Urologic view in the management of genitourinary syndrome of menopause.

Genitourinary syndrome of menopause (GSM) has a variety of effects on the urinary system and is an important consideration in the care provided to perimenopausal and postmenopausal patients when addressing urinary pathology. Here we discuss the common pathologies of the urinary system related to GSM including lower urinary tract symptoms and recurrent urinary tract infections. Female sexual dysfunction is not to be excluded as a critical part of a urologist's management of GSM but will be discussed elsewhere in this issue.

Severe hydralazine-induced lupus presenting as systemic lupus erythematosus.

Despite its long history of untoward side effects of a systemic autoimmune disease, drug-induced lupus can be difficult to recognize because of the disconnect between chronic drug usage and onset of symptoms. In this case, the patient was treated with hydralazine for two years when symptoms were initially reported, but a diagnosis of hydralazine-induced lupus was not considered for another half year. Despite treatment with steroidal and nonsteroidal anti-inflammatory medications during this period, rheumatologic symptoms and signs continued to deteriorate, consistent with the diagnosis of systemic lupus erythematosus. Not until the patient voluntarily discontinued hydralazine did symptoms begin to improve, fully resolving over the subsequent 6-12 months largely in the absence of anti-inflammatory medication. This patient demonstrates that failure to recognize a drug-induced disease etiology can result in substantial worsening of rheumatologic symptoms over the subsequent six months, ultimately satisfying criteria for systemic lupus erythematosus. While symptoms and signs largely normalized, some laboratory abnormalities and occasional arthralgia remained two years after discontinuing hydralazine, suggesting smoldering inflammatory disease.

Constraints on Primordial Gravitational Waves Using Planck, WMAP, and New BICEP2/Keck Observations through the 2015 Season.

We present results from an analysis of all data taken by the bicep2/Keck CMB polarization experiments up to and including the 2015 observing season. This includes the first Keck Array observations at 220 GHz and additional observations at 95 and 150 GHz. The Q and U maps reach depths of 5.2, 2.9, and 26 µK_{CMB} arcmin at 95, 150, and 220 GHz, respectively, over an effective area of ≈400 square degrees. The 220 GHz maps achieve a signal to noise on polarized dust emission approximately equal to that of Planck at 353 GHz. We take auto and cross spectra between these maps and publicly available WMAP and Planck maps at frequencies from 23 to 353 GHz. We evaluate the joint likelihood of the spectra versus a multicomponent model of lensed-ΛCDM+r+dust+synchrotron+noise. The foreground model has seven parameters, and we impose priors on some of these using external information from Planck and WMAP derived from larger regions of sky. The model is shown to be an adequate description of the data at the current noise levels. The likelihood analysis yields the constraint r_{0.05}<0.07 at 95% confidence, which tightens to r_{0.05}<0.06 in conjunction with Planck temperature measurements and other data. The lensing signal is detected at 8.8σ significance. Running a maximum likelihood search on simulations we obtain unbiased results and find that σ(r)=0.020. These are the strongest constraints to date on primordial gravitational waves.

Improved Constraints on Cosmology and Foregrounds from BICEP2 and Keck Array Cosmic Microwave Background Data with Inclusion of 95 GHz Band.

We present results from an analysis of all data taken by the BICEP2 and Keck Array cosmic microwave background (CMB) polarization experiments up to and including the 2014 observing season. This includes the first Keck Array observations at 95 GHz. The maps reach a depth of 50 nK deg in Stokes Q and U in the 150 GHz band and 127 nK deg in the 95 GHz band. We take auto- and cross-spectra between these maps and publicly available maps from WMAP and Planck at frequencies from 23 to 353 GHz. An excess over lensed ΛCDM is detected at modest significance in the 95×150 BB spectrum, and is consistent with the dust contribution expected from our previous work. No significant evidence for synchrotron emission is found in spectra such as 23×95, or for correlation between the dust and synchrotron sky patterns in spectra such as 23×353. We take the likelihood of all the spectra for a multicomponent model including lensed ΛCDM, dust, synchrotron, and a possible contribution from inflationary gravitational waves (as parametrized by the tensor-to-scalar ratio r) using priors on the frequency spectral behaviors of dust and synchrotron emission from previous analyses of WMAP and Planck data in other regions of the sky. This analysis yields an upper limit r_{0.05}<0.09 at 95% confidence, which is robust to variations explored in analysis and priors. Combining these B-mode results with the (more model-dependent) constraints from Planck analysis of CMB temperature plus baryon acoustic oscillations and other data yields a combined limit r_{0.05}<0.07 at 95% confidence. These are the strongest constraints to date on inflationary gravitational waves.

