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Objective: Agitation is a common and significant problem in Alzheimer disease (AD). In the recent Citalopram for Agitation in Alzheimer's Disease (CitAD) study, citalopram was efficacious for the treatment of AD agitation. Here we examined the time course and predictors of response to treatment., Methods: Response in CitAD was defined as a modified Alzheimer Disease Cooperative Study Clinical Global Impression of Change (CGIC) score of 1 or 2 or a Neurobehavioral Rating Scale agitation subscale (NBRS-A) score reduction ≥ 50% from baseline. "Stable early response" was defined as meeting the aforementioned criteria at both weeks 3 and 9, "late response" was response at week 9 but not at week 3, and "unstable response" was response at week 3 but not at week 9., Results: In the primary analyses, citalopram was superior to placebo on both the CGIC and the NBRS-A response measures. Little between-group differences were found in response rates in the first 3 weeks of the study (21% versus 19% on the CGIC). Citalopram patients were more likely than placebo patients to be a late responder (18% versus 8% on CGIC, Fisher's exact p = 0.09; 31% versus 15% on NBRS-A, Fisher's exact p = 0.02). Approximately half of citalopram responders (45%-56%) at end of study achieved response later in the study compared with 30%-44% of placebo responders., Conclusion: Treatment with citalopram for agitation in AD needs to be at least 9 weeks in duration to allow sufficient time for full response. Study duration is an important factor to consider in the design of clinical trials for agitation in AD., (Copyright © 2015 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Safe and effective therapies are needed for pediatric patients with psoriasis., Objective: The purpose of this study was to evaluate ustekinumab in patients age 12 to 17 years who had moderate-to-severe psoriasis., Methods: Patients (n = 110) were randomly assigned to ustekinumab standard dosing (SD; 0.75 mg/kg [≤60 kg], 45 mg [>60-≤100 kg], and 90 mg [>100 kg]) or half-standard dosing (HSD; 0.375 mg/kg [≤60 kg], 22.5 mg [>60-≤100 kg], and 45 mg [>100 kg]) at weeks 0 and 4 and every 12 weeks or placebo at weeks 0 and 4 with crossover to ustekinumab SD or HSD at week 12. Clinical assessments included the proportion of patients achieving a Physician's Global Assessment of cleared/minimal (PGA 0/1), at least 75% improvement in Psoriasis Area and Severity Index (PASI 75), and at least 90% in PASI (PASI 90). Adverse events (AEs) were monitored through week 60., Results: At week 12, 67.6% and 69.4% of patients receiving ustekinumab HSD and SD, respectively, achieved PGA 0/1 versus 5.4% for placebo (P < .001). Significantly greater proportions receiving ustekinumab achieved PASI 75 (HSD, 78.4%; SD, 80.6%; placebo, 10.8%) or PASI 90 (HSD, 54.1%; SD, 61.1%; placebo, 5.4%) at week 12 (P < .001). Through week 12, 56.8% of placebo patients, 51.4% of HSD patients, and 44.4% of SD patients reported at least one AE; through week 60, 81.8% reported AEs., Limitations: The study was small relative to adult trials., Conclusions: In this patient population (12-17 years), the standard ustekinumab dose provided response comparable to that in adults with no unexpected AEs through 1 year., (Copyright © 2015 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: US residents make 60 million international trips annually. Family practice providers need to be aware of travel-associated diseases affecting this growing mobile population., Objective: To describe demographics, travel characteristics and clinical diagnoses of US residents who present ill after international travel., Methods: Descriptive analysis of travel-associated morbidity and mortality among US travellers seeking care at 1 of the 22 US practices and clinics participating in the GeoSentinel Global Surveillance Network from January 2000 to December 2012., Results: Of the 9624 ill US travellers included in the analysis, 3656 (38%) were tourist travellers, 2379 (25%) missionary/volunteer/research/aid workers (MVRA), 1580 (16%) travellers visiting friends and relatives (VFRs), 1394 (15%) business travellers and 593 (6%) student travellers. Median (interquartile range) travel duration was 20 days (10-60 days). Pre-travel advice was sought by 45%. Hospitalization was required by 7%. Compared with other groups of travellers, ill MVRA travellers returned from longer trips (median duration 61 days), while VFR travellers disproportionately required higher rates of inpatient care (24%) and less frequently had received pre-travel medical advice (20%). Illnesses of the gastrointestinal tract were the most common (58%), followed by systemic febrile illnesses (18%) and dermatologic disorders (17%). Three deaths were reported. Diagnoses varied according to the purpose of travel and region of exposure., Conclusions: Returning ill US international travellers present with a broad spectrum of travel-associated diseases. Destination and reason for travel may help primary health care providers to generate an accurate differential diagnosis for the most common disorders and for those that may be life-threatening., (© The Author 2014. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Information regarding acute otitis media (AOM) aetiology is important for developing effective vaccines. Here, bacterial aetiology and antimicrobial susceptibility of AOM were determined in young Saudi children., Methods: Children aged 3-60months with a new episode of AOM, who had not received antibiotics or had received antibiotics for 48-72h but remained symptomatic, were enrolled in this prospective, observational, epidemiological study in Riyadh. Middle ear fluid (MEF) samples were collected by tympanocentesis or from spontaneous otorrhea, and tested for the presence of Streptococcus pneumoniae, Haemophilus influenzae, Streptococcus pyogenes and Moraxella catarrhalis. Antimicrobial susceptibility of the identified pathogens was assessed using E-tests., Results: Between June 2009 and May 2011, 66 children were enrolled. S. pneumoniae was detected in 6 episodes and non-typeable H. influenzae (NTHi) in 8 episodes. Moreover, Staphylococcus aureus, which is an uncommon cause of AOM, was detected in 17 episodes. Pneumococcal serotypes were 7F (n=2), 23F (n=2), 19F (n=1) and 15F (n=1). Susceptibility to cefotaxime was observed in all pneumococcal and H. influenzae isolates, to cefuroxime in 4/6 pneumococcal and 8/8 H. influenzae isolates, and to penicillin in 5/6 pneumococcal isolates., Conclusions: S. pneumoniae and NTHi were major bacterial contributors for AOM in Saudi children., (Copyright © 2014. Published by Elsevier Ltd.)

Background: A Food and Drug Administration (FDA) safety communication in August 2011 warned that citalopram was associated with a dose dependent risk of QT prolongation and recommended dose restriction in patients over the age of 60 but did not provide data for this age group., Methods: CitAD was a randomized, double-masked, placebo-controlled, multicenter clinical trial for agitation in Alzheimer's disease (AD). Participants were assigned to citalopram (target dose of 30 mg/day) or placebo in a 1 ∶ 1 ratio. 186 people, 181 of whom were over the age of 60, having probable AD with clinically significant agitation were recruited from September 2009 to January 2013. After the FDA safety communication about citalopram, ECG was added to the required study procedures before enrollment and repeated at week 3 to monitor change in QTc interval. Forty-eight participants were enrolled after enhanced monitoring began., Results: Citalopram treatment was associated with a larger increase in QTc interval than placebo (difference in week 3 QTc adjusting for baseline QTc: 18.1 ms [95% CI: 6.1, 30.1]; p = 0.004). More participants in the citalopram group had an increase ≥ 30 ms from baseline to week 3 (7 in citalopram versus 1 in placebo; Fisher's exact p = 0.046), but only slightly more in the citalopram group met a gender-specific threshold for prolonged QTc (450 ms for males; 470 ms for females) at any point during follow-up (3 in citalopram versus 1 in placebo, Fisher's exact p = 0.611). One of the citalopram participants who developed prolonged QTc also displayed ventricular bigeminy. No participants in either group had a cardiovascular-related death., Conclusion: Citalopram at 30 mg/day was associated with improvement in agitation in patients with AD but was also associated with QT prolongation., Trial Registration: ClinicalTrials.gov NCT00898807.

