Methicillin-resistant Staphylococcus aureus (MRSA) nasal real-time PCR: a predictive tool for contamination of the hospital environment.
OBJECTIVE We sought to determine whether the bacterial burden in the nares, as determined by the cycle threshold (CT) value from real-time MRSA PCR, is predictive of environmental contamination with MRSA. METHODS Patients identified as MRSA nasal carriers per hospital protocol were enrolled within 72 hours of room admission. Patients were excluded if (1) nasal mupirocin or chlorhexidine body wash was used within the past month or (2) an active MRSA infection was suspected. Four environmental sites, 6 body sites and a wound, if present, were cultured with premoistened swabs. All nasal swabs were submitted for both a quantitative culture and real-time PCR (Roche Lightcycler, Indianapolis, IN). RESULTS At study enrollment, 82 patients had a positive MRSA-PCR. A negative correlation of moderate strength was observed between the CT value and the number of MRSA colonies in the nares (r=-0.61; P<0.01). Current antibiotic use was associated with lower levels of MRSA nasal colonization (CT value, 30.2 vs 27.7; P<0.01). Patients with concomitant environmental contamination had a higher median log MRSA nares count (3.9 vs 2.5, P=0.01) and lower CT values (28.0 vs 30.2; P<0.01). However, a ROC curve was unable to identify a threshold MRSA nares count that reliably excluded environmental contamination. CONCLUSIONS Patients with a higher burden of MRSA in their nares, based on the CT value, were more likely to contaminate their environment with MRSA. However, contamination of the environment cannot be predicted solely by the degree of MRSA nasal colonization.


Novel oral glucose-lowering drugs are associated with lower risk of all-cause mortality, cardiovascular events and severe hypoglycaemia compared with insulin in patients with type 2 diabetes.
To investigate the association of novel oral glucose-lowering drugs (GLDs), compared with that of insulin, with risk of all-cause mortality, cardiovascular disease (CVD) and severe hypoglycaemia. During 2013 to 2014 all patients with type 2 diabetes in Sweden identified as new users of novel oral GLDs, either dipeptidyl peptidase-4 (DPP-4) inhibitors or sodium-glucose cotransporter-2 (SGLT2) inhibitors (only dapagliflozin available in Sweden during the study period), with those initiating insulin as a comparison group, in the Prescribed Drug Register were included and followed in the Patient and Cause of Death Registers. The novel GLD group and insulin group were matched 1:1 using propensity score. Cox regression models were used to estimate risks. Of 37 603 patients, 21 758 were matched 1:1 to novel GLD vs insulin groups, with median follow-up times of 1.51 years (16 304 patient-years) and 1.53 years (16 306 patient-years), respectively. Treatment with novel GLDs was associated with a 44% (hazard ratio [HR] 0.56 [95% confidence interval {CI} 0.49-0.64]), 15% (HR 0.85 [95% CI 0.73-0.99]) and 74% (0.26 [95% CI 0.12-0.57]) lower risk of all-cause mortality, CVD and hypoglycaemia, respectively, compared with insulin treatment. In separate analyses for the two novel GLDs, dapagliflozin was associated with lower risks of all-cause mortality and CVD (56% [HR 0.44, 95% CI 0.28-0.70] and 49% [HR 0.51, 95% CI 0.30-0.86], respectively), while DPP-4 inhibitor treatment was associated with lower risk of all-cause mortality (41% [HR 0.59, 95% CI 0.51-0.67]), but not with CVD (HR 0.87, 95% CI 0.75-1.01). Novel oral GLD treatment was associated with lower risk of all-cause mortality, CVD and severe hypoglycaemia compared with insulin treatment. Dapagliflozin was associated with a lower risk of both all-cause mortality and CVD, whereas DPP-4 inhibitor treatment was only associated with lower risk of all-cause mortality.


The quantification and monitoring of intraoperative nociception levels in thoracic surgery: a review.
Nociception is the unconscious perception of a stimulus applied by trauma or surgery and expressed through a response of the autonomous nervous system. Local anaesthetics (LAs), opioids and other modulating agents such as ketamine are usually utilised to blunt nociception as a component during general anaesthesia (GA) and surgery. The effectiveness of these measures, however, are still difficult to quantify and monitoring of anti-nociception has been confined to assess variation of heart rate (HR) or blood pressure (BP). Recently, various monitoring concepts have been introduced to quantify nociception more systematically and on the other hand guide anti-nociceptive interventions more appropriately. This review describes the various technologies, their performance in clinical studies and provides a critical appraisal with particular application to thoracic anaesthesia and surgery and their relevance in the context of chronic pain after surgery.


Single-cell genomics reveals hundreds of coexisting subpopulations in wild Prochlorococcus.
Extensive genomic diversity within coexisting members of a microbial species has been revealed through selected cultured isolates and metagenomic assemblies. Yet, the cell-by-cell genomic composition of wild uncultured populations of co-occurring cells is largely unknown. In this work, we applied large-scale single-cell genomics to study populations of the globally abundant marine cyanobacterium Prochlorococcus. We show that they are composed of hundreds of subpopulations with distinct "genomic backbones," each backbone consisting of a different set of core gene alleles linked to a small distinctive set of flexible genes. These subpopulations are estimated to have diverged at least a few million years ago, suggesting ancient, stable niche partitioning. Such a large set of coexisting subpopulations may be a general feature of free-living bacterial species with huge populations in highly mixed habitats.


Evidence to support the early introduction of laparoscopic suturing skills into the surgical training curriculum.
The objectives of this study were to investigate the relationship between the acquisition of laparoscopic suturing skills and other operative laparoscopic skills and to provide evidence to determine ideal time and duration to introduce laparoscopic suturing training. The first part of the study explored the relationship between the acquisition of laparoscopic suturing skills and proficiency of other operative laparoscopic skills. The second part of the study consisted of an opinion survey from senior and junior trainees on aspects of training in laparoscopic suturing. One hundred twenty-eight surgical trainees participated in this study. The total scores of task performance of 57 senior surgical trainees in laparoscopic suturing skills consisting of needle manipulation and intracoporeal knot tying were improved significantly after the training course (46.9 ± 5.3 vs 29.5 ± 9.4, P < .001), the improvement rate was 59%. No statistically significant correlations were observed between intracorporeal laparoscopic suturing skills and proficiency in the basic laparoscopic manipulative skills assessed before (r = 0.193; P = 0.149) and after (r = 0.024; P = 0.857) the training course. 91% of senior trainees and 94% junior trainees expressed that intracorporeal suturing should be introduced at an early stage of the training curriculum. There was no statistically significant correlation between the performance on basic operative laparoscopic skills (non-suturing skills) and laparoscopic suturing skills observed in this study. The acquisition of basic laparoscopic skills is not a prerequisite for training in intracorporeal suturing and it may be beneficial for the surgical trainees to learn this skill early in the surgical training curriculum. Surgical trainees want to learn and practice laparoscopic suturing earlier than later in their training.


Diffusion tensor tractography and neuropsychological assessment in patients with vitamin B12 deficiency.
Structural imaging of the brain does not demonstrate any changes in a vast majority of patients with vitamin B12 deficiency, even in advanced stages. In this study, we aimed to assess and correlate the functional integrity of the brain fiber tracts using diffusion tensor tractography with neuropsychological examination in patients with vitamin B12 deficiency. The study was conducted at two tertiary care centers. Thirty-two patients with vitamin B12 deficiency were enrolled and subjected to diffusion tensor tractography, as an extension of diffusion tensor imaging, and neuropsychological assessment. Tests of significance were done to detect changes, pre- and post-vitamin B12 supplementation in the diffusivity parameters (fractional anisotropy and mean diffusivity) and the neuropsychological test scores. Statistically significant changes were observed in the diffusivity parameters and the neuropsychological test scores between the controls and the patients with vitamin B12deficiency in the pre- and post-treatment phases. This is the first study to evaluate the diffusion tensor tractography (DTT) parameters in the light of clinical neuropsychological assessment in patients with vitamin B12 deficiency. Utilization of DTT parameters may antedate structural changes and may quantify the neurocognitive deficits.


Light regulation of Fed-1 mRNA requires an element in the 5' untranslated region and correlates with differential polyribosome association.
Light regulation of Fed-1 mRNA abundance in the leaves of green plants is primarily a post-transcriptional process. Previously, we have shown that the Fed-1 mRNA light response requires an open reading frame, indicating that the light regulation of the mRNA depends on its concurrent translation. We now show that light-induced increases in Fed-1 mRNA abundance are associated with increases in polyribosome association that require both a functional AUG and a normal Fed-1 translational start context. We also present evidence that light regulation of Fed-1 mRNA levels requires more than efficient translation per se. Substitution of the efficiently translated tobacco mosaic virus Omega 5' untranslated region resulted in a loss of Fed-1 light regulation. In addition, we identified a CAT T repeat element located near the 5' terminus of the Fed-1 5' untranslated region that is essential for light regulation. We introduced two different mutations in the CAT T repeat element, but only one of these substitutions blocked the normal light effect on polyribosome association, whereas both altered dark-induced Fed-1 mRNA disappearance. The element may thus be important for Fed-1 mRNA stability rather than polyribosome loading. We propose a model in which Fed-1 mRNA is relatively stable when it is associated with polyribosomes in illuminated plants but in darkness is not polyribosome associated and is thus rapidly degraded by a process involving the CAT T repeat element.


Pharmacovigilance of Miltefosine in Treatment of Visceral Leishmaniasis in Endemic Areas of Bihar, India.
Miltefosine, the only oral drug for visceral leishmaniasis (VL), is being used as the first-line drug under the VL elimination program in the Indian subcontinent. Miltefosine is an oral drug which was used as a topical application for skin metastasis of breast cancer. It was found to be effective against Leishmania donovani The main adverse events (AE) reported previously with miltefosine use includes diarrhea, vomiting, and dehydration. Other AEs include, raised serum alanine transaminase/aspartate aminotransferase and renal parameters such as creatinine. In this study, we report AEs in a large patient cohort of VL treated with miltefosine. The purpose of this pharmacovigilance study was to assess adverse drug reactions (ADRs)/AE of miltefosine treatment under unrestricted condition in the field setup. Patients were followed up to 6 months for therapeutic effectiveness. Outcomes of a larger data set of patients treated with this regimen from April 2012 to March 2015 were recorded. In the present study, 646 patients of VL were given miltefosine. Majority of the study subjects (58%) were male. Relapse occurred in 7% during follow-up period. Main causes of death were VL-pulmonary tuberculosis coinfection, extreme diarrhea, and acute pancreatitis which were reported in 1.7% subjects. Of 553 (85.6%) patients completing full course of treatment, 463 (83.7%) showed ADR with miltefosine during the study period. About 2.3% were suffering severe ADR, 51% from moderate, and the rest had mild ADR. The initial and final cure rate was 97.4% and 85.6%, respectively.