Development and validation of the Diabetes Medication System Rating Questionnaire-Short Form.

AIMS: To develop and validate a short form of the 54-item Diabetes Medication System Rating Questionnaire that maintains the domains and performance characteristics of the long-form questionnaire. METHODS: Data from the Diabetes Medication System Rating Questionnaire validation study were analysed to select items representing the nine scales (convenience, negative events, interference, self-monitoring of blood glucose burden, efficacy, social burden, psychological well-being, treatment satisfaction and treatment preference). The resulting 20-item Diabetes Medication System Rating Questionnaire Short-Form was administered online, with validated criterion measures of treatment satisfaction and medication adherence, with a retest within 2 weeks. Participants were US adults (N = 413) with Type 2 diabetes using oral agents alone; insulin by syringe and/or pen with or without oral agents; or glucagon-like peptide-1 agents. Most participants (82%) completed the retest. RESULTS: The median inter-item agreement of scales was 0.76 and the total composite (mean of all items except treatment preference) was 0.88. The median test-retest reliability of scales was 0.86, and of the total composite was 0.95. All statistically significant correlations between Diabetes Medication System Rating Questionnaire Short-Form scales and criterion measures of treatment satisfaction and adherence were in the expected direction. The median correlation of the Diabetes Medication System Rating Questionnaire Short-Form with corresponding criterion measures of treatment satisfaction was 0.59; the mean correlation of the same Diabetes Medication System Rating Questionnaire Short-Form measures with adherence was 0.42. The Diabetes Medication System Rating Questionnaire Short-Form scales were more powerful predictors of adherence than were the criterion measures of treatment satisfaction. The Diabetes Medication System Rating Questionnaire Short-Form scales differentiated between those taking different medications and between those using different insulin delivery devices. CONCLUSIONS: This study suggests that the Diabetes Medication System Rating Questionnaire Short-Form provides a comprehensive set of measures with acceptable reliability and validity and a reduced burden of administration.

Options for prandial glucose management in type 2 diabetes patients using basal insulin: addition of a short-acting GLP-1 analogue versus progression to basal-bolus therapy.

Integrating patient-centered diabetes care and algorithmic medicine poses particular challenges when optimized basal insulin fails to maintain glycaemic control in patients with type 2 diabetes. Multiple entwined physiological, psychosocial and systems barriers to insulin adherence are not easily studied and are not adequately considered in most treatment algorithms. Moreover, the limited number of alternatives to add-on prandial insulin therapy has hindered shared decision-making, a central feature of patient-centered care. This article considers how the addition of a glucagon-like peptide 1 (GLP-1) analogue to basal insulin may provide new opportunities at this stage of treatment, especially for patients concerned about weight gain and risk of hypoglycaemia. A flexible framework for patient-clinician discussions is presented to encourage development of decision-support tools applicable to both specialty and primary care practice.

Impact of diagnosis of diabetes on health-related quality of life among high risk individuals: the Diabetes Prevention Program outcomes study.