Importance: Agitation is common, persistent, and associated with adverse consequences for patients with Alzheimer disease. Pharmacological treatment options, including antipsychotics are not satisfactory., Objective: The primary objective was to evaluate the efficacy of citalopram for agitation in patients with Alzheimer disease. Key secondary objectives examined effects of citalopram on function, caregiver distress, safety, cognitive safety, and tolerability., Design, Setting, and Participants: The Citalopram for Agitation in Alzheimer Disease Study (CitAD) was a randomized, placebo-controlled, double-blind, parallel group trial that enrolled 186 patients with probable Alzheimer disease and clinically significant agitation from 8 academic centers in the United States and Canada from August 2009 to January 2013., Interventions: Participants (n = 186) were randomized to receive a psychosocial intervention plus either citalopram (n = 94) or placebo (n = 92) for 9 weeks. Dosage began at 10 mg per day with planned titration to 30 mg per day over 3 weeks based on response and tolerability., Main Outcomes and Measures: Primary outcome measures were based on scores from the 18-point Neurobehavioral Rating Scale agitation subscale (NBRS-A) and the modified Alzheimer Disease Cooperative Study-Clinical Global Impression of Change (mADCS-CGIC). Other outcomes were based on scores from the Cohen-Mansfield Agitation Inventory (CMAI) and the Neuropsychiatric Inventory (NPI), ability to complete activities of daily living (ADLs), caregiver distress, cognitive safety (based on scores from the 30-point Mini Mental State Examination [MMSE]), and adverse events., Results: Participants who received citalopram showed significant improvement compared with those who received placebo on both primary outcome measures. The NBRS-A estimated treatment difference at week 9 (citalopram minus placebo) was -0.93 (95% CI, -1.80 to -0.06), P = .04. Results from the mADCS-CGIC showed 40% of citalopram participants having moderate or marked improvement from baseline compared with 26% of placebo recipients, with estimated treatment effect (odds ratio [OR] of being at or better than a given CGIC category) of 2.13 (95% CI, 1.23-3.69), P = .01. Participants who received citalopram showed significant improvement on the CMAI, total NPI, and caregiver distress scores but not on the NPI agitation subscale, ADLs, or in less use of rescue lorazepam. Worsening of cognition (-1.05 points; 95% CI, -1.97 to -0.13; P = .03) and QT interval prolongation (18.1 ms; 95% CI, 6.1-30.1; P = .01) were seen in the citalopram group., Conclusions and Relevance: Among patients with probable Alzheimer disease and agitation who were receiving psychosocial intervention, the addition of citalopram compared with placebo significantly reduced agitation and caregiver distress; however, cognitive and cardiac adverse effects of citalopram may limit its practical application at the dosage of 30 mg per day., Trial Registration: clinicaltrials.gov Identifier: NCT00898807.

Background & Aims: Subcutaneous golimumab, a fully human monoclonal antibody to tumor necrosis factor-α (TNFα), was evaluated as maintenance therapy in TNFα antagonist-naive adults with moderate-to-severe active ulcerative colitis, despite conventional therapy, who responded to golimumab induction therapy., Methods: We performed a phase 3, double-blind trial of patients who completed golimumab induction trials (Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment, eg, PURSUIT). Patients who responded to induction therapy with golimumab (n = 464) were assigned randomly to groups given placebo or injections of 50 or 100 mg golimumab every 4 weeks through week 52. Patients who responded to placebo in the induction study continued to receive placebo. Nonresponders in the induction study received 100 mg golimumab. The primary end point was clinical response maintained through week 54; secondary end points included clinical remission and mucosal healing at both weeks 30 and 54., Results: Clinical response was maintained through week 54 in 47.0% of patients receiving 50 mg golimumab, 49.7% of patients receiving 100 mg golimumab, and 31.2% of patients receiving placebo (P = .010 and P < .001, respectively). At weeks 30 and 54, a higher percentage of patients who received 100 mg golimumab were in clinical remission and had mucosal healing (27.8% and 42.4%) than patients given placebo (15.6% and 26.6%; P = .004 and P = .002, respectively) or 50 mg golimumab (23.2% and 41.7%, respectively). Percentages of serious adverse events were 7.7%, 8.4%, and 14.3% among patients given placebo, 50 mg, or 100 mg golimumab, respectively; percentages of serious infections were 1.9%, 3.2%, and 3.2%, respectively. Among all patients given golimumab in the study, 3 died (from sepsis, tuberculosis, and cardiac failure, all in patients who received 100 mg golimumab) and 4 developed active tuberculosis., Conclusions: Golimumab (50 mg or 100 mg) maintained clinical response through week 54 in patients who responded to induction therapy with golimumab and had moderate-to-severe active ulcerative colitis; patients who received 100 mg golimumab had clinical remission and mucosal healing at weeks 30 and 54. Safety was consistent with that reported for other TNFα antagonists and golimumab in other approved indications. ClinicalTrials.gov number: NCT00488631., (Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Little is known about the efficacy of golimumab, a fully human monoclonal antibody to tumor necrosis factor (TNF) -α, for treatment of ulcerative colitis (UC). We evaluated subcutaneous golimumab induction therapy in TNF-α antagonist-naïve patients with moderate-to-severe UC despite conventional treatment., Methods: We integrated double-blind phase 2 dose-finding and phase 3 dose-confirmation trials in a study of 1064 adults with UC (Mayo score: 6-12; endoscopic subscore ≥ 2; 774 patients in phase 3). Patients were randomly assigned to groups given golimumab doses of 100 mg and then 50 mg (phase 2 only), 200 mg and then 100 mg, or 400 mg and then 200 mg, 2 weeks apart. The phase 3 primary end point was week-6 clinical response. Secondary end points included week-6 clinical remission, mucosal healing, and Inflammatory Bowel Disease Questionnaire (IBDQ) score change., Results: In phase 2, median changes from baseline in the Mayo score were -1.0, -3.0, -2.0, and -3.0, in the groups given placebo, 100 mg/50 mg, 200/100 mg, and 400/200 mg golimumab, respectively. In phase 3, rates of clinical response at week 6 were 51.0% and 54.9% among patients given 200 mg/100 mg and 400 mg/200 mg golimumab, respectively, vs 30.3% among those given placebo (both, P ≤ .0001). Rates of clinical remission and mucosal healing and mean changes in IBDQ scores were significantly greater in both golimumab groups vs the placebo group (P ≤ .0014, all comparisons). Rates of serious adverse events were 6.1% and 3.0%, and rates of serious infection were 1.8% and 0.5%, in the placebo and golimumab groups, respectively. One patient in the 400 mg/200 mg group died as a result of surgical complications of an ischiorectal abscess., Conclusions: Treatment with subcutaneous golimumab induces clinical response, remission, and mucosal healing, and increases quality of life in larger percentages of patients with active UC than placebo. ClinicalTrials.gov Number: NCT00487539., (Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Importance: Peripheral glucose homeostasis has been implicated in the pathogenesis of Alzheimer disease (AD). The relationship among diabetes mellitus, insulin, and AD is an important area of investigation. However, whether cognitive impairment seen in those with diabetes is mediated by excess pathological features of AD or other related abnormalities, such as vascular disease, remains unclear., Objective: To investigate the association between serial measures of glucose intolerance and insulin resistance and in vivo brain β-amyloid burden, measured with carbon 11–labeled Pittsburgh Compound B (11C-PiB), and AD pathology at autopsy., Design: Scores calculated from the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) and Braak criteria were correlated with measures of hyperglycemia, hyperinsulinemia, glucose intolerance, and insulin resistance in 197 participants who underwent autopsy after death and who had undergone 2 or more oral glucose tolerance tests (OGTT) using grouped analyses and a continuous mixed-models analysis. The same measures of glucose intolerance and insulin resistance were also correlated with brain 11C-PiB retention in an additional 53 living subjects from the Baltimore Longitudinal Study of Aging neuroimaging study., Setting: Prospective, serially assessed cohort of community-dwelling subjects., Participants: Cohort 1 consisted of 197 participants enrolled in the Baltimore Longitudinal Study of Aging who had 2 or more OGTTs during life and a complete brain autopsy after death. Cohort 2 consisted of 53 living subjects who had 2 or more OGTTs and underwent brain 11C-PiB positron emission tomography., Exposures: Autopsy and 11C-PiB positron emission tomography., Main Outcomes and Measures: The correlation of brain markers of AD, including CERAD score, Braak score, and 11C-PiB retention, with serum markers of glucose homeostasis using grouped and continuous mixed-models analyses., Results: We found no significant correlations between measures of brain AD pathology or 11C-PiB β-amyloid load and glucose intolerance or insulin resistance in subjects who had a mean (SD) of 6.4 (3.2) OGTTs during 22.1 (8.0) years of follow-up. Thirty subjects with frank diabetes mellitus who received medications also had AD pathology scores that were similar to those of the cohort as a whole., Conclusions and Relevance: In this prospective cohort with multiple assessments of glucose intolerance and insulin resistance, measures of glucose and insulin homeostasis are not associated with AD pathology and likely play little role in AD pathogenesis. Long-term therapeutic trials are important to elucidate this issue.

