Clozapine is associated with secondary antibody deficiency.

BACKGROUND: Schizophrenia affects 1% of the population. Clozapine is the only medication licensed for treatment-resistant schizophrenia and is intensively monitored to prevent harm from neutropenia. Clozapine is also associated with increased risk of pneumonia although the mechanism is poorly understood.AimsTo investigate the potential association between clozapine and antibody deficiency. METHODS: Patients taking clozapine and patients who were clozapine-naive and receiving alternative antipsychotics were recruited and completed a lifestyle, medication and infection-burden questionnaire. Serum total immunoglobulins (immunoglobulin (Ig)G, IgA, IgM) and specific IgG antibodies to haemophilus influenzae type B, tetanus and IgG, IgA and IgM to pneumococcus were measured. RESULTS: Immunoglobulins were all significantly reduced in the clozapine-treated group (n = 123) compared with the clozapine-naive group (n = 111). Odds ratios (ORs) for a reduction in clozapine:control immunoglobulin values below the fifth percentile were IgG, OR = 6.00 (95% CI 1.31-27.44); IgA, OR = 16.75 (95% CI 2.18-128.60); and IgM, OR = 3.26 (95% CI 1.75-6.08). These findings remained significant despite exclusion of other potential causes of hypogammaglobulinaemia. In addition, duration on clozapine was associated with decline in IgG. A higher proportion of the clozapine-treated group reported taking more than five courses of antibiotics in the preceding year (5.3% (n = 5) versus 1% (n = 1). CONCLUSIONS: Clozapine use was associated with significantly reduced immunoglobulin levels and an increased proportion of patients using more than five antibiotic courses in a year. Antibody testing is not included in existing clozapine monitoring programmes but may represent a mechanistic explanation and modifiable risk factor for the increased rates of pneumonia and sepsis-related mortality previously reported in this vulnerable cohort.Declaration of interestS.J. has received support from CSL Behring, Shire, LFB, Biotest, Binding Site, Sanofi, GSK, UCB Pharma, Grifols, BPL SOBI, Weatherden, Zarodex and Octapharma for projects, advisory boards, meetings, studies, speaker and clinical trials.

NEOSCOPE: a randomised Phase II study of induction chemotherapy followed by either oxaliplatin/capecitabine or paclitaxel/carboplatin based chemoradiation as pre-operative regimen for resectable oesophageal adenocarcinoma.

BACKGROUND: Both oxaliplatin/capecitabine-based chemoradiation (OXCAP-RT) and carboplatin-paclitaxel based radiation (CarPac-RT) are active regimens in oesophageal adenocarcinoma, but no randomised study has compared their efficacy and toxicity. This randomised phase II "pick a winner" trial will identify the optimum regimen to take forward to a future phase III trial against neo-adjuvant chemotherapy, the current standard in the UK. METHODS/DESIGN: Patients with resectable adenocarcinoma of the oesophagus or Siewert Type 1-2 gastro-oesophageal junction (GOJ), ≥T3 and/or ≥ N1 are eligible for the study. Following two cycles of induction OXCAP chemotherapy (oxaliplatin 130 mg/m2 D1, Cape 625 mg/m(2) D1-21, q 3 wk), patients are randomised 1:1 to OXCAP-RT (oxaliplatin 85 mg/m(2) Day 1,15,29; capecitabine 625 mg/m(2) twice daily on days of RT; RT-45 Gy/25 fractions/5 weeks) or CarPac-RT (Carboplatin AUC2 and paclitaxel 50 mg/m2 Day 1,8,15,22,29; RT-45 Gy/25 fractions/5 weeks). Restaging CT/PET-CT is performed 4-6 weeks after CRT, and a two-phase oesophagectomy with two-field lymphadenectomy is performed six to eight weeks after CRT. The primary end-point is pathological complete response rate (pCR) at resection and will include central review. Secondary endpoints include: recruitment rate, toxicity, 30-day surgical morbidity/mortality, resection margin positivity rate and overall survival (median, 3- and 5-yr OS. 76 patients (38/arm) gives 90% power and one-sided type 1 error of 10% if patients on one novel treatment have a response rate of 35% while the second treatment has a response rate of 15%. A detailed RT Quality Assurance (RTQA) programme includes a detailed RT protocol and guidance document, pre-accrual RT workshop, outlining exercise, and central evaluation of contouring and planning. This trial has been funded by Cancer Research UK (C44694/A14614), sponsored by Velindre NHS Trust and conducted through the Wales Cancer Trials Unit at Cardiff University on behalf of the NCRI Upper GI CSG. DISCUSSION: Following encouraging results from previous trials, there is an interest in neo-adjuvant chemotherapy and CRT containing regimens for treatment of oesophageal adenocarcinoma. NEOSCOPE will first establish the efficacy, safety and feasibility of two different neo-adjuvant CRT regimens prior to a potential phase III trial. TRIAL REGISTRATION: Eudract No: 2012-000640-10. ClinicalTrials.gov: NCT01843829 .