PURPOSE: The purpose of this study is to assess if diagnosis of type 2 diabetes affected health-related quality of life (HRQoL) among participants in the Diabetes Prevention Program/Diabetes Prevention Program Outcome Study and changes with treatment or diabetes duration. METHODS: 3,210 participants with pre-diabetes were randomized to metformin (MET), intensive lifestyle intervention (ILS), or placebo (PLB). HRQoL was assessed using the SF-36 including: (1) 8 SF-36 subscales; (2) the physical component (PCS) and mental component summary (MCS) scores; and (3) the SF-6D. The sample was categorized by diabetes free versus diagnosed. For diagnosed subgroup, mean scores in the diabetes-free period, at 6 months, 2, 4 and 6 years post-diagnosis, were compared. RESULTS: PCS and SF-6D scores declined in all participants in all treatment arms (P < .001). MCS scores did not change significantly in any treatment arm regardless of diagnosis. ILS participants reported a greater decrease in PCS scores at 6 months post-diagnosis (P < .001) and a more rapid decline immediately post-diagnosis in SF-6D scores (P = .003) than the MET or PLB arms. ILS participants reported a significant decrease in the social functioning subscale at 6 months (P < .001) and two years (P < .001) post-diagnosis. CONCLUSIONS: Participants reported a decline in measures of overall health state (SF-6D) and overall physical HRQoL, whether or not they were diagnosed with diabetes during the study. There was no change in overall mental HRQoL. Participants in the ILS arm with diabetes reported a more significant decline in some HRQoL measures than those in the MET and PLB arms that developed diabetes.

Treatment satisfaction in the sensor-augmented pump therapy for A1C reduction 3 (STAR 3) trial.

AIM: To identify insulin delivery system perceptions that contributed to improvements in overall satisfaction with insulin therapy (treatment satisfaction) that were larger in those using sensor-augmented pump therapy than those using multiple daily injections with self monitoring of blood glucose. METHODS: The Sensor-Augmented Pump Therapy for A1C Reduction 3 (STAR 3), a randomized 12-month clinical trial, compared sensor-augmented pump therapy to multiple daily injections + self monitoring of blood glucose in adult and paediatric patients. The Insulin Delivery System Rating Questionnaire measured perceptions of convenience, problems, interference with daily activities, blood glucose monitoring burden, social burden, clinical efficacy, diabetes worries and psychological well-being, as well as treatment satisfaction. We conducted separate multiple regression analyses for the 334 adult patients and 147 paediatric patients and their caregivers to assess the independent associations (P < 0.05) between change from baseline to follow-up in user perceptions and treatment satisfaction. RESULTS: Increased convenience was associated with improved treatment satisfaction in all user groups. Reduced interference with daily activities (caregivers), reduced social burden (adults) and increased efficacy (both) also were associated with improved treatment satisfaction. CONCLUSIONS: Treatment satisfaction among children was primarily a function of convenience, while perceived clinical efficacy was also a primary determinant among adults, reflecting different emphases on the treatment process itself vs. treatment consequences. Among adult patients and caregivers, improved treatment satisfaction was also a function of reductions in social burden and interference with daily activities (respectively), reflecting concern with the broader psychosocial impact of sensor-augmented pump therapy on their lives.

Patient-reported outcomes in the practice-based opportunities for weight reduction (POWER) trial.

PURPOSE: To evaluate effects of two behavioral weight-loss interventions (in-person, remote) on health-related quality of life (HRQOL) compared to a control intervention. METHODS: Four hundred and fifty-one obese US adults with at least one cardiovascular risk factor completed five measures of HRQOL and depression: MOS SF-12 physical component summary (PCS) and mental component summary; EuroQoL-5 dimensions single index and visual analog scale; PHQ-8 depression symptoms; and PSQI sleep quality scores at baseline and 6 and 24 months after randomization. Change in each outcome was analyzed using outcome-specific mixed-effects models controlling for participant demographic characteristics. RESULTS: PCS-12 scores over 24 months improved more among participants in the in-person active intervention arm than among control arm participants (P < 0.05, ES = 0.21); there were no other statistically significant treatment arm differences in HRQOL change. Greater weight loss was associated with improvements in most outcomes (P < 0.05 to < 0.0001). CONCLUSIONS: Participants in the in-person active intervention improved more in physical function HRQOL than participants in the control arm did. Greater weight loss during the study was associated with greater improvement in all PRO except for sleep quality, suggesting that weight loss is a key factor in improving HRQOL.

[Substance use associated disorders: frequency in patients with schizophrenic and affective psychoses]. / Substanzbezogene Störungen: Häufigkeit bei Patienten mit schizophrenen oder affektiven Störungsbildern.