Objective: To prospectively identify the bacterial aetiology and antimicrobial susceptibility of problematic (recurrent and treatment failure) acute otitis media in Spanish children several years after the introduction of 7-valent pneumococcal conjugate vaccine., Methods: Tympanocentesis or careful sampling of spontaneous otorrhoea was performed on children aged 3 to <36 months with recurrent acute otitis media, acute otitis media treatment failure or unresolved acute otitis media., Results: 105 acute otitis media episodes (77 sampled by tympanocentesis, 28 otorrhoea samples) were evaluated: 46 recurrent, 35 treatment failures, 24 unresolved acute otitis media. 74 episodes (70.4%) had at least one bacterium identified on culture: Streptococcus pneumoniae was identified in 21 episodes, Haemophilus influenzae (all non-typeable) in 44, Streptococcus pyogenes in 2, Moraxella catarrhalis in 2. No statistically significant difference in bacterial aetiology by episode type was detected. Non-typeable H. influenzae was the most commonly isolated pathogen in all acute otitis media types and in all age sub-groups. Forty percent of S. pneumoniae isolates were multi-drug resistant. Pneumococcal serotype 19A was the most frequently identified serotype (7/21 episodes). Multi-drug resistance was found in 56% of 19A isolates. Of non-typeable H. influenzae isolates, 15% were ampicillin resistant and 13% were amoxicillin/clavulanate resistant. S. pneumoniae and non-typeable H. influenzae DNA were each detected in 57% of samples culture negative for these pathogens, including 12 co-infections., Conclusion: Combining culture and polymerase chain reaction results, H. influenzae and S. pneumoniae may be implicated in 70% and 43% of clinically problematic bacterial acute otitis media episodes, respectively. The impact of new vaccines to prevent both S. pneumoniae and non-typeable H. influenzae acute otitis media may be substantial in this population and is worth investigating., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Purpose: To systematically review the accuracy of the variation in pulse oxymetry plethysmographic waveform amplitude (∆POP) and the Pleth Variability Index (PVI) as predictors of fluid responsiveness in mechanically ventilated adults., Methods: MEDLINE, Scopus and the Cochrane Database of Systematic Reviews were screened for clinical studies in which the accuracy of ∆POP/PVI in predicting the hemodynamic response to a subsequent fluid bolus had been investigated. Random-effects meta-analysis was used to summarize the results. Data were stratified according to the amount of fluid bolus (large vs. small) and to the study index (∆POP vs. PVI)., Results: Ten studies in 233 patients were included in this meta-analysis. All patients were in normal sinus rhythm. The pooled area under the receiver operating characteristic curve (AUC) for identification of fluid responders was 0.85 [95 % confidence interval (CI) 0.79-0.92]. Pooled sensitivity and specificity were 0.80 (95 % CI 0.74-0.85) and 0.76 (0.68-0.82), respectively. No heterogeneity was found within studies with the same amount of fluid bolus, nor between studies on ∆POP and those on PVI. The AUC was significantly larger in studies with a large bolus amount than in those with a small bolus [0.92 (95 % CI 0.87-0.96) vs. 0.70 (0.62-0.79); p < 0.0001]. Sensitivity and specificity were also higher in studies with a large bolus [0.84 (95 % CI 0.77-0.90) vs. 0.72 (0.60-0.82) (small bolus), p = 0.08 and 0.86 (95 % CI 0.75-0.93) vs. 0.68 (0.56-0.77) (small bolus), p = 0.02], respectively., Conclusions: Based on our meta-analysis, we conclude that ∆POP and PVI are equally effective for predicting fluid responsiveness in ventilated adult patients in sinus rhythm. Prediction is more accurate when a large fluid bolus is administered.

There are indications of a shift in the pattern of hepatitis A (HAV) in Mexico from high to intermediate endemicity, progressively increasing the mean age of infection and the proportion of cases which are symptomatic. This study estimated the potential impact of universal infant HAV vaccination in Mexico with two doses of Havrix™ at 12 and 18 mo of age on all HAV infections and symptomatic HAV infections. We developed a dynamic transmission model that accounts for changes in demography and HAV epidemiology. It was calibrated using Mexican age-specific seroprevalence and symptomatic HAV incidence data. With 70% first-dose coverage and 85% second-dose coverage, the calibrated model projected that HAV vaccination would reduce the incidence of all HAV infections (symptomatic and asymptomatic) after the first 25 y of vaccination by 71-76% (minimum and maximum for different transmission scenarios). The projected reduction in cumulative incidence of symptomatic HAV infections over the first 25 y of vaccination was 45-51%. With 90% first-dose coverage and 85% second-dose coverage, the projected reduction in incidence of all HAV infections was 85-93%, and the projected reduction in the cumulative incidence of symptomatic HAV infections was 61-67%, over a 25-y time frame. Sensitivity analyses indicated that second-dose coverage is important under the conservative base-case assumptions made about the duration of vaccine protection. The model indicated that universal infant HAV vaccination could substantially reduce the burden of HAV disease in Mexico.

