bluuebunny/crossref_metadata_2025 huggingface dataset:
Heavy Drinking Trajectories Among Men Who Have Sex with Men: A Longitudinal, Group‐Based Analysis
Authors: Marshall Brandon D. L. , Shoveller Jean A. , Kahler Christopher W. , Koblin Beryl A. , Mayer Kenneth H. , Mimiaga Matthew J. , van den Berg Jacob J. , Zaller Nickolas D. , Operario Don
Published: February 2015

Background

Heavy episodic drinking (HED) is associated with sexual risk behavior and HIV seroconversion among men who have sex with men (MSM), yet few studies have examined heavy drinking typologies in this population.

Methods

We analyzed data from 4,075 HIV‐uninfected MSM (aged 16 to 88) participating in EXPLORE, a 48‐month behavioral intervention trial, to determine the patterns and predictors of HED trajectories. HED was defined as the number of days in which ≥5 alcohol drinks were consumed in the past 6 months. Longitudinal group‐based mixture models were used to identify HED trajectories, and multinomial logistic regression was used to determine correlates of membership in each group.

Results

We identified 5 distinct HED trajectories: nonheavy drinkers (31.9%); infrequent heavy drinkers (i.e., <10 heavy drinking days per 6‐month period, 54.3%); regular heavy drinkers (30 to 45 heavy drinking days per 6 months, 8.4%); drinkers who increased HED over time (average 33 days in the past 6 months to 77 days at end of follow‐up, 3.6%); and very frequent heavy drinkers (>100 days per 6 months, 1.7%). Intervention arm did not predict drinking trajectory patterns. Younger age, self‐identifying as white, lower educational attainment, depressive symptoms, and stimulant use were associated with reporting heavier drinking trajectories. Compared to nonheavy drinkers, participants who increased HED more often experienced a history of childhood sexual abuse (CSA). Over the study period, depressive symptomatology increased significantly among very frequent heavy drinkers.

Conclusions

Socioeconomic factors, substance use, depression, and CSA were associated with heavier drinking patterns among MSM. Multicomponent interventions to reduce HED should seek to mitigate the adverse impacts of low educational attainment, depression, and early traumatic life events on the initiation, continuation, or escalation of frequent HED among MSM.
Delay Discounting for Sucrose in Alcohol‐Preferring and Nonpreferring Rats Using a Sipper Tube Within‐Sessions Task
Authors: Perkel Jessica K. , Bentzley Brandon S. , Andrzejewski Matthew E. , Martinetti Margaret P.
Published: February 2015

Background

Delay discounting (DD) is a measure of impulsivity that quantifies preference for a small reward delivered immediately over a large reward delivered after a delay. It has been hypothesized that impulsivity is an endophenotype associated with increased risk for development of alcohol use disorders (AUDs); however, a causal role of impulsivity is difficult to determine with human studies. We tested this hypothesis by assessing the degree of DD present in alcohol‐naïve rats selectively bred for either high‐ or low‐alcohol preference.

Methods

A novel adaptation of a within‐sessions DD procedure was used to compare impulsivity differences between male alcohol‐preferring (P) and nonpreferring (NP) rat lines (n = 6 per line) using a 5% sucrose reward. Animals chose between 2 options: 2‐second sipper tube access delivered immediately (small reward) or 8‐second access after a variable delay (large reward). Each 50‐minute session consisted of 5 blocks of ten 60‐second trials. Within each session, the delay to the large reward increased in each block of trials. Delays were gradually increased over 3 sets to attain a final delay set of 3, 8, 15, 18, and 25 seconds.

Results

Prior to starting delays, there were no significant differences between lines in sucrose consumption or percent choice for the large reward, and both lines exhibited a clear preference for the large reward. After delays were initiated, choice for the large reward decreased as the delay to its presentation increased. Although discounting of the large, delayed reward was observed for both lines, the degree of discounting, or “impulsivity,” was greater for P rats compared with NP rats.

Conclusions

P rats are more impulsive for sucrose rewards before exposure to alcohol compared with NP rats. Thus, individuals genetically predisposed toward developing AUDs may be more likely to engage in impulsive decision making prior to alcohol exposure.
Development and Validation of the Craving Automated Scale for Alcohol
Authors: Vollstädt‐Klein Sabine , Leménager Tagrid , Jorde Anne , Kiefer Falk , Nakovics Helmut
Published: February 2015

Background

Alcohol consumption has been suggested to be associated with a dysregulation in habit formation and execution in dependent patients. Although there are established craving questionnaires assessing various components of craving, to our knowledge, no questionnaire exists to assess habitual and automated substance intake. In this study, we present and validate the “Craving Automated Scale for Alcohol” (CAS‐A), a newly developed questionnaire assessing craving and other components of automated addictive behavior.

Methods

Forty‐three recently detoxified alcohol‐dependent patients were examined in an inpatient setting using a cross‐sectional design. TheCAS‐A, a self‐report questionnaire, was applied. According to classical test theory, we conducted principal component analyses (PCAs) to identify the components ofCAS‐A, after which we validated it using established craving questionnaires. Thirty‐two healthy participants served as a control group.

Results

Our first‐order PCA identified a 5‐factor solution. A second‐order analysis then identified 2 general factors. These factors were partially associated with established craving measures and with the severity of dependence.

