Linkage and mutation analysis in two Taiwanese families with long QT syndrome.
Long QT syndrome (LQT) is a cardiovascular disorder causing syncope and sudden death from arrhythmias. Mutations in KCNQ1, KCNH2, KCNE1, KCNE2, and SCN5A genes encoding cardiac potassium and sodium ion channels cause LQT. Two Taiwanese LQT families were screened for mutations in these ion channel genes. In family H87, the diagnosis was made in the 25-year-old female proband and six family members based on recurrent syncope and/or a prolonged QT interval. Genotyping revealed a novel nonsense mutation, R744X (C to T transition in codon 744), in the KCNH2 potassium channel gene, resulting in truncation of the putative cyclic nucleotide-binding domain and C-terminal region of the HERG K(+)-channel in all affected family members. The mutation was confirmed by DdeI endonuclease digestion of the DNA from each family member. The 26-year-old female proband in family L89 developed repeated syncope with QTc of 0.61 seconds. After linkage and mutation analysis, the syndrome in this family was associated with a novel KCNQ1 missense mutation, T309I, causing the substitution of a threonine residue at position 309, in the pore region of the KvLQT1 K(+)-channel, with an isoleucine. By Tsp45I restriction analysis, the mutation was noted in the proband and the proband's asymptomatic brother, but was not detected in 100 unrelated normal individuals. Identification of a mutation has clinical implications for presymptomatic diagnosis and therapy.


Electric Control of Dirac Quasiparticles by Spin-Orbit Torque in an Antiferromagnet.
Spin orbitronics and Dirac quasiparticles are two fields of condensed matter physics initiated independently about a decade ago. Here we predict that Dirac quasiparticles can be controlled by the spin-orbit torque reorientation of the Néel vector in an antiferromagnet. Using CuMnAs as an example, we formulate symmetry criteria allowing for the coexistence of topological Dirac quasiparticles and Néel spin-orbit torques. We identify the nonsymmorphic crystal symmetry protection of Dirac band crossings whose on and off switching is mediated by the Néel vector reorientation. We predict that this concept verified by minimal model and density functional calculations in the CuMnAs semimetal antiferromagnet can lead to a topological metal-insulator transition driven by the Néel vector and to the topological anisotropic magnetoresistance.


Epigenetic regulation is a crucial factor in the repression of UGT1A1 expression in the human kidney.
Human uridine 5'-diphospho-glucuronosyltransferase (UGT) 1A1 catalyzes the metabolism of numerous clinically and pharmacologically important compounds, such as bilirubin and SN-38. UGT1A1 is predominantly expressed in the liver and intestine but not in the kidney. The purpose of this study was to uncover the mechanism of the tissue-specific expression of UGT1A1, focusing on its epigenetic regulation. Bisulfite sequence analysis revealed that the CpG-rich region near the UGT1A1 promoter (-85 to +40) was hypermethylated (83%) in the kidney, whereas it was hypomethylated (37%) in the liver. A chromatin immunoprecipitation assay demonstrated that histone H3 near the promoter was hypoacetylated in the kidney but hyperacetylated in the liver; this hyperacetylation was accompanied by the recruitment of hepatocyte nuclear factor (HNF) 1α to the promoter. The UGT1A1 promoter in human kidney-derived HK-2 cells that do not express UGT1A1 was fully methylated, but this promoter was relatively unmethylated in human liver-derived HuH-7 cells that express UGT1A1. Treatment with 5-aza-2'-deoxycytidine (5-aza-dC), an inhibitor of DNA methylation, resulted in an increase of UGT1A1 mRNA expression in both cell types, but the increase was much larger in HK-2 cells than in HuH-7 cells. The transfection of an HNF1α expression plasmid into the HK-2 cells resulted in an increase of UGT1A1 mRNA only in the presence of 5-aza-dC. In summary, we found that DNA hypermethylation, along with histone hypoacetylation, interferes with the binding of HNF1α, resulting in the defective expression of UGT1A1 in the human kidney. Thus, epigenetic regulation is a crucial determinant of tissue-specific expression of UGT1A1.


Tactic responses to oxygen in the phototrophic bacterium Rhodobacter sphaeroides WS8N.
The temporal and spatial behavior of a number of mutants of the photosynthetic, facultative anaerobe Rhodobacter sphaeroides to both step changes and to gradients of oxygen was analyzed. Wild-type cells, grown under a range of conditions, showed microaerophilic behavior, accumulating in a 1.3-mm band about 1.3 mm from the meniscus of capillaries. Evidence suggests this is the result of two signaling pathways. The strength of any response depended on the growth and incubation conditions. Deletion of either the complete chemosensory operons 1 and 2 plus the response regulator genes cheY(4) and cheY(5) or cheA(2) alone led to the loss of all aerotactic responses, although the cells still swam normally. The Prr system of R. sphaeroides responds to electron flow through the alternative high-affinity cytochrome oxidase, cbb(3), controlling expression of a wide range of metabolic pathways. Mutants with deletions of either the complete Prr operon or the histidine kinase, PrrB, accumulated up to the meniscus but still formed a thick band 1.3 mm from the aerobic interface. This indicates that the negative aerotactic response to high oxygen levels depends on PrrB, but the mutant cells still retain the positive response. Tethered PrrB(-) cells also showed no response to a step-down in oxygen concentration, although those with deletions of the whole operon showed some response. In gradients of oxygen where the concentration was reduced at 0.4 micro M/s, tethered wild-type cells showed two different phases of response, with an increase in stopping frequency when the oxygen concentration fell from 80 to 50% dissolved oxygen and a decrease in stopping at 50 to 20% dissolved oxygen, with cells returning to their normal stopping frequency in 0% oxygen. PrrB and CheA(2) mutants showed no response, while PrrCBA mutants still showed some response.


Phospholipid methylation unmasks cryptic beta-adrenergic receptors in rat reticulocytes.
The effect of phospholipid methylation on the number of beta-adrenergic receptor binding sites was examined in rat reticulocyte membranes. Stimulation of phosphatidylcholine synthesis by the introduction of the methyl donor S-adenosyl-L-methionine into reticulocyte ghosts increased the number of beta-adrenergic receptor sites. The appearance of beta-adrenergic binding sites was dependent on the formation of phosphatidylcholine by the enzyme that converts phosphatidyl-N-monomethylethanolamine from phosphatidylethanolamine. Both the synthesis of phosphatidylcholine and the unmasking of cryptic receptors were time and temperature dependent and did not occur in the presence of the methyl transferase inhibitor, S-adenosyl-L-homocysteine.