Background: Alterations in intestinal permeability have been implicated in ulcerative colitis (UC). Infliximab, a monoclonal anti-tumor necrosis factor alpha (TNFα) antibody, can induce clinical response in UC. Gene expression in colonic biopsies taken from responders and nonresponders to infliximab can provide insight into the mechanisms of the altered intestinal permeability at a molecular level., Methods: Colonic biopsies (n = 18 anti-TNFα naïve UC patients; n = 8 normal controls; n = 80 Active Ulcerative Colitis Trial [ACT] 1 patients) were analyzed for mRNA expression using gene expression microarrays. Computational reverse causal reasoning was applied to build causal network models of UC and response and nonresponse of UC to treatment. Quantitative reverse-transcription polymerase chain reaction (qPCR) was used to confirm differentially expressed genes., Results: Reverse causal reasoning on mRNA expression data from anti-TNFα-naïve UC and normal samples provided a mechanistic disease model of the biology of gene expression observed in UC. mRNA expression data from the ACT 1 study enabled construction of a mechanistic model describing the biology of nonresponders to infliximab, including evidence for increased intestinal permeability compared with normal and responder samples. Gene expression changes identified as central to intestinal permeability dysregulation were confirmed in normal, UC, and infliximab-treated patients by qPCR analysis. Gene expression returned toward normal levels in infliximab responders, but not in nonresponders., Conclusion: Gene expression analysis and causal network modeling in combination showed that aberrant mRNA expression of genes involved in intestinal epithelial permeability for infliximab responders was restored toward levels observed in normal samples. Infliximab nonresponders showed no equivalent restoration in the expression of these genes., (Copyright © 2012 Crohn's & Colitis Foundation of America, Inc.)

Background: Infectious disease specialists who evaluate international travelers before or after their trips need skills to prevent, recognize, and treat an increasingly broad range of infectious diseases. Wide variation exists in training and percentage effort among providers of this care. In parallel, there may be variations in approach to pre-travel consultation and the types of travel-related illness encountered. Aggregate information from travel-medicine providers may reveal practice patterns and novel trends in infectious illness acquired through travel., Methods: The 1,265 members of the Infectious Disease Society of America's Emerging Infections Network were queried by electronic survey about their training in travel medicine, resources used, pre-travel consultations, and evaluation of ill-returning travelers. The survey also captured information on whether any of 10 particular conditions had been diagnosed among ill-returning travelers, and if these diagnoses were perceived to be changing in frequency., Results: A majority of respondents (69%) provided both pre-travel counseling and post-travel evaluations, with significant variation in the numbers of such consultations. A majority of all respondents (61%) reported inadequate training in travel medicine during their fellowship years. However, a majority of recent graduates (55%) reported adequate preparation. Diagnoses of malaria, traveler's diarrhea, and typhoid fever were reported by the most respondents (84, 71, and 53%, respectively)., Conclusions: The percent effort dedicated to pre-travel evaluation and care of the ill-returning traveler vary widely among infectious disease specialists, although a majority participate in these activities. On the basis of respondents' self-assessment, recent fellowship training is reported to equip graduates with better skills in these areas than more remote training. Ongoing monitoring of epidemiologic trends of travel-related illness is warranted., (© 2012 International Society of Travel Medicine.)

Background: Agitation is one of the most common neuropsychiatric symptoms of Alzheimer's disease (AD), and is associated with serious adverse consequences for patients and caregivers. Evidence-supported treatment options for agitation are limited. The citalopram for agitation in Alzheimer's disease (CitAD) study was designed to evaluate the potential of citalopram to ameliorate these symptoms., Methods: CitAD is a randomized, double-masked, placebo-controlled multicenter clinical trial, with two parallel treatment groups assigned in a 1:1 ratio and randomization stratified by clinical center. The study included eight recruiting clinical centers, a chair's office, and a coordinating center located in university settings in the United States and Canada. A total of 200 individuals having probable AD with clinically significant agitation and without major depression were recruited for this study. Patients were randomized to receive citalopram (target dose of 30 mg/d) or matching placebo. Caregivers of patients in both treatment groups received a structured psychosocial therapy. Agitation was compared between treatment groups using the NeuroBehavioral Rating Scale and the AD Cooperative Study- Clinical Global Impression of Change, which are the primary outcomes. Functional performance, cognition, caregiver distress, and rates of adverse and serious adverse events were also measured., Conclusion: The authors believe the design elements in CitAD are important features to be included in trials assessing the safety and efficacy of psychotropic medications for clinically significant agitation in AD., (Copyright © 2012 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Objectives: Infliximab has been shown to induce clinical response and remission in ulcerative colitis (UC). To characterize the biological response of patients to infliximab, we analyzed the mRNA expression patterns of mucosal colonic biopsies taken from UC patients enrolled in the Active Ulcerative Colitis Trial 1 (ACT1) study., Methods: Biopsies were obtained from 48 UC patients before treatment with 5 or 10 mg/kg infliximab, and at 8 and 30 weeks after treatment (n = 113 biopsies). Global gene expression profiling was performed using Affimetrix GeneChip Human Genome U133 Plus 2.0 arrays. Expression profiling results for selected genes were confirmed using qPCR., Results: Infliximab had a significant effect on mRNA expression in treatment responders, with both infliximab dose and duration of treatment having an effect. Genes affected are primarily involved with inflammatory response, cell-mediated immune responses, and cell-to-cell signaling. Unlike responders, non-responders do not effectively modulate T(H₁), T(H₂), and T(H₁₇) pathways. Gene expression can differentiate placebo and infliximab responders., Conclusions: Analysis of mRNA expression in mucosal biopsies following infliximab treatment provided insight into the response to therapy and molecular mechanisms of non-response.