Conclusions

Our findings suggest thatCAS‐A assesses additional components of addictive behavior compared to established measures. We interpret the 5CAS‐A factors as “only aware in hindsight,” “no deliberate decision,” “contrary to intention,” “no perception,” and “no control.” We suggest the 2 general factors be interpreted as “unaware” and “nonvolitional.” Our results indicate that theCAS‐A indeed assesses some components of automated craving and automated drinking behavior in a more sophisticated way than established questionnaires. TheCAS‐A as a retrospective questionnaire can be considered to be a trait rather than a state measure.
Cognitive Regulation of Craving in Alcohol‐Dependent and Social Drinkers
Authors: Naqvi Nasir H. , Ochsner Kevin N. , Kober Hedy , Kuerbis Alexis , Feng Tianshu , Wall Melanie , Morgenstern Jon
Published: February 2015

Background

Helping alcohol‐dependent individuals to cope with, or regulate, cue‐induced craving using cognitive strategies is a therapeutic goal of cognitive behavioral therapy (CBT) for alcohol dependence. An assumption that underlies this approach is that alcohol dependence is associated with deficits in such cognitive regulation abilities. To date, however, the ability to utilize such strategies for regulation of craving has never been tested in a laboratory setting.

Methods

Here we compared 19 non‐treatment‐seeking, alcohol‐dependent drinkers (AD) to 21 social drinkers (SD), using a laboratory task that measured the ability to reduce cue‐induced alcohol craving by thinking about long‐term negative consequences of drinking, which is a specific cognitive regulation strategy that is taught in CBT. The task also assessed the ability to reduce food craving elicited by high‐calorie food cues using a similar strategy.

Results

The reduction in craving when using this cognitive regulation strategy was approximately double in SD, compared to AD, for both alcohol and food cues. Furthermore, in SD but not AD, the ability to regulate cue‐induced alcohol craving was correlated with the ability to regulate food craving. There were no significant correlations found between the ability to regulate cue‐induced alcohol craving and a number of self‐report measures related to severity of alcohol dependence, baseline craving, impulsivity, and general self‐regulation ability, for either AD or SD.

Conclusions

The results suggest that alcohol dependence is associated with deficits in cognitive regulation of cue‐induced craving and that these deficits are not specific to the regulation of alcohol craving, but generalize to the regulation of other appetitive states, such as food craving. Future studies may use similar procedures to address the neural and cognitive processes that underlie such regulation deficits, as well as the effects of treatments such as CBT on these processes.
Cholinergic receptor activation on epithelia protects against cytokine‐induced barrier dysfunction
Authors: Dhawan S. , Hiemstra I. H. , Verseijden C. , Hilbers F. W. , te Velde A. A. , Willemsen L. E. M. , Stap J. , den Haan J. M. , de Jonge W. J.
Published: February 2015

Aim

Various types of cholinergic receptors are expressed on intestinal epithelia. Their function is not completely understood. We hypothesize that cholinergic receptor activation on epithelium may serve a protective function in cytokine‐induced barrier dysfunction.

Methods

The effect of cholinergic receptor activation on cellular barrier function in epithelial cells was assessed by measuring electrical impedance, and by determining para‐cellular transport in transwell experiments. Cell lysates treated with cytokine and/or cholinergic agonists were analysed for cyto‐ and chemokine production, and tight junction (TJ) protein rearrangement was assessed. Primary colonic epithelial cells were isolated from surgically resected colon tissue of patients with inflammatory bowel disease.

Results

IL‐1β induced production of chemokines (CXCL‐1, CXCL‐10, IL‐8, CCL‐7) and led to a rearrangement of TJ proteins (occludin and ZO‐1). This response was inhibited by pre‐treatment with muscarinic, rather than nicotinic, acetylcholine receptor agonists. Treatment with IL‐1β enhanced paracellular permeability (4kD dextran) and reduced impedance across the monolayer, which was counteracted by pre‐incubation with acetylcholine, or muscarinic receptor agonist bethanechol. The protective effect of acetylcholine was antagonized by atropine, underscoring muscarinic receptor involvement. IL‐1β induced transcription of myosin light chain kinase and phosphorylation of myosin light chain, and this cytokine‐induced phosphorylation of MLC was inhibited by muscarinic receptor agonists. Furthermore, in epithelial cells from resection material of patients with Crohn's disease and ulcerative colitis, high expression of CXCL‐8 was associated with a reduced choline acetyl transferase expression, suggesting an aberrant epithelial production of ACh in inflammatory context.

Conclusion

Acetylcholine acts on muscarinic receptors on epithelial cells to maintain epithelial barrier function under inflammatory conditions.
T lymphocytes possess the machinery for 5‐HT synthesis, storage, degradation and release
Authors: Chen Y. , Leon‐Ponte M. , Pingle S. C. , O'Connell P. J. , Ahern G. P.
Published: February 2015

Aim

Although activated T lymphocytes express tryptophan hydroxylase 1 and produce 5‐HT, the metabolic fate and cellular handling of this 5‐HT is unclear. Here, we investigated key proteins in T cells linked to 5‐HT metabolism and storage and compare differences in 5‐HT synthesis and metabolism between T‐cell subsets.

Methods

We cultured human Jurkat T cells and mouse splenic CD3+, CD4+ and CD8+ T cells with or without T‐cell activators (phorbol ester/ionomycin, concavalin A or plate‐bound anti‐CD3 antibody). Subsequently, we measured mRNA and/or protein for monoamine oxidase A and B, vesicular monoamine transporter 1 and 2, N‐acetyl transferase and tryptophan hydroxylase 1. In addition, we measured the release of exogenously loaded [3H]5‐HT and endogenously synthesized 5‐HT from CD4+ and CD8+ T‐cell subsets.

Results

Human and mouse T cells selectively express monoamine oxidase A. Following T‐cell activation, mRNA levels of MAO‐A increase robustly in parallel with tryptophan hydroxylase 1. Concomitant with these changes, T cells increase the expression of the type 1 vesicular monoamine transporter. Raised intracellular [Ca2+] rapidly releases preloaded [3H]5‐HT from CD4+ and CD8+ T cells indicating that these cells have the capacity for the storage and regulated secretion of 5‐HT. Notably, both the expression of tryptophan hydroxylase 1 and monoamine oxidase A, and 5‐HT production are significantly greater in CD8+ compared with CD4+ T cells.