BACKGROUND: Alcohol and substance use disorders (ASUD) are considered to be among the most frequent comorbidities in schizophrenic and affective psychoses and have a significant negative influence on their course and prognosis. In the present study patients with diagnosis from the ICD-10 category F2 or F3 were examined regarding a substance use disorder in a multicentre cross-section evaluation at nine psychiatric hospitals in Baden-Württemberg. The aim of this study is to discuss the current research on substance use disorders and psychosis comorbidity regarding the theoretical models by means of collected data. METHODS: The examination of 50 consecutive admissions per centre is based on a shortened version of the European Severity Index (Europ ASI). An initial urine drug screening was carried out with all patients after admission. Statistical assessment was based on percentage distributions, mean values, standard deviations and suitable correlation analysis. RESULTS: The representative sample included 448 patients. A proportion of 169 patients (37.7%) had a dual diagnosis F2 and F1 and a proportion of 144 patients (32.1%) had a dual diagnosis F3 and F1; 64 patients (14.3%) had an F2 diagnosis and 71 patients (15.8%) had an F3 diagnosis without ASUD. Apart from lifetime use of alcohol (n = 268) and tobacco (n = 325) hypnotics/tranquilizers (n = 214), cannabis (n = 156), opioids (n = 71), stimulants (n = 96) and hallucinogens (n = 36) were consumed. The most frequent combination and long-term intake consisted of tobacco, alcohol, hypnotics/tranquilizer, cannabis and psychostimulants especially in men with schizophrenic disorders. Regarding motivation before first substance use general psychological adjustment disorders (51%), peer impact (42%) and unspecific affective symptoms were predominant. CONCLUSIONS: Altogether the present study clearly demonstrates that patients suffering from schizophrenia, affective disorders and ASUD have significantly higher rates of more severe substance use disorders in their psychosocial environment and more suicidal behaviour than patients without substance misuse. The high rate in the cross-sectional prevalence of tobacco, alcohol, cannabis and psychostimulant use calls for more effective drug prevention.

Use of antidepressant medication and risk of type 2 diabetes: results from three cohorts of US adults.

AIMS/HYPOTHESIS: The results of several studies have suggested a potential positive association between use of antidepressant medication (ADM) and incident type 2 diabetes mellitus. We examined this association in three cohorts of US adults. METHODS: We followed 29,776 men in the Health Professionals Follow-up Study (HPFS, 1990-2006), 61,791 women in the Nurses' Health Study I (NHS I, 1996-2008) and 76,868 women in NHS II (1993-2005), who were free of diabetes mellitus, cardiovascular disease or cancer at baseline. The mean baseline ages for participants from the HPFS and NHS I and II were 56.4, 61.3 and 38.1 years, respectively. ADM use and other covariates were assessed at baseline and updated every 2 years. A time-dependent Cox proportional hazards model was used, and HRs were pooled together across the three cohorts. RESULTS: During 1,644,679 person-years of follow-up, we documented 6,641 new cases of type 2 diabetes. ADM use was associated with an increased risk of diabetes in all three cohorts in age-adjusted models (pooled HR 1.68 [95% CI 1.27, 2.23]). The association was attenuated after adjustment for diabetes risk factors and histories of high cholesterol and hypertension (1.30 [1.14, 1.49]), and further attenuated by controlling for updated BMI (1.17 [1.09, 1.25]). Use of selective serotonin reuptake inhibitors and other antidepressants (mainly tricyclic antidepressants) were both associated with an elevated risk of diabetes, with pooled multivariate-adjusted HRs of 1.10 (1.00, 1.22) and 1.26 (1.11, 1.42), respectively. CONCLUSIONS/INTERPRETATION: The results suggest that ADM users had a moderately elevated risk of type 2 diabetes mellitus compared with non-users, even after adjustment for BMI.

Validation of a tool to assess medication treatment satisfaction in patients with Type 2 diabetes: the Diabetes Medication System Rating Questionnaire (DMSRQ).