Aim: To compare the outcome of organs retrieved from patients brain dead due to cardiac arrest (CA) with that of organs retrieved from patients brain dead due to other causes (non-CA)., Methods: Systematic review. Clinical studies comparing the outcome of patients and organs retrieved from donors brain dead after being resuscitated from cardiac arrest with that of patients and organs retrieved from donors brain dead not due to cardiac arrest were considered for inclusion. Full-text articles were searched on MEDLINE, EmBASE, Cochrane Register of Controlled Trials and Cochrane Register of Systematic Reviews., Main Outcome Measure: One-year patient or organ survival rate., Results: Four studies fulfilling inclusion criteria were found and three had sufficient quality to be included in final analysis. A total of 858 organs were transplanted from 741 donors. Since the transplanted organs (heart, liver, kidney, lung and intestine) were different in the three studies, metanalysis was not performed. There were no significant differences in 1-year survival rates between CA and non-CA groups. No significant differences were reported for 5-year survival rates, early recovery of transplanted organ function, and organ rejection rates., Conclusion: Survival rates of kidneys, livers, hearts and intestines retrieved from CA donors were not significantly different from that of organs transplanted from non-CA donors. Patients brain dead after having been resuscitated from cardiac arrest can be considered as potential donors for organ transplantation., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Background: International travel to developing countries is increasing with rising levels of disposable income; this trend is seen in both adults and children. Risk-taking attitude is fundamental to research on the prevention of risky health behaviors, which can be an indicator of the likelihood of experiencing illness or injury during travel. The aim of this study is to investigate whether risk-taking attitudes of youths are associated with travel characteristics and likelihood of experiencing illness or injury while traveling to nonindustrialized countries., Methods: Data were analyzed from the 2008 YouthStyles survey, an annual mail survey gathering demographics and health knowledge, attitudes, and practices of individuals from 9 through 18 years of age. Travelers were defined as respondents who reported traveling in the last 12 months to a destination other than the United States, Canada, Europe, Japan, Australia, or New Zealand. Risk-taking attitude was measured by using a four-item Brief Sensation-Seeking Scale. All p values ≤ 0.05 were considered significant., Results: Of 1,704 respondents, 131 (7.7%) traveled in the last 12 months. Females and those with higher household income were more likely to travel (odds ratio = 1.6,1.1). Of those who traveled, 16.7% reported seeking pretravel medical care, with most visiting a family doctor for that care (84.0%). However, one-fifth of respondents reported illness and injury during travel; of these, 83.3% traveled with their parents. Males and older youths had higher mean sensation-seeking scores. Further, travelers had a higher mean sensation-seeking score than nontravelers. Those who did not seek pretravel medical care also had higher mean sensation-seeking scores (p = 0.1, not significant)., Conclusions: Our results show an association between risk-taking attitudes and youth travel behavior. However, adult supervision during travel and parental directives prior to travel should be taken into consideration. Communication messages should emphasize the importance of pretravel advice, target parents of children who are traveling, and be communicated through family doctors., (© 2010 International Society of Travel Medicine.)

Purpose: To systematically review the published evidence on the ability of passive leg raising-induced changes in cardiac output (PLR-cCO) and in arterial pulse pressure (PLR-cPP) to predict fluid responsiveness., Methods: MEDLINE, EMBASE and the Cochrane Database of Systematic Reviews were screened. Clinical trials on human adults published as full-text articles in indexed journals were included. Two authors independently used a standardized form to extract data about study characteristics and results. Study quality was assessed by using the QUADAS scale., Results: Nine articles including a total of 353 patients were included in the final analysis. Data are reported as point estimate (95% confidence intervals). The pooled sensitivity and specificity of PLR-cCO were 89.4% (84.1-93.4%) and 91.4% (85.9-95.2%) respectively. Diagnostic odds ratio was 89.0 (40.2-197.3). The pooled area under the receiver operating characteristics curve (AUC) was 0.95 (0.92-0.97). The pooled correlation coefficient r between baseline value of PLR-cCO and CO increase after fluid load was 0.81 (0.75-0.86). The pooled difference in mean PLR-cCO values between responders and non-responders was 17.7% (13.6-21.8%). No significant differences were identified between patients adapted to ventilator versus those with inspiratory efforts nor between patients in sinus rhythm versus those with arrhythmias. The pooled AUC for PLR-cPP was 0.76 (0.67-0.86) and was significantly lower than the AUC for PLR-cCO (p < 0.001). The pooled difference in mean PLR-cPP values between responders and non-responders was 10.3% (6.5-14.1%)., Conclusions: Passive leg raising-induced changes in cardiac output can reliably predict fluid responsiveness regardless of ventilation mode and cardiac rhythm. PLR-cCO has a significantly higher predictive value than PLR-cPP.

Systolic anterior motion (SAM) of mitral valve is the prolapse of a mitral leaflet into the left ventricle outflow tract (LVOT) during systole, causing LVOT obstruction and mitral valve regurgitation. We report the case of a patient who developed SAM-induced hemodynamic instability during bleeding with a clinical picture resembling pulmonary edema. A 77-year-old woman was admitted to our emergency room for abdominal bleeding in polycystic renal disease. Upon arrival, she was normotensive, despite being anuric and acidotic. After infusion of fluids and packed red blood cells (total 3 680 mL in 6 hours) she developed atrial fibrillation and clinical and radiological signs of pulmonary edema. Sedation and non-invasive ventilation brought to immediate severe hypotension. A transesophageal echocardiogram showed an "empty" hypertrophic hypercontractile left ventricle, SAM with LVOT obstruction (intraventricular gradient 154 mmHg) and moderate-to-severe mitral regurgitation. With further fluid infusion hemodynamic stability and sinus rhythm were recovered. SAM, LVOT obstruction and mitral regurgitation disappeared. SAM is a rare but dangerous cause of hemodynamic instability. It has been described in patients with and without left ventricular hypertrophy, in presence of hypovolemia and sympathetic stimulation. In our case it presented with a misleading clinical picture of pulmonary edema simulating fluid overload in an actually hypovolemic patient. In fact, SAM-associated mitral regurgitation together with diastolic dysfunction and tachycardia induced a pulmonary edema whose treatment worsened hypovolemia and precipitated LVOT obstruction and hypotension. Further fluid infusion was resolutive. Echocardiography was fundamental for diagnosis and treatment.

Ustekinumab, a human anti-interleukin (IL)-12/IL-23p40 monoclonal antibody has demonstrated significant efficacy in patients with moderate-to-severe psoriasis. Skin lesion biopsies, cell surface markers on peripheral blood lymphocytes, and ex vivo T-helper (Th)1/Th2 cytokine responses from peripheral blood mononuclear cells (PBMC) from patients receiving ustekinumab 45 or 90 mg, or placebo were evaluated at baseline and week 12. Inflammatory serum protein levels were measured at baseline, week 2 and week 12. At week 12, median epidermal thickness decreased from 312.1 to 132.7 microm, and median levels of cellular proliferation (Ki67) and T-cell infiltration (CD3) decreased by 84.3% and 70.7%, respectively, in the combined ustekinumab group (all P < or = 0.002). Serum levels of tumor necrosis factor (TNF)-alpha, C-C motif ligand 27 (CCL27) and other inflammatory cytokines remained unchanged. Minimal variation in the percentage of T cells expressing cutaneous lymphocyte antigen (CLA) was observed following ustekinumab treatment, with no significant variation in the percentage of cells expressing CD45RA, CD45RO, CD25, human leukocyte antigen-DR (HLA-DR), and C-X-C motif receptor 3 (CXCR3). No apparent effect on the magnitude of Th1/Th2 responses to external stimuli in PBMC was observed following placebo or ustekinumab treatment. Ustekinumab improves histological psoriasis measures, with minimal impact on the systemic immune system.

