Polyuria in patients with lower urinary tract symptoms: Prevalence and etiology.

INTRODUCTION: Patients with lower urinary tract symptoms (LUTS) can be subcategorized into polyuria, normal or oliguria groups. Polyuria may be caused by pathologies including diabetes mellitus (DM), chronic kidney disease (CKD), diabetes insipidus (DI), or primary polydipsia (PPD). While fluid restriction is appropriate for some, doing so in all may result in serious complications. This study investigates the prevalence of these pathologies in LUTS patients with polyuria. MATERIALS AND METHODS: Two databases were retrospectively queried for men and women who filled out a lower urinary tract symptom score (LUTSS) questionnaire, 24-h bladder diary (24HBD) and were polyuric (>2.5 L/day). Patients were divided into four groups: poorly controlled DM, DI, an CKD grade 3 and PPD. One-way analysis of variance compared 24HBD and LUTSS questionnaires. Pearson correlation examined LUTSS and bother with 24-h voided volume (24 HVV), maximum voided volume (MVV) and total voids. RESULTS: Among 814 patients who completed a 24HBD, 176 had polyuria (22%). Of the patients with complete data, 7.8% had poorly-controlled DM, 3.1% had DI, 4.7% had CKD grade 3% and 84.4% had PPD. Amongst the four different sub-groups, significant differences were seen in 24 HVV (p < 0.001), nocturnal urine volume (NUV) (p < 0.001), MVV (p = 0.003), daytime voids (p = 0.05), nocturnal polyuria index (NPi) (p < 0.001) and nocturia index (Ni) (p = 0.002). Significance was also seen between LUTSS and bother subscore (r = 0.68, p < 0.001), LUTSS and total voids (r = 0.29, p = 0.001) and bother sub-score and total voids (r = 0.21, p = 0.019). CONCLUSIONS: 22% of patients with LUTS were found to have polyuria based on a 24HBD. Within this cohort, four sub-populations were identified as being demonstrating statistically significant differences in 24 HVV, NUV, MVV, daytime voids, NPi and Ni. Identifying the underlying etiology of polyuria should be carried out to safely treat patients with LUTS.

Does traditional pharmacotherapy augment behavioral modification in the treatment of nocturia?

AIMS: To assess the efficacy of traditional first-line non-antidiuretic pharmacotherapy for nocturia in the real-world outpatient urology setting. METHODS: We retrospectively analyzed voiding diaries from adult men treated for lower urinary tract symptoms (LUTS) at an outpatient urology clinic to identify pairs of voiding diaries with ≥1 nocturnal void at baseline and a corresponding follow-up diary completed within 1 year. We compared the odds of nocturia improvement (decrease of ≥1 nocturnal void) in patients started on LUTS pharmacotherapy versus behavioral modification alone. RESULTS: Two hundred and thirteen diary pairs from 93 patients were included. Fifty-seven diary pairs were identified from patients prescribed at least one LUTS drug on the initial visit and 156 diary pairs were identified from patients receiving behavioral modification alone. All standard voiding diary parameters were assessed, and only maximum voided volume differed at baseline (240 ml [interquartile range: 200-330 ml] vs. 280 ml [200-400 ml] with and without pharmacotherapy, respectively, p = 0.04). The odds of nocturia improvement did not significantly differ between pharmacotherapy and behavioral modification treatment groups (crude odds ratio [OR]: 1.16 [95% confidence interval: 0.63-2.16], p = 0.63; maximum voided volume [MVV]-adjusted OR: 1.19 [0.63-2.22], p = 0.59). In contrast, improvement in 24-h urinary frequency was more likely with pharmacotherapy versus behavioral modification alone (crude OR: 2.36 [1.22-4.56], p = 0.01; MVV-adjusted OR: 2.05 [1.05-4.01], p = 0.04). Results were consistent on subgroup analyses restricted to first diary pairs from each patient. CONCLUSION: Despite improvement in 24-h voiding frequency, there was no evidence that adjunctive pharmacotherapy provided a benefit in the treatment of nocturia in men receiving behavioral counseling.