Catholic mass and its healing implications for the addicted person.

A convenience sample of 12 recovering alcoholics/addicts were interviewed, using open-ended interviews, during 2009 regarding their experience of Catholic Mass in relation to their recovery. Half of the participants had been raised Catholic, whereas the other half had converted. All have participated in Alcoholics Anonymous and lived in various areas in California. Data analysis used a phenomenological method allowing for use of the participant's own vocabulary. Implications and study limitations are noted, as well as suggestions for further research.

Relation of a coronary artery calcium score higher than 400 to coronary stenoses detected using multidetector computed tomography and to traditional cardiovascular risk factors.

Coronary artery calcium (CAC) is an excellent surrogate for atherosclerosis. However, this calcium is nonspecific for obstructive heart disease. This study sought to determine (1) the frequency of significant computed tomographic (CT) angiographic stenoses as a function of CAC scores, and (2) whether high CAC scores were associated with these stenoses independent of traditional risk factors. Subjects (n = 664) underwent Agatston CAC scoring and multidetector CT angiography using current 64-slice technology. Significant stenoses were defined as >60% diameter compromise. Self-reported risk factors and frequency of stenoses were analyzed as a function of CAC scores. The prevalence of risk factors increased significantly as CAC scores increased. Significant univariate associations included age (p <0.001), male gender (p <0.001), hypertension (p <0.001), and hyperlipidemia (p <0.001). There was also a significant association between CAC scores and the frequency of significant CT angiographic stenoses (p <0.001 for trend). The frequency of CT angiographic stenoses increased as CAC scores increased, with 7.9%, 8.3%, 14.5%, and 27.2% prevalences of significant stenoses in those with CAC scores of 1 to 100, 101 to 400, 401 to 1,000, and >1,000, respectively. Conversely, no significant lesions were found in those with no CAC. Multivariable logistic regression analysis controlling for traditional risk factors showed odds ratios for CAC score of 401 to 1,000 and >1,000 for having significant stenoses of 3.1 (95% confidence interval 1.6 to 6.0) and 6.9 (95% confidence interval 3.5 to 13.5), respectively. In conclusion, a CAC score >400 was significantly associated with multidetector CT angiographic stenoses independently of traditional risk factors.

Relation of Coronary Artery Diameters With Cardiorespiratory Fitness.

Cardiorespiratory fitness is associated with reduced cardiovascular morbidity and mortality when adjusted for traditional risk factors. Mechanisms by which fitness reduces risk have been studied but remain incompletely understood. We hypothesize that higher fitness is associated with larger coronary artery diameters independent of its effect on traditional risk factors. Two independent measurements of the proximal diameters of the left main, left anterior descending, left circumflex, and right coronary arteries were obtained from gated multidetector computed tomography scans in 500 men from the Cooper Center Longitudinal Study (CCLS). Men with coronary artery calcium scores ≥10 were excluded. Fitness was measured with a maximal exercise treadmill test and reported by quintiles and as a function of METs. We then evaluated the relation between coronary artery diameters and fitness using mixed effect regression models. Higher fitness was associated with larger coronary artery diameters after adjustment for body surface area, smoking status, low-density lipoprotein and high-density lipoprotein cholesterol, resting systolic blood pressure, and serum glucose. When examined continuously, each MET increase in fitness was associated with a mean 0.03 ± 0.01 mm larger diameter of the left main, a 0.04 ± 0.01 mm larger diameter of the left anterior descending, a 0.05 ± 0.01 mm larger diameter of the left circumflex, and a 0.07 ± 0.01 mm larger diameter of the right coronary artery (p = 0.002). This correlation between fitness and coronary artery diameters was most prominent for fitness levels above 10 METs. In conclusion, higher fitness is associated with larger coronary artery diameters.