During the 2008 Olympic and Paralympic Games, we conducted surveillance of illnesses among travelers at six Beijing clinics. Surveys asked about demographic, pre-travel, and vaccination information, and physician-provided diagnoses. Of 807 respondents, 38% and 57% were classified as foreign visitors (FV) and expatriates, respectively. Less than one-half of FV sought pre-travel advice; sources included health-care providers and friends/family. FV vaccination rate was also low; however, most vaccines given were recommended by the Centers for Disease Control and Prevention. The most common FV diagnoses were respiratory, injury/musculoskeletal, and gastrointestinal illnesses; for expatriates, injury/musculoskeletal, respiratory, and dermatologic were the most common illnesses. Respiratory illnesses in expatriates were significantly less in 2008 than during 2004-2007 (chi(2) = 10.2; P = 0.0014), suggesting that control programs may have reduced pollutants/respiratory irritants during the 2008 Games. We found no previous studies of health outcomes among expatriates living in cities with mass travel events. These findings highlight the need to continuously disseminate information to health-care providers advising travelers.

Objective: The implementation of policies that prohibit tobacco smoking in public places has resulted in a significant reduction in secondhand smoke (SHS) exposure in the US population; however, such policies do not extend to private homes, where children continue to be exposed. Our objective was to assess SHS exposure among US children and adolescents by using serum cotinine measures to compare those who were exposed to SHS in the home and those without home exposure., Methods: We analyzed serum cotinine data from the 2003-2006 National Health and Nutrition Examination Survey for 5518 children (3-11 years) and nonsmoking adolescents (12-19 years). We calculated geometric mean serum cotinine levels by sociodemographic and household characteristics according to self-reported home SHS exposure. Multiple regression analysis was conducted to evaluate independent predictors of serum cotinine levels., Results: Geometric mean serum cotinine levels were 1.05 ng/mL among those with home SHS exposure and 0.05 ng/mL among those without home exposure. Among children who were exposed to SHS at home, serum cotinine levels were inversely associated with age and were similar for non-Hispanic black and non-Hispanic white children. Conversely, among children without SHS exposure at home, serum cotinine levels were higher among non-Hispanic black compared with non-Hispanic white children, and there was no relationship with age. Mexican American children had the lowest level of SHS exposure., Conclusions: Serum cotinine levels were an order of magnitude higher among children with reported SHS exposure at home compared with those with no exposure in the home.

Association between Myosin IXB (MYO9B) gene polymorphisms and celiac disease (CD) was recently detected by a case-control association study in the Dutch, but not confirmed in the British and Swedish/Norwegian populations. We tested the association between CD and the three most associated single nucleotide polymorphisms (SNPs) in the Dutch study by the transmission disequilibrium test in the Italian population. A total of 252 pediatric patients and 504 parents were genotyped. No transmission distortion was detected either for the single SNPs or for their haplotypic combinations. Control allele frequencies, calculated from untransmitted alleles, were significantly different from those of the Dutch control population. Conversely, allele frequencies were very similar in Italian, British, Swedish/Norwegian and Dutch patients. In conclusion, MYO9B is not involved in CD susceptibility in the Italian population. The difference with the Dutch result might be explained by an imperfect selection of the Dutch controls.

Concentrations of trace elements (Hg, Cd, Pb, Zn, Cu, Fe, and Se) in different organs and tissues (liver, kidney, muscle tissue, spleen, heart, lung, and fat tissue) of loggerhead turtles Caretta caretta from eastern Mediterranean Sea were determined. The highest levels of mercury and cadmium were found in liver (Hg: 0.43 microg g(-1) wet weight; Cd: 3.36 microg g(-1) wet weight) and kidney (Hg: 0.16 microg g(-1) wet weight; Cd: 8.35 microg g(-1) wet weight). For lead the overall concentrations were low and often below the limit of detection. Copper and selenium tended to be higher in liver than in other tissues and organs, while for zinc the concentrations were quite homogenous in the different organs and tissues, except fat tissue (64.7 microg g(-1) wet weight) which showed a higher accumulation of this element. For iron the greatest concentrations were observed in liver (409 microg g(-1) wet weight) and spleen (221 microg g(-1) wet weight).

Background: Magnetic resonance imaging (MRI) white matter hyperintensities (WMHs) are found at higher rates in patients with affective disorders, particularly late-life or treatment-resistant disorders. Studies support a vascular pathogenesis for WMHs in late-life onset disorders; however, pathogenesis in typical early-life onset disorders is less clear. Based on associations between diabetes mellitus and both WMHs and affective disorders, this study investigated the relationship between WMHs and brain glucose metabolism by the polyol pathway-a pathway linked to nervous tissue disease in diabetes., Methods: Burdens of fluid-attenuated inversion recovery (FLAIR) WMHs were quantified and correlated with cerebrospinal fluid (CSF) concentrations of glucose metabolites in 10 nondiabetic inpatients with treatment-resistant bipolar, unipolar, and schizoaffective disorders and 10 nondiabetic control patients who had been investigated clinically for transient neurological symptoms., Results: Deep but not periventricular WMH burden correlated positively and significantly with elevated CSF concentrations of sorbitol, the specific polyol pathway metabolite of glucose (rho=0.86, p=0.002), in the affective disorders but not the control group., Limitations: This was a pilot study with a relatively small number of subjects; therefore, conclusions are tentative. Controls were not healthy subjects; they were patients with transient neurological symptoms., Conclusions: This is the first reported evidence of a relationship between WMHs and increased brain glucose metabolism by the polyol pathway in patients with affective disorders. More extensive studies are necessary to determine whether this preliminary finding represents a pathogenetic relationship.

Objective: Type 2 diabetes is an important comorbid medical condition associated with schizophrenia. The objective of this study was to compare glycosylated hemoglobin (HbA(1c)) levels of patients who had type 2 diabetes and schizophrenia with those of patients who had type 2 diabetes and major mood disorders and those who had type 2 diabetes but who did not have severe mental illness., Methods: A sample of 300 patients with type 2 diabetes was recruited from community mental health centers in the greater Baltimore region and nearby primary care clinics. Of these, 100 had schizophrenia, 101 had a major mood disorder, and 99 had no identified severe mental illness. HbA(1c), the main outcome measure, was compared between the group with schizophrenia and the other two groups., Results: All three groups had HbA(1c) values above recommended levels. HbA(1c) levels were significantly lower among patients with schizophrenia than among patients who did not have severe mental illness but were not significantly different from those of patients who had major mood disorders. Patients for whom olanzapine was prescribed had higher HbA(1c) levels than those for whom other antipsychotic agents were prescribed., Conclusions: All three groups of patients require improved diabetes treatment to achieve acceptable HbA(1c) levels. There may be previously unrecognized benefits for diabetes management among persons with severe mental illnesses who are receiving regular mental heath care, but these individuals may also have risk factors that can influence diabetes outcomes and HbA(1c) levels.