AGTR1 overexpression defines a subset of breast cancer and confers sensitivity to losartan, an AGTR1 antagonist.
Breast cancer patients have benefited from the use of targeted therapies directed at specific molecular alterations. To identify additional opportunities for targeted therapy, we searched for genes with marked overexpression in subsets of tumors across a panel of breast cancer profiling studies comprising 3,200 microarray experiments. In addition to prioritizing ERBB2, we found AGTR1, the angiotensin II receptor type I, to be markedly overexpressed in 10-20% of breast cancer cases across multiple independent patient cohorts. Validation experiments confirmed that AGTR1 is highly overexpressed, in several cases more than 100-fold. AGTR1 overexpression was restricted to estrogen receptor-positive tumors and was mutually exclusive with ERBB2 overexpression across all samples. Ectopic overexpression of AGTR1 in primary mammary epithelial cells, combined with angiotensin II stimulation, led to a highly invasive phenotype that was attenuated by the AGTR1 antagonist losartan. Similarly, losartan reduced tumor growth by 30% in AGTR1-positive breast cancer xenografts. Taken together, these observations indicate that marked AGTR1 overexpression defines a subpopulation of ER-positive, ERBB2-negative breast cancer that may benefit from targeted therapy with AGTR1 antagonists, such as losartan.


Association Study of a Functional Variant on ABCG2 Gene with Sunitinib-Induced Severe Adverse Drug Reaction.
Sunitinib is a tyrosine kinase inhibitor and used as the first-line treatment for advanced renal cell carcinoma (RCC). Nevertheless, inter-individual variability of drug's toxicity was often observed among patients who received sunitinib treatment. This study is to investigate the association of a functional germline variant on ABCG2 that affects the pharmacokinetics of sunitinib with sunitinib-induced toxicity of RCC patients in the Japanese population. A total of 219 RCC patients were recruited to this pharmacogenetic study. ABCG2 421C>A (Q141K) was genotyped by using PCR-Invader assay. The associations of both clinical and genetic variables were evaluated with logistic regression analysis and subsequently receiver operating characteristic (ROC) curve was plotted. About 43% (92/216) of RCC patients that received sunitinib treatment developed severe grade 3 or grade 4 thrombocytopenia according to the National Cancer Institute-Common Terminology Criteria for Adverse Events version 3.0, the most common sunitinib-induced adverse reaction in this study. In the univariate analysis, both age (P = 7.77x10(-3), odds ratio (OR) = 1.04, 95%CI = 1.01-1.07) and ABCG2 421C>A (P = 1.87x10(-2), OR = 1.71, 95%CI = 1.09-2.68) showed association with sunitinib-induced severe thrombocytopenia. Multivariate analysis indicated that the variant ABCG2 421C>A is suggestively associated with severe thrombocytopenia (P = 8.41x10(-3), OR = 1.86, 95% CI = 1.17-2.94) after adjustment of age as a confounding factor. The area under curve (AUC) of the risk prediction model that utilized age and ABCG2 421C>A was 0.648 with sensitivity of 0.859 and specificity of 0.415. Severe thrombocytopenia is the most common adverse reaction of sunitinib treatment in Japanese RCC patients. ABCG2 421C>A could explain part of the inter-individual variability of sunitinib-induced severe thrombocytopenia.


Biomechanical risk factors in the development of medial tibial stress syndrome in distance runners.
We investigated the relationship between functional and static foot posture and medial tibial stress syndrome in distance runners. Twenty-eight runners with a clinical diagnosis of medial tibial stress syndrome and 12 asymptomatic runners were assessed with the Foot Posture Index to measure static overpronation. Range of motion was measured at the talocrural joint, with the knee extended and flexed as was range of motion at the first metatarsophalangeal joint and the angular difference between the neutral and relaxed calcaneal stance positions. Each participant was then videotaped while running on a treadmill shod and unshod. This videotape was analyzed using freeze frame to identify abnormal or mistimed pronation at each phase of gait. The results were analyzed using logistic regression to give the probability that a runner is likely to experience medial tibial stress syndrome, predicted from the static measurements and dynamic observations. Variables identified as being significant predictors of medial tibial stress syndrome were the difference between the neutral and relaxed calcaneal stance positions, range of motion of the talocrural joint with the knee extended, early heel lift and abductory twist during gait, and apropulsive gait. Runners with suspected symptoms of medial tibial stress syndrome should be assessed dynamically and statically for abnormal or mistimed pronation.


A new role of the membrane-type matrix metalloproteinase 16 (MMP16/MT3-MMP) in neural crest cell migration.
Neural crest cells (NCCs) are a transient population of neuroectodermal-originated cells that populate the dorsal neural tube (dNT), before migrating and giving rise to multiple cell lineages in the developing embryo. Prior to their migration, NCCs undergo epithelial-to-mesenchymal-transition (EMT) through which they lose cell contacts and detach from the dNT to invade their surrounding environment. Multiple signals and transcription factors have been identified to regulate these events. Yet, less is known regarding effectors that act downstream to execute the actual NCC separation and migration. Matrix metalloproteinases (MMPs) are a family of proteases that degrade the extracellular matrix as well as other pericellular proteins during processes of tissue remodeling, angiogenesis and metastasis. Previously, we and others have demonstrated the role of the gelatinases MMP2 and MMP9 during the onset of NCC migration. Several evidences link the cleavage and activation of these secreted gelatinases to the activity of membrane-type MMPs (MT-MMP), such as MMP14 and MMP16, which are tethered to plasma membrane and affect various cellular behaviors. The aim of this study was to investigate whether MMP16 acts in NCCs. Here we demonstrate the expression of MMP16 mRNA and protein in cranial NCCs in avian embryos. Knockdown of MMP16 inhibited NCC migration. This inhibition was rescued by the addition of recombinant MMP16, which was also sufficient to increase proper NCC migration. Furthermore, excess MMP16 caused enhanced NCC EMT, concomitant with degradation of dNT-related proteins, laminin and N-cadherin. Altogether, these results uncover MMP16 as a new effector participating in EMT and in the migration of NCCs.


Reliability and validity of the Massachusetts general hospital cognitive and physical functioning questionnaire.
We have recently developed the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ), a brief scale to measure cognitive and executive dysfunction in mood and anxiety disorders, and we here report on its reliability and validity. The internal consistency of the CPFQ was assessed by computing Cronbach's coefficient alpha based upon the average intercorrelation of the 7 items of the CPFQ in a sample of depressed outpatients and by factor analyzing data from the same sample to confirm that the scale is unifactorial and measuring a single construct. Test-retest reliability of the CPFQ was assessed in a different sample of depressed outpatients by computing Pearson's correlation coefficient between pretreatment screening scores and pretreatment baseline scores. Sensitivity to change of the CPFQ was assessed by computing the dependent t test for the subjects in the active treatment condition in the second sample of depressed outpatients. Finally, convergent validity for the CPFQ was assessed in two different ways. We found that the CPFQ is a unifactorial scale, with strong internal consistency. It has good temporal stability as indicated by high test-retest reliability. The CPFQ was also found to be sensitive to change with treatment and displayed convergent validity by significant correlations with other measures of sleepiness, fatigue, apathy and neuropsychological functioning. Although, as expected, the CPFQ was significantly correlated with a measure of depression, the moderate correlation (r approximately 0.30) indicates that the CPFQ is measuring a different construct. In summary, the CPFQ is a unifactorial scale, with strong internal consistency, good temporal stability and sensitivity to change with treatment. Further studies will be needed to assess the validity and reliability of this instrument in other psychiatric and neuropsychiatric conditions associated with cognitive dysfunction.