Low 25-OH vitamin D levels are not associated with coronary artery calcium or obstructive stenoses.

BACKGROUND: It is unclear whether low vitamin D is a significant risk factor for the presence of either calcific atherosclerosis or obstructive coronary artery stenoses. DESIGN: In this study, we measured the 25-OH vitamin D levels of 1131 consecutive individuals who underwent coronary artery calcium (CAC) scoring and coronary computed tomographic angiography at our institution. PARTICIPANTS AND METHODS: We looked for any association of 25-OH vitamin D levels with CAC scores. We also studied the relation of 25-OH vitamin D levels with the presence of 70% or more obstructive coronary artery stenoses, found initially by coronary computed tomographic angiography and confirmed subsequently by invasive angiography. RESULTS: There were 132 (11.7%) 25-OH vitamin D deficient (<20 ng/ml) and 295 (26.1%) 25-OH vitamin D insufficient (21-29 ng/ml) individuals in this study. There was no detectable association between 25-OH vitamin D levels and CAC scores. The median (interquartile range) CAC score of 25-OH vitamin D deficient, insufficient, and adequate patients was 451 (80-1083), 338 (52-830), and 450 (100-1062), respectively. Also, no relation was noted between 25-OH vitamin D levels and the presence of severely obstructive coronary artery disease. The frequency of severe coronary artery disease in 25-OH vitamin D deficient, insufficient, and adequate patients was 3.8, 2.0, and 4.0%, respectively. CONCLUSION: Low 25-OH vitamin D levels were not associated with CAC or severely obstructive stenoses.

Effectiveness of cognitive therapy for depression in a community mental health center: a benchmarking study.

The current study examined the feasibility and effectiveness of transporting an empirically supported treatment for depression, cognitive therapy (CT), to a community mental health center setting. CT was delivered to 192 adult outpatients with major depression, and a benchmarking strategy compared results with those of 2 randomized controlled trials (RCTs). The 3 samples were largely similar in terms of initial severity of depression, and CT was as effective in reducing depressive symptoms in the current sample as in the RCTs. More favorable outcome was associated with less severe initial depression, more therapy sessions, more years of education, and absence of a comorbid personality disorder. This study demonstrates that an empirically supported treatment can be transported effectively to a clinical setting.

Proteolytic yeasts isolated from raw, ripe tomatoes and metabiotic association of Geotrichum candidum with Salmonella.

Metabiotic associations between food-borne fungi and bacteria capable of causing human diseases are a public health concern. A survey of decayed and damaged, uncooked, ripe tomatoes was done to determine the presence and prevalence of yeasts capable of increasing the pH pulp tissue, thus creating a more favorable environment for survival and growth of enteric pathogens. Sixty-two of the 371 (16.7%) fungi isolated from 215 decayed or damaged tomatoes; 12 of the 62 (19.4%) yeasts showed proteolytic activity on gelatin agar (GA) and/or standard methods caseinate (SMC) agar. The pH of tomato pericarp (pulp) tissue from which 9 of the 12 yeasts were isolated ranged from 4.3 to 7.5 (mean=5.3) compared to 4.2-5.1 (mean=4.8) for sound pulp tissue in the same tomatoes. The 12 proteolytic yeasts consisted of four strains of Cryptococcus albidus, two strains each of Debaryomyces hansenii and Trichosporon pullulans, and one strain each of Cryptococcus humicolus, Cryptococcus laurentii, Geotrichum candidum, and Sporidiobolus pararoseus. Survival and growth characteristics of a five-serotype mixture of Salmonella co-inoculated with G. candidum into sound (not chill injured) and chill-injured tomatoes were studied. Storage of sound tomatoes at 15 degrees C for 10 days resulted in an increase in population of 7.6 log(10) cfu of Salmonella/g of a 2-g sample of co-infected pulp tissue. Increases were less in tissue inoculated with Salmonella only, Salmonella on day 0 followed by G. candidum on day 3, or G. candidum on day 0 followed by Salmonella on day 3. Trends were similar in sound inoculated tomatoes stored at 25 degrees C. Growth of Salmonella was enhanced in chill-injured tomatoes compared to sound tomatoes; a population of 10 log(10) cfu/g of chill-injured pulp tissue was reached within 10 days at 25 degrees C. Results clearly show that growth of a proteolytic, alkalinizing yeast such as G. candidum in raw tomatoes enhances conditions for growth of Salmonella. The removal of tomatoes infected with proteolytic yeasts and other fungi from lots intended for minimally processed tomato products is an essential step in reducing the risk of human diseases caused by pathogenic bacteria favored by increased pH of decayed pulp tissue.