AIM: To assess the reliability and validity of the Diabetes Medication System Rating Questionnaire among 537 US adults with Type 2 diabetes using five different diabetes medication regimens (oral agents with and without insulin; insulin only by syringe and by pen; glucagon-like peptide 1 agents). METHODS: The Diabetes Medication System Rating Questionnaire assesses the treatment experience of patients using any diabetes medication system that uses nine measures (Convenience, Negative Events, Interference, Self-Monitoring of Blood Glucose Burden, Efficacy, Social Burden, Psychological Well-Being, Treatment Satisfaction, Treatment Preference). It was administered via an initial online survey, along with other validated measures of treatment satisfaction and medication adherence, with a retest administered within 2 weeks. Participants were 52.5% male, 57.4% aged 40-64 years, 83.6% white and 95.2% non-Hispanic. Most (75.6%) had attended college and 58.3% had been diagnosed with diabetes for more than 10 years. RESULTS: Median inter-item agreement was 0.86. Median test-retest reliability was also 0.86. All correlations between Diabetes Medication System Rating Questionnaire measures and criterion measures of treatment satisfaction and adherence were statistically significant (P<0.01) in the expected direction. Correlations between Diabetes Medication System Rating Questionnaire and the corresponding criterion measures of treatment satisfaction ranged from 0.349 to 0.629 (absolute values; interpolated median 0.568); correlations of the same measures with adherence ranged from 0.384 to 0.450 (absolute values; mean 0.411). Diabetes Medication System Rating Questionnaire measures differentiated among groups taking different medications and those using different delivery systems for the same medication. CONCLUSIONS: This study suggests that the Diabetes Medication System Rating Questionnaire has good reliability and validity and provides a more comprehensive set of measures than existing medication satisfaction questionnaires.

Disruption of positive selection of thymocytes causes autoimmunity.

To differentiate into T cells, immature thymocytes must engage, through their antigen-specific T-cell receptor, peptides derived from self proteins presented by cortical epithelial cells in the thymus, a process called positive selection. Despite this requirement for self-recognition during development, mature T cells do not normally show autoreactivity. Mice injected in the thymus with procainamide-hydroxylamine, a metabolite of procainamide, develop autoimmune features resembling drug-induced lupus. Here, we show that when thymocytes undergo positive selection in the presence of procainamide-hydroxylamine, they fail to establish unresponsiveness to low affinity selecting self antigens, resulting in systemic autoimmunity.

Cardiovascular disease risk factors, depression symptoms and antidepressant medicine use in the Look AHEAD (Action for Health in Diabetes) clinical trial of weight loss in diabetes.

AIMS/HYPOTHESIS: To determine the associations of baseline depression symptoms and use of antidepressant medicines (ADMs) with baseline cardiovascular disease (CVD) risk factors in Look AHEAD (Action for Health in Diabetes) trial participants. METHODS: Look AHEAD participants (n = 5,145; age 58.7 +/- 6.8 years; BMI 35.8 +/- 5.8 kg/m(2)) were assessed for CVD risk factors (elevated HbA(1c) or insulin use, elevated BP or antihypertensive use, elevated lipid levels or lipid-lowering medication, current smoking, BMI > or = 30 kg/m(2), lower peak exercise capacity assessed as metabolic equivalents [METs], and ankle-brachial index <0.9 or >1.3). Participants also completed the Beck Depression Inventory (BDI) and reported their use of ADMs. RESULTS: Of the participants, 14.7% had BDI scores > or = 11, consistent with mild-moderate depression, and 16.5% took ADMs; 4.4% had both depression markers (i.e. elevated symptom scores and took ADMs). In logistic regression analyses of CVD risk (elevated risk factor or use of medication to control the risk factor), controlled for demographic factors, continuous BDI scores and ADM use were each independently associated with elevated BP (or medication), current smoking, BMI > or = 30 kg/m(2) and lower MET values. ADM use was also associated with elevated serum lipids or use of lipid-lowering medication. CONCLUSIONS/INTERPRETATION: Among Look AHEAD participants, depression symptoms or ADM use on entry to the study were each independently associated with a wide range of CVD risk factors. Future research should assess the temporal dynamics of the relationships of depression symptoms and ADM use with CVD risk factors. TRIAL REGISTRATION: Clinicaltrials.gov NCT00017953 FUNDING: This study is funded by the National Institutes of Health with additional support from the Centers for Disease Control and Prevention.

Depression predicts first but not recurrent diabetic foot ulcers.