Determinants of neoadjuvant chemotherapy for urothelial muscle-invasive bladder cancer: Does location matter?

INTRODUCTION: Bladder cancer care has been increasingly concentrated in high-volume metropolitan medical centres (ie, "regionalisation" of care). We aimed to assess the potential role of geographic factors, including facility region and distance to treatment centre, as determinants of neoadjuvant chemotherapy (NAC) delivery in patients with non-metastatic urothelial muscle-invasive bladder cancer (MIBC) using nationally representative data from the United States. METHODS: We queried the National Cancer Database to identify patients with cT2-cT4a, N0M0 urothelial MIBC who underwent radical cystectomy (RC) from 2006 to 2015. Patients who received radiation therapy, single-agent chemotherapy, adjuvant chemotherapy or systemic therapies other than multi-agent chemotherapy were excluded. Multivariate logistic regression analysis was performed to identify independent predictors of receiving NAC. RESULTS: A total of 5986 patients met the criteria for inclusion, of whom 1788 (29.9%) received NAC and 4108 received RC alone. Younger age, increased Charlson-Deyo score, increased cT stage, increased annual income, increased distance from cancer treatment centre, treatment at an Academic Research Program or Integrated Network Cancer Program and a later year of diagnosis were independently predictive of NAC receipt. Older age, Medicare insurance and treatment in the East South Central or West South Central regions were independently associated with decreased odds of NAC receipt. CONCLUSIONS: Distance to treatment centre and United States geographic region were found to affect the likelihood of NAC receipt independently of other established predictors of success in this quality-of-care metric. Access to transportation and related resources merits consideration as additional pertinent social determinants of health in bladder cancer care.

Identifying men with global polyuria on a nocturnal-only voiding diary.

AIMS: Nocturnal polyuria (NP) and global polyuria (GP) are not mutually exclusive. However, by rate, the common criteria for GP (40 mL/kg/24 hours [117 mL/kg/hour in a 70-kg individual] or 3000 mL/24 hours [125 mL/h]) are more stringent than those for NP (90 mL/hour during the sleep period or NP index [NPi; nocturnal volume/24-hour volume] > 0.33 [no minimum rate]). It remains unclear whether total nocturnal urine volume (NUV) may reliably delineate between NP patients with and without comorbid GP. METHODS: A clinical database of men with lower urinary tract symptoms was searched for voiding diaries completed by patients reporting greater than or equal to 1 nocturnal void(s). Four separate analyses were performed using all combinations of the two NP and two GP criteria listed above. For each analysis, patients were included if they met the criteria for NP, and then stratified by presence or absence of GP (ie, NP + GP vs isolated NP). RESULTS: Median NUV was greater among patients with NP + GP for all criteria combinations. Sensitivities greater than or equal to 80%/90%/100% for NP + GP were observed at 1275/1230/1085 mL for {NPi > 0.33 + 24-hour volume > 3000 mL}; 1075/1035/1035 mL for {NPi > 0.33 + 24-hour volume > 40 mL/kg}; 900/745/630 mL for {NUP > 90 mL/hour + 24-hour volume > 3000 mL}; and 1074/1035/990 mL for {NUP > 90 mL/hour + 24-hour volume > 40 mL/kg}. CONCLUSIONS: An inordinate NUV among men with NP is fairly sensitive for comorbid GP. In the appropriate clinical setting, nocturnal-only diaries may suffice in the evaluation and follow-up of patients with NP, so long as outlying nocturnal volumes prompt a 24-hour diary/urine collection.

Human Metabolome-derived Cofactors Are Required for the Antibacterial Activity of Siderocalin in Urine.