Genome-wide association analysis of hippocampal volume identifies enrichment of neurogenesis-related pathways.
Adult neurogenesis occurs in the dentate gyrus of the hippocampus during adulthood and contributes to sustaining the hippocampal formation. To investigate whether neurogenesis-related pathways are associated with hippocampal volume, we performed gene-set enrichment analysis using summary statistics from a large-scale genome-wide association study (N = 13,163) of hippocampal volume from the Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Consortium and two year hippocampal volume changes from baseline in cognitively normal individuals from Alzheimer's Disease Neuroimaging Initiative Cohort (ADNI). Gene-set enrichment analysis of hippocampal volume identified 44 significantly enriched biological pathways (FDR corrected p-value < 0.05), of which 38 pathways were related to neurogenesis-related processes including neurogenesis, generation of new neurons, neuronal development, and neuronal migration and differentiation. For genes highly represented in the significantly enriched neurogenesis-related pathways, gene-based association analysis identified TESC, ACVR1, MSRB3, and DPP4 as significantly associated with hippocampal volume. Furthermore, co-expression network-based functional analysis of gene expression data in the hippocampal subfields, CA1 and CA3, from 32 normal controls showed that distinct co-expression modules were mostly enriched in neurogenesis related pathways. Our results suggest that neurogenesis-related pathways may be enriched for hippocampal volume and that hippocampal volume may serve as a potential phenotype for the investigation of human adult neurogenesis.


Selective phagocytosis of gram-positive bacteria and interleukin 1-like factor production by a subpopulation of large granular lymphocytes.
There has been a consensus that a large granular lymphocyte (LGL) population with natural killer (NK) function is nonadherent and nonphagocytic. However, a significant proportion of the nonadherent cells purified by the two-step depletion of adherent cells with a plastic surface and nylon wool columns engulfed Sta. aureus into their cytoplasm. These cells were morphologically identified as LGL in light and electron microscopies. Two-color immunofluorescence tests, furthermore, demonstrated that Leu-11+ LGL, Leu-11+7-, and Leu-11+7+, but not Leu-11-7+, phagocytosed Sta. aureus. Among the particles tested here, only Gram(+) bacteria were preferentially phagocytosed, whereas Gram(-) bacteria, other large-sized microbes (e.g., baker's yeast and Candida albicans), latex, silica, and carbonyl iron were not. LGL exhibited a substantial level of bactericidal activity against Sta. aureus, although the level was one third of that mediated by monocytes. When Gram(+) bacteria were incubated with nonadherent cells for 18 hr, significant amounts of interleukin 1 (IL 1)-like factors (or IL 1 itself) as well as interferon were detected in the supernatants. On the other hand, this incubation did not induce interleukin 2 (IL 2). The IL 1-like factor producer cells were demonstrated to be the low-density lymphocytes on Percoll separation and to have the Leu-11+ phenotype. The phagocytosis was suggested to be an important stimulus in producing IL 1-like factors from LGL. Thus, the treatment of cells with cytochalasin B, a microfilament disrupting agent, completely abrogated both phagocytosis and IL 1-like factor production. Some cell wall components of Gram(+) bacteria might be important to a recognition process of the phagocytosis, since the protoplasts of Sta. aureus, when prepared by the treatment of bacteria with lysostaphin, were no longer phagocytosed by LGL. The present results therefore identify an additional unique characteristic similar to, but not identical with, the myelomonocytic nature of Leu-11+ LGL.


The Influence of Physical Fitness on Reasons for Academy Separation in Law Enforcement Recruits.
This study analyzed the effects physical fitness may have on reasons for academy separation in law enforcement recruits. A retrospective analysis was conducted on 401 recruits; 330 recruits graduated (GRAD), and 71 recruits separated at various times during academy. Twenty-eight recruits separated for personal reasons (SEPPR); 18 due to physical training failures (i.e., poor fitness) or injury (SEPFI); and 25 due to academic or scenario failures (SEPAS). Fitness testing occurred prior to academy, and included: Push-ups and sit-ups in 60s; a 75-yard pursuit run (75PR); vertical jump; medicine ball throw; and multistage fitness test (MSFT). A one-way ANOVA with Bonferroni post hoc compared between-group fitness test performance. A multiple stepwise regression calculated whether recruit characteristics or fitness could predict separation. The GRAD group was younger than the SEPAS group (p < 0.01), faster in the 75PR than the SEPFI group (p = 0.02), and completed more MSFT shuttles than the SEPPR and SEPFI groups (p = 0.01). Age predicted GRAD and SEPAS group inclusion; MSFT predicted GRAD, SEPPR, and SEPFI group inclusion. Recruits who had superior high-intensity running capacity (75PR) and aerobic fitness (MSFT) should have a better chance of completing academy. However, this could be influenced by training practices adopted during academy.


Knowledge and attitudes of pharmacists regarding oral health care and oral hygiene products in Chennai city.
This study was done to find out the knowledge and attitudes of pharmacists regarding oral health care and oral hygiene products in Chennai city. A cross-sectional survey among a sample of the pharmacists in Chennai city was done and data regarding their knowledge and attitudes towards oral health care and oral hygiene products were obtained using a closed-ended questionnaire. Among the 60 pharmacies approached, 50 pharmacists participated in the study and completed the questionnaire. Though 48% of the participants gave a positive answer when asked whether they had met the dentist practicing close to their pharmacies, the frequency with which they met the dentist ranged from once a week (24%) to once a month (28%). Most of the pharmacists stocked oral health-related products, which comprised 15-25% of their total stock. Of these products toothpaste was the most common (62%), followed by mouth rinses (12%). Toothache or painful teeth was the most common dental problem (78%) for which patients approached the pharmacists for advice. With regard to the advice given, 38.5% of the pharmacists asked the patient to consult a nearby dentist after dispensing medications, while 22.4% of the pharmacists dispensed antibiotics and painkillers without any referral. Seventy percent of the pharmacists expressed interest in giving oral health care advice to patients. However, many of them (38%) felt that lack of proper knowledge is a barrier to providing oral health care advice. It is clear from the present study that pharmacists are presently an underutilized resource, and there is a definitive need to improve their training and access to information on available dental services.