AIMS/HYPOTHESIS: This study examined the relationship between symptoms of depression and the development of diabetic foot ulcers. METHODS: Participants were 333 patients (71% male; mean age 62 years; 73% with type 2 diabetes) with diabetic peripheral neuropathy (DPN), but without peripheral vascular disease (PVD). Severity of DPN and the presence of PVD were assessed by clinical examination. Depression, other diabetes complications and foot self-care were assessed by self-report. Cox regression tested whether depression was an independent predictor of foot ulceration over 18 months, whether this relationship was moderated by foot ulcer history, and whether foot self-care mediated this relationship. RESULTS: During follow-up, 63 patients developed a foot ulcer. Those with prior foot ulcers had more than four-fold greater risk of subsequent foot ulceration compared with those without a history of foot ulcer. A significant interaction effect showed that depression was significantly related to the development of first but not recurrent foot ulcers. This relationship was independent of biological risk factors. In the final model, each standard deviation increase in depression symptoms was significantly associated with increased risk of developing first foot ulcers (HR 1.68, 95% CI 1.20-2.35), while foot self-care was associated with lower risk (HR 0.61, 95% CI 0.40-0.94). Foot self-care did not mediate the relationship between depression and foot ulceration. CONCLUSIONS/INTERPRETATION: These data suggest that depression is associated with increased risk of first foot ulcers in DPN patients and that this relationship is independent of biological risk factors and foot self-care. Interventions that target depression and foot self-care before the development of foot ulcers may maximise the likelihood of successful prevention of foot ulceration.

Multiple autoantigen binding capabilities of mouse monoclonal antibodies selected for rheumatoid factor activity.

We report that approximately 1/4 of monoclonal rheumatoid factors produced by hybridomas derived from fusions of spleen cells from MRL/lpr/lpr mice with systemic lupus erythematosus (SLE) and arthritis exhibited multiple reactivities with other autoantigens, including dDNA , histones, and/or cytoskeletal-cytoplasmic elements. The patterns of reactivities of most of these clones differed, indicating that each had a separate B cell ancestor. Studies with eluted antibodies demonstrated that a single species of antibody molecules was responsible for the observed multiple reactivities. Inhibition experiments suggested that an antibody combining site may be large enough to accommodate dissimilar epitopes. These findings may provide further insights into the generation and extent of antibody diversity as well as the etiopathogenesis of systemic autoimmune diseases.

Predictors of depressive symptoms in persons with diabetic peripheral neuropathy: a longitudinal study.

AIMS/HYPOTHESIS: The aim of the study was to determine whether diabetic peripheral neuropathy (DPN) is a risk factor for depressive symptoms and examine the potential mechanisms for this relationship. METHODS: This longitudinal study (9 and 18 month follow-up) of 338 DPN patients (mean age 61 years; 71% male; 73% type 2 diabetes) examined the temporal relationships between DPN severity (mean +/- SD; neuropathy disability score [NDS], 7.4 +/- 2.2; mean vibration perception threshold, 41.5 +/- 9.5 V), DPN somatic experiences (symptoms and foot ulceration), DPN psychosocial consequences (restrictions in activities of daily living [ADL] and social self-perception) and the Hospital Anxiety and Depression subscale measuring depressive symptoms (HADS-D; mean 4.9 +/- 3.7). RESULTS: Controlling for baseline HADS-D and demographic/disease variables, NDS at baseline significantly predicted increased HADS-D over 18 months. This association was mediated by baseline unsteadiness, which was significantly associated with increased HADS-D. Baseline ADL restrictions significantly predicted increased HADS-D and partly mediated the association between baseline unsteadiness and change in HADS-D. Increased pain, unsteadiness and ADL restrictions from baseline to 9 months each significantly predicted increased HADS-D over 18 months. Change in social self-perception from baseline to 9 months significantly predicted increased HADS-D and partly mediated the relationships of change in unsteadiness and ADL restrictions with change in HADS-D. CONCLUSIONS/INTERPRETATION: These results confirm that neuropathy is a risk factor for depressive symptoms because it generates pain and unsteadiness. Unsteadiness is the symptom with the strongest association with depression, and is linked to depressive symptoms by perceptions of diminished self-worth as a result of inability to perform social roles.