Conclusion

These data reveal coordinated changes in 5‐HT production, metabolism and storage that may optimize 5‐HT secretion from the CD8+ T cell subset in response to activation stimuli.
Purinergic receptors in tubulointerstitial inflammatory cells: a pathophysiological mechanism of salt‐sensitive hypertension
Authors: Franco M. , Bautista‐Pérez R. , Pérez‐Méndez O.
Published: February 2015

Recent studies have suggested that both the tubulointerstitial inflammatory cells and the activation of purinergic receptors integrate common mechanisms that result in salt‐sensitive hypertension. The basis of this hypothesis is that renal endothelial cells release ATP in response to shear stress in the setting of hypertension. It has been demonstrated that the over‐expression and activation of the P2X7, P2Y12 and P2X1 receptors favour the elevation of blood pressure induced by high‐salt intake. In addition, the release of interleukins and inflammatory mediators in the tubulointerstitial area appears to be related to the activation of these receptors. Renal vasoconstriction and tubulointerstitial injury develop as a result, which increase sodium reabsorption by epithelial cells. Consistent with these effects, the reduction of tubulointerstitial inflammation caused by immunosuppressants, such as mycophenolate mofetil, prevents the development of salt‐sensitive hypertension. Also, P2X7‐receptor knockout mice develop minor renal injury when hypertension is induced via the administration of deoxycorticosterone acetate and a high‐salt diet. In the setting of angiotensin II‐induced hypertension, which is an early stage in the development of salt‐sensitive hypertension, an acute blockade with the specific, non‐selective P2 antagonist pyridoxalphosphate‐6‐azophenyl‐2’,4’‐disulfonic acid prevented the renal vasoconstriction induced by angiotensin II. In addition, it normalized glomerular haemodynamics and restored sodium excretion to control values. These findings suggest that chronic administration of P2 purinergic antagonists may prevent the deleterious effects of purinergic receptors during the development of salt‐sensitive hypertension.
Phase Ib/II trial of CYKLONE (cyclophosphamide, carfilzomib, thalidomide and dexamethasone) for newly diagnosed myeloma
Authors: Mikhael Joseph R. , Reeder Craig B. , Libby Edward N. , Costa Luciano J. , Bergsagel P. Leif , Buadi Francis , Mayo Angela , Nagi Reddy Sravan K. , Gano Katherine , Dueck Amylou C. , Stewart A. Keith
Published: February 2015

Sixty‐four transplant‐eligible patients with newly diagnosed multiple myeloma (NDMM) received carfilzomib (days 1, 2, 8, 9, 15, 16), 300 mg/m2 cyclophosphamide (days 1, 8, 15), 100 mg thalidomide (days 1–28) and 40 mg dexamethasone (days 1, 8, 15, 22) in 28‐day cycles (CYKLONE regimen). Carfilzomib was dose‐escalated to 15/20, 20/27, 20/36 and 20/45 mg/m2 to determine the maximum tolerated dose (MTD), which was 20/36 mg/m2. Regardless of attribution, common Grade 3 or higher adverse events were lymphopenia (38%), neutropenia (23%) and anaemia (20%). All peripheral neuropathy (31%) was Grade 1 and considered most likely to be thalidomide‐related. Common cardiac or pulmonary events of any grade in ≥5% of patients included dyspnoea (20%) and cough (6%). Overall (N = 64), 91% of patients achieved a best response of partial response or better across all cycles of treatment, including five patients with complete responses. At the MTD (n = 29), 59% of patients achieved a very good partial response or better after four cycles (primary end point). Stem cell collection was successful in all patients in whom it was attempted (n = 42). Progression‐free survival and overall survival at 24 months was 76% and 96%, respectively (median follow‐up of 17·5 months). CYKLONE appears highly efficacious in NDMM patients, with manageable toxicities.
Outcome of aplastic anaemia in children. A study by the severe aplastic anaemia and paediatric disease working parties of the European group blood and bone marrow transplant
Authors: Dufour Carlo , Pillon Marta , Sociè Gerard , Rovò Alicia , Carraro Elisa , Bacigalupo Andrea , Oneto Rosi , Passweg Jakob , Risitano Antonio , Tichelli Andrè , Peffault de Latour Regis , Schrezenmeier Hubert , Hocshmann Britta , Peters Christina , Kulasekararaj Austin , Van Biezen Anja , Samarasinghe Sujith , Hussein Ayad Ahmed , Ayas Mouhab , Aljurf Mahmoud , Marsh Judith
Published: February 2015

This study analysed the outcome of 563 Aplastic Anaemia (AA) children aged 0–12 years reported to the Severe Aplastic Anaemia Working Party database of the European Society for Blood and Marrow Transplantation, according to treatment received. Overall survival (OS) after upfront human leucocyte antigen‐matched family donor (MFD) haematopoietic stem cell transplantation (HSCT) or immunosuppressive treatment (IST) was 91% vs. 87% (P 0·18). Event‐free survival (EFS) after upfront MFD HSCT or IST was 87% vs. 33% (P 0·001). Ninety‐one of 167 patients (55%) failed front‐line IST and underwent rescue HSCT. The OS of this rescue group was 83% compared with 91% for upfront MFD HSCT patients and 97% for those who did not fail IST up‐front (P 0·017). Rejection was 2% for MFD HSCT and HSCT post‐IST failure (P 0·73). Acute graft‐versus‐host disease (GVHD) grade II‐IV was 8% in MFD graft vs. 25% for HSCT post‐IST failure (P < 0·0001). Chronic GVHD was 6% in MFD HSCT vs. 20% in HSCT post‐IST failure (P < 0·0001). MFD HSCT is an excellent therapy for children with AA. IST has a high failure rate, but remains a reasonable first‐line choice if MFD HSCT is not available because high OS enables access to HSCT, which is a very good rescue option.
Management and controversies of classical Hodgkin lymphoma in pregnancy
Authors: Eyre Toby A. , Lau I‐Jun , Mackillop Lucy , Collins Graham P.
Published: February 2015