In human urinary tract infections, host cells release the antimicrobial protein siderocalin (SCN; also known as lipocalin-2, neutrophil gelatinase-associated lipocalin, or 24p3) into the urinary tract. By binding to ferric catechol complexes, SCN can sequester iron, a growth-limiting nutrient for most bacterial pathogens. Recent evidence links the antibacterial activity of SCN in human urine to iron sequestration and metabolomic variation between individuals. To determine whether these metabolomic associations correspond to functional Fe(III)-binding SCN ligands, we devised a biophysical protein binding screen to identify SCN ligands through direct analysis of human urine. This screen revealed a series of physiologic unconjugated urinary catechols that were able to function as SCN ligands of which pyrogallol in particular was positively associated with high urinary SCN activity. In a purified, defined culture system, these physiologic SCN ligands were sufficient to activate SCN antibacterial activity against Escherichia coli In the presence of multiple SCN ligands, native mass spectrometry demonstrated that SCN may preferentially combine different ligands to coordinate iron, suggesting that availability of specific ligand combinations affects in vivo SCN antibacterial activity. These results support a mechanistic link between the human urinary metabolome and innate immune function.

Buzz off! An evaluation of ultrasonic acoustic vibration for the disruption of marine micro-organisms on sensor-housing materials.

Biofouling is a process of ecological succession which begins with the attachment and colonization of micro-organisms to a submerged surface. For marine sensors and their housings, biofouling can be one of the principle limitations to long-term deployment and reliability. Conventional antibiofouling strategies using biocides can be hazardous to the environment, and therefore alternative chemical-free methods are preferred. In this study, custom-made testing assemblies were used to evaluate ultrasonic vibration as an antibiofouling process for marine sensor-housing materials over a 28-day time course. Microbial biofouling was measured based on (i) surface coverage, using fluorescence microscopy and (ii) bacterial 16S rDNA gene copies, using Quantitative polymerase chain reaction (PCR). Ultrasonic vibrations (20 KHz, 200 ms pulses at 2-s intervals; total power 16·08 W) significantly reduced the surface coverage on two plastics, poly(methyl methacrylate) and polyvinyl chloride (PVC) for up to 28 days. Bacterial gene copy number was similarly reduced, but the results were only statistically significant for PVC, which displayed the greatest overall resistance to biofouling, regardless of whether ultrasonic vibration was applied. Copper sheet, which has intrinsic biocidal properties was resistant to biofouling during the early stages of the experiment, but inhibited measurements made by PCR and generated inconsistent results later on. SIGNIFICANCE AND IMPACT OF THE STUDY: In this study, ultrasonic acoustic vibration is presented as a chemical-free, ecologically friendly alternative to conventional methods for the perturbation of microbial attachment to submerged surfaces. The results indicate the potential of an ultrasonic antibiofouling method for the disruption of microbial biofilms on marine sensor housings, which is typically a principle limiting factor in their long-term operation in the oceans. With increasing deployment of scientific apparatus in aquatic environments, including further offshore and for longer duration, the identification and evaluation of novel antifouling strategies that do not employ hazardous chemicals are widely sought.

Cardiovascular risk independently predicts small functional bladder storage capacity.

PURPOSE: We aimed to determine the potential relationship between atherosclerotic cardiovascular disease (ASCVD) score, which equates to 10-year risk of atherosclerotic cardiovascular events, and functional bladder capacity (FBC) among men in the outpatient urology setting. METHODS: We secondarily analyzed voiding diaries from men aged 40 to 79 years with nocturia. Patients with a history of cardiovascular disease or who had nocturnal polyuria were excluded. Patients were stratified by whether they met the high-risk ASCVD threshold (≥ 20%) following current cardiology consensus guidelines and assessed for the presence of small FBC (24-h maximum voided volume ≤ 200 ml). Logistic regression analyses were employed to explore associations between small FBC and ASCVD. RESULTS: Eighty-four men (median ASCVD score 18.4 [IQR 12.8-26.9] %, age 66 [61-71] years, body mass index [BMI] 29.4 [26.4-32.7] kg/m2) were included, of whom 36 (42.9%) were high-risk and 48 (57.1%) fell below the high-risk threshold. High-risk patients were more likely to have small FBC (23 [63.9%] vs. 14 [29.2%], p = 0.002). ASCVD risk predicted small FBC on univariate analysis (p = 0.002). No such effect was observed with age (p = 0.116), BMI (p = 0.523), or benign prostatic obstruction (p = 0.180). The association between ASCVD risk and small FBC persisted on multivariate analysis after controlling for BMI and benign prostatic obstruction (p = 0.002). No significant predictors of small FBC were observed when age, a major determinant of ASCVD risk and independent correlate of small FBC, was substituted for ASCVD score (p = 0.108). CONCLUSIONS: Small FBC is related to a higher predicted cardiovascular event rate in men with nocturia.