Innovative primary care delivery in rural Alaska: a review of patient encounters seen by community health aides.
For more than 50 years, Community Health Aides and Community Health Practitioners (CHA/Ps) have resided in and provided care for the residents of their villages. This study is a systematic description of the clinical practice of primary care health workers in rural Alaska communities. This is the first evaluation of the scope of health problems seen by these lay health workers in their remote communities. Retrospective observational review of administrative records for outpatient visits seen by CHA/Ps in 150 rural Alaska villages (approximate population 47,370). Analysis of electronic records for outpatient visits to CHA/Ps in village clinics from October 2004 through September 2006. Data included all outpatient visits from the Indian Health Service National Patient Information Reporting System. Descriptive analysis included comparisons by region, age, sex, clinical assessment and treatment. In total 272,242 visits were reviewed. CHA/Ps provided care for acute, chronic, preventive, and emergency problems at 176,957 (65%) visits. The remaining 95,285 (35%) of records did not include a diagnostic code, most of which were for administrative or medication-related encounters. The most common diagnostic codes were: pharyngitis (11%), respiratory infections (10%), otitis media (8%), hypertension (6%), skin infections (4%), and chronic lung disease (4%). Respiratory distress and chest pain accounted for 75% (n=10,552) of all emergency visits. CHA/Ps provide a broad range of primary care in remote Alaskan communities whose residents would otherwise be without consistent medical care. Alaska's CHA/P program could serve as a health-care delivery model for other remote communities with health care access challenges.


Morbidity, including fatal morbidity, throughout life in men entering adult life as obese.
The association between obesity in adults and excess morbidity and mortality is well established, but the health impact throughout adult life of being obese in early adulthood needs elucidation. We investigated somatic morbidity, including fatal morbidity, throughout adulthood in men starting adult life as obese. Among 362,200 Danish young men, examined for military service between 1943 and 1977, all obese (defined as BMI≥31.0 kg/m(2)), and, as controls, a random 1% sample of the others was identified. In the age range of 18-25 years, there were 1,862 obese, which encompass the men above the 99.5 percentile, and 3,476 controls. Information on morbidity was obtained via national registers. Cox regression models were used to estimate the relative morbidity assessed as first incidence of disease, occurrence of disease in the year preceding death and prevalent disease at time of death. From age 18 through 80 years the obese had an increased risk of becoming diseased by or die from a broad range of diseases. Generally, the incidence of first event, occurrence in the year prior to death, and prevalence at time of death showed the same pattern. As an example, the relative hazard of type 2 diabetes was constant throughout life at 4.9 (95% confidence intervals [CI]: 4.1-5.9), 5.2 (95% CI: 3.6-7.5), and 6.8 (95% CI: 4.6-10.1), respectively. Our findings strongly support the continued need to avoid beginning adult life as obese, as obese young men experience an increased morbidity, including fatal morbidity, from many diseases throughout life.


Evaluation of a joint Bioinformatics and Medical Informatics international course in Peru.
New technologies that emerge at the interface of computational and biomedical science could drive new advances in global health, therefore more training in technology is needed among health care workers. To assess the potential for informatics training using an approach designed to foster interaction at this interface, the University of Washington and the Universidad Peruana Cayetano Heredia developed and assessed a one-week course that included a new Bioinformatics (BIO) track along with an established Medical/Public Health Informatics track (MI) for participants in Peru. We assessed the background of the participants, and measured the knowledge gained by track-specific (MI or BIO) 30-minute pre- and post-tests. Participants' attitudes were evaluated both by daily evaluations and by an end-course evaluation. Forty-three participants enrolled in the course - 20 in the MI track and 23 in the BIO track. Of 20 questions, the mean % score for the MI track increased from 49.7 pre-test (standard deviation or SD = 17.0) to 59.7 (SD = 15.2) for the post-test (P = 0.002, n = 18). The BIO track mean score increased from 33.6 pre-test to 51.2 post-test (P < 0.001, n = 21). Most comments (76%) about any aspect of the course were positive. The main perceived strength of the course was the quality of the speakers, and the main perceived weakness was the short duration of the course. Overall, the course acceptability was very good to excellent with a rating of 4.1 (scale 1-5), and the usefulness of the course was rated as very good. Most participants (62.9%) expressed a positive opinion about having had the BIO and MI tracks come together for some of the lectures. Pre- and post-test results and the positive evaluations by the participants indicate that this first joint Bioinformatics and Medical/Public Health Informatics (MI and BIO) course was a success.


Length and weight of newborns in Croatia from 1985 to 2009.
Constitutional characteristics of humans are changing. People are becoming taller and they weigh more. These changes influence birth weight and birth length as well. A study was conducted on 2414 mothers and their newborns from 1985 to 2009 in Zagreb, Croatia, to establish a secular change in the weight and length of infants and the factors that are most related to these changes. Birth weight has increased significantly in the past 25 years, and it is higher in male newborns. Taller mothers, with higher weight and body mass index, deliver newborns with higher birth weight. Weight gain in pregnancy has positive impact on birth weight. Multiparas and older and more educated women deliver newborns with higher weight. Birth weight does not depend on father's education. The number of newborns with birth weight more than 4000 g is increasing, but not significantly. Birth length was not significantly higher. Birth length is higher in male newborns, in newborns with higher birth weight and newborns of older and more educated mothers. Better life conditions and better health care improves population constitutional characteristics that have implications in higher birth weight and birth length. This could be an important change that influences delivery modalities.


Safety of protocol violations in acute stroke tPA administration.
Intravenous (IV) tissue plasminogen activator remains the only approved therapy for acute ischemic stroke (AIS) in the United States; however, less than 10% of patients receive treatment. This is partially because of the large number of contraindications, narrow treatment window, and physician reluctance to deviate from these criteria. We retrospectively analyzed consecutive patients who received IV thrombolysis at our stroke center for National Institute of Neurological Disorders and Stroke (NINDS) protocol violations and rates of symptomatic intracerebral hemorrhage (sICH). Other outcome variables included systemic hemorrhage, modified Rankin Scale at discharge, and discharge disposition. A total of 212 patients were identified in our stroke registry between 2009 and 2011 and included in the analysis. Protocol violations occurred in 76 patients (36%). The most common violations were thrombolysis beyond 3 hours (26%), aggressive blood pressure management (15%), elevated prothrombin time (PT) or partial thromboplastin time (PTT) (6.6%), minor or resolving deficits (4.2%), unclear time of onset (3.9%), and stroke within 3 months (3%). There were no significant differences in any of the safety outcomes or discharge disposition between patients with or without protocol violations. Controlling for age, National Institutes of Health Stroke Scale on admission, and glucose on admission, there was no significant increase in sICH (odds ratio: 3.8; 95% confidence interval: .37-38.72) in the patients who had protocol violations. Despite more than one third of patients receiving thrombolysis with protocol violations, overall rates of hemorrhage remained low and did not differ from those who did not have violations. Our data support the need to expand access to thrombolysis in AIS patients.