The goal of managing classical Hodgkin lymphoma (cHL) in pregnancy is to obtain good long‐term outcomes for both the mother and fetus. Given the excellent outcomes outside of pregnancy, the goal of treatment should remain curative. There remains a tension and debate regarding the timing of chemotherapy, the curative nature of such treatment and the timing of delivery. Moreover, the aim during pregnancy should be to minimize fetal toxicity and optimize perinatal outcomes. The management of cHL within pregnancy was covered within the excellent recent British Committee for Standards in Haematology guidelines, but with necessary brevity. By reviewing the literature over the last 30 years, herein we discuss the options for management during each trimester. Critical organogenesis occurs between 2 and 8 weeks post‐conception; during which time the immature fetus is vulnerable to cytotoxic exposure. We discuss the evidence for using ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) and single agent vinblastine in the first trimester. cHL presenting in pregnancy raises complex and difficult ethical dilemmas that can cause anxiety for patients, families and physicians. Decision‐making must be multi‐disciplinary and holistic, taking into account the patient's wishes, psycho‐social and religious beliefs and personal circumstances. Clear communication between the haemato‐oncologist, medical obstetrician, nurse specialists, midwives and neonatologists is paramount to a successful outcome.
Guideline of guidelines: kidney stones
Authors: Ziemba Justin B. , Matlaga Brian R.
Published: February 2015

Several professional organizations have developed evidence‐based guidelines for the initial evaluation, diagnostic imaging selection, symptomatic management, surgical treatment, medical therapy, and prevention of recurrence for both ureteric and renal stones. The purpose of this article is to summarize these guidelines with reference to the strength of evidence. All guidelines endorse an initial evaluation to exclude concomitant infection, imaging with a non‐contrast computed tomography scan, and consideration of medical expulsive therapy or surgical intervention depending on stone size and location. Recommends for metabolic evaluation vary by guideline, but all endorse increasing fluid intake to reduce the risk of recurrence.
Utility and significance of ureteric frozen section analysis during radical cystectomy
Authors: Satkunasivam Raj , Hu Brian , Metcalfe Charles , Ghodoussipour Saum B. , Aron Manju , Cai Jie , Miranda Gus , Gill Inderbir , Daneshmand Siamak
Published: February 2015

Objective

To assess the utility of routine frozen section analysis of ureters at the time of radical cystectomy (RC) for urothelial cancer (UC), and the long‐term outcomes of adverse ureteric pathology.

Patients and Methods

Pathological data on 2 047 patients undergoing RC for UC with routine frozen section analysis of ureters (January 1971 to December 2009) were analysed. Univariate and multivariable logistic and Cox proportional hazards models were used to determine the risk of upper tract UC (UTUC) recurrence, local recurrence and overall survival in those identified as having adverse pathology (severe atypia/carcinoma in situ [CIS] or UC) at time of frozen section analysis.

Results

Adverse pathology was identified by frozen section analysis in 178 patients (8.6%). Frozen section analysis was found to have poor sensitivity in identifying adverse pathology (59.1%), which was improved in patients with preoperative CIS (68.0%). After a median (interquartile range) follow‐up of 12.4 (1.9–10.1) years, 28 patients (1.4%) developed UTUC recurrence. There were no uretero‐enteric anastomotic recurrences. Adverse pathology on frozen section analysis was associated with UTUC recurrence on univariate analysis (hazard ratio [HR] 6.2, 95% confidence interval [CI] 2.9–13.5), but 15/28 patients (54%) with UTUC recurrence had benign ureteric frozen section analysis on initial sectioning. Adverse pathology on frozen section analysis was not independently associated with the risk of local recurrence (HR 1.08, 95% CI 0.61–1.89) or overall survival (HR 1.12, 95% CI 0.94–1.35) in multivariate models.

Conclusions

Ureteric frozen section analysis has poor sensitivity and may be marginally improved in pre‐existing CIS. UTUC recurrence is rare and can occur despite negative frozen section analysis. Our data question the utility of routine frozen section analysis of the distal ureteric margin at the time of RC.
Does the addition of targeted prostate biopsies to standard systemic biopsies influence treatment management for radiation oncologists?
Authors: Kamrava Mitchell , Hegde John V. , Abgaryan Narine , Chang Edward , Le Jesse D. , Wang Jason , Kupelian Patrick A. , Marks Leonard S.
Published: February 2015

Objectives

To study the management impact that magnetic resonance imaging (MRI)‐guided targeted prostate biopsies could provide relative to using only non‐targeted systematic biopsies in men with clinically localized prostate cancer (PCa).

Patients and Methods

A consecutive series of untreated men undergoing Artemis (MRI‐ultrasonography fusion) biopsies between March 2010 and June 2013 was evaluated in this retrospective, institutional review board‐approved study. Fusion biopsy included MRI‐targeted and systematic sampling at the same session. 3‐Tesla multiparametric MRI was performed at a median of 2 weeks before biopsy. Patients were included if ≥1 systematic core was found to harbour PCa. The impact of the information obtained from targeted vs systematic biopsies was studied with regard to the following: Gleason score (GS), National Comprehensive Cancer Network (NCCN) risk reclassification, cancer core length, percentage of core positive for tumour involvement, and percentage of positive biopsy cores.