Overlap between nocturnal polyuria, diurnal polyuria, and 24-h polyuria among men with nocturia.

PURPOSE: A recent update in International Continence Society (ICS) terminology now recognizes nocturnal polyuria (NP) and diurnal polyuria (DP) as related subcategories of "Polyuria (global symptom)". This study determines the real-world clinical overlap between NP, DP, and 24-h polyuria (24hP) among men with nocturia. METHODS: Analysis of frequency-volume charts from men ≥ 18 years with ≥ 1 nocturnal void(s). Three separate analyses were performed using different rate criteria for NP, DP, and 24hP: (1) urine production > 90 mL/h (extrapolated from a proposed definition for NP); (2) > 125 mL/h (extrapolated from a proposed definition for 24hP [3000 mL/24 h]); and (3) > 1.67 mL/kg/h (extrapolated from the current ICS definition for 24hP [> 40 mL/kg/24 h]). Subjects were categorized as having one of five mathematically permissible phenotypic combinations: (1) isolated NP, (2) isolated DP, (3) NP + 24hP, (4) DP + 24hP, and (5) NP + DP + 24hP. RESULTS: 167, 95, and 61 patients were included at criteria 1, 2, and 3, respectively, with 56%, 43%, and 30% of patients demonstrating overlapping phenotypes (i.e., phenotypic combinations 3-5) at cut-offs 1-3, respectively. The prevalence of NP was similar across cut-offs (81-87%), but the prevalence of NP without 24hP was highly threshold-dependent (43-73%). CONCLUSION: Consistent with current ICS terminology, there exists a substantial overlap between NP, DP, and 24hP. As demonstrated in the current study, absolute volume-based criteria for NP/DP/24hP are indeed conducive to the diagnosis of concurrent NP + 24hP, and may be preferred over proportion-based NP criteria when both NP + 24hP are suspected.

Fitbit Activity Trackers Interrupt Workplace Sedentary Behavior: A New Application.

This study investigated whether Fitbit devices can reduce sedentary behavior among employees in the workplace. Participants were asked to wear Fitbits during 8-hour work shifts, 5 days per week, for 8 weeks. They were instructed to stand at least once every 30 minutes throughout the workday. The goal of the study was to determine whether standing once every 30 minutes was a feasible strategy for reducing sedentary workplace behavior. On average, participants completed 36 of 40 workdays using Fitbits. The number of times participants stood during an 8-hour workday averaged 12 stands per day (maximum 16 stands per day). These results indicate that Fitbit technology is effective for recording and tracking interruptions in sitting time; however, to reduce sitting behavior, alternate approaches are required to motivate larger numbers of workers to participate.

Stability of dissolved and soluble Fe(II) in shelf sediment pore waters and release to an oxic water column.