Proteolytic fungi isolated from decayed and damaged raw tomatoes and implications associated with changes in pericarp pH favorable for survival and growth of foodborne pathogens.

Raw and minimally processed high-acid fruits and vegetables are considered to be at low or no risk for supporting growth of foodborne pathogens. The potential increase in the pH of tissues as a result of fungal growth, however, may enhance the potential for survival and growth. We examined 77 decayed and 138 damaged, raw, ripe tomatoes for the presence of yeasts and molds that produce proteolytic enzymes and other metabolites that can potentially increase the pH of pulp tissue. The pH of decayed and sound radial pericarp tissues (pulp) of decayed tomatoes ranged from 4.7 to 7.8 (mean = 6.2) and 4.3 to 5.8 (mean = 5.0), respectively, whereas the pH of damaged and sound pericarp of damaged tomatoes ranged from 4.2 to 7.8 (mean = 5.2) and 4.2 to 8.0 (mean = 4.9), respectively. The pH of sound pericarp of 8.5% of decayed tomatoes and 3.4% of damaged tomatoes, respectively, was > 5.41. In contrast, the pH of 70% of the decayed tissue and 18% of the damaged tissue was > 5.41. Fungal isolates (n = 371) recovered from decayed and damaged tomatoes on dichloran rose bengal chloramphenicol agar were examined for proteolytic activity on gelatin agar and standard methods caseinate agar. One hundred eight (29%) of the isolates exhibited proteolytic activity on one or both differential media; 96 (89%) were molds, and 12 (11%) were yeasts. The pH of both media increased at the edge of proteolytic fungal colonies. Growth of proteolytic isolates from decayed tomatoes on tomato juice agar (pH = 4.3) and on the surface of tomato juice (pH = 4.1) caused an increase in mean pH values at the colony/medium interface to 7.2 and 6.4, respectively. Results show that some fungi capable of infecting raw tomatoes, as well as the mycoflora incident on tomato surfaces, can increase the pH of pericarp and juice to levels favorable for growth of most foodborne pathogenic bacteria.

Utility of high-sensitivity C-reactive protein versus coronary artery calcium for the detection of obstructive stenoses in stable patients.

The inflammatory biomarker high-sensitivity C-reactive protein (hs-CRP) has emerged as a predictor of future cardiovascular events. Screening for coronary artery calcium (CAC) is an alternative method for stratifying subjects by their cardiovascular risk. It is unclear, however, how hs-CRP compares with CAC scoring for the detection of obstructive coronary artery stenoses. We, thus, evaluated the association, if any, between hs-CRP and CAC scores for the detection of obstructive stenoses in a low-risk population with well-controlled traditional cardiovascular risk factors. In the present study of 1,079 stable subjects, 38 (3.5%) severely obstructive stenoses were found initially by coronary computed tomographic angiography and confirmed subsequently using invasive coronary angiography. The univariate predictors of severely obstructive coronary artery disease included the use of antihypertensive agents (p = 0.03), angina (p <0.001), and an elevated CAC score (p <0.001). The biomarker hs-CRP was not significantly associated with the presence of a severely obstructive stenosis. As the CAC scores increased, the frequency of obstructive stenosis also increased (p for trend <0.001). In contrast, the frequency of obstructive stenoses was low when CAC was not detected. This relation remained significant after adjustment for antihypertensive medication use and angina. In conclusion, hs-CRP was not useful for the prediction of obstructive stenoses in stable subjects. CAC was found to be a better predictor of obstructive heart disease than hs-CRP.

Computed tomography detection of carotid calcium and subclinical carotid atherosclerosis.