Health literacy not race predicts end-of-life care preferences.
Several studies have reported that African Americans are more likely than whites to prefer aggressive treatments at the end of life. Since the medical information presented to subjects is frequently complex, we hypothesized that apparent differences in end-of-life preferences and decision making may be due to disparities in health literacy. A video of a patient with advanced dementia may overcome communication barriers associated with low health literacy. Before and after oral survey. Subjects presenting to their primary care doctors. Subjects were asked their preferences for end-of-life care after they heard a verbal description of advanced dementia. Subjects then viewed a 2-minute video of a patient with advanced dementia and were asked again about their preferences. For the analysis, preferences were dichotomized into comfort care and aggressive care. Health literacy was measured using the Rapid Estimate of Adult Literacy in Medicine (REALM) and subjects were divided into three literacy categories: low (0-45, sixth grade and below), marginal (46-60, seventh to eighth grade) and adequate (61-66, ninth grade and above). Unadjusted and adjusted logistic regression models were fit using stepwise algorithms to examine factors related to initial preferences before the video. A total of 80 African Americans and 64 whites completed the interview. In unadjusted analyses, African Americans were more likely than whites to have preferences for aggressive care after the verbal description, odds ratio (OR) 4.8 (95% confidence interval [CI] 2.1-10.9). Subjects with low or marginal health literacy were also more likely than subjects with adequate health literacy to have preferences for aggressive care after the verbal description, OR 17.3 (95% CI 6.0-49.9) and OR 11.3 (95% CI 4.2-30.8) respectively. In adjusted analyses, health literacy (low health literacy: OR 7.1, 95% CI 2.1-24.2; marginal health literacy OR 5.1, 95% CI 1.6-16.3) but not race (OR 1.1, 95% CI 0.3-3.2) was an independent predictor of preferences after the verbal description. After watching a video of advanced dementia, there were no significant differences in the distribution of preferences by race or health literacy. Health literacy and not race was an independent predictor of end-of-life preferences after hearing a verbal description of advanced dementia. In addition, after viewing a video of a patient with advanced dementia there were no longer any differences in the distribution of preferences according to race and health literacy. These findings suggest that clinical practice and research relating to end-of-life preferences may need to focus on a patient education model incorporating the use of decision aids such as video to ensure informed decision-making.


The metabolism of ethionine in rats.
The L-[ethyl-1-14C]ethionine metabolites soluble in trichloroacetic acid were studied in rats by the use of column chromatography. After p.o. application of ethionine, its absorption from intestinal lumen was rapid and was complete in less than 2 hr. Any unabsorbed ethionine was later excreted in the feces. During the passage through the gastrointestinal tract, a portion of ethionine was metabolized. The chemical nature and biological significance of these metabolites is not yet known. The fate of absorbed ethionine was investigated in the small intestine, liver, blood, kidney, and urine as a function of time after application. A great part of ethionine was quickly oxidized to ethionine sulfoxide. In liver and kidney, the concentration of ethionine sulfoxide was higher than that of free ethionine. In all organs, the presence of N-acetylethionine sulfoxide was also demonstrated. Ethionine sulfoxide can be reduced and N-acetylethionine can be deacetylated in vivo as demonstrated by the formation of S-adenosylethionine from ethionine sulfoxide and N-acetylethionine. In urine, 4 main components were observed: N-acetylethionine sulfoxide, S-adenosylethionine, ethionine sulfoxide, and free ethionine. Some minor components, as yet unidentified, were also present in the urine and in different organs. The probable site of origin of urinary S-adenosylethionine is the kidney.


Comparison of Monaco treatment planning system algorithms and Monte Carlo simulation for small fields in anthropomorphic RANDO phantom: The esophagus case.
In this study, the dose distributions obtained by the algorithms used in Monaco treatment planning system (TPS) and Monte Carlo (MC) simulation were compared for small fields in the anthropomorphic RANDO phantom, and then, the results were analyzed using the gamma analysis method. In the study, dose distributions obtained from the collapse cone algorithm, MC algorithm, and MC simulation were examined. The EGSnrc was utilized for MC simulation. In radiation fields smaller than 3 cm × 3 cm, the doses calculated by the CC algorithm are particularly high in the region of lung/soft-tissue interfaces. In the region of soft-tissue/vertebral interfaces, the doses calculated by the CC algorithm and the MC algorithm are compatible with the MC simulation. For each algorithm, the main reason for the non-overlapping dose curves in small fields compared to MC simulation is that the lateral electronic equilibrium loss is not taken into account by the algorithms. The doses calculated by the algorithms used in TPS may differ, especially in environments where density changes are sharp. Even if the radiation dose from different angles is calculated similarly in the target area by the algorithms, the calculated doses in the tissues in each radiation field path may be different. Therefore, to increase the quality of radiotherapy and to protect critical organs more accurately, the accuracy of the algorithms in TPS should be checked before treatment, especially in multi-field treatments such as stereotactic body radiation therapy and intensity-modulated radiotherapy for tumors in the abdominal region.


Clinical review 110: Diagnosis and treatment of pituitary tumors.
We are fortunate to have multiple safe and effective therapeutic options available for the treatment of pituitary tumors. These options include medical therapy, transsphenoidal surgery and radiotherapy. The treatment of choice depends on the type of pituitary tumor. The majority, of PRL-secreting tumors can be effectively treated with dopamine agonists. Transsphenoidal surgery is also an effective option for patients who are resistant to or intolerant of these drugs. Transsphenoidal surgery remains the treatment of choice for the majority of patients with GH, ACTH, and TSH-secreting tumors and for large nonsecreting tumors. Medical therapy with somatostatin analogs and/or dopamine agonists should be undertaken in patients with persistent elevations of GH and IGF-I levels; radiotherapy should be considered for patients with significant residual tumor in whom medical therapy is unsuccessful. Radiotherapy is also indicated for ACTH-secreting tumors not cured by surgery; medical therapy with ketoconazole and other adrenal enzyme inhibitors can be used as adjunctive therapy to lower cortisol levels. Postoperative radiotherapy for nonsecreting tumors is also an option if there is considerable residual tumor or evidence of tumor growth on follow-up MRI. Evaluation and treatment of hypopituitarism is an important part of the management of all patients with pituitary tumors. Patients also should be monitored for the development of new deficits, particularly after radiotherapy. The development of new medical therapies, such as GH antagonists, as well as refinements of surgical, radiotherapy, and imaging techniques should continue to improve our management of pituitary tumors.


The relationship between the rate of molecular evolution and the rate of genome rearrangement in animal mitochondrial genomes.
Evolution of mitochondrial genes is far from clock-like. The substitution rate varies considerably between species, and there are many species that have a significantly increased rate with respect to their close relatives. There is also considerable variation among species in the rate of gene order rearrangement. Using a set of 55 complete arthropod mitochondrial genomes, we estimate the evolutionary distance from the common ancestor to each species using protein sequences, tRNA sequences, and breakpoint distances (a measure of the degree of genome rearrangement). All these distance measures are correlated. We use relative rate tests to compare pairs of related species in several animal phyla. In the majority of cases, the species with the more highly rearranged genome also has a significantly higher rate of sequence evolution. Species with higher amino acid substitution rates in mitochondria also have more variable amino acid composition in response to mutation pressure. We discuss the possible causes of variation in rates of sequence evolution and gene rearrangement among species and the possible reasons for the observed correlation between the two rates.


Rhizosphere persistence of three Pythium oligandrum strains in tomato soilless culture assessed by DNA macroarray and real-time PCR.
In tomato soilless culture, plant-disease optimal control and growth promotion are achieved when the rhizosphere is heavily colonized by the biocontrol agent Pythium oligandrum. Discrepancies in performance are generally attributed to the poor persistence of P. oligandrum on roots. In this study, three selected strains of P. oligandrum were introduced into the rhizosphere of greenhouse-grown tomato plants, and their persistence was assessed by DNA macroarray hybridization and real-time PCR. The experimental data from DNA detection and plate counting were compared. PCR-based methods detected P. oligandrum throughout the 6-month growing season, whereas plate counting indicated its presence only over the first 3 months. Moreover, the DNA array method provided information about the various Pythium species present in the rhizosphere: P. dissotocum was frequently detected on roots of plants, without distinction between plants inoculated or not inoculated with the antagonist. The detection of other Pythium species was noticed sporadically (P. ultimum, P. sylvaticum and P. intermedium), independent of the treatment. Even though the yield enhancement is not significant throughout the entire growing season, data obtained from epidemiological studies demonstrate an enhancement of P. oligandrum persistence on the rhizosphere of plants and less use of mycoparasitism.


Mucosal healing in ulcerative colitis: where do we stand?
Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) characterized by chronic inflammation affecting the colonic mucosa, that can extend to the whole large bowel. The severity of mucosal lesions directly reflects the disease activity and severity and may be prognostic for an aggressive behavior of the pathology. Remission, is usually defined as resolution of symptoms. Recently, mucosal healing (MH) has emerged as an important end point of any short-term medical therapy for IBD. It may predict long-term remission and may impact on the natural history of the disease in Crohn's disease (CD), while data in UC patients are still limited. This review of the literature is focused on the recent evidence on the impact of medications on MH in UC and on the impact of MH on the natural course of UC.


Aspergillus nidulans flippase DnfA is cargo of the endocytic collar and plays complementary roles in growth and phosphatidylserine asymmetry with another flippase, DnfB.
Endocytosis and exocytosis are strictly segregated at the ends of hyphal cells of filamentous fungi, with a collar of endocytic activity encircling the growing cell tip, which elongates through directed membrane fusion. It has been proposed that this separation supports an endocytic recycling pathway that maintains polar localization of proteins at the growing apex. In a search for proteins in the filamentous fungus Aspergillus nidulans that possess an NPFxD motif, which signals for endocytosis, a Type 4 P-Type ATPase was identified and named DnfA. Interestingly, NPFxD is at a different region of DnfA than the same motif in the Saccharomyces cerevisiae ortholog, although endocytosis is dependent on this motif for both proteins. DnfA is involved in asexual sporulation and polarized growth. Additionally, it is segregated within the Spitzenkörper from another Type 4 P-type ATPase, DnfB. Next, the phosphatidylserine marker GFP::Lact-C2 was expressed in growing hyphae, which revealed that this phospholipid is enriched on the cytosolic face of secretory vesicles. This distribution is affected by deleting either dnfA or dnfB. These findings provide evidence for the spatial and temporal segregation of Type4-ATPases in filamentous fungi, and the asymmetric distribution of phosphatidylserine to the Spitzenkörper in A. nidulans.