Results

The study sample included 215 men (mean ± sd age 66 ± 8 years). The median (range) prostate‐specific antigen (PSA) was 6.0 (0.7–181) ng/mL. The mean number of total biopsy samples was 18 (12 systematic and six targeted samples). Of 215 men, 34 (16%) had a higher GS on targeted vs systematic biopsy. A total of 21/183 men (12%) were stratified into a higher NCCN risk group when incorporating targeted biopsy GS results and 18/101 men (18%) were upgraded to intermediate‐ or high‐risk from the low‐risk group. Among the 34 men whose cancer severity was upgraded, increases in cancer core length, percentage of tumour involvement and percentage of cores involved were all statistically significant (P < 0.01).

Conclusion

Targeted prostate biopsy provided information about GS, NCCN risk and tumour volume beyond that obtained in systematic biopsies, specifically increasing the proportions of men in the intermediate‐ and high‐risk groups. Such men may be recommended for additional treatments (pelvic nodal irradiation or hormonal therapy). The appropriateness of changing treatment because of targeted biopsy results is still unclear.
Serum luteinizing hormone concentration is significantly associated with recovery of urinary function after radical prostatectomy
Authors: Namiki Shunichi , Mitsuzuka Koji , Kaiho Yasuhiro , Yamada Shigeyuki , Adachi Hisanobu , Yamashita Shinichi , Saito Hideo , Ito Akihiro , Nakagawa Haruo , Takegami Misa , Arai Yoichi
Published: February 2015

Objective

To perform a longitudinal investigation of the correlation between functional recovery and sex hormone concentrations after radical prostatectomy (RP).

Patients and Methods

A total of 72 consecutive patients undergoing RP between January 2012 and June 2013 were prospectively included and serially followed after surgery for comparative analysis. Their luteinizing hormone (LH) and total testosterone (TT) concentrations were measured before surgery and 3 and 12 months after surgery. They also filled out a health‐related quality of life questionnaire before and at 1, 3, 6 and 12 months after surgery.

Results

The mean LH concentration increased from 4.28 U/L at baseline to 5.53 U/L at 3 months and remained high at 12 months after RP (both P < 0.001). There were no significant changes in the TT concentration after RP. LH at baseline was negatively correlated with the urinary function (UF) score at 3 and 12 months after RP (P = 0.030 and 0.032, respectively). After RP, subjects with high baseline LH (n = 37) were more likely than those with low LH concentrations to report lower UF scores (P = 0.014). Multivariate analysis of variance in an interaction of time × LH concentration for UF scores indicated a significant relationship between changes in UF score and LH concentration (P = 0.004).

Conclusions

Radical prostatectomy affects sex hormones by increasing LH concentrations, while TT concentrations remain stable after surgery. Baseline LH concentrations are significantly associated with the recovery of urinary outcomes after RP.
Outcomes of robotic‐assisted laparoscopic upper urinary tract reconstruction: 250 consecutive patients
Authors: Marien Tracy , Bjurlin Marc A. , Wynia Blake , Bilbily Matthew , Rao Gaurav , Zhao Lee C. , Shah Ojas , Stifelman Michael D.
Published: February 2015

Objective

To evaluate the long‐term outcomes of robotic‐assisted laparoscopic (RAL) upper urinary tract (UUT) reconstruction performed at a tertiary referral centre.

Materials and Methods

Data from 250 consecutive patients undergoing RAL UUT reconstruction, including pyeloplasty with or without stone extraction, ureterolysis, uretero‐ureterostomy, ureterocalicostomy, ureteropyelostomy, ureteric reimplantation and buccal mucosa graft ureteroplasty, were collected at a tertiary referral centre between March 2003 and December 2013. The primary outcomes were symptomatic and radiographic improvement of obstruction and complication rate. The mean follow‐up was 17.1 months.

Results

Radiographic and symptomatic success rates ranged from 85% to 100% for each procedure, with a 98% radiographic success rate and 97% symptomatic success rate for the entire series. There were a total of 34 complications, none greater than Clavien grade 3.

Conclusion

Robotic‐assisted laparoscopic UUT can be performed with few complications, with durable long‐term success, and is a reasonable alternative to the open procedure in experienced robotic surgeons.
Preoperative predictive model of recovery of urinary continence after radical prostatectomy
Authors: Matsushita Kazuhito , Kent Matthew T. , Vickers Andrew J. , von Bodman Christian , Bernstein Melanie , Touijer Karim A. , Coleman Jonathan A. , Laudone Vincent T. , Scardino Peter T. , Eastham James A. , Akin Oguz , Sandhu Jaspreet S.
Published: February 2015

Objective

To build a predictive model of urinary continence recovery after radical prostatectomy (RP) that incorporates magnetic resonance imaging (MRI) parameters and clinical data.

Patients and Methods

We conducted a retrospective review of data from 2 849 patients who underwent pelvic staging MRI before RP from November 2001 to June 2010. We used logistic regression to evaluate the association between each MRI variable and continence at 6 or 12 months, adjusting for age, body mass index (BMI) and American Society of Anesthesiologists (ASA) score, and then used multivariable logistic regression to create our model. A nomogram was constructed using the multivariable logistic regression models.

Results

In all, 68% (1 742/2 559) and 82% (2 205/2 689) regained function at 6 and 12 months, respectively. In the base model, age, BMI and ASA score were significant predictors of continence at 6 or 12 months on univariate analysis (P < 0.005). Among the preoperative MRI measurements, membranous urethral length, which showed great significance, was incorporated into the base model to create the full model. For continence recovery at 6 months, the addition of membranous urethral length increased the area under the curve (AUC) to 0.664 for the validation set, an increase of 0.064 over the base model. For continence recovery at 12 months, the AUC was 0.674, an increase of 0.085 over the base model.