Computed tomography (CT) detection of coronary calcium has become a popular technique for assessing coronary atherosclerosis. Whether CT detection of carotid calcium could similarly assess carotid atherosclerosis is unknown. We thus performed a study evaluating the feasibility of carotid calcium scoring by CT. We also looked for an association between carotid calcium and subclinical carotid atherosclerosis. Subjects (n = 876) underwent non-contrast CT scanning of their carotid arteries. Carotid calcium was quantified by the Agatston method. Stenoses were detected by subsequent CT angiography. Significant subclinical atherosclerosis was defined by the presence of a ≥30% carotid stenosis. The frequency of a ≥30% carotid stenosis was then analyzed as a function of carotid calcium scores and various cardiovascular risk factors. CT detection of carotid calcium was feasible, robust, and reliable. Significant univariate associations for a ≥30% carotid stenosis included age (P < 0.001), diabetes (P = 0.02), hypertension (P = 0.01), and the carotid calcium score (P < 0.001). Those with a ≥30% carotid stenosis exhibited a median (25th, 75th percentile) carotid calcium score of 153 (19, 489), while those without a ≥30% carotid stenosis had a median (25th, 75th percentile) carotid calcium score of 0 (0, 89). Conversely, when no carotid calcium was detected, there was a low (1%) frequency of significant carotid atherosclerosis. The frequency of a ≥30% carotid stenosis increased as the carotid calcium score increased (P < 0.001 for trend). This association remained significant after adjustment for age, hypertension, diabetes, hyperlipidemia, and tobacco use. CT detection of carotid calcium can assess the burden of carotid atherosclerosis.

Effect of increasing body mass index on image quality and positive predictive value of 100-kV coronary computed tomographic angiography.

Lowering the voltage to 100 kV is an effective method of reducing the radiation of coronary computed tomographic angiography (CTA). It is unknown, however, whether one could use a 100-kV CTA protocol with overweight or obese patients. We, thus, evaluated the effect of increasing body mass index (BMI) on various image quality parameters of 100-kV CTA. We also compared the radiation dose and diagnostic accuracy of 100-kV CTA with CTA performed at 120 kV. Three different protocols were studied: 120 kV, retrospective; 100 kV, retrospective; and 100 kV, prospective. The image quality and radiation doses were analyzed for each protocol. The effect of increasing BMI was also examined. A worsening of the noise, contrast-to-noise, and signal-to-noise ratios occurred with increasing BMI and decreasing voltages. The radiation exposure was significantly lowered with the 100-kV protocol and with prospective gating. Despite this image degradation, however, diagnostic images were obtained with 100-kV CTA, even in overweight and many obese subjects. Of the 66 subjects referred for invasive angiography because of the findings from CTA, 55 were correctly characterized (overall positive predictive value [PPV] of 83.3%). This PPV remained reasonable, irrespective of the voltage, until a BMI of 35 kg/m(2) was reached (PPV for 100-kV protocol 90.0% [27 of 30]; PPV for a BMI of ≥ 25 kg/m(2) but < 30 kg/m(2) 84.4% [27 of 32]; and PPV for a BMI of ≥ 30 kg/m(2) but < 35 kg/m(2) 81.8% [18 of 22]). In conclusion, 100-kV coronary CTA is feasible in overweight and many obese subjects.

Resilience in children of substance users: in their own words.

Understanding what children of alcoholics and other substance users experience has dominated the scientific literature and popular press for the past several decades. To date, the empirical studies have relied primarily on quantitative data to understand the individual and environmental factors associated with the lives, the developmental trajectories, and the growth of children of alcoholics and other substance users. Many of these studies focus on their risks, and very few of them focus on their strengths. Additionally, very few studies have used qualitative techniques to collect data. While quantitative studies have given us great insight, perhaps we could learn a great deal more if we employed data collection methods which would actually provide us with the child's perception of their strengths, or resilience, and what they think it takes to grow into happy, healthy adults. For this reason, this study presents data from the interviews of 50 children of substance users who present their views on resilience.

Genistein and vitamin D synergistically inhibit human prostatic epithelial cell growth.