Histochemical and immunohistochemical evidence of a bacterium associated with lesions of epizootic bovine abortion.
Epizootic bovine abortion (EBA), a tick-transmitted disease of pregnant cattle grazing foothill pastures, is a major cause of reproductive failure in California and adjacent states. Affected fetuses develop a chronic disease, resulting in late-term abortion or premature calving. Despite investigations spanning 50 years, to the authors' knowledge, the etiologic agent of EBA has not yet been isolated from affected fetuses or the tick vector. The diagnosis of EBA is based on gross and microscopic lesions. Recently, documentation that the etiologic agent is susceptible to antibiotics and identification of a unique 16S deltaproteobacterial rDNA gene sequence in 90% of thymus tissues from aborted fetuses have supported the role of a bacterial infection as the cause of EBA. To determine whether bacteria could be detected in the tissues, histochemical staining and immunohistochemical procedures were used on formalin-fixed, paraffin-embedded tissues. Use of a modified Steiner silver stain revealed small numbers of intracytoplasmic bacterial rods in 37 of 42 thymic samples from EBA-affected fetuses. Improved detection was achieved by use of immunohistochemical staining with serum from EBA-affected fetuses that resulted in detection of numerous bacterial rods in the cytoplasm of histiocytic cells in the thymus from all 42 EBA-affected fetuses. Immunohistochemical examination of additional tissues from 21 field and experimental EBA cases revealed positively stained intracytoplasmic bacterial rods in many organs with inflammatory lesions. Use of the modified Steiner stain and immunohistochemical staining of tissues from negative-control fetuses failed to reveal organisms. To the authors' knowledge, this is the first report to document morphologic evidence of a bacterium associated with the lesions of EBA.


Tisseel in hypospadias repair.
Tisseel (Immuno AG, Vienna, Austria), a fibrin sealant, adhesive and hemostatic agent made up of sterilized human and bovine components, was used in hypospadias repairs. The incidence of fistula and significant edema and the duration of hospitalization were all reduced in 30 patients who underwent modified Mustardé repairs in which Tisseel was used when compared with a matched group of 30 repairs without Tisseel. In addition, the rate of complications in fistula repairs and complex revisions was reduced when Tisseel was used on urethral suture lines and under all skin flaps.


Hydrothermal synthesis of bi-functional nanostructured manganese tungstate catalysts for selective oxidation.
The mechanism of C-H activation in selective oxidation reactions of short-chain alkane molecules over transition metal oxides is critically affected by the balance of acid-base and redox sites at the surface of the catalyst. Using the example of manganese tungstate we discuss how the relative abundance of these sites can be controlled via synthetic techniques. Phase-pure catalysts composed of the thermodynamic stable monoclinic MnWO4 phase have been prepared using hydrothermal synthesis. Variation of the initial pH value resulted in rod-shaped nano-crystalline MnWO4 catalysts composed of particles with varying aspect ratio. The synthesis products have been analysed using transmission electron microscopy, X-ray diffraction, infrared, and photoelectron spectroscopy. In situ Raman spectroscopy was used to investigate the dissolution-re-crystallization processes occurring under hydrothermal conditions. Ethanol oxidation was applied to probe the surface functionalities in terms of acid-base and redox properties. Changes in the aspect ratio of the primary catalyst particles are reflected in the product distribution induced by altering the fraction of acid-base and redox sites exposed at the surface of the catalysts in agreement with the proposed mechanism of particle growth by re-crystallization during ageing under hydrothermal conditions.


Infant acceptance of a bitter-tasting liquid medication: a randomized controlled trial comparing the Rx Medibottle with an oral syringe.
The calibrated oral syringe is considered the standard system for administering liquid formulations of medications to infants. Medication acceptance using the syringe may not always be favorable, particularly with unpleasant-tasting liquids. The Rx Medibottle (The Medicine Bottle Co, Hinsdale, Illinois), an alternate drug-delivery device, is an infant-feeding bottle that contains a central sleeve within its body into which a syringe is inserted. Depressing the syringe's plunger in quick, short squirts synchronized with an infant's sucking allows drug ingestion, preventing dilution of the drug in the formula within the bottle's nipple. The Rx Medibottle costs $14.95 retail. Kraus et al demonstrated that it was more efficacious, with a higher level of infant acceptance compared with the syringe, when used to administer a 1-time dose of a pleasant-tasting liquid (acetaminophen, Tempra Syrup; Mead Johnson Nutritionals, Evansville, Indiana). Our study tests the efficacy of this bottle in administering a single dose of generic prednisolone liquid, a bitter-tasting drug, with an oral syringe serving as the control method of delivery.


Post-kala-azar dermal leishmaniasis in the Sudan: clinical presentation and differential diagnosis.
Post-kala-azar dermal leishmaniasis (PKDL) is a common complication following kala-azar (visceral leishmaniasis). In a prospective study in a village in the endemic area for kala-azar in the Sudan, 105 of 183 (57%) kala-azar patients developed PKDL. There was a significantly higher PKDL rate (69%) in those who received inadequate and irregular treatment of kala-azar than in those who were treated with stibogluconate 20 mg kg-1 daily for 15 days (35%). The group of patients who developed PKDL did not differ from those who did not develop PKDL with regard to age and sex distribution, reduction in spleen size, and conversion in the leishmanin skin test (LST). In a clinical study, 416 PKDL patients were analysed and divided according to grade of severity. Severe PKDL was more frequent in younger age groups (P < 0.001); there was an inverse correlation between grade and conversion in the LST (P < 0.01). In 16% of patients tested, parasites were demonstrated in inguinal lymph node or bone marrow aspirates, indicating still visceral disease (para-kala-azar dermal leishmaniasis); there was no correlation between the presence of parasites and grade of severity. Conversion rates in the LST were lower than in those who did not have demonstrable parasites (11% and 37%, respectively; P < 0.01). In the absence of reliable and practical diagnostic tests, PKDL may be diagnosed on clinical grounds and differentiated from other conditions, of which miliaria rubra was the most common. Differentiation from leprosy was most difficult.


T-cell responses to SARS-CoV-2 in multiple sclerosis patients treated with ocrelizumab healed from COVID-19 with absent or low anti-spike antibody titers.
Disease modifying therapies for multiple sclerosis (MS) can impair the specific immune response to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Specifically, it is recognized that ocrelizumab reduces or abrogates anti-SARS-CoV-2 antibody production after natural infection or vaccination, while very little is known about T-cell responses. We developed an interferon (IFN)-γ release assay (IGRA) to detect T-cell responses specific to SARS-CoV-2 after overnight stimulation of whole blood with peptide libraries covering the immunodominant sequence domains of the Spike glycoprotein (S) and the Nucleocapsid phosphoprotein (N). Five patients with MS receiving ocrelizumab treatment for at least 1 year and recovered from SARS-CoV-2 infection were enrolled in the study. Despite the absence or the very low concentration of anti-S antibodies, a T-cell response was detectable in all the five MS patients. These results are in accordance with the marked reduction of peripheral B-lymphocyte absolute counts induced by ocrelizumab, that, conversely, did not affect peripheral blood T-lymphocyte subset absolute and relative counts and CD4/CD8 ratio. The detection of specific T-cell responses to SARS-CoV-2 in patients receiving B-cell depleting therapies represents a useful tool to improve the diagnostic approach in SARS-CoV-2 infection and to accurately assess the immunological response after natural infection or vaccination.


Environmental Factors and Seasonality Affect the Concentration of Rotundone in Vitis vinifera L. cv. Shiraz Wine.
Rotundone is a sesquiterpene that gives grapes and wine a desirable 'peppery' aroma. Previous research has reported that growing grapevines in a cool climate is an important factor that drives rotundone accumulation in grape berries and wine. This study used historical data sets to investigate which weather parameters are mostly influencing rotundone concentration in grape berries and wine. For this purpose, wines produced from 15 vintages from the same Shiraz vineyard (The Old Block, Mount Langi Ghiran, Victoria, Australia) were analysed for rotundone concentration and compared to comprehensive weather data and minimal temperature information. Degree hours were obtained by interpolating available temperature information from the vineyard site using a simple piecewise cubic hermite interpolating polynomial method (PCHIP). Results showed that the highest concentrations of rotundone were consistently found in wines from cool and wet seasons. The Principal Component Analysis (PCA) showed that the concentration of rotundone in wine was negatively correlated with daily solar exposure and grape bunch zone temperature, and positively correlated with vineyard water balance. Finally, models were constructed based on the Gompertz function to describe the dynamics of rotundone concentration in berries through the ripening process according to phenological and thermal times. This characterisation is an important step forward to potentially predict the final quality of the resultant wines based on the evolution of specific compounds in berries according to critical environmental and micrometeorological variables. The modelling techniques described in this paper were able to describe the behaviour of rotundone concentration based on seasonal weather conditions and grapevine phenological stages, and could be potentially used to predict the final rotundone concentration early in future growing seasons. This could enable the adoption of precision irrigation and canopy management strategies to effectively mitigate adverse impacts related to climate change and microclimatic variability, such as heat waves, within a vineyard on wine quality.


Efficacy and safety of biologicals against immune-mediated diseases: do benefits outweigh risks?
The success of molecular biology in identifying molecular pathways underlying chronic immune-mediated diseases and the rapid development of gene/cell engineering biotechnologies has resulted in the development of a number of targeted biological drugs, which have revolutionized the therapy of these diseases. Numerous data published over the last 10-15 years demonstrate a dramatic improvement in the clinical efficacy of biologics compared with conventional drugs. However, professional and public concern about serious biological drug-associated adverse events has also been growing steadily. We critically analyze recent literature on the efficacy and safety of biologics in the management of rheumatoid arthritis, psoriasis, psoriatic arthritis and immune thrombocytopenia. Our analysis of benefits, resistance to the therapy, risk of infections, tumors and other serious complications related to chronic administration of biologics is based on the molecular/cellular mechanisms of their interaction with the immune system. We also address whether it is feasible to attenuate the risks associated with biologics without limiting their benefits.