Conclusion

Using our model, the likelihood of continence recovery increases with membranous urethral length and decreases with age, BMI and ASA score. This model could be used for patient counselling and for the identification of patients at high risk for urinary incontinence in whom to study changes in operative technique that improve urinary function after RP.
Intravesical gemcitabine in combination with mitomycin C as salvage treatment in recurrent non‐muscle‐invasive bladder cancer
Authors: Cockerill Patrick A. , Knoedler John J. , Frank Igor , Tarrell Robert , Karnes Robert J.
Published: February 2015

Objectives

To evaluate oncological outcomes after combination intravesical therapy with gemcitabine (GC) and mitomycin C (MMC) in the setting of recurrent non‐muscle‐invasive bladder cancer (NMIBC) after failure of previous intravesical therapy.

Patients and Methods

We retrospectively identified patients with recurrent NMIBC after previous intravesical therapy, who refused or were not candidates for cystectomy, between 2005 and 2011. GC and MMC were sequentially instilled weekly for 6–8 weeks. Data were collected regarding patient demographics, bladder cancer history, and number and type of intravesical therapies before GC/MMC. Outcomes evaluated included time to recurrence and/or progression after GC/MMC. Recurrence‐free outcomes were estimated using the Kaplan–Meier method, and Cox proportional hazards regression models were used to test the association of clinicopathological features with outcomes.

Results

In all, 27 patients were identified, 23 with high‐risk disease (high‐grade or carcinoma in situ) and four with intermediate‐risk disease (multifocal or recurrent low‐grade). All patients received prior intravesical therapy, and 17 patients (63%) received multiple courses. Twenty‐four patients were treated with BCG. The median (range) disease‐free survival of all patients was 15.2 (1.7–39.3) months. Seventeen patients (63%) developed recurrent bladder cancer, a median of 15.2 months after therapy. One patient progressed to muscle‐invasive disease 5 months after treatment, and one developed metastatic disease 22 months after treatment. Three patients went on to cystectomy. Ten patients (37%) had no evidence of disease at last follow‐up, with a median follow‐up of 22.1 months.

Conclusion

The combination of intravesical GC and MMC could offer durable recurrence‐free survival to some patients with recurrent NMIBC who are not candidates for, or refuse, cystectomy.
FORECASTING US INFLATION USING DYNAMIC GENERAL‐TO‐SPECIFIC MODEL SELECTION
Authors: Bagdatoglou George , Kontonikas Alexandros , Wohar Mark E.
Published: February 2015

We forecast US inflation using a standard set of macroeconomic predictors and a dynamic model selection and averaging methodology that allows the forecasting model to change over time. Pseudo out‐of‐sample forecasts are generated from models identified from a multipath general‐to‐specific algorithm that is applied dynamically using rolling regressions. Our results indicate that the inflation forecasts that we obtain employing a short rolling window substantially outperform those from a well‐established univariate benchmark, and contrary to previous evidence, are considerably robust to alternative forecast periods.
Luminescence dating ofMiddlePleistocene proglacial deposits from northernSwitzerland: methodological aspects and stratigraphical conclusions
Authors: Lowick Sally E. , Buechi Marius W. , Gaar Dorian , Graf Hans R. , Preusser Frank
Published: February 2015

Optically stimulated luminescence (OSL) dating was applied to proglacial deposits from theKlettgauValley in northernSwitzerland, which is understood to record several phases of glaciation prior to theLastInterglacial. The aim was to provide an independent chronology for the different sedimentary units to understand better the complex depositional history of the region. This time range requires care when assessing the reliability of the luminescence protocols applied. Equivalent doses for fine‐ and coarse‐grain quartz remained below 300Gy, while dose response curves for both fractions continued to display growth above 500Gy. Dose recovery tests confirmed the ability of the single aliquot regenerative (SAR) protocol to recover laboratory doses of a similar size to burial doses, and isothermal decay measurements confirmed the stability of the quartz signal. Having passed rigorous testing criteria, quartzOSLages of up to ∼200 ka were considered reliable but significantly underestimated expected ages and prompt a reconsideration of earlier interpretations of the stratigraphy for this site. Rather than representing three separate glaciations, quartz luminescence ages instead suggest that these deposits record up to four independent ice advances duringMarineIsotopeStage 6. For both single grain and single aliquot feldspar dating, it was not possible to separate the conflicting influences of anomalous fading and partial bleaching. However, uncorrected feldspar central age model ages were found to be in reasonable agreement with quartz age estimates, and suggest that feldspar ages may still offer useful additional information in this region.
Effects of receptor tyrosine kinase inhibitors on VEGF165a‐ and VEGF165b‐stimulated gene transcription in HEK‐293 cells expressing human VEGFR2
Authors: Carter Joanne J , Wheal Amanda J , Hill Stephen J , Woolard Jeanette
Published: February 2015

Background and Purpose

Receptor tyrosine kinase inhibitors (RTKIs) targeted at VEGF receptor 2 (VEGFR2) have proved to be attractive approaches to cancer therapy based on their ability to reduce angiogenesis. Here we have undertaken a quantitative analysis of the interaction of RTKIs and two VEGF splice variants, VEGF165a and VEGF165b, with VEGFR2 by studying nuclear factor of activated T‐cells (NFAT) reporter gene activity in live HEK‐293 cells.

Experimental Approach

HEK‐293 cells expressing the human VEGFR2 and a firefly luciferase reporter gene regulated by an NFAT response element were used for quantitative analysis of the effect of RTKIs on VEGF165a‐ and VEGF165b‐stimulated luciferase gene expression.