Fast multiphase MR imaging of aqueductal CSF flow: 2. Study in patients with hydrocephalus.
The signal intensity in the region corresponding to the cerebral aqueduct was evaluated in three patients with noncommunicating tension hydrocephalus (caused by aqueductal obstruction in two and type I Arnold-Chiari malformation in the other), seven patients with suspected normal-pressure hydrocephalus (three of whom subsequently underwent successful shunting), and 10 patients with ex vacuo (atrophic) hydrocephalus. A gradient-echo MR sequence, called fast multiphase imaging, was used. Serial images corresponding to different phases of the cardiac cycle were acquired. No flow-related enhancement was observed over the entire cardiac cycle in the patients with noncommunicating hydrocephalus. Patients with normal-pressure hydrocephalus showed a higher aqueductal CSF signal intensity, consistent with increased systolic flow rates, than patients with ex vacuo hydrocephalus. When comparing the above two groups of patients with a control group of healthy volunteers, significantly higher and lower values of the (mean) maximum aqueductal signal intensity were found in the normal-pressure hydrocephalus patients and the ex vacuo hydrocephalus patients, respectively. Fast multiphase MR evaluation of aqueductal CSF flow may help to differentiate patients with different types of hydrocephalus.


Cost disparities in lung cancer treatment by disability status, sex, and race.
The recent literature contains numerous reports of disparities in the diagnosis, treatment, and outcomes of lung cancer across a growing list of population subgroups, including disability status. A common assumption is that disparities stem mainly from variations in the level and type of treatment resources available to specific subgroups. Few studies, however, have directly measured resource differentials. Since policy makers identify reducing health disparities as a critical priority, this study examined whether cumulative Medicare costs (resource consumption) for lung cancer treatment differ across eight patient subgroups defined by disability status, sex, and race. Treatment disparities across the eight subgroups will be reflected in variations in the cumulative cost profiles of those subgroups, controlling for other plausible cost drivers. Failure to detect statistically significant differentials in these cost profiles implies that treatment disparities stem from factors other than access to, and utilization of, health care services. Linked SEER-Medicare data were used to construct cost profiles by service type and treatment phase for roughly 80,000 incident lung cancer cases in patients aged 45 to 85 years at diagnosis. Multiple regression models then tested for cost differentials across the eight subgroups, controlling for various patient and disease characteristics. Significant cost differentials were detected, some unanticipated. Women tended to have higher treatment costs than men; they also had more favorable survivals. Nonwhites also tended to have higher treatment costs than whites, although they had significantly shorter survivals. On average, men with disabilities consumed the fewest treatment resources and had the shortest survivals. Mixed results were obtained for women with disabilities. Among others, the findings suggest that reducing disparities will take more than just improving access to health care. Special attention must be paid to lung cancer patients with disabilities by both policy makers and clinicians.


Hydralazine-induced anti-neutrophil cytoplasmic antibody-positive renal vasculitis presenting with a vasculitic syndrome, acute nephritis and a puzzling skin rash: a case report.
Anti-neutrophil cytoplasmic antibody-associated vasculitis has been associated with many drugs and it is a relatively rare side effect of the antihypertensive drug hydralazine. The diagnosis and management of patients who have anti-neutrophil cytoplasmic antibody-associated vasculitis may be challenging because of its relative infrequency, variability of clinical expression and changing nomenclature. The spectrum of anti-neutrophil cytoplasmic antibody-associated vasculitis is wide and can be fatal. This case documents a 62-year-old woman who presented with hydralazine-induced anti-neutrophil cytoplasmic antibody-positive renal vasculitis with a puzzling cutaneous rash. We report a rare case of hydralazine-induced anti-neutrophil cytoplasmic antibody-associated vasculitis in a 62-year-old Caucasian woman who presented with a vasculitic syndrome with a sore throat, mouth ulcers and otalgia after several months of constitutional symptoms. She then proceeded to develop a rash over her right lower limb. Clinically, the rash had features to suggest Sweet's syndrome, but also had some appearances consistent with embolic phenomena and did not have the appearance of palpable purpure usually associated with cutaneous vasculitis. Differential diagnoses were hydralazine-associated Sweet's syndrome, streptococcal-induced cutaneous eruption or an unrelated contact dermatitis. A midstream urine sample detected glomerular blood cells in the setting of anti-neutrophil cytoplasmic antibody-positive renal vasculitis and Streptococcus pyogenes bacteremia. A renal biopsy revealed a pauci-immune, focally necrotizing glomerulonephritis with small crescents. Her skin biopsy revealed a heavy neutrophil infiltrate involving the full thickness of the dermis with no evidence of a leucocytoclastic vasculitis, but was non-specific. She was initially commenced on intravenous lincomycin for her bloodstream infection and subsequently commenced on immunosuppression after cessation of hydralazine. The patient was subsequently discharged from hospital after a rapid clinical improvement. Hydralazine-induced anti-neutrophil cytoplasmic antibody-positive renal vasculitis is a rare adverse effect and can present with a severe vasculitic syndrome with multiple organ involvement. Features of this association include the presence of high titres of anti-myeloperoxidase-anti-neutrophil cytoplasmic antibody with multi-antigenicity, positive anti-histone antibodies and the lack of immunoglobulin and complement deposition histopathogically. A rash that is characteristic of Sweet's syndrome has also been described as an association. Prompt cessation of hydralazine may be sufficient to reverse disease activity but immunosuppression may be needed for definite treatment.


Pupillometric evaluation of the dynamics of the pupillary response to a brief light stimulus in healthy subjects.
To investigate the correlation between measurements of amplitude (A) and peak velocity (V) of constriction in the pupil light reflex of normal subjects, and to determine the effects of stimulus intensity, pupil size, and age on this relationship. The pupil response to a variable intensity 1.0 second light stimulus presented under open-loop conditions (Maxwellian optics) was measured using infrared video techniques in 43 healthy subjects aged 20 to 75 years old. In response to the "standard-intensity" light stimulus, mean measurements of A and V were 1.92 mm (SD 0.39) and 5.65 mm/s (SD 1.17), respectively. Over a 4.0 log unit range of stimulus intensities measurements of A and V were seen to co-vary with the data being best fit by the equation V=0.86+2.65A (linear regression coefficient, R = 0.919, P < 0.001). In each subject the regression plot was used to normalize the velocity estimates for A = 1.0 mm; these normalized velocity estimates showed no significant correlation with the starting size of the pupil or the age of the subject. There is a strong linear correlation between amplitude and peak velocity of constriction for the pupil light reflex in normal subjects. This relationship is unaffected by the stimulus intensity, size of the pupil, or age of the subject. Clinicians and researchers must keep this interdependence in mind when drawing inferences from the observed (or measured) speed of the pupillary constriction to light.