Shelf sediments underlying temperate and oxic waters of the Celtic Sea (NW European Shelf) were found to have shallow oxygen penetrations depths from late spring to late summer (2.2-5.8 mm below seafloor) with the shallowest during/after the spring-bloom (mid-April to mid-May) when the organic carbon content was highest. Sediment porewater dissolved iron (dFe, <0.15 µm) mainly (>85%) consisted of Fe(II) and gradually increased from 0.4 to 15 µM at the sediment surface to ~100-170 µM at about 6 cm depth. During the late spring this Fe(II) was found to be mainly present as soluble Fe(II) (>85% sFe, <0.02 µm). Sub-surface dFe(II) maxima were enriched in light isotopes (δ56Fe -2.0 to -1.5‰), which is attributed to dissimilatory iron reduction (DIR) during the bacterial decomposition of organic matter. As porewater Fe(II) was oxidised to insoluble Fe(III) in the surface sediment layer, residual Fe(II) was further enriched in light isotopes (down to -3.0‰). Ferrozine-reactive Fe(II) was found in surface porewaters and in overlying core top waters, and was highest in the late spring period. Shipboard experiments showed that depletion of bottom water oxygen in late spring can lead to a substantial release of Fe(II). Reoxygenation of bottom water caused this Fe(II) to be rapidly lost from solution, but residual dFe(II) and dFe(III) remained (12 and 33 nM) after >7 h. Iron(II) oxidation experiments in core top and bottom waters also showed removal from solution but at rates up to 5-times slower than predicted from theoretical reaction kinetics. These data imply the presence of ligands capable of complexing Fe(II) and supressing oxidation. The lower oxidation rate allows more time for the diffusion of Fe(II) from the sediments into the overlying water column. Modelling indicates significant diffusive fluxes of Fe(II) (on the order of 23-31 µmol m-2 day-1) are possible during late spring when oxygen penetration depths are shallow, and pore water Fe(II) concentrations are highest. In the water column this stabilised Fe(II) will gradually be oxidised and become part of the dFe(III) pool. Thus oxic continental shelves can supply dFe to the water column, which is enhanced during a small period of the year after phytoplankton bloom events when organic matter is transferred to the seafloor. This input is based on conservative assumptions for solute exchange (diffusion-reaction), whereas (bio)physical advection and resuspension events are likely to accelerate these solute exchanges in shelf-seas.

A review of the evidence on the effects and costs of implantable cardioverter defibrillator therapy in different patient groups, and modelling of cost-effectiveness and cost-utility for these groups in a UK context.