Key Results

VEGF165a produced a concentration‐dependent activation of the NFAT‐luciferase reporter gene in living cells that was inhibited in a non‐competitive fashion by four different RTKIs (cediranib, pazopanib, sorafenib and vandetanib). The potency obtained for each RTKI from this analysis was similar to those obtained in binding studies using purified VEGFR2 kinase domains. VEGF165b was a lower‐efficacy agonist of the NFAT‐luciferase response when compared with VEGF165a. Analysis of the concentration–response data using the operational model of agonism indicated that both VEGF165 isoforms had similar affinity for VEGFR2.

Conclusions and Implications

Quantitative pharmacological analysis of the interaction of VEGF165 isoforms and RTKIs with VEGFR2 in intact living cells has provided important insights into the relative affinity and efficacy of VEGF165a and VEGF165b for activation of the calcineurin‐ NFAT signalling pathway by this tyrosine kinase receptor.
From Flexibility to Constraint: The Contrastive Use of Lexical Tone in Early Word Learning
Authors: Hay Jessica F. , Graf Estes Katharine , Wang Tianlin , Saffran Jenny R.
Published: February 2015

Infants must develop both flexibility and constraint in their interpretation of acceptable word forms. The current experiments examined the development of infants' lexical interpretation of non‐native variations in pitch contour. Fourteen‐, 17‐, and 19‐month‐olds (Experiments 1 and 2, N = 72) heard labels for two novel objects; labels contained the same syllable produced with distinct pitch contours (Mandarin lexical tones). The youngest infants learned the label–object mappings, but the older groups did not, despite being able to discriminate pitch differences in an object‐free task (Experiment 3, N = 14). Results indicate that 14‐month‐olds remain flexible regarding what sounds make meaningful distinctions between words. By 17–19 months, experience with a nontonal native language constrains infants' interpretation of lexical tone.
Novel therapies for memory cells in autoimmune diseases
Authors: Bhargava P , Calabresi P A
Published: February 2015

Autoimmune diseases are a major cause of morbidity, and their incidence and prevalence continue to rise. Treatments for these diseases are non-specific and result in significant adverse effects. Targeted therapies may help in improving the risk : benefit ratio associated with treatment. Immunological memory is an important feature of the vertebrate immune system that results in the production of cells that are long-lived and able to respond to antigens in a more robust manner. In the setting of autoimmunity this characteristic becomes detrimental due to the ongoing response to a self-antigen(s). These memory cells have been shown to play key roles in various autoimmune diseases such as type 1 diabetes, multiple sclerosis and psoriasis. Memory T cells and B cells can be identified based on various molecules expressed on their surface. Memory T cells can be divided into three main categories – central memory, effector memory and resident memory cells. These subsets have different proliferative potential and cytokine-producing abilities. Utilizing differentially expressed surface molecules or downstream signalling pathway proteins in these cells it is now possible to target memory cells while sparing naive cells. We will discuss the various available options for such a strategy and several potential strategies that may yield successful therapies in the future.
Common genetic variants associated with thyroid function may be risk alleles for Hashimoto's disease and Graves' disease
Authors: Campbell Purdey , Brix Thomas H. , Wilson Scott G. , Ward Lynley C. , Hui Jennie , Beilby John P. , Hegedüs Laszlo , Walsh John P.
Published: February 2015

Background

Recent studies have identified common genetic variants associated with TSH, free T4 and thyroid peroxidase antibodies, but it is unclear whether these differ between patients with Hashimoto's disease and Graves' disease.

Objective

To examine whether 11 common genetic variants differ between Graves' disease and Hashimoto's disease.

Patients and measurements

We genotyped 11 common variants in a discovery cohort of 203 Australian patients with autoimmune thyroid disease (AITD). Two variants with significant or suggestive associations were analysed in a replication cohort of 384 Danish patients.

Results

For rs753760 (PDE10A), the minor allele frequency in Graves' disease and Hashimoto's disease was 0·38 vs. 0·23, respectively, (P = 6·42 × 10−4) in the discovery cohort, 0·29 vs. 0·24 (P = 0·147) in the replication cohort and 0·32 vs. 0·24 in combined analysis (P = 0·0021; all analyses adjusted for sex). In healthy controls from Busselton, the frequency was 0·29, significantly different from Hashimoto's disease but not Graves' disease. For rs4889009 (MAF gene region), the frequency of the minor G‐allele in Graves' disease and Hashimoto's disease was 0·48 vs. 0·36 (P = 0·0156) in the discovery cohort, 0·48 vs. 0·34 (P = 1·83 × 10−4) in the replication cohort and 0·48 vs. 0·35 in the combined analysis (P = 7·53 × 10−6); in controls, the frequency was 0·38, significantly different from Graves' disease but not Hashimoto's disease. After further adjustment for smoking, associations with rs4889009 remained significant, whereas those with rs753760 were not.

Conclusion

Common variants in PDE10A and MAF gene regions may influence whether patients with AITD develop Graves' disease or Hashimoto's disease.
Metabolic and hormonal effects of ‘catch‐up’ sleep in men with chronic, repetitive, lifestyle‐driven sleep restriction
Authors: Killick Roo , Hoyos Camilla M. , Melehan Kerri L. , Dungan George C. , Poh Jonathon , Liu Peter Y.
Published: February 2015

Objective

Acutely restricting sleep worsens insulin sensitivity in healthy individuals whose usual sleep is normal in duration and pattern. The effect of recovery or weekend ‘catch‐up’ sleep on insulin sensitivity and metabolically active hormones in individuals with chronic sleep restriction who regularly ‘catch‐up’ on sleep at weekends is as yet unstudied.