[Diagnosis, treatment and prevention of measles].
Measles is a highly contagious disease characterized by respiratory symptoms, rash and fever. Complications are common. Despite national recommendations concerning the need to vaccinate children with 2 doses of MMR vaccine (at age 12 months and between 15 and 24 months), epidemic outbursts still happen. The treatment of infected children is purely supportive, whereas susceptible household contacts may benefit from IVIG or catch up with vaccination depending on their age and the time spent since the contact. This paper defines a practical approach for measles infected cases and contact patients.


Glucoprivation in the ventrolateral medulla decreases brown adipose tissue sympathetic nerve activity by decreasing the activity of neurons in raphe pallidus.
In urethane/α-chloralose anesthetized rats, cold exposure increased brown adipose tissue sympathetic nerve activity (BAT SNA: +699 ± 104% control). Intravenous administration of 2-deoxy-D-glucose (2-DG; 200 mg·ml(-1)·kg(-1)) reversed the cold-evoked activation of BAT SNA (nadir: 139 ± 36% of control) and decreased BAT temperature (-1.1 ± 0.2°C), expired CO(2) (-0.4 ± 0.1%), and core temperature (-0.5 ± 0.0). Similarly, unilateral nanoinjection of the glucoprivic agent 5-thioglucose (5-TG; 12 μg/100 nl) in the ventrolateral medulla (VLM) completely reversed the cold-evoked increase in BAT SNA (nadir: 104 ± 7% of control), and decreased T(BAT) (-1.4 ± 0.3°C), expired CO(2) (-0.2 ± 0.0%), and heart rate (-35 ± 10 beats/min). The percentage of rostral raphé pallidus (RPa)-projecting neurons in the dorsal hypothalamic area/dorsomedial hypothalamus that expressed Fos in response to cold exposure (ambient temperature: 4-10°C) did not differ between saline (28 ± 6%) and 2-DG (30 ± 5%) pretreated rats, whereas the percentage of spinally projecting neurons in the RPa/raphé magnus that expressed Fos in response to cold exposure was lower in 2-DG- compared with saline-pretreated rats (22 ± 6% vs. 42 ± 5%, respectively). The increases in BAT SNA evoked by nanoinjection of bicuculline in the RPa or by transection of the neuraxis at the pontomedullary border were resistant to inhibition by glucoprivation. These results suggest that neurons within the VLM play a role in the glucoprivic inhibition of BAT SNA and metabolism, that this inhibition requires neural structures rostral to the pontomedullary border, and that this inhibition is mediated by a GABAergic input to the RPa.


Niacin treatment prevents bone loss in iron overload osteoporotic rats via activation of SIRT1 signaling pathway.
Recently, more and more studies have revealed that iron overload can lead to osteoporosis by inducing oxidative stress. Niacin (NAN), also known as nicotinate or vitamin B3, has been confirmed to possess potent antioxidative effects. In addition, very little is currently known about the protective effects of NAN on iron overload in osteoporotic bone tissue. Therefore, we aimed to evaluate the protective effect of niacin on iron overload-induced bone injury and to investigate the effect and underlying mechanisms of the niacin and iron overload on intracellular antioxidant properties. When MC3T3-E1 and RAW264.7 cells were cultured in the presence of ammonium ferric citrate(FAC), NAN therapy could increase the matrix mineralization and promote expression of osteogenic markers in MC3T3-E1, inhibit osteoclastic differentiation of RAW264.7 cells, while increasing intracellular reactive oxygen species (ROS) levels and strengthening mitochondrial membrane potential (MMP). In the ovariectomized (OVX) rat model, NAN had an obvious protective effect against iron-overloaded injury. Meanwhile, superoxide dismutase 2 (SOD2), intracellular antioxidant enzymes and silent information regulator type 1 (SIRT1), were up-regulated in response to NAN exposures in MC3T3-E1. Furthermore, SIRT1 inhibitor EX527 attenuated the protective effects of NAN. Results revealed that NAN could stimulate osteogenic differentiation, inhibit osteoclastic differentiation and markedly increased antioxidant properties in cells through the induction of SIRT1. Studies suggest that niacin is a promising agent for preventing bone loss in iron overload conditions.


Tissue deconjugation of urolithin A glucuronide to free urolithin A in systemic inflammation.
Urolithin A (Uro-A) is an anti-inflammatory and cancer chemopreventive metabolite produced by the gut microbiota from the polyphenol ellagic acid. However, in vivo conjugation of Uro-A to Uro-A glucuronide (Uro-A glur) dramatically hampers its activity. We describe here for the first time the tissue deconjugation of Uro-A glur to Uro-A after lipopolysaccharide (LPS)-induced inflammation, which could explain the systemic in vivo activity of free Uro-A in microenvironments subjected to inflammatory stimuli.


Significance of the N-terminal histidine-rich region for the function of the human toll-like receptor 3 ectodomain.
Toll-like receptors (TLRs) are an essential component of the innate immune response to microbial pathogens. TLR3 is localized in intracellular compartments such as endosomes and signals in response to virus-derived double-stranded RNA (dsRNA). TLR3 localization within endosomes is required for ligand recognition, suggesting that acidic pH is the driving force for TLR3 ligand binding. To clarify the pH-dependent binding mechanism of TLR3 at the structural level, we focused on 3 highly conserved histidine residues clustered at the N-terminal region of the TLR3 ectodomain (ECD): H39, H60 and H108. Mutagenesis of these residues showed that H39, H60, and H108 were essential for ligand-dependent TLR3 activation in a cell-based assay. Furthermore, dsRNA binding to the recombinant TLR3 ECD depended strongly on pH and dsRNA length, and was reduced by mutations of H39, H60, and H108, demonstrating that TLR3 signaling is initiated from the endosome through a pH-dependent binding mechanism, and that a second dsRNA binding site exists in the N-terminal region of the TLR3 ECD. We propose a novel model for the formation of TLR3 ECD dimers complexed with dsRNA that incorporates this second binding site.


Selective photo-reduction of p-nitrophenol to p-aminophenol by Au deposited CdS nanostructures of different shapes having large surface area.
The preparation and photocatalytic reductive ability of a new spongy flower or cotton bud like amorphous CdS microstructures (size = 200-300 nm) having intermediate crystal phase between cubic and hexagonal structure and possesses much larger surface area ca. 119 m2 g(-1) is demonstrated here. Structural analysis has been done by TEM, XRD, BET surface area, UV-Vis absorption, luminescence analysis, and photocatalytic study. The photoreactivity of as-prepared CdS for p-nitrophenol reduction to p-aminophenol conversion under visible light (150 W halogen lamp) irradiation has been found to be greatly enhanced from 62% to 94% (yield) and 81% to 100% (selectivity) after 1 wt% Au deposition. The obtained p-aminophenol yield is always better than 32% for CdS nanosphere (size 10-12 nm) and 40% for CdS nanorod (length/width in nm = 126/6). Surface passivation with a thin layer of SiO2 coating over this flower like spongy CdS appreciably increased the BET surface area to 158 m2 g(-1) and displayed stable photocatalytic activity for p-nitrophenol reduction up to 30 h of light exposure as compared to bare CdS of low activity because of its easy photodissolution. A good co-relation between the BET surface area and surface photoactivity of as-prepared CdS with the conventional cubic and hexagonal CdS nanoparticles of different dimensions is established here.


Antimyelin antibodies in clinically isolated syndromes correlate with inflammation in MRI and CSF.
We investigated the correlation of antimyelin oligodendrocyte glycoprotein-(anti-MOG) and anti-myelin basic protein antibodies (anti-MBP) in serum of CIS patients with inflammatory signs in MRI and in CSF and, as previously suggested,the incidence of more frequent and rapid progression to clinically definite MS (CDMS). 133CIS patients were analysed for anti-MOG and anti-MBP (Western blot). Routine CSF and cranial MRI (quantitatively and qualitatively) measures were analyzed. 55 patients had a follow-up of at least 12 months or until conversion to CDMS. Patients with anti-MOG and anti-MBP had an increased intrathecal IgG production and CSF white blood cell count(p = 0.048 and p = 0.036). When anti-MBP alone, or both antibodies were present the cranial MRI showed significantly more T2 lesions (p = 0.007 and p = 0.01,respectively). There was a trend for more lesion dissemination in anti-MBP positive patients (p = 0.076).Conversely, anti-MOG- and/or anti-MBP failed to predict conversion to CDMS in our follow-up group (n = 55). Only in female patients with at least one MRI lesion (n = 34) did the presence of anti-MOG correlate with more frequent (p = 0.028) and more rapid (p = 0.0209) transition to CDMS. Presence of anti-MOG or anti-MBP or both was not significantly associated with conversion to CDMS in our CIS cohort. However, patients with anti-MOG and anti-MBP had higher lesion load and more disseminated lesions in cranial MRI as well as higher values for CSF leucocytes and intrathecal IgG production. Our data support a correlation of anti-MOG and anti-MBP to inflammatory signs in MRI and CSF. The prognostic value of these antibodies for CDMS, however, seems to be less pronounced than previously reported.


[A review of side effects and complications with cannabinoid treatment].
In the last few years, the use of cannabinoids has been advocated for several indications, and evaluation of the side effect profile is necessary. Euphoric mood changes are among the most frequent side effects, while dysphoric reactions are less frequent. Triggering of acute psychotic episodes has been reported. Cannabinoids can initiate or exacerbate schizophrenic psychosis in predisposed persons. Cannabinoids impede cognitive and psychomotor performance, resulting in impaired driving ability. Chronic use can lead to the development of tolerance. Tachycardia and hypotension frequently are documented as adverse events in the cardiovascular system. A few cases of myocardial ischemia have been reported in young and previously healthy patients. Side effects on the respiratory system are induced by inhaling the smoke of cannabis cigarettes. Some reports have indicated a carcinogenic risk for the children when cannabis was used during pregnancy. In summary, a low risk profile is evident from the literature available. Life-threatening complications are very rare and were not reported after use of cannabinoids for medical indications. Cannabinoids are contraindicated during pregnancy or for patients with a history of cardiac ischemias.