OBJECTIVES: To update the systematic review evidence on the effectiveness, health-related quality of life (HRQoL) and cost-effectiveness of implantable cardioverter defibrillators (ICDs); compilation of new data on the service provision in the UK; and on the clinical characteristics, survival, quality of life and costs of ICD patients in the UK, and a new cost-effectiveness model using both international RCT and UK-specific data. DATA SOURCES: Electronic databases searched from November 1999 to March 2003, this was supplemented by a systematic review of research published during 2003-5. Survey data. REVIEW METHODS: Studies were selected and assessed. A survey of ICD centres was carried out. Basic data were obtained from two major implanting centres including 535 patients (approximately 10% of overall UK activity) implanted between 1991 and 2002, and retrieval of fuller data, on patient characteristics, management and resource use, from patient notes for a sample of 426 patients was attempted. A cross-sectional survey collected HRQoL data (using the Nottingham Health Profile, Short Form 36, Hospital Anxiety and Depression questionnaire, EuroQoL 5 Dimensions and disease-specific questions) on a sample of 229 patients. A Markov model combined UK patient data with data from published randomised controlled trials (RCTs) to estimate incremental costs per life-year or quality-adjusted life-year (QALY) gained. RESULTS: None of the economic analyses in the studies found could be directly applied to the UK. The multiple sources of routine data available (including the national ICD database) provide an imperfect picture of the need for and use of ICDs. Implantation rates have been rising to a rate of around 20 per million population. Mean age is increasing and most ICDs are implanted into men aged 45-74 years. There is significant geographical variation. A survey of 41 UK centres provided additional evidence, particularly of variation in level of activity and resourcing. Most detailed data were obtained for 380 patients (89%). The postal survey produced a 73% response rate. Demographic characteristics of these patients were similar to ICD recipients in the UK as a whole and patients included in secondary prevention RCTs. Mean actuarial survival at 1, 3 and 5 years was 92%, 86% and 71%, respectively. Patient age at implantation and functional status significantly affected survival. Levels of most of the HRQoL measures were lower than for a UK general population. There was no evidence of a change with time from implantation. Patients who had suffered ICD shocks had significantly poorer HRQoL. Most patients nevertheless expressed a high level of satisfaction with ICD therapy. Mean initial costs of implantation showed little variation between centres (23,300 pounds versus 22,100 pounds) or between earlier and more recent implants. There appeared to be greater variation between patients presenting along different pathways. Postdischarge costs (tests, medications and follow-up consultations) and costs of additional hospitalisations were also calculated. Using the Markov model it was found that over a 20-year horizon, mean discounted incremental costs were 70,900 pounds (35,000-142,400 pounds). Mean discounted gain was 1.24 years (0.29-2.32) or 0.93 QALYs. Cost-effectiveness was most favourable for men aged over 70 years with a left ventricular ejection fraction (LVEF) below 35%. If the treatment effect were to continue, then the cost per life-year over a lifetime might fall to around 32,000 pounds. Five RCTs of ICDs, a meta-analysis and, a cost-effectiveness analysis of ICDs used in primary prevention, and a meta-analysis of ICDs in patients with non-ischaemic cardiomyopathy have been published recently. These trials provide confirmation of survival benefit of ICDs used in primary prevention in both ischaemic and non-ischaemic cardiomyopathy patients. Costs per QALY ranged from US$34,000 in older trials to controls being both less expensive and more effective (CABG Patch, DINAMIT). More recent trials estimated cost per QALY between $50,300 and $70,200. The inconsistency in evidence for a HRQoL benefit has not been resolved and further work on risk stratification is necessary. CONCLUSIONS: The evidence of short- to medium-term patient benefit from ICDs is strong but cost-effectiveness modelling indicates that the extent of that benefit is probably not sufficient to make the technology cost-effective as used currently in the UK. One reason is the high rates of postimplantation hospitalisation. Better patient targeting and efforts to reduce the need for such hospitalisation may improve cost-effectiveness. Further cost-effectiveness modelling, underpinned by an improved ICD database with reliable long-term follow-up, is required. The absence of a robust measure of the incidence of sudden cardiac death is noted and this may be an area where further organisational changes with improved data collection would help.

Cross-validation of protein structural class prediction using statistical clustering and neural networks.

We present an approach to predicting protein structural class that uses amino acid composition and hydrophobic pattern frequency information as input to two types of neural networks: (1) a three-layer back-propagation network and (2) a learning vector quantization network. The results of these methods are compared to those obtained from a modified Euclidean statistical clustering algorithm. The protein sequence data used to drive these algorithms consist of the normalized frequency of up to 20 amino acid types and six hydrophobic amino acid patterns. From these frequency values the structural class predictions for each protein (all-alpha, all-beta, or alpha-beta classes) are derived. Examples consisting of 64 previously classified proteins were randomly divided into multiple training (56 proteins) and test (8 proteins) sets. The best performing algorithm on the test sets was the learning vector quantization network using 17 inputs, obtaining a prediction accuracy of 80.2%. The Matthews correlation coefficients are statistically significant for all algorithms and all structural classes. The differences between algorithms are in general not statistically significant. These results show that information exists in protein primary sequences that is easily obtainable and useful for the prediction of protein structural class by neural networks as well as by standard statistical clustering algorithms.

Evidence for an informal clinical policy resulting in high use of a very-low-yield test.