We performed studies to test synergism between the growth inhibitory effects of genistein and vitamin D compounds on prostatic epithelial cells. Isobolographic analysis demonstrated that genistein, in combination with the hormonally active form of cholecalciferol, 1alpha,25-dihydroxycholecalciferol, synergistically inhibited the growth of primary human prostatic epithelial cells (HPEC) and prostate cancer cells. Synergistic growth inhibition of HPEC was also observed between genistein and the low-calcemic vitamin D compound 25-hydroxycholecalciferol. Flow cytometry with HPEC indicated that genistein induced arrest in the G(2)M phase, whereas 1alpha,25-dihydroxycholecalciferol or 25-hydroxycholecalciferol induced arrest in the G(1/0) phase of the cell cycle. Combining genistein with either vitamin D compound resulted in both G(2)M and G(1/0) arrest in HPEC. In contrast, flow cytometry of prostate cancer cells indicated that both genistein and 1alpha,25-dihydroxycholecalciferol induced a G(1/0) arrest either alone or in combination. These are the first studies that demonstrate synergism between the prostatic cell growth inhibition elicited by genistein and that elicited by vitamin D compounds.

p27Kip1 is essential for the antiproliferative action of 1,25-dihydroxyvitamin D3 in primary, but not immortalized, mouse embryonic fibroblasts.

1alpha,25-Dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) inhibits the growth of numerous cancer cell types. The intracellular proteins that mediate 1,25(OH)(2)D(3)-induced growth inhibition are poorly defined, although it is speculated that p21 and p27 are involved. We tested the requirement of p21 and p27 by treating primary wild-type, p21(-/-), and p27(-/-) mouse embryonic fibroblasts (MEFs) with 100 nm 1,25(OH)(2)D(3). In response to treatment, the wild-type and p21(-/-) MEFs exhibited 54 and 60% growth inhibition (p < 0.05), respectively, whereas the growth of p27(-/-) MEFs was unaffected. Western analyses indicated that p27 expression is induced by 1,25(OH)(2)D(3) treatment in wild-type and p21(-/-) MEFs. p21 expression is also induced by 1,25(OH)(2)D(3) treatment in wild-type and p27(-/-) MEFs, although the effect is less robust than for p27. Next, we spontaneously immortalized each MEF strain, which resulted in a gain of responsiveness to 1,25(OH)(2)D(3) by the p27(-/-) MEFs, as exhibited by 87% growth inhibition (p < 0.05). Both wild-type and p21(-/-) MEFs retained responsiveness (43 and 72% growth inhibition (p < 0.05), respectively). These data from primary and immortalized MEFs demonstrate that there are both p27-dependent and -independent pathways that mediate the antiproliferative action of 1,25(OH)(2)D(3).

Association between genetic polymorphisms in the prostate-specific antigen gene promoter and serum prostate-specific antigen levels.

BACKGROUND: Recent evidence suggests that genetic variation in the promoter of the prostate-specific antigen (PSA) gene may contribute to individual variation in serum PSA levels. However, polymorphisms associated with variations in PSA levels have not been identified. METHODS: We used the polymerase chain reaction to amplify the promoter region of the PSA genes (nucleotide positions -3873 to -5749 with respect to the start of transcription) of 409 healthy white men at risk for lung disease. Polymerase chain reaction products were sequenced to identify polymorphisms in the PSA gene promoter and to genotype the men for common single nucleotide polymorphisms (SNPs) and were cloned into luciferase reporter constructs to assay PSA promoter activity in human LNCaP prostate cancer cells. Analysis of variance was used to test the association of polymorphism frequencies with mean serum PSA levels. All statistical tests were two-sided. RESULTS: The -4643G/A SNP (G allele) had a 21.2% prevalence and was associated with increases in serum PSA levels (P =.017) and PSA promoter activity (P<.001). The -5412C/T SNP (C allele) had a 22.0% prevalence and was associated with an increase in serum PSA levels (P =.0015). The -5429T/G SNP (G allele) had a 23.0% prevalence, was associated with an increase in serum PSA levels (P =.021), and was in linkage disequilibrium with the -5412C/T SNP. The promoter activity of the -5412 C/-5429 G haplotype was higher than that of the -5412 T/-5429 T haplotype (P<.001). CONCLUSIONS: Genetic variations in the PSA promoter are associated with serum PSA levels in men without prostatic disease. PSA promoter genotype information may help to refine models of PSA cutoff values.