[Polytherapy in cardiovascular prevention: open issues].
Despite the considerable advances in preventive treatment achieved over the last two decades, the increasing burden of cardiovascular disease represents an urgent need for new therapeutic strategies to reduce cardiovascular mortality and morbidity. The current pandemic of obesity, hypertension and diabetes, as a result of unhealthy lifestyle and dietary habits together with predisposing genetic backgrounds, is the main cause of increased cardiovascular mortality and raised overall health expenditure. Despite the growing number of cardiovascular prevention campaigns, the control of cardiovascular risk factors remains largely unsatisfactory worldwide. Unhealthy lifestyles lead to an increased consumption of drugs to achieve target levels of cardiovascular risk factors, namely blood pressure and low-density lipoprotein cholesterol. This phenomenon results in a disproportionate increase in the number of cardiovascular drugs, already in the early stages of disease. Despite current guidelines encourage combination therapies in cardiovascular prevention, the adoption of polytherapy, commonly defined as the use of 5 or more drugs, is extremely frequent and is often paradoxically unsuccessful due to poor patient education and adherence, increased adverse effects and inappropriate drug prescribing. Moreover, increased life-expectancy resulting from early treatment of myocardial infarction and improved heart failure management has led to an older population characterized by an increased prevalence of comorbid conditions. This is a further reason for increased prescription of drugs leading to an impairment of patient adherence and increased adverse effects. In order to overcome the emerging problem of polytherapy, the use of a single "polypill" containing a combination of drugs for cardiovascular prevention has been postulated. Such an approach is providing promising results in the management of hypertension and dyslipidemia. However, available evidence is still preliminary and prospective data on cardiovascular outcomes are still lacking. This present article proposes a critical analysis of some open issues related to polytherapy in cardiovascular prevention.


Characterizing the proteome of the human dorsolateral prefrontal cortex by shotgun mass spectrometry.
The studies of neuropsychiatric disorders would be facilitated by enhanced knowledge of the dorsolateral prefrontal cortex (DLPFC) proteome. To construct a data set of human DLPFC proteins, protein extracts were prepared from 12 postmortem brains focussing on the DLPFC region (Brodmann area 9) and analyzed using a combined gel electrophoresis and shotgun mass spectrometry approach, featuring data-independent label-free nanoflow liquid chromatography mass spectrometry (nLC-MS(E)). The detected mass/time features were aligned and annotated using the results from ProteinLynx Global Server. The resulting data set comprised 488 unique and accurately identified proteins, with stringent identification by a minimum of two distinct peptides detected at least in >75% of samples. These proteins were involved predominantly in cytoskeletal architecture, metabolism, transcription/translation, and synaptic function. Combination of this data set with that obtained by our previous characterization of the same brain region results in a total of 755 unique proteins, making this the most comprehensive analysis of this important brain region to date.


Developing counseling skills through pre-recorded videos and role play: a pre- and post-intervention study in a Pakistani medical school.
Interactive methods like role play, recorded video scenarios and objective structured clinical exam (OSCE) are being regularly used to teach and assess communication skills of medical students in the western world. In developing countries however, they are still in the preliminary phases of execution in most institutes. Our study was conducted in a naïve under resourced setup to assess the impact of such teaching methodologies on the counseling skills of medical students. Fifty four 4th year MBBS students were identified to be evaluated for communication skills by trained facilitators in a pre-intervention OSCE. The same group of students was given a demonstration of ideal skill level by means of videos and role playing sessions in addition to real life interaction with patients during hospital and community rotations. A post-intervention evaluation was carried out six months later through OSCE and direct observation through structured checklist (DOS) in hospital and community settings. The combined and individual performance levels of these students were analyzed. There was a statistically significant difference in the communication skills of students when assessed in the post-intervention OSCE (p = 0.000). Individual post-intervention percentages of study participants displayed improvement as well (n = 45, p = 0.02). No difference was observed between the scores of male and female students when assessed for two specific competencies of antenatal care and breast feeding counseling (p = 0.11). The mean DOS (%) score of 12 randomly selected students was much lower as compared to the post-intervention (%) score but the difference between them was statistically non significant, a result that may have been affected by the small sample size as well as other factors that may come into play in real clinical settings and were not explored in this study (59.41 +/- 7.8 against 82.43 +/- 22.08, p = 0.88). Videos and role play in combination with community and clinical exposure are effective modes of teaching counseling skills to medical students. They can be successfully utilized even in a limited resource setup, as demonstrated by our trial.


Dust exposure and mortality in an American factory using chrysotile, amosite, and crocidolite in mainly textile manufacture.
This report describes the second in a series of three parallel cohort studies of asbestos factories in South Carolina, Pennsylvania, and Connecticut to assess the effects of mineral fibre type and industrial process on mortality from malignant mesothelioma, respiratory cancer, and asbestosis. In the present plant (in Pennsylvania) mainly chrysotile, with some amosite and a small amount of crocidolite, were used primarily in textile manufacture. Of a cohort of 4137 men comprising all those employed 1938-59 for at least a month, 97% were traced. By the end of 1974, 1400 (35%) had died, 74 from asbestosis and 70 from lung cancer. Mesothelioma was mentioned on the certificate in 14 deaths mostly coded to other causes. All these deaths occurred after 1959, and there were indications that additional cases of mesothelioma may have gone unrecognised, especially before that date. The exposure for each man was estimated in terms of duration and dust concentration in millions of dust particles per cubic foot (mpcf) from available measurements. Analyses were made both by life table and case referent methods. The standardised mortality ratio for respiratory cancer for the whole cohort was 105.0, but the risk rose linearly from 66.9 for men with less than 10 mpcf.y to 416.1 for those with 80 mpcf.y or more. Lines fitted to relative risks derived from SMRs in this and the textile plant studied in South Carolina were almost identical in slope. This was confirmed by case referent analysis. These findings support the conclusion from the South Carolina study that the risk of lung cancer in textile processing is very much greater than in chrysotile production and probably than in the friction products industry. The much greater risk of mesothelioma from exposure to processes in which even quite small quantities of amphiboles were used was also confirmed.


Clinical study of a new Modified Early Warning System scoring system for rapidly evaluating shock in adults.
Shock, the most common severe emergency syndrome, has a complicated etiopathogenesis, is difficult to identify, progresses quickly, and is dangerous. Early identification and intervention play determining roles in the final outcomes of shock patients, but no specific scoring system for shock has been established to date. We collected 292 shock patients and analyzed the correlation between 28-day prognosis and the Acute Physiologic Assessment and Chronic Health Evaluation II (APACHE II), Modified Early Warning System (MEWS), and Sequential Organ Failure Assessment scoring systems. According to the previous result, we established a new MEWS scoring system based on the conventional MEWS, which also included age and transcutaneous oxygen saturation. Some of the items with a strong correlation with the 28-day prognosis were selected to establish the new MEWS scoring system. We then evaluated the predictive efficacy of the new MEWS scoring system on 28-day prognosis and the correlation with other scoring systems. Some indexes, including age, transcutaneous oxygen saturation, arterial blood pH and blood lactic acid, serum sodium, serum potassium, HCO3, and red blood cells deposited, differed significantly between the nonsurviving and surviving groups (P<.05). The area under the curve (AUC) of the APACHE II, MEWS, shock index, and Sequential Organ Failure Assessment scoring systems for 28-day prognosis indicated a critical predictive efficacy. Receiver operating characteristic curves indicated that the MEWS AUC was 0.614, new MEWS AUC was 0.696, and APACHE II AUC was 0.785, suggesting superiority of the new MEWS to the conventional MEWS but inferiority to the APACHE II. Interestingly, the correlation efficient of the traditional MEWS and the new MEWS was 0.81. The correlation efficient of these scoring systems with other indexes, including lactic acid and hemoglobin, was less than 0.3. The new MEWS scoring system could be an independent indicator to reflect shock severity. It has higher predictive efficacy in septic shock, especially for 28-day prognosis.


How the multiple antioxidant properties of ascorbic acid affect lipid oxidation in oil-in-water emulsions.
Lipid oxidation is a serious problem for oil-containing food products because it negatively affects shelf life and nutritional composition. An antioxidant strategy commonly employed to prevent or delay oxidation in foods is to remove oxygen from the closed food-packaging system. An alternative technique is use of an edible oxygen scavenger to remove oxygen within the food. Ascorbic acid (AA) is a particularly promising antioxidant because of its natural label and multiple antioxidative functions. In this study, AA was tested as an oxygen scavenger in buffer and an oil-in-water (O/W) emulsion. The effects of transition metals on the ability of AA to scavenge oxygen were determined. Headspace oxygen decrease less than 1% in the medium-chain triacylglycerol (MCT) O/W emulsion system (pH 3 and 7). AA was able to almost completely remove dissolved oxygen (DO) in a buffered solution. Transition metals (Fe(2+) and Cu(+)) significantly accelerated the degradation of AA; however, iron and copper only increased DO depletion rates, by 10.6-16.4% from day 1 to 7, compared to the control. AA (2.5-20 mM) decreased DO in a 1% O/W emulsion system 32.0-64.0% and delayed the formation of headspace hexanal in the emulsion from 7 to over 20 days. This research shows that, when AA is used in an O/W emulsion system, oxidation of the emulsion system can be delay by multiple mechanisms.


Histone deacetylase inhibitors down-regulate bcl-2 expression and induce apoptosis in t(14;18) lymphomas.
Histone deacetylase (HDAC) inhibitors are promising antitumor agents, but they have not been extensively explored in B-cell lymphomas. Many of these lymphomas have the t(14;18) translocation, which results in increased bcl-2 expression and resistance to apoptosis. In this study, we examined the effects of two structurally different HDAC inhibitors, trichostatin A (TSA) and sodium butyrate (NaB), on the cell cycle, apoptosis, and bcl-2 expression in t(14;18) lymphoma cells. We found that in addition to potent cell cycle arrest, TSA and NaB also dramatically induced apoptosis and down-regulated bcl-2 expression, and overexpression of bcl-2 inhibited TSA-induced apoptosis. The repression of bcl-2 by TSA occurred at the transcriptional level. Western blot analysis and quantitative chromatin immunoprecipitation (ChIP) assay showed that even though HDAC inhibitors increased overall acetylation of histones, localized histone H3 deacetylation occurred at both bcl-2 promoters. TSA treatment increased the acetylation of the transcription factors Sp1 and C/EBPalpha and decreased their binding as well as the binding of CBP and HDAC2 to the bcl-2 promoters. Mutation of Sp1 and C/EBPalpha binding sites reduced the TSA-induced repression of bcl-2 promoter activity. This study provides a mechanistic rationale for the use of HDAC inhibitors in the treatment of human t(14;18) lymphomas.