The actual and self-reported practice regarding the use of cerebrospinal fluid cultures for Mycobacterium tuberculosis was examined. All neurology house staff members surveyed, 62 percent of internal medicine house staff members, and none of pediatric house staff members reported that they would order mycobacterial cultures of cerebrospinal fluid routinely. The actual practice was comparable, with 71 percent of cerebrospinal fluid specimens being subjected to culture for mycobacteria on the neurology service, 65 percent on the internal medicine service, and 6 percent on the pediatric service. In this practice, medicine and neurology house staff differ significantly from their pediatric colleagues (p less than 0.001) and from the stated practice of their respective faculties (p less than 0.01). For at least six years, most medicine and neurology house staff have commonly applied an informal clinical policy of routinely culturing cerebrospinal fluid specimens for mycobacteria, despite a low suspicion of disease, lack of faculty support for the practice, and a zero yield for the test. Informal clinical policies such as this may be an important contributor to the problem of technology overuse.

Radical improvements in the display of clinical microbiology results: a Web-based clinical information system.

OBJECTIVE: To evaluate the performance of a novel computerized system for reporting clinical microbiology results. The new system provides a summarized overview of a patient's current (or past) microbiological status, with the option to selectively explore in greater depth. It is deployed using World Wide Web technology, which supports virtually any kind of computer and allows physicians to obtain results via the internet using personal computers in the office or at home. METHODS: In an unblinded crossover study at a university-affiliated medical center, participants used both the new system and a conventional display system to retrieve selected microbiology results for two actual patients, according to standardized questionnaires, with balanced allocation of sequence of system use. Participants also subjectively rated the two systems. The participants were 16 physician, pharmacist, and nurse volunteers. Outcome measures included completion time and number of errors (categorized as major and minor) associated with results retrieval, and participants' ratings of the new system. RESULTS: Mean completion time was 45% shorter (13.9 versus 25.5 minutes; P < 0.001), and there were fewer associated major errors (0 versus 13; P = 0.01) and minor errors (10 versus 21; P = 0.003) with the summarized display system. All participants rated the new system as easier to learn and use than the conventional system. CONCLUSIONS: A system that appropriately summarizes and groups microbiology results can significantly shorten retrieval times and reduce interpretive errors, while providing users with information needed for cost-effective therapy. Such a system can be deployed by leveraging the rapidly evolving technology of the World Wide Web.

Methylenedioxymethamphetamine (MDMA; 'Ecstasy') suppresses antigen specific IgG2a and IFN-gamma production.

Methylenedioxymethiamphetamine (MDMA; "Ecstasy") is a widely abused amphetamine derivative. In the present study, we examined the effect of acute MDMA administration on an antigen specific immune response. Responsiveness to an in vivo challenge with the soluble protein antigen keyhole limpet haemocyanin (KLH) was examined in rats following MDMA administration (2.5, 5 or 10 mg/kg; i.p.). KLH-specific serum IgM concentrations were measured 7 days following challenge, and serum IgG concentrations were measured 14 days following the KLH challenge. In addition, antigen-specific IFN-gamma and IL-6 production was measured in KLH-stimulated splenocytes. MDMA did not alter the KLH-specific IgM response. In contrast, MDMA (5 and 10 mg/kg) provoked a significant suppression of KLH-specific IgG production. Thus, MDMA administration did not alter the initial generation of the antibody response but rather inhibited antibody class switching from IgM to IgG. Two pathways for the genetic switch from IgM to IgG production were investigated. One pathway requires the Th(1) type cytokine IFN-gamma to stimulate IgM-secreting cells to switch to IgG(2a)-secreting cells. Another pathway requires the Th(2) type cytokines IL-4 and IL-6 to stimulate IgM-secreting cells to switch to IgG(1)-secreting cells. IgG(1) and IgG(2a) levels were measured to determine if these two pathways were differentially affected. The results indicate that only IgG(2a) levels were decreased following MDMA administration. Furthermore, this decrease in IgG(2a) was accompanied by decreased KLH-specific IFN-gamma production 14 days post KLH administration. In conclusion, these data indicate that MDMA alters the ability to switch from IgM to IgG(2a) production, possibly by reducing IFN-gamma. Potential health consequences for MDMA users are discussed.