Adsorption of methylene blue and methyl red dyes from aqueous solutions onto modified zeolites.
Zeolite, hematite, modified zeolite and commercial activated charcoal were examined for their ability to remove methylene blue (MB) and methyl red (MR) from their aqueous solutions. Modified zeolite and hematite were produced according to the Schwertmann and Cornell method while zeolite and commercial activated charcoal were obtained from S&B and Fluka AG companies, respectively. Adsorption experiments were conducted at three different adsorbent-to-solution ratios, namely 8, 16 and 24 g/L under environmental conditions and continuous stirring. Equilibrium isotherms of MB and MR were studied at different initial concentrations (from 5 × 10(-4) to 5 × 10(-3) g/L). MB adsorption kinetics were also studied. The maximum adsorption of MB and MR from their aqueous solutions was achieved at 24 g/L (adsorbent-to-dye solution ratio) after 1 h and was equal to 100% (MB) on modified zeolite and 99% (MR) on commercial activated charcoal, respectively. All the other materials achieved intermediate values of dye adsorption. From the applied kinetic models, the pseudo-second-order equation best described the adsorption of MB and MR. Consequently, modified zeolite showed the highest adsorption capacity for MB, while commercial activated charcoal showed the highest adsorption capacity of MR. The studied adsorbents can be used as filters to remove dyes from wastewaters.


Differential enrichment of TTF-I and Tip5 in the T-like promoter structures of the rDNA contribute to the epigenetic response of Cyprinus carpio during environmental adaptation.
To ensure homeostasis, ectothermic organisms adapt to environmental variations through molecular mechanisms. We previously reported that during the seasonal acclimatization of the common carp Cyprinus carpio, molecular and cellular functions are reprogrammed, resulting in distinctive traits. Importantly, the carp undergoes a drastic rearrangement of nucleolar components during adaptation. This ultrastructural feature reflects a fine modulation of rRNA gene transcription. Specifically, we identified the involvement of the transcription termination factor I (TTF-I) and Tip-5 (member of nucleolar remodeling complex, NoRC) in the control of rRNA transcription. Our results suggest that differential Tip5 enrichment is essential for silencing carp ribosomal genes and that the T0 element is key for regulating the ribosomal gene during the acclimatization process. Interestingly, the expression and content of Tip5 were significantly higher in winter than in summer. Since carp ribosomal gene expression is lower in the winter than in summer, and considering that expression concomitantly occurs with nucleolar ultrastructural changes of the acclimatization process, these results indicate that Tip5 importantly contributes to silencing the ribosomal genes. In conclusion, the current study provides novel evidence on the contributions of TTF-I and NoRC in the environmental reprogramming of ribosomal genes during the seasonal adaptation process in carp.


Silver halide colloid precursors for the synthesis of monolayer-protected clusters.
A new method for the synthesis of monolayer-protected silver clusters (MPCs) based on the two-phase reduction of a stable negatively charged silver bromide sol is described. Phase transfer of the colloid to toluene is accomplished using tetra-n-octylammonium bromide as the phase transfer reagent. The advantage of this synthesis is to uncouple the formation of the silver halide colloid from its transfer and reduction in the organic phase, thus allowing control over each reaction step. The silver colloid in toluene was reduced with aqueous borohydride in the presence of 4-bromobenzenethiol as the passivating agent. The UV-visible absorption spectra indicate the intermediate formation of Ag(core)AgBr(shell) clusters during reduction. The resulting MPCs have been characterized by optical and transmission electron microscopy, energy-dispersive X-ray analysis, thermogravimetry, and UV-vis absorption spectroscopy. The formation of spiral cracks in the nanoparticulate agglomerates on solvent evaporation was observed. The spectra of thin films obtained by solvent evaporation have been analyzed using an effective medium theory.


Morphological Control of Anisotropic Self-Assemblies from Alternating Poly(p-dioxanone)-poly(ethylene glycol) Multiblock Copolymer Depending on the Combination Effect of Crystallization and Micellization.
A novel and facile method was developed for morphological controlling of self-assemblies prepared by crystallization induced self-assembly of crystalline-coil copolymer depending on the combination effect of crystallization and micellization. The morphological evolution of the self-assemblies of alternating poly(p-dioxanone)-block-poly(ethylene glycol) (PPDO-PEG) multiblock copolymer prepared by different solvent mixing methods in aqueous solution were investigated. "Chrysanthemum"-like and "star anise"-like self-assemblies were obtained at different rates of solvent mixing. The results suggested gradually change in solvent quality (slowly dropping water into DMF solution) leaded to a hierarchical micellization-crystallization process of core-forming PPDO blocks, and flake-like particles were formed at the initial stage of crystallization. Meanwhile, crystallization induced micellization process occurred when solvent quality changed drastically. Shuttle-like particles, which have much smaller size than those of flake-like particles, were formed at the initial stage of crystallization when quickly injecting water into DMF solution of the copolymer. Therefore, owing to the different changing rate of solvent quality, which may result in different combination effect of crystallization and micellization during self-assembly of the copolymer, PPDO-PEG self-assemblies with different hierarchical morphology in nano scale could be obtained.


Recurrent phosphaturic mesenchymal tumour of the temporal bone causing deafness and facial nerve palsy.
We describe the first reported case of a phosphaturic mesenchymal tumour, mixed connective tissue variant, invading the temporal bone. A female patient presented with increasing deafness. On examination there appeared to be a mass behind an intact tympanic membrane. Further radiological investigation showed a vascular mass occupying the middle ear, mastoid and internal auditory meatus. This was surgically resected and revealed to be a benign phosphaturic mesenchymal tumour, mixed connective tissue variant. The tumour recurred a year later, presenting as facial nerve palsy. A revision procedure was carried out; the tumour was excised with the sacrifice of a segment of the facial nerve, and a facial-hypoglossal nerve anastomosis was performed. This case report highlights the occurrence of this benign but sometimes aggressive tumour, of which both clinicians and pathologists should be aware. Early recognition of the condition remains of utmost importance to minimise the debilitating consequences of long-term osteomalacia in affected patients, and to prevent extracranial and intracranial complications caused by the tumour.