Improved treatment satisfaction and weight-related quality of life with exenatide once weekly or twice daily.

AIMS: To assess treatment satisfaction and weight-related quality of life (QOL) in subjects with Type 2 diabetes treated with exenatide once weekly (QW) or twice daily (BID). METHODS: In this 52-week randomized, multi-centre, open-label study, 295 subjects managed with diet and exercise and/or oral glucose-lowering medications received either exenatide QW or BID during weeks 1-30; thereafter, subjects receiving exenatide BID were switched to exenatide QW, with 258 total subjects receiving exenatide QW during weeks 30-52. Diabetes Treatment Satisfaction Questionnaire-status (DTSQ-s) and Impact of Weight on Quality of Life-Lite (IWQOL-Lite) were assessed at baseline and weeks 30 and 52. Mean group changes from baseline to week 30 were estimated by ancova; changes from week 30 to week 52 were assessed by Student's t-test. RESULTS: Statistically significant improvements from baseline to week 30 were observed in both treatment groups for DTSQ-s and IWQOL-Lite measures, with significantly greater reduction in perceived frequency of hyperglycaemia and greater satisfaction with continuing treatment in the QW group compared with the BID group. Effect sizes for change in DTSQ-s total scores were 0.84 QW, 0.64 BID; for IWQOL-Lite: 0.96 QW, 0.82 BID. Treatment satisfaction and QOL improved significantly between weeks 30 and 52 for those switching from BID to QW. Occurrence of adverse events did not affect patients' improvements in treatment satisfaction and QOL. CONCLUSIONS: Patients treated with exenatide QW or BID experienced significant and clinically meaningful improvements in treatment satisfaction and QOL. Patients who switched from exenatide BID to exenatide QW administration reported further significant improvements.

Adenosine 3',5'-cyclic monophosphate in Chlamydomonas reinhardtii. Influence on flagellar function and regeneration.

Adenosine 3',5'-cyclic monophosphate (cAMP) influences both flagellar function and flagellar regeneration in Chlamydomonas reinhardtii. The methylxanthine, aminophylline, which can cause a tenfold increase in cAMP level in C. reinhardtii, inhibits flagellar movement and flagellar regeneration by wild-type cells, without inhibiting cell multiplication. Caffeine, a closely related inhibitor, also inhibits flagellar movement and regeneration, but it inhibits cell multiplication too. Regeneration by a mutant lacking the central pair of flagellar microtubules was found to be more sensitive than wild type to inhibition by caffeine and to be subject to synergistic inhibition by aminophylline plus dibutyryl cAMP. Regeneration by three out of seven mutants with different flagellar abnormalities was more sensitive than wild type to these inhibitors. We interpret these results to mean that cAMP affects a component of the flagellum directly or indirectly, and that the responsiveness of that component to cAMP is enhanced by mutations which affect the integrity of the flagellum. The component in question could be microtubule protein.

Evidence for a novel route of wheat storage proteins to vacuoles.

Wheat seed storage proteins are deposited in protein bodies (PB) inside vacuoles, but their subcellular site of aggregation and their route to vacuoles are still controversial. In the present work, an ultra structural analysis of developing wheat endosperm at early to mid maturation was performed to address these issues. Golgi complexes were rarely detected, indicating that their role in wheat storage protein transport is limited. In contrast, a considerable amount of PB was detected in the cytoplasm. Many of these PB were surrounded by RER membranes and were enlarged by fusion of smaller PB. Small, electron lucent vesicles were detected around the surfaces of the PB in the cytoplasm, or attached to them, suggesting that such attachments and subsequent fusion of the vesicles with each other lead to the formation of small vacuoles containing PB inclusions. Immunogold labeling with serum raised against yeast-BiP, an ER-localized protein, demonstrated that the wheat BiP homolog was present within the PB in the cytoplasm as well as inside vacuoles. This confirmed that the PB were formed within the RER and that the Golgi complex was not involved in their transport to vacuoles. It is concluded that a considerable part of the wheat storage proteins aggregate into PB within the RER and are then transported as intact PB to the vacuoles by a novel route that does not utilize the Golgi complex.