Cost savings with nonthoracotomy implantable cardioverter-defibrillators.

We analyzed hospital and physician charges for 99 consecutive patients who underwent implantable cardioverter-defibrillator (ICD) implantation at our institution. Eighteen patients received an epicardial lead system and 81 were scheduled to receive a nonthoracotomy lead system, the generator being implanted either abdominally (n = 62) or pectorally (n = 19). The epicardial group had a significantly longer convalescent stay (11.6 +/- 2.5 days; mean +/- SEM) than the abdominal nonthoracotomy group, analyzed by intention to treat (4.6 +/- 0.5 days) or by treatment received (3.8 +/- 0.2 days; p <0.0001). Postoperative stay for the pectoral group was shorter still (2.9 +/- 0.4 days; p <0.033). Total charges for the epicardial group were $99,081 +/- $25,094, significantly higher than those for any of the nonthoracotomy groups (p <0.017). Total charges for the pectoral group were $44,128 +/- $2,465, significantly less than those for the abdominal nonthoracotomy group, analyzed by intention to treat ($59,961 +/- $1,369; p <0.05) or by treatment received ($56,679 +/- $635; p <0.05). Cost reductions in the nonthoracotomy groups were primarily due to decreased in-hospital convalescence period, lower surgeon and anesthesiologist fees, and lower procedure-day hospital charges in the pectoral group. The use of ICDs with nonthoracotomy leads can result in significantly shorter in-hospital convalescence and a reduction in total implant-related charges of 40% to 55%. The use of pectorally implanted ICDs results in further reduction in hospital stay and further cost reduction of 22% to 26%. The trend toward shorter convalescent stay without postimplant testing is likely to reduce further the overall costs of ICD implantation.

Reduced insulin binding to liver plasma membranes in inherently obese diabetic CBA/Ca mice.

Insulin binding to isolated liver plasma membranes was measured in mice from C57BL and LACG strains, and in normal and obese diabetic mice from the Bristol CBA/Ca colony. A simple and rapid three-step method for the preparation and purification of liver plasma membranes, using Percoll density gradient centrifugation was used. Both high and low affinity binding was detected in membranes from all four groups of mice. The Kd values for binding were similar in all groups, but the insulin binding capacity (Bmax) at low and high affinity was significantly reduced in obese CBA mice compared to age-matched lean controls. It is proposed that insulin receptor down-regulation may account for the insulin resistance observed in spontaneously obese diabetic CBA mice.

The role of the blood glucose level in determining voluntary ethanol consumption in the LACG and diabetogenic C57BL strains of mice.

The influence of the blood glucose level (BGL) on the voluntary consumption of ethanol by two strains of mice has been investigated. LACG mice show an aversion towards ethanol whereas C57BL mice which are mildly hyperglycaemic show a preference for ethanol. Chronic compulsory ethanol drinking produced hypoglycaemia only in C57BL mice. The oral antidiabetic drugs phenformin and glibenclamide lowered the BGL of C57BL mice which then showed an aversion to ethanol. Raising the BGL of LACG mice by acute alloxan or streptozotocin treatment did not reduce ethanol aversion significantly, but alloxan significantly increased total fluid intake. Diazoxide chronically increased the BGL and slightly increased ethanol consumption in LACG mice. It is concluded that the BGL in C57BL mice may be a factor in determining their innate preference for alcohol. The relationship between alcoholism and diabetes is discussed.

The medical problem solving process.

Understanding the medical problem solving process has implications for medical education and the effectiveness of medical services. Through adaptation to the task at hand the human problem solver is able to ameliorate the effects of inherent limitations. In adapting to the medical problem solving task demands related to diagnosis and therapy, the physician uses the hypotheticodeductive process. The process draws upon the problem solver's disease centered and data centered knowledge and can be made more effective through the use of various heuristic rules and strategies that the physician develops with increasing expertise. Additional and more refined modes of laboratory support for the medical problem solver can evolve through further understanding of the problem solving process.