Implementation of high resolution 43Ca solid state NMR spectroscopy: toward the elucidation of calcium sites in biological materials.
Calcium is one of the most abundant cations in living organisms. It is found in the mineral phase of bone and in proteins like calmodulin. However, its exact environment beyond the first coordination sphere is often unknown, thus hampering the understanding of many biological processes. Here, calcium benzoate trihydrate (Ca(C(6)H(5)COO)(2) x 3 H(2)O) was used as a model for the NMR analysis of calcium sites in biological materials, because of the similarity of its calcium coordination, to water and carboxylate ligands, to that in several calcium-proteins. First, calcium-43 magic angle spinning (MAS) and static NMR spectra of a (43)Ca enriched sample were recorded at different magnetic fields, to investigate the electronic environment of calcium. Complex static lineshapes were obtained because of the presence of anisotropic NMR interactions of similar magnitude (chemical shift anisotropy and quadrupolar interaction), and the full interpretation of the spectra required simulations and gauge-including projector augmented wave (GIPAW) DFT calculations. An NMR investigation of the coordination environment of Ca(2+) was carried out, using high resolution (13)C-(43)Ca MAS NMR experiments such as TRAPDOR (transfer of population double resonance) and heteronuclear J-spin-echoes. It was shown that despite the weakness of (13)C-(43)Ca interactions, it is possible to discriminate carbon atoms according to their calcium environment. Long-range calcium-carbon correlations were even evidenced by TRAPDOR, reaching distances >5.6 A. This work demonstrates that by combining solid state NMR experiments, DFT calculations, and simulations, it will be possible to elucidate the electronic and coordination environment of calcium in many important and complex materials.


Evaluation of cardiac functions of patients with benign joint hypermobility syndrome.
We sought to investigate whether echocardiography with tissue Doppler imaging identifies myocardial dysfunction in children with benign joint hypermobility syndrome (BJHS). This cross-sectional study enrolled 75 children with BJHS and 70 healthy children. We performed detailed echocardiography in individuals with BJHS without inherited connective tissue disorders. Any congenital or acquired cardiac disease was excluded by clinical and echocardiographic examination. Both groups were similar in terms of age, sex, and body mass index. The diameter of the aortic annulus and sinus valsalva were wider in patients with BJHS. There was no significant differences in ejection fraction or mitral and tricuspid annular plane systolic excursion between the two groups. Pulsed-wave Doppler-derived E/A ratios in mitral and tricuspid valves were similar in both groups. Deceleration time of early mitral inflow was prolonged in patients with BJHS. Mitral and tricuspid annulus Ea velocity were significantly lower in children with BJHS. Ea, Aa, and Ea/Aa ratios in the interventricular septum, left ventricle posterior wall, and right ventricle free wall were lower in patients with BJHS than in the control group. The E/Ea ratio was greater in patients with BJHS than in the control group. Isovolumic relaxation time and right-ventricular (RV) and left-ventricular (LV) myocardial performance indices (MPIs) were greater in patients with BJHS. This study showed the diastolic dysfunction in patients with BJHS. In addition, we detected increased LV and RV MPI. We believe that BJHS may affect proteins of the myocardial cytoskeleton and extracellular matrix.


Mycophenolate mofetil in refractory inflammatory bowel disease.
Mycophenolate mofetil has been claimed to be effective and well tolerated in refractory inflammatory bowel disease although there is little information regarding its use in clinical practice. To review our experience in achieving and maintaining remission in refractory inflammatory bowel disease and to document tolerability, major toxicity and efficacy. A retrospective audit was performed of the records of all patients with inflammatory bowel disease treated with mycophenolate mofetil (1-2 g/day) over a 3-year period. Thirty-nine patients were identified. Almost all had been intolerant of, or had not responded to azathioprine, and 38 were steroid-dependent. mycophenolate mofetil was discontinued in 22 patients, 11 due to intolerance and 10 because of lack of efficacy. Of the 17 on treatment at the end of the study period 16 were in remission and off all steroid therapy, but one needed infliximab to maintain remission. No major toxicity was noted and there was no major sepsis. Approximately 40% of patients with severe refractory inflammatory bowel disease achieved remission and complete steroid withdrawal on mycophenolate mofetil therapy, almost 30% could not tolerate the drug, and a further 30% did not respond. Mycophenolate mofetil therapy may have a role for steroid-dependent patients refractory to azathioprine.


Predictive factors for the development of central line-associated bloodstream infection due to gram-negative bacteria in intensive care unit patients after surgery.
To examine the relative proportions of central line-associated bloodstream infection (BSI) due to gram-negative bacteria and due to gram-positive bacteria among patients who had undergone surgery and patients who had not. The study also evaluated clinical predictive factors and unadjusted outcomes associated with central line-associated BSI caused by gram-negative bacteria in the postoperative period. Observational, case-control study based on a retrospective review of medical records. University of Chicago Medical Center, a 500-bed tertiary care center located on Chicago's south side. Adult intensive care unit (ICU) patients who developed central line-associated BSI. There were a total of 142 adult patients who met the Centers for Disease Control and Prevention National Nosocomial Infection Surveillance System definition for central line-associated BSI. Of those, 66 patients (46.5%) had infections due to gram-positive bacteria, 49 patients (34.5%) had infections due to gram-negative bacteria, 23 patients (16.2%) had infections due to yeast, and 4 patients (2.8%) had mixed infections. Patients who underwent surgery were more likely to develop central line-associated BSI due to gram-negative bacteria within 28 days of the surgery, compared with patients who had not had surgery recently (57.6% vs 27.3%; P= .002). On multivariable logistic regression analysis, diabetes mellitus (adjusted odds ratio [OR], 4.6 [95% CI, 1.2-18.1]; P= .03) and the presence of hypotension at the time of the first blood culture positive for a pathogen (adjusted OR, 9.8 [95% CI, 2.5-39.1]; P= .001) were found to be independently predictive of central line-associated BSI caused by gram-negative bacteria. Unadjusted outcomes were not different in the group with BSI due to gram-negative pathogens, compared to the group with BSI due to gram-positive pathogens. Clinicians caring for critically ill patients after surgery should be especially concerned about the possibility of central line-associated BSI caused by gram-negative pathogens. The presence of diabetes and hypotension appear to be significant associated factors.