Blood group antigen expression is involved in C. albicans interaction with buccal epithelial cells.
Human blood group polymorphisms are known to be determined by the expression of A, B or H antigens and the Lewis antigens. Protection against microbial infections has been associated with inheritance of polymorphisms in genes encoding and regulating the expression of ABH and Lewis antigens in bodily secretions and epithelial tissue surfaces, subsequently resulting in the presentation of different glycosylated terminal antigens on the cell surface. We investigated the role of blood group antigens in diversifying the glycosylation of buccal epithelial cells (BEC) that line the oral cavity. Specifically, we characterized and statistically evaluated the expression of histo-blood group (A, B, O) antigens on N-and O-linked glycans from BEC membrane proteins of various individuals that represented different blood group type and secretor status using a porous graphitic carbon liquid chromatography electrospray ionization mass spectrometry (PGC-LC-ESI-MS) based glycomics approach. From these BEC membrane proteins a total of 77 N-glycan and 96 O-glycan structures were structurally characterized from 19 individuals and relatively quantitated. The N-glycans from the secretor individuals did not express any A/B blood group determinants, but contained several terminal H-antigens. Apart from the non-secretors, the N-glycan profiles of BEC from all blood groups displayed similar glycan types, while varying in their relative intensities between individuals. However, multivariate analysis of the O-glycans from individuals displayed segregation patterns clearly associated with their blood group type and secretor status. In adhesion assays the oral pathogen Candida albicans showed a significantly higher interaction to blood group O type BECs relative to other blood groups.


Altered cholesterol and fatty acid metabolism in Huntington disease.
Huntington disease is an autosomal dominant neurodegenerative disorder characterized by behavioral abnormalities, cognitive decline, and involuntary movements that lead to a progressive decline in functional capacity, independence, and ultimately death. The pathophysiology of Huntington disease is linked to an expanded trinucleotide repeat of cytosine-adenine-guanine (CAG) in the IT-15 gene on chromosome 4. There is no disease-modifying treatment for Huntington disease, and novel pathophysiological insights and therapeutic strategies are needed. Lipids are vital to the health of the central nervous system, and research in animals and humans has revealed that cholesterol metabolism is disrupted in Huntington disease. This lipid dysregulation has been linked to specific actions of the mutant huntingtin on sterol regulatory element binding proteins. This results in lower cholesterol levels in affected areas of the brain with evidence that this depletion is pathologic. Huntington disease is also associated with a pattern of insulin resistance characterized by a catabolic state resulting in weight loss and a lower body mass index than individuals without Huntington disease. Insulin resistance appears to act as a metabolic stressor attending disease progression. The fish-derived omega-3 fatty acids, eicosapentaenoic acid and docosahexaenoic acid, have been examined in clinical trials of Huntington disease patients. Drugs that combat the dysregulated lipid milieu in Huntington disease may help treat this perplexing and catastrophic genetic disease.


Can Mild-to-Moderate Iodine Deficiency during Pregnancy Alter Thyroid Function? Lessons from a Mother-Newborn Cohort.
Severe iodine deficiency during pregnancy has substantial hormonal consequences, such as fetal brain damage. Data on the potential effects of mild-to-moderate iodine deficiency on the thyroid function of pregnant women and their newborns are scarce and divergent. We investigated the association between iodine intake in pregnancy and maternal and neonatal thyroid function in a region with mild-to-moderate iodine deficiency. Pregnant women's iodine status was evaluated using an iodine food frequency questionnaire, serum thyroglobulin (Tg), and urinary iodine concentration (UIC). Neonatal thyrotropin (nTSH) values were measured after birth. Obstetrics and anthropometric data were also collected. Among the 178 women (median age 31 years) included in the study, median (interquartile range) estimated dietary iodine intake, Tg and UIC were 179 (94−268) μg/day, 18 (11−33) μg/L, and 60 (41−95) μg/L, respectively. There was a significant inverse association of iodine intake with Tg values among the study population (β = −0.2, F = 7.5, p < 0.01). Women with high free triiodothyronine (FT3) values were more likely to exhibit an estimated iodine intake below the estimated average requirement (160 μg/day, odds ratio [OR] = 2.6; 95% confidence interval [CI], 1.1−6.4; p = 0.04) and less likely to consume iodine-containing supplements (OR = 0.3, 95% CI, 0.1−0.8; p = 0.01). It is possible that thyroid function may be affected by iodine insufficiency during pregnancy in regions with mild-to-moderate iodine deficiency. The relatively small sample size of the studied population warrants further investigation.


Comparison of a novel polytitanium chloride coagulant with polyaluminium chloride: coagulation performance and floc characteristics.
Polymerized inorganic coagulants are increasingly being used in the water supply and wastewater treatment process, yet there is limited research on the development of polytitanium coagulants. The aim of this study is to synthesize polytitanium chloride (PTC) coagulants and investigate their coagulation behavior and floc characteristics for humic acid removal in comparison to polyaluminum chloride (PAC). The PTC samples with different B (molar ratios of OH/Ti) values were prepared using an instantaneous base-feeding method, employing sodium carbonate as the basification agent. The coagulation efficiency was significantly influenced by different B values. The results suggest that the humic acid removal increased with the increasing B value for PAC, while the inverse trend was observed for PTC. The optimum B value was chosen at 1.0 and 2.0 for PTC and PAC, respectively. Under the optimum coagulant dose and initial solution pH conditions, the PTC coagulant performed better than the PAC coagulant and the floc properties were significantly improved in terms of floc growth rate and floc size. However, the PAC coagulants produced flocs with better floc recoverability than the PTC coagulants.


Personalized Treatment for Small Renal Tumors: Decision Analysis of Competing Causes of Mortality.
Purpose To compare the effectiveness of personalized treatment for small (≤4 cm) renal tumors versus routine partial nephrectomy (PN), accounting for various competing causes of mortality. Materials and Methods A state-transition microsimulation model was constructed to compare life expectancy of management strategies for small renal tumors by using 1 000 000 simulations in the following ways: routine PN or personalized treatment involving percutaneous ablation for risk factors for worsening chronic kidney disease (CKD), and otherwise PN; biopsy, with triage of renal cell carcinoma (RCC) to PN or ablation depending on risk factors for worsening CKD; active surveillance for growth; and active surveillance when MRI findings are indicative of papillary RCC. Transition probabilities were incorporated from the literature. Effects of parameter variability were assessed in sensitivity analysis. Results In patients of all ages with normal renal function, routine PN yielded the longest life expectancy (eg, 0.67 years in 65-year-old men with nephrometry score [NS] of 4). Otherwise, personalized strategies extended life expectancy versus routine PN: in CKD stages 2 or 3a, moderate or high NS, and no comorbidities, MRI guidance for active surveillance extended life expectancy (eg, 2.60 years for MRI vs PN in CKD 3a, NS 10); and with Charlson comorbidity index of 1 or more, biopsy or active surveillance for growth extended life expectancy (eg, 2.70 years for surveillance for growth in CKD 3a, NS 10). CKD 3b was most effectively managed by using MRI to help predict papillary RCC for surveillance. Conclusion For patients with chronic kidney disease and small renal tumors, personalized treatment selection likely extends life expectancy. © RSNA, 2019 Online supplemental material is available for this article.


Associations among four modalities of experimental pain in women.
The aim of this study was to investigate the associations among 4 measures of pain induction procedures in 244 healthy women. The procedures were (1) pressure pain threshold assessed over the temporalis muscles, masseter muscles, temporomandibular joints, and the wrists; (2) C fiber-mediated heat pain threshold/tolerance assessed on the skin over the forearm, cheek, and dorsal aspect of the foot; (3) temporal summation of C fiber-mediated heat pain; and (4) ischemic pain threshold/tolerance. Strong associations among pressure pain thresholds at the 4 sites examined (rho = 0.7 to 0.8, P values < or = .001) and among heat pain threshold/tolerance values at the 3 sites examined (rho = 0.6 to 0.9, P values < or = .001) were observed. Pressure pain threshold was moderately correlated with each of the heat pain threshold/tolerance values (rho = 0.2 to 0.4, P values < or = .001). Ischemic pain threshold/tolerance was moderately associated with each of the pressure and heat pain measures (rho = 0.2 to 0.3, P values < or = .05 to .001). Derived measures of the temporal summation of heat pain did not correlate strongly with threshold or tolerance measures of pressure, ischemic, or heat pain. We concluded (1) that for a specific pain modality, the correlation between threshold and tolerance values across anatomic sites is high, and (2) that measures of pressure, ischemic, and thermal pain threshold/tolerance are significantly correlated, although the strength of these associations is moderate. These findings demonstrate that a battery of pain-assessing procedures is required to determine an individual's pain sensitivity profile or phenotype. By investigating the relationship between pain sensitivity produced by different forms of stimuli, this study demonstrates that a battery of tests should be used to assess an individual's pain sensitivity and one should be careful in making inferences about an individual's sensitivity to pain by using only one pain modality.


Molecular evolution of the histone deacetylase family: functional implications of phylogenetic analysis.
Histone deacetylases (HDACs) modify core histones and participate in large regulatory complexes that both suppress and enhance transcription. Recent studies indicate that some HDACs can act on non-histone proteins as well. Interest in these enzymes is growing because HDAC inhibitors appear to be promising therapeutic agents against cancer and a variety of other diseases. Thus far, 11 members of the HDAC family have been identified in humans, but few have been characterized in detail. To better define the biological function of these proteins, make maximal use of studies performed in other systems, and assist in drug development efforts, we have performed a phylogenetic analysis of all HDAC-related proteins in all fully sequenced free-living organisms. Previous analyses have divided non-sirtuin HDACs into two groups, classes 1 and 2. We find that HDACs can be divided into three equally distinct groups: class 1, class 2, and a third class consisting of proteins related to the recently identified human HDAC11 gene. We term this novel group "class 4" to distinguish it from the unrelated "class 3" sirtuin deacetylases. Analysis of gene duplication events indicates that the common ancestor of metazoan organisms contained two class 1, two class 2, and a single class 4 HDAC. Examination of HDAC characteristics in light of these evolutionary relationships leads to functional predictions, among them that self-association is common among HDAC proteins. All three HDAC classes (including class 4) exist in eubacteria. Phylogenetic analysis of bacterial HDAC relatives suggests that all three HDAC classes precede the evolution of histone proteins and raises the possibility that the primary activity of some "histone deacetylase" enzymes is directed against non-histone substrates.