Design

19 men (mean ± SEM age 28·6 ± 2·0 years, BMI 26·0 ± 0·8 kg/m2) with at least 6 months’ history (5·1 ± 0·9 years) of lifestyle‐driven, restricted sleep during the working week (373 ± 6·6 min/night) with regular weekend ‘catch‐up’ sleep (weekend sleep extension 37·4 ± 2·3%) completed an in‐laboratory, randomized, crossover study comprising two of three conditions, stratified by age. Conditions were 3 weekend nights of 10 hours, 6 hours or 10 hours time‐in‐bed with slow wave sleep (SWS) suppression using targeted acoustic stimuli.

Measurements

Insulin sensitivity was measured in the morning following the 3rd intervention night by minimal modelling of 19 samples collected during a 2‐h oral glucose tolerance test. Glucose, insulin, c‐peptide, leptin, peptide YY (PYY), ghrelin, cortisol, testosterone and luteinizing hormone (LH) were measured from daily fasting blood samples; HOMA‐IR, HOMA‐β and QUICKI were calculated.

Results

Insulin sensitivity was higher following three nights of sleep extension compared to sustained sleep restriction. Fasting insulin, c‐peptide, HOMA‐IR, HOMA‐β, leptin and PYY decreased with ‘catch‐up’ sleep, QUICKI and testosterone increased, while morning cortisol and LH did not change. Targeted acoustic stimuli reduced SWS by 23%, but did not alter insulin sensitivity.

Conclusions

Three nights of ‘catch‐up’ sleep improved insulin sensitivity in men with chronic, repetitive sleep restriction. Methods to improve metabolic health by optimizing sleep are plausible.
Does concomitant autonomous adrenal cortisol overproduction have the potential to confound the interpretation of adrenal venous sampling in primary aldosteronism?
Authors: Goupil Rémi , Wolley Martin , Ahmed Ashraf H. , Gordon Richard D. , Stowasser Michael
Published: February 2015

Objective

Demonstration of unilateral aldosterone production by adrenal venous sampling (AVS) is required to select appropriate candidates for adrenalectomy in patients with primary aldosteronism (PA). During AVS, aldosterone and cortisol levels are measured to assess successful cannulation and lateralization. In patients with aldosterone‐producing adenoma (APA), concurrent autonomous cortisol secretion might confound AVS results.

Design and patients

We retrospectively examined results in eight patients with cortisol‐producing adenoma (CPA), but without PA, who underwent AVS.

Results

In all eight, cortisol was higher on the CPA side than contralateral (CL) (median 6·7‐fold [range 2·4–27·2]; P = 0·012]). By cortisol criteria, CL catheter placement would have been labelled inadequate in six despite adrenal venous aldosterone levels markedly higher than peripheral (41·6‐fold [7·2–510·5]; P < 0·001), suggesting successful cannulation. In all eight, adrenal venous aldosterone/cortisol (A/C) ratios on the CL side were indicative of increased aldosterone production (≥2 times peripheral), but in only three patients on the CPA side (difference CL side 44·5‐fold [6·0–109·0] vs CPA side 1·65‐fold [1·0–23·0]; P = 0·017). A/C ratios were higher on the CL vs the CPA side in seven (20·0‐fold [4·7–76·0]).

Conclusion

These results in patients with CPA suggest that in patients with APA, concurrent autonomous unilateral cortisol hypersecretion could confound AVS accuracy by increasing cortisol levels (reducing A/C ratio) on the CPA side, while reducing levels (increasing A/C ratio and suggesting failed cannulation) on the CL side. Misclassification of PA subtype or repeat AVS could result, underscoring the importance of adequately assessing cortisol production prior to AVS and the need to consider alternatives.
Supplementation of vitamin D in pregnancy and its correlation with feto‐maternal outcome
Authors: Sablok Aanchal , Batra Aruna , Thariani Karishma , Batra Achla , Bharti Rekha , Aggarwal Abha Rani , Kabi B.C. , Chellani Harish
Published: February 2015

Context

Vitamin D deficiency is widely prevalent throughout the world. Pregnant women, neonates and infants form most vulnerable groups for vitamin D deficiency.

Objective

(1) To find prevalence of vitamin D deficiency in pregnant women. (2) To evaluate the effect of supplementation with cholecalciferol in improving vitamin D levels in pregnant women and evaluate its correlation with feto‐maternal outcome.

Design

Randomized control trial from years 2010 to 2012.

Setting

Tertiary care centre, Delhi, India.

Participants

One‐hundred and eighty pregnant women. Study population divided randomly into two groups: group A: nonintervention (60 women) and group B: intervention (120 women).

Intervention

The intervention group received supplementation of vitamin D in dosages depending upon 25(OH)‐D levels.

Main outcome measures

Risk of maternal complications such as preterm labour, pre‐eclampsia and gestational diabetes associated with vitamin D deficiency and risk of low birthweight and poor Apgar score in infants of mothers with vitamin D deficiency.

Results

Adjusted serum 25(OH)‐D concentration was lower in group A as compared to group B (mean 46·11 ± 74·21 nmol/l vs 80 ± 51·53 nmol/l). Forty‐four percent patients in group A and 20·3% patients in group B developed preterm labour/pre‐eclampsia/gestational diabetes. Newborns of mothers in group A had lower cord blood levels of 25(OH)‐D levels as compared to group B (mean 43·11 ± 81·32 nmol/l vs 56·8 ± 47·52 nmol/l). They also had lower birthweight of mean 2·4 ± 0·38 kg as compared to group B 2·6 ± 0·33 kg.

Conclusions

Vitamin D supplementation reduces risk of maternal comorbidities and helps improve neonatal outcomes.