Background: There are numerous reports of abnormal glucose metabolism, including increased rates of type 2 diabetes mellitus, in psychiatric patients. It remains unclear, however, whether there is an intrinsic relationship between abnormal glucose metabolism and particular psychiatric disorders, because the relationship is complicated by treatment with psychotropic medications that promote weight gain and hyperglycemia. This study aimed to clarify this relationship., Methods: The medical records of 243 inpatients, aged 50-74 years, with diagnoses of major depression, bipolar I disorder, schizoaffective disorder, schizophrenia, and dementia were reviewed. Psychiatric and type 2 diabetes mellitus diagnoses, medications, body mass index (BMI), age, gender, and race were recorded. Diabetes rates were compared to age, race, and gender-matched rates in the US general population., Results: Rates of type 2 diabetes mellitus were: schizoaffective (50%) > bipolar I (26%) > major depression (18%) = dementia (18%) > schizophrenia (13%) (p < 0.006). Diabetic patients had a higher mean BMI (p = 0.01), but not a significantly higher use of psychotropic medications previously reported to be associated with new-onset type 2 diabetes (e.g., phenothiazines, clozapine, olanzapine). Logistic regression revealed that psychiatric diagnosis and BMI were the only significant and independent predictors of diabetes diagnosis. Compared to national norms, diabetes rates were significantly elevated only in bipolar I affective and schizoaffective patients., Limitations: This study was a retrospective chart review of older, hospitalized patients., Conclusions: This is the first published study to show an increased prevalence of type 2 diabetes mellitus among psychiatric patients with particular psychiatric illnesses independent of the effects of age, race, gender, medication, and body mass. This finding, which requires replication in a larger scale, prospective study, suggests an intrinsic relationship between abnormal glucose metabolism and bipolar I affective and schizoaffective disorders.

The phorbol ester, TPA, transiently increases the transepithelial permeability across the gastrointestinal epithelium formed by IEC-18. There was a significant decrease in transepithelial resistance (R(T)) between 0 and 1.5 hr, accompanied by increased flux of polyethylene glycol (4000 MW), suggesting that the increase was across the tight junction. By 2 hr, the decrease in R(T) reversed and maintained control level. The transepithelial permeability increase was prevented by coincubation with the protein kinase C (PKC) inhibitor bisindolylmaleimide. There was a rapid (within 15 min) translocation of PKC-alpha from the cytosolic to the "membrane-associated" compartment, followed by a down-regulation that was detectable within 60 min of TPA treatment. The down-regulation of PKC-alpha from the membrane was prevented by either calpain inhibitor I or MG-132 and resulted in a sustained permeability increase. The permeability changes were not accompanied by significant effects on the amount or localization of the tight junctional proteins, occludin and ZO-1. However, occludin did show a reversible increase in phosphorylation with TPA treatment. Together these data support a role for PKC-alpha-mediated regulation of barrier permeability in an in vitro model of small intestinal epithelium, perhaps through modulation of the phosphorylation state of the tight junctional protein, occludin.

Background: Tumor necrosis factor-alpha (TNF) has been implicated in the development of postoperative morbidity after cardiopulmonary bypass for myocardial revascularization. Despite their postulated roles as modulators of TNF bioavailability, soluble TNF receptors have not been characterized in patients undergoing this procedure and is the focus of this study., Methods: Soluble tumor necrosis factor receptor I (sTNFRI) and TNF were measured by immunoassay in plasma samples collected from 36 patients at events before, during, and after cardiopulmonary bypass., Results: Plasma concentrations of sTNFRI averaged 1.39 ng/mL at the start of the operation. Preoperative sTNFRI concentrations were found to significantly correlate with a preoperative morbidity assessment score, age, duration of bypass, duration of supplemental oxygen, and length of hospital stay. Plasma sTNFRI increased in all of the patients during the procedure. Plasma concentrations of sTNFRI and TNF did not correlate at any time., Conclusions: Preoperative measurement of sTNFRI could potentially serve as a reliable indicator for prophylactic treatment with an anti-TNF therapy. Such a therapeutic approach might help attenuate inflammatory processes thought to underlie postoperative morbidity associated with cardiopulmonary bypass.

Exposure of LLC-PK1 epithelial cell cultures to phorbol ester tumor promoters causes immediate translocation of protein kinase C-alpha (PKC-alpha) from cytosolic to membrane-associated compartments. With a very similar time course, a dramatic and sustained increase in tight junctional (paracellular) permeability occurs. This increased permeability extends not only to salts and sugars but macromolecules as well. Fortyfold increases of transepithelial fluxes of biologically active EGF and insulin occur. Recovery of tight junction barrier function coincides with proteasomal downregulation of PKC-alpha. The failure to downregulate activated membrane-associated PKC-alpha has correlated with the appearance of multilayered cell growth and persistent leakiness of tight junctions. Accelerated downregulation of PKC-alpha results in only a partial and transient increase in tight junction permeability. Transfection of a dominant/negative PKC-alpha results in a slower increase in tight junction permeability in response to phorbol esters. In a separate study using rat colon, dimethylhydrazine (DMH)-induced colon carcinogenesis has been preceded by linear increases in both the number of aberrant crypts and transepithelial permeability, as a function of weeks of DMH treatment. Adenocarcinomas of both rat and human colon have been found to have uniformly leaky tight junctions. Whereas most human colon hyperplastic and adenomatous polyps contain nonleaky tight junctions, adenomatous polyps with dysplastic changes did possess leaky tight junctions. Our overall hypothesis is that tight junctional leakiness is a late event in epithelial carcinogenesis but will allow for growth factors in luminal fluid compartments to enter the intercellular and interstitial fluid spaces for the first time, binding to receptors that are located on only the basal-lateral cell surface, and causing changes in epithelial cell kinetics. Tight junctional leakiness is therefore a promotional event that would be unique to epithelial cancers.

Tumor necrosis factor-alpha (TNF) induces apoptosis in confluent LLC-PK1 epithelial cells, but also activates NF-kappaB, a negative regulator of apoptosis. The presence of increased TNF-induced apoptosis causes a transient increase in epithelial permeability, but the epithelial barrier function recovers, as assessed by measuring the transepithelial electrical resistance, the paracellular flux of mannitol and by the electron microscopic evaluation of the penetration of the electron-dense dye ruthenium red across the tight junctions. The integrity of the epithelial cell layer is maintained by rearrangement of non-apoptotic cells in the monolayer and by the phagocytosis of apoptotic fragments. To study the role of NF-kappaB in an epithelium exposed to TNF, NF-kappaB was inhibited in LLC-PK1 epithelial cells with either the dietary compound, curcumin, or by transfection with a dominant negative mutant inhibitor I kappaB alpha. Replacement of serine 32 and 36 by alanine has been shown to prevent its phosphorylation and degradation, blocking NF-kappaB activation. Inhibition of NF-kappaB altered the morphology of TNF-induced apoptotic cells, which showed lack of fragmentation and membrane blebbings, and absence of phagocytosis by neighboring cells. TNF treatment of NF-kappaB-inhibited cells also caused altered distribution of the tight junction-associated protein ZO-1, increased epithelial leakiness, and impaired the recovery of the epithelial barrier function, which normally occurs 6 hours after TNF treatment of LLC-PK1 cells. These data demonstrate that NF-kappaB activation is required for the maintenance of the barrier function of an epithelium undergoing TNF-induced apoptosis.