Engineering a more sustainable world through catalysis and green chemistry.
The grand challenge facing the chemical and allied industries in the twenty-first century is the transition to greener, more sustainable manufacturing processes that efficiently use raw materials, eliminate waste and avoid the use of toxic and hazardous materials. It requires a paradigm shift from traditional concepts of process efficiency, focusing on chemical yield, to one that assigns economic value to replacing fossil resources with renewable raw materials, eliminating waste and avoiding the use of toxic and/or hazardous substances. The need for a greening of chemicals manufacture is readily apparent from a consideration of the amounts of waste generated per kilogram of product (the E factors) in various segments of the chemical industry. A primary source of this waste is the use of antiquated 'stoichiometric' technologies and a major challenge is to develop green, catalytic alternatives. Another grand challenge for the twenty-first century, driven by the pressing need for climate change mitigation, is the transition from an unsustainable economy based on fossil resources--oil, coal and natural gas--to a sustainable one based on renewable biomass. In this context, the valorization of waste biomass, which is currently incinerated or goes to landfill, is particularly attractive. The bio-based economy involves cross-disciplinary research at the interface of biotechnology and chemical engineering, focusing on the development of green, chemo- and biocatalytic technologies for waste biomass conversion to biofuels, chemicals and bio-based materials. Biocatalysis has many benefits to offer in this respect. The catalyst is derived from renewable biomass and is biodegradable. Processes are performed under mild conditions and generally produce less waste and are more energy efficient than conventional ones. Thanks to modern advances in biotechnology 'tailor-made' enzymes can be economically produced on a large scale. However, for economic viability it is generally necessary to recover and re-use the enzyme and this can be achieved by immobilization, e.g. as solid cross-linked enzyme aggregates (CLEAs), enabling separation by filtration or centrifugation. A recent advance is the use of 'smart', magnetic CLEAs, which can be separated magnetically from reaction mixtures containing suspensions of solids; truly an example of cross-disciplinary research at the interface of physical and life sciences, which is particularly relevant to biomass conversion processes.


Absorption and disposition of moclobemide in patients with advanced age or reduced liver or kidney function.
Three different studies were conducted to assess the pharmacokinetics of moclobemide in subjects with conditions complicating dose determination. The first examined the absorption and disposition of moclobemide in an elderly population and compared these with results obtained in a group of normal young subjects. No significant differences were found between the groups in the intravenous (i.v.) parameters of disposition, and no differences with regard to disposition of the metabolite, Ro 12-8095. In addition, the minimum steady-state concentrations of moclobemide and the main plasma metabolite did not differ between the elderly and younger patients. In the second study, clearance tests in patients with cirrhosis of the liver confirmed that hepatic function is drastically reduced in this group of patients; it is therefore possible that moclobemide absorption and distribution might be influenced. In only 3 of the 12 patients investigated, slowly declining plasma concentrations after administration pointed to a severely limited elimination capacity for moclobemide. In the remaining 9 subjects, average values of several parameters changed significantly (t 1/2 beta, MRT and C1), whereas Vss and renal clearance were not significantly altered. In patients with kidney dysfunction, there were no differences in kinetics between patients undergoing hemodialysis and those who were not. Compared with normal healthy volunteers, no differences were found for renal patients, with the exception of the mean absorption time, which was significantly prolonged. From these studies it can be concluded that, pharmacokinetically, neither age nor renal impairment require adjusting the dosage of moclobemide. Patients with liver cirrhosis, however, need to have the usual dose reduced to one half or one third, or else the dosage intervals can be increased to prevent cumulation.


[Influence of HLA compatibility on cytomegalovirus infection in kidney transplantation].
The influence of HLA A, B, DR on the incidence and symptoms of cytomegalovirus (CMV) infection was investigated in 143 patients who, between October 1st, 1987 and December 31st, 1989, received kidneys from cadaveric donors. Systematic virological monitoring was carried out weekly during the first hospitalization and thereafter at each new hospitalization or in the presence of clinical signs suggestive of viral infection. The diagnosis of CMV was based on positive isolation in blood or urine, or seroconversion, or 4-dilution rise in the anti-CMV antibodies titre. HLA grouping of all recipients was made in the same histocompatibility laboratory. Immunosuppression was obtained with a quadruple therapy consisting of corticosteroids (15 mg/kg before transplantation, then 1 mg/kg for 10 days, then gradually tapering off dosage), azathioprine (2 to 3 mg/day), cyclosporin A (2 mg/kg i.v. followed by an oral dose adjusted to the residual levels) and a randomized treatment with either monoclonal anti-CD3 antibody or anti-thymocyte globulins administered during the first 10 days. The incidence of CMV infection was 56 percent (80/143), with 25 percent of primary infection (20/80). The number of DR compatibilities was found to have a significant influence on the incidence of CMV infection, which rose from 22 to 50 and 65 percent respectively in the group of patients with 2.1 or 0 DR compatibility (P less than 0.02). The degree of B + DR compatibility was also associated with the occurrence of CMV infection, the incidence of which rose from 0 to 36, 59, 43.5 and 71 percent respectively in the group of patients with 4, 3, 2, 1, 0 B + DR compatibility (P less than 0.03). The incidence of primary CMV infection increased with the number of DR incompatibilities, rising from 0 to 29 and 52 percent respectively in the group of patients with 0, 1 or 2 DR incompatibilities. The symptoms and severity of CMV infection were significantly influenced by the degree of DR and B + DR compatibility. Despite a very strong association between graft rejection and CMV infection (P less than 0.000001), no influence of HLA, and particularly DR or B + DR compatibility on the incidence and number of graft rejections could be demonstrated. It is concluded that, under the above-described quadruple therapy, the HLA DR and B + DR compatibility exerts a predominant influence on the occurrence and severity of CMV infection, and that this effect is independent of any action on graft rejection.(ABSTRACT TRUNCATED AT 400 WORDS)


Comparison of hospital-wide and age and location - stratified antibiograms of S. aureus, E. coli, and S. pneumoniae: age- and location-stratified antibiograms.
Antibiograms created by aggregating hospital-wide susceptibility data from diverse patients can be misleading. To demonstrate the utility of age- and location-stratified antibiograms, we compared stratified antibiograms for three common bacterial pathogens, E. coli, S. aureus, and S. pneumoniae. We created stratified antibiograms based on patient age (<18 years, 18-64 years, >/=65 years), and inpatient or outpatient location using all 2009 E. coli and S. aureus, and all 2008-2009 S. pneumoniae isolates submitted to our clinical microbiology laboratory. We compared susceptibility rates among cumulative and stratified antibiograms using descriptive statistics. For E. coli and S. aureus, the institution-wide antibiogram overestimated resistance in pediatic isolates and underestimated resistance in isolates from the elderly. For E. coli, pediatric isolates were less susceptible to ampicillin and ampicillin-sulbactam and more susceptible to gentamicin and ciprofloxacin compared to adult isolates (p < 0.05 for all), and isolates from patients >65 years were least susceptible to ciprofloxacin (71%). For S. aureus, susceptibility to oxacillin, clindamycin, and levofloxacin was highest among children and decreased with increasing age (p < .001 for all). For S. pneumoniae, pediatric isolates were less susceptible than adult isolates to all agents except penicillin (IV breakpoint). Within children there were significant differences in susceptibility of inpatient and outpatient isolates of E. coli but not of S. aureus or S. pneumoniae. Stratified antibiograms reveal age - associated differences in susceptibility of E. coli, S. aureus, and S. pneumoniae that are obscured by hospital-wide antibiograms. Age-stratified antibiograms have potential to influence antibiotic selection.


Serologic survey for Toxoplasma gondii in selected wildlife species from Alaska.
Blood was collected from selected wildlife species in specific areas of Alaska (USA) during 1976-96. A modified agglutination test was used to test sera for evidence of exposure to Toxoplasma gondii. Serum antibody prevalence was 43% (62 positive of 143 tested) for black bears (Ursus americanus), 9% (11/125) for wolves (Canis lupus), 7% (22/319) for Dall sheep (Ovis dalli), 6% (14/241) for caribou (Rangifer tarandus), 1% (3/240) for moose (Alces alces), and 1% (2/241) for bison (Bison bison). A predictive model was developed to determine the effect of sex, age, location, and year of collection on antibody prevalence for each species. Prevalence was higher in older black bears, caribou, and wolves. For black bears, prevalence was highest in the southeast region of the state. For caribou, prevalence was lowest on the Alaska Peninsula.


Calculating virtual log P in the alkane/water system (log P(N)(alk)) and its derived parameters deltalog P(N)(oct-alk) and log D(pH)(alk).
Growing interest in the use of both the logarithm of the partition coefficient of the neutral species in the alkane/water system (log P(N)(alk)) and the difference between log P(N)(oct) (the logarithm of the partition coefficient of the neutral species in the n-octanol/water system) and log P(N)(alk) (Deltalog P(N)(oct-alk)) in the early stages of drug design has stimulated development of a computational tool based on the Volsurf software to predict virtual (=of each conformer) log P(N)(alk) and virtual log P(N)(oct). From these two pieces of data, it is then possible to calculate Deltalog P(N)(oct-alk) for a given compound as the difference between log P(N)(oct) and log P(N)(alk). Once the pK(a) is known and the legitimacy of neglecting the contribution made by the ionized species has been checked, it is also possible to calculate log D(pH)(alk), which might be an important lipophilicity descriptor in absorption, distribution, metabolism, and excretion (ADME) prediction, from log P(N)(alk).


[Calculation of body fat by skinfold thickness].
This paper describes the method of determining the sizes of the subcutaneous fat folds found in the biceps, triceps, subscapular, suprailiac and submandibular. One is shown how to make the calculation of body fat and the areas of the section of the arm as related to the sizes of the folds and, finally, the author provides some recommendations so that one may correctly evaluate the data obtained.


