaline droplets in proximal convoluted tubules was replaced by angular droplet accumulation, and identified precursors of granular casts in the outer medulla, changes typical of alpha(2u)-globulin (α(2u)-g) nephropathy. In the 2-year study, the PWG confirmed the NTP observation of increased renal tubule tumors in treated male groups. Linear papillary mineralization, another hallmark of the α(2u)-g pathway was present only in treated male rats. Chronic progressive nephropathy (CPN) was exacerbated in high-dose males and females, with a relationship between advanced grades of CPN and renal tumor occurrence. Hyperplasia of the papilla lining was a component of CPN in both sexes, but there was no pelvic urothelial hyperplasia. High-dose females showed no TBA-related nephrotoxicity. The PWG concluded that both α(2u)-g nephropathy and exacerbated CPN modes of action were operative in TBA renal tumorigenicity in male rats, neither of which has relevance for human cancer risk.