In addition to the concentrative, Na(+)-dependent inositol transport system demonstrated in many cell types, carrier-mediated, Na(+)-independent inositol transport is also shown to exist in LLC-PK1 renal epithelia. Inhibition of inositol uptake in Na(+)-free saline by 0.1 mM phloretin, and self-inhibition by net concentrations of inositol exceeding 10 mM, demonstrate the carrier-mediation of the Na(+)-independent uptake and distinguish it from flux through anion channels. The Na(+)-dependent uptake exhibits higher affinity for inositol, as seen by the stronger self-inhibition at lower inositol concentrations in Na+ saline. Kinetic analyses indicate a Km of 178 microM and a Vmax of 2447 pmol/min per microgram DNA for the Na(+)-dependent system, whereas the lower affinity, lower capacity Na(+)-independent system manifests a Km of 5.2 mM and a Vmax of 249 pmol/min per microgram DNA. the Na(+)-independent uptake further differs from the Na(+)-dependent transport by the lack of inhibitory effect of 10 microM glucose, and the greater relative inhibition of phloretin compared to that of phlorizin. Both types of uptake appear to localize predominantly to the basal-lateral cell surface. The Na(+)-independent transport is bidirectional, functioning in efflux as well as influx of inositol.

The transepithelial paracellular permeability of an epithelium formed by LLC-PK1 cells increases upon activation of protein kinase C (PKC) by the phorbol ester tumor promoter, TPA, or in response to the cytokine tumor necrosis factor-alpha (TNF). Until recently, however, we have not been able to inhibit the permeability effects of TPA or TNF using any of the currently available serine-threonine kinase inhibitors. In this study we report the treatment of epithelial cell sheets with the selective PKC inhibitor bisindolylmaleimide, GF109203X, completely prevents the TPA-induced but not the TNF-alpha induced increase in tight junction permeability. While PKC-alpha still translocates from the cytosol to the membrane of TPA-stimulated epithelial cells overall PKC activity in the membrane fraction is markedly reduced in the presence of GFX.

Transport defects by retinal pigment epithelial (RPE) and other cells are observed in experimental models of diabetes mellitus. Recent studies have established that glucose concentration, per se, is the critical risk factor in the pathogenesis of diabetic complications. This study was designed to test whether transport alterations could be produced in the simplest model of diabetes, sustained exposure of cultured cells to a high-glucose environment. The regulatory transport responses to acute changes in cell volume were measured in order to assess the effects of glucose on a range of transport processes. Continuous lines of nontransformed human retinal pigment epithelial (hRPE) cells were grown for two weeks with either 5.6 low glucose (LG) or 26.0 high glucose (HG) mM in paired experiments. The cell volumes of suspended cells were studied in hypo-, iso- and hypertonic solutions containing the same ionic composition. Hypotonic swelling triggered a regulatory volume decrease (RVD), inhibited by reducing the chemical driving force for K+ efflux, or blocking K+ channels (with Ba2+) or Cl- channels (with NPPB). Thus, the RVD of the hRPE cells likely reflects efflux of K+ and Cl- through parallel channels. Shrinkage caused a regulatory volume increase (RVI), which was inhibited by blocking Na+/H+ (with dimethylamiloride) or Cl-/HCO3- exchange (with DIDS). Bumetanide inhibited the RVI significantly only when the K+ concentration was increased above the baseline level. Therefore, the RVI under our baseline conditions likely reflects primarily Na+/H+ and Cl-/HCO3- antiport exchange. Growth in high-glucose medium had no substantial effect on the RVD, but reduced the rate constant of the RVI by approximately 50%. The RVI was unaffected by growth in high-mannitol medium. Stimulation of protein kinase C (PKC) with DiC8 increased the RVI of HG-cells, but not of LG-cells. The DiC8-induced stimulation was bumetanide insensitive and abolished by 1 mM amiloride. Other transport effects of PKC (on the RVD) were unaltered in the HG-cells. We conclude that sustained elevation of extracellular glucose, per se, can downregulate the Na+/H+ antiport of target cells, an effect noted in streptozotocin-treated rats, and that this downregulation does not reflect interruption of the PKC-signaling pathway.

Confluent human retinal pigmented epithelial cells were cultured on microcarrier beads in the presence of 5.6 or 26 mmol/l glucose with or without the aldose-reductase inhibitor Sorbinil (200 microM) for 2 wk. At the end of the incubation period, perchloric acid extracts were prepared and analyzed by 31P nuclear magnetic resonance spectroscopy. As assessed by this method, the phosphorylated metabolites of cells incubated with 5.6 or 26 mmol/l glucose differed significantly in the concentrations of a number of uridine diphosphate (UDP)-conjugated monosaccharides, which were elevated two- to threefold in cells incubated in 26 mmol/l glucose over control samples. The affected metabolites were identified (through a series of spiking experiments) to be UDP-N-acetylglucosamine, UDP-N-acetylgalactosamine, and UDP-glucuronic acid. Coincubation of the cells with Sorbinil 200 microM in the presence of 26 mmol/l glucose had no effect on this accumulation. Under normal circumstances, these molecules selectively and sequentially are incorporated into the polysaccharide chains of glycosaminoglycans (GAGs), whose presence and distribution in the basement membranes is affected adversely by diabetes mellitus. These data suggest that the availability of the monosaccharide precursor is not the rate-limiting step for GAG synthesis in the presence of pathologic glucose concentrations. Thus, the lost GAG content in the basement membranes of diabetic patients may be caused by changes elsewhere in the biosynthesis and/or catabolism of the polysaccharide-linked protein molecules.

This study demonstrated that there were basic differences in facial morphology between patients with cleft lip and palate and subjects with non clefting. The findings are obtained on cephalometric analysis of skull's teleradiograph L-L. These differences are for all pratical purposes confined to the maxillary complex. The mandible appear, instead, normal unless in the position in every respect in the not cleft lip and palate subjects.

Biochemical evidence of glucose toxicity was found in the retinal and corneal layers of diabetic rabbits. It can be reasonably assumed that the observed changes are causally related to the morphological and physiological diabetic pathologies of the retinal and corneal cells. Intracellular glucose is greatly increased, and the polyol pathway activity appears to be enhanced, resulting in an accumulation of intracellular sorbitol, which can be assumed to be oxidized to fructose. Accompanying the alterations of glucose metabolism are disturbances in myoinositol and Na+ handling by the affected structures. The detailed relationship of the observed metabolic effects of hyperglycemia to changes in cellular ion handling and the observed morphological and functional disturbances has yet to be elucidated. The morphologically and functionally discrete populations of RPE and CEN cells, which are readily amenable to experimental manipulation in situ and in cell culture may serve as unique models for systematic examination of the causes and the consequences of diabetes leading to ocular complications in particular and to the complications of other more complex tissues such as nerve and kidney. The present data show that the findings in one population of cells may not be completely reproducible in another as can be seen in the diverse myoinositol responses of the retinal and corneal layers to diabetes mellitus. The diverse responses perhaps reflect unique adaptive capabilities of individual tissues to the diabetic condition. It is a challenge for complications research to fully appreciate diverse responses of various tissues to persistent glucose intoxication and to delineate meticulously the time courses of such heterogeneous responses, which might result in debilitating pathology in certain cases but in a compensated chronic disease state in others. The corneal endothelium and the RPE are relatively resilient structures compared with the mural and endothelial cells of the retinal microvessels which are destroyed by the diabetic condition. Factors and components that protect tissues against the persistent effects of hyperglycemia need to be uncovered. Success in such an endeavor could be of benefit in the management of diabetic complications.