Change in telomere length and cardiovascular risk factors in testicular cancer survivors.
Testicular cancer (TC) survivors cured with chemotherapy (CT) are prone to develop cardiovascular diseases, as part of an accelerated aging phenotype. A mechanism contributing to these events can be telomere shortening. In a prospective cohort of patients with disseminated TC who received cisplatin-based CT, mean absolute leukocyte telomere length (TL) was measured before and 1 year after start of treatment. Cardiovascular risk factors, including development of the metabolic syndrome and hypogonadism, were assessed before and up to 5 years after CT. For the whole group (n = 55), TL did not change 1 year after CT (5.7 (2.2-13.4) vs. 5.8 kb (1.6-19.2), P = 0.335). At baseline, patients with a BMI >30 kg/m2 (n = 12) had shorter TL (4.9 (2.2-13.4) vs. 6.3 kb (3.1-12.9), P = 0.045), while no age-dependent differences were measured. Patients with TL shortening after 1 year (n = 7) showed a significant increase in diastolic blood pressure (P = 0.007) and triglycerides (P = 0.003), compared to those with unchanged TL. There was no association between telomere shortening after 1 year or short TL at baseline (n = 7+11) and development of metabolic syndrome (25% vs. 21%; P = 0.777), or hypogonadism (38% vs. 17%; P = 0.120) after 5 years. A small subset of TC patients treated with cisplatin-based CT showed telomere shortening 1 year after treatment. This shortening was associated to a rise in diastolic blood pressure and triglycerides, but not to newly developed metabolic syndrome and hypogonadism after 5 years.


[Separation and characterization of human T G and T M lymphocyte populations].
During the last few years a number of experimental evidences have shown the presence of Fc receptors for IgG or IgM on the membrane of human T cells. These two different receptors are detectable and mutually exclusive on distinct cell populations named respectively TG, TM and T "null" (which lack detectable receptors). Studies on the functional activities of these cells have shown that TM and TG lymphocytes play an antitetical role in regulating B cell response, TM exerting an "helper" activity on the differentiation of B lymphocytes while TG having a "suppressor" one. The aim of this study has been to determine the values of these two subpopulations in a group of twenty control subjects. Our results have shown that TG constitute 10%, whereas TM represent 40% of the total T cells. After EA-G rosetting, the purification of this subpopulation on a density gradient has shown an enrichment of more than 90% in TG cells, while TM contaminate this fraction for less than 4%. The purity of the fraction containing TM has been evaluated using the localization of alpha-naphthyl acetate esterase activity, which has shown that more than 88% of the cells in this fraction are positive for this enzyme.


Splenic function and IgM-memory B cells in Crohn's disease patients treated with infliximab.
Under experimental chronic inflammation, tumor necrosis factor (TNF)-alpha plays a role in damaging spleen marginal zone. This latter has a crucial function in mounting B cell-dependent immune responses against infections by encapsulated bacteria. In Crohn's disease (CD), a chronic inflammatory disorder where TNF-alpha is centrally involved, impaired splenic function may increase the susceptibility to bacterial infections. On this basis, we aimed to investigate the influence of anti-TNF therapy on splenic function in CD patients. Peripheral blood samples were obtained from 15 CD patients before and after treatment with infliximab administered at weeks 0, 2, and 6 at a dose of 5 mg/kg. Counting of erythrocytes with membrane abnormalities (pitted red cells) was used as an indicator of splenic function. Multicolor flow cytometry was performed to analyze circulating B cells. A substantial clinical improvement in 10 of the 15 CD patients was associated with a significant reduction of pitted red cells (from median 6.0% to 3.6%; P < 0.01) after 10 weeks of treatment. In responder patients the improvement of splenic function was accompanied by a parallel increase of circulating IgM-memory B cells (from median 6.9% to 13.3%; P < 0.005). Splenic function was not ameliorated in nonresponder patients. Splenic function improved in CD patients who responded to infliximab and was accompanied by a concomitant restoration of the IgM-memory B cell pool responsible for the protection against encapsulated bacteria. Restoration of splenic function after infliximab treatment is intriguing and requires further investigation.


Sleep disturbances and risk of falls in older community-dwelling men: the outcomes of Sleep Disorders in Older Men (MrOS Sleep) Study.
To test the hypothesis that subjective and objective sleep disturbances are associated with risk of incident falls in older men. The prospective observational MrOS Sleep Study. Six academic clinical centers in the United States. Community-dwelling men aged 67 and older (mean 76) (n = 3,101). Subjective sleep measurements included daytime sleepiness (Epworth Sleepiness Scale (ESS)), sleep quality (Pittsburgh Sleep Quality Index (PSQI)), and total sleep time (TST). Objective sleep measurements included actigraphic TST and sleep efficiency (an index of fragmentation) and sleep disordered breathing (measured using in-home polysomnography). Fall frequency during the subsequent year was ascertained three times per year using questionnaires. Recurrent falling was defined as having two or more falls in the subsequent year. In multivariable-adjusted models, participants with excessive daytime sleepiness (ESS > 10) but not poor subjective sleep quality (PSQI > 5) had greater odds of experiencing two or more falls in the subsequent year (odds ratio (OR) = 1.52 95% confidence interval (CI) = 1.14-2.03). Based on actigraphic recordings, the odds of having recurrent falls was higher for men who slept 5 hours or less (OR = 1.79, 95% CI = 1.22-2.60) than for those who slept 7 to 8 hours. Actigraphically measured sleep efficiency was also associated with greater risk of falls, as was nocturnal hypoxemia (≥ 10% of sleep time with arterial oxygen saturation <90%; OR = 1.62, 95% CI = 1.17-2.24) but not apnea hypopnea index. Subjective and objective sleep disturbances were associated with risk of falls in older men, independent of confounders.


Diversity and partial characterization of putative virulence determinants in Pasteuria penetrans, the hyperparasitic bacterium of root-knot nematodes (Meloidogyne spp.).
Antigens recognized by monoclonal antibodies (Mabs) raised to the surface of the obligate nematode hyperparasite Pasteuria penetrans were characterized. Using the attachment of spores of the bacterium to host nematodes to determine the biological variability present on the spore surface greatly underestimated the amount of surface heterogeneity present compared with estimates from immunological techniques. This heterogeneity differed not only between different individual spores from the same population but also between different spore populations. None of the Mabs completely inhibited any spore population from attaching to the nematode cuticle, suggesting that the mechanism of attachment may be more complex than previously supposed. Chemical degradation of one particular epitope recognized by monoclonal antibody PP1/117, and designated ep117, occurred after treatment with NaOH, periodate or Proteinase K, suggesting that an O-linked glycoprotein may be involved. Fibronectin, which had been found to bind to Pasteuria spores through hydrophobic interactions, also prohibited the Mab from recognizing ep117. However, SDS-PAGE of spore extracts followed by immunoblotting showed that none of the Mabs could detect this epitope and so ep117 may be conformational in nature. Thus, the conformation of any particular epitope recognized by a Mab may be important in determining to which nematode a particular spore will attach. The distribution of a particular epitope within a population of spores will in turn therefore determine its virulence on a particular nematode.


Online Discriminative Kernel Density Estimator With Gaussian Kernels.
We propose a new method for a supervised online estimation of probabilistic discriminative models for classification tasks. The method estimates the class distributions from a stream of data in the form of Gaussian mixture models (GMMs). The reconstructive updates of the distributions are based on the recently proposed online kernel density estimator (oKDE). We maintain the number of components in the model low by compressing the GMMs from time to time. We propose a new cost function that measures loss of interclass discrimination during compression, thus guiding the compression toward simpler models that still retain discriminative properties. The resulting classifier thus independently updates the GMM of each class, but these GMMs interact during their compression through the proposed cost function. We call the proposed method the online discriminative kernel density estimator (odKDE). We compare the odKDE to oKDE, batch state-of-the-art kernel density estimators (KDEs), and batch/incremental support vector machines (SVM) on the publicly available datasets. The odKDE achieves comparable classification performance to that of best batch KDEs and SVM, while allowing online adaptation from large datasets, and produces models of lower complexity than the oKDE.


Interest and informational preferences regarding genomic testing for modest increases in colorectal cancer risk.
This study explored the interest in genomic testing for modest changes in colorectal cancer risk and preferences for receiving genomic risk communications among individuals with intermediate disease risk due to a family history of colorectal cancer. Surveys were conducted on 272 men and women at intermediate risk for colorectal cancer enrolled in a randomized trial comparing a remote personalized risk communication intervention (TeleCARE) aimed at promoting colonoscopy to a generic print control condition. Guided by Leventhal's Common Sense Model of Self-Regulation, we examined demographic and psychosocial factors possibly associated with interest in SNP testing. Descriptive statistics and logistic regression models were used to identify factors associated with interest in SNP testing and preferences for receiving genomic risk communications. Three-fourths of participants expressed interest in SNP testing for colorectal cancer risk. Testing interest did not markedly change across behavior modifier scenarios. Participants preferred to receive genomic risk communications from a variety of sources: printed materials (69.5%), oncologists (54.8%), primary-care physicians (58.4%), and the web (58.1%). Overall, persons who were unmarried (p = 0.029), younger (p = 0.003) and with greater cancer-related fear (p = 0.019) were more likely to express interest in predictive genomic testing for colorectal cancer risk. In a stratified analysis, cancer-related fear was associated with the interest in predictive genomic testing in the intervention group (p = 0.017), but not the control group. Individuals with intermediate familial risk for colorectal cancer are highly interested in genomic testing for modest increases in disease risk, specifically unmarried persons, younger age groups and those with greater cancer fear.


Lycopene uptake and tissue disposition in male and female rats.
Epidemiologic and clinical studies suggest that tomato consumption may reduce the risk of cancer. Lycopene, a hydrocarbon carotenoid, is the major carotenoid in tomatoes and, as a potent singlet oxygen quencher, has been considered by some to be the biologically active agent responsible for the reduction of cancer risk associated with tomato consumption. However, little is known concerning lycopene absorption or biological activity in rodent models of cancer. Therefore, the present study was designed to provide information regarding the uptake and tissue disposition of lycopene and related carotenoid after feeding a diet containing a carotenoid mixture extracted from tomatoes (Betatene). Betatene was added to the diet at 2.3, 0.9, 0.45, 0.23, 0.09 and 0 (mM/kg diet) and fed to male and female Fischer-344 rats for a period of 10 weeks. Using reverse phase HPLC methods, it was found that approximately 55% of administered lycopene was excreted in the feces. In both males and females, lycopene concentrations were highest in the liver (120-42 microg/g wet wt.); physiologically significant levels were detected in prostate (97-47 ng/g), lung (227-134 ng/g), mammary gland (309-174 ng/g) and serum (285-160 ng/ml). Tissue concentrations were related to dose with the exception of serum, and differences between males and females were minimal. Other carotenoids present in Betatene (i.e., phytoene, phytofluene, z-carotene and beta-carotene) were also absorbed and stored in the liver. These results indicate that lycopene, when incorporated into the semipurified AIN-76A diet, is absorbed in both male and female rats in a dose-related manner and can be detected at nanogram levels in a variety of target organs.