Structures of E. coli σS-transcription initiation complexes provide new insights into polymerase mechanism.
In bacteria, multiple σ factors compete to associate with the RNA polymerase (RNAP) core enzyme to form a holoenzyme that is required for promoter recognition. During transcription initiation RNAP remains associated with the upstream promoter DNA via sequence-specific interactions between the σ factor and the promoter DNA while moving downstream for RNA synthesis. As RNA polymerase repetitively adds nucleotides to the 3'-end of the RNA, a pyrophosphate ion is generated after each nucleotide incorporation. It is currently unknown how the release of pyrophosphate affects transcription. Here we report the crystal structures of E coli transcription initiation complexes (TICs) containing the stress-responsive σ(S) factor, a de novo synthesized RNA oligonucleotide, and a complete transcription bubble (σ(S)-TIC) at about 3.9-Å resolution. The structures show the 3D topology of the σ(S) factor and how it recognizes the promoter DNA, including likely specific interactions with the template-strand residues of the -10 element. In addition, σ(S)-TIC structures display a highly stressed pretranslocated initiation complex that traps a pyrophosphate at the active site that remains closed. The position of the pyrophosphate and the unusual phosphodiester linkage between the two terminal RNA residues suggest an unfinished nucleotide-addition reaction that is likely at equilibrium between nucleotide addition and pyrophosphorolysis. Although these σ(S)-TIC crystals are enzymatically active, they are slow in nucleotide addition, as suggested by an NTP soaking experiment. Pyrophosphate release completes the nucleotide addition reaction and is associated with extensive conformational changes around the secondary channel but causes neither active site opening nor transcript translocation.


Strong-LAMP Assay Based on a Strongyloides spp.-Derived Partial Sequence in the 18S rRNA as Potential Biomarker for Strongyloidiasis Diagnosis in Human Urine Samples.
Human strongyloidiasis a soil-transmitted infection caused by Strongyloides stercoralis is one of the most neglected amongst the so-called Neglected Tropical Diseases (NTDs). S. stercoralis is a nematode, which is distributed worldwide; it has been estimated that it could affect millions of people, mainly in tropical and subtropical endemic regions. The difficulties of diagnosis lead to infection rates being underreported. Asymptomatic patients have chronic infections that can lead to severe hyperinfection syndrome or disseminated strongyloidiasis in immunocompromised patients. Strongyloidiasis can easily be misdiagnosed because conventional faecal-based techniques lack of sensitivity for the morphological identification of infective larvae in faeces. None of the currently used molecular methods have used urine samples as an alternative to faecal samples for diagnosing strongyloidiasis. This study was thus aimed at comparing, for the first time, the use of a new loop-mediated isothermal amplification (LAMP) molecular assay (Strong-LAMP) to traditional methods on patients' urine samples. Twenty-four urine samples were taken from patients included in a study involving two Spanish hospitals for strongyloidiasis screening using parasitological and serological tests. Strongyloides larvae were found in 11 patients' faecal samples, thereby ascertaining that they had the disease. Other patients had high antibody titres but no larvae were found in their faeces. All urine samples were analysed by PCR and Strong-LAMP assay. No amplification occurred when using PCR. Strong-LAMP led to detecting S. stercoralis DNA in urine samples from patients having previously confirmed strongyloidiasis by parasitological tests and/or a suspicion of being infected by serological ones. The Strong-LAMP assay is a useful molecular tool for research regarding strongyloidiasis in human urine samples. After further validation, the Strong-LAMP assay could also be used for complementary and effective diagnosis of strongyloidiasis in a clinical setting.


Advances in the development of retinoids as chemopreventive agents.
With the inclusion of brief discussions of retinoid drug development in animal carcinogenesis models (e.g., skin, breast, oral cavity, lung, prostate or bladder) and clinical trials (e.g., head and neck or cervix), this review will focus on recent advances in retinoid molecular targeting studies designed primarily to develop retinoids with reduced toxicity, while maintaining or enhancing activity in the context of chemoprevention. Major current retinoid molecular targets include the six known nuclear retinoid receptors (RAR and RXR). Receptor numbers, distinct functions, tissue-expression patterns, ligand specificities, functional redundancy and regulation of multiple pathways make retinoid signaling highly complex. Development of receptor-selective synthetic retinoids is a major focus of molecular retinoid development. RAR heterodimerize with RXR and mediate classic retinoid activity/toxicity. RXR are more promiscuous, heterodimerizing with several other members of the steroid receptor superfamily [e.g., peroxisome proliferator-activated receptors (PPAR) or vitamin D receptors]. RXR-selective ligands are less toxic and more active in animal breast cancer prevention studies and less toxic than RAR ligands in clinical trials. Other new avenues of retinoid molecular drug development include newly identified retinoid-regulated genes, orphan-receptor ligands/functions, novel retinoid mechanisms involving potent receptor-independent apoptosis-inducing activity (e.g., 4-HPR or anhydroretinol), synergistic combinations [e.g., RXR agonists plus selective estrogen receptor modulators (SERM)], activity in other diseases and novel delivery systems.


Triangulating Amsterdam's illicit stimulant use trends by wastewater analysis and recreational drug use monitoring.
Drug consumption estimates are of relevance because of public health effects as well as associated criminal activities. Wastewater analysis of drug residues enables the estimation of drug consumption and drug markets. Short-term and long-term trends of cocaine, MDMA (ecstasy), amphetamine (speed) and methamphetamine (crystal meth), were studied for the city of Amsterdam. MDMA (+41%) and cocaine (+26%) showed significantly higher weekend vs. week consumption, while no differences were observed for the other drugs. The consumption of MDMA, cocaine, amphetamine and methamphetamine significantly increased between 2011 and 2019. Weekly trends emerging from wastewater analyses were supported by qualitative and quantitative data from a recreational drug use monitoring scheme. However, information collected in panel interviews within nightlife networks and surveys among visitors of pubs, clubs and festivals only partially reflected the long term increase in consumption as registered from wastewater analysis. Furthermore, methamphetamine use was not well presented in survey data, panel studies and test service samples, but could be monitored trough wastewater analysis. This illustrates that wastewater analysis can function as an early warning if use and user groups are small or difficult to reach trough other forms of research. All in all, this study illustrates that wastewater-based epidemiology is complementary to research among user groups, and vice versa. These different types of information enable to connect observed trends in total drug consumption to behaviour of users and the social context in which the use takes place as well as validate qualitative signals about (increased) consumption of psychoactive substances. Such a multi angular approach to map the illicit drug situation on local or regional scale can provide valuable information for public health.


Kappa-bungarotoxin blocks nicotinic transmission at an identified invertebrate central synapse.
A comparison was made between the effects of kappa-bungarotoxin and alpha-bungarotoxin upon nicotinic cholinergic transmission at an identified synapse (the cereal afferent, giant interneurone 2 synapse) in the central nervous system of the cockroach (Periplaneta americana). kappa-Bungarotoxin, a snake venom kappa-neurotoxin, completely blocked nicotinic unitary excitatory postsynaptic potentials (EPSPs) and evoked composite EPSPs when applied at a concentration of 1.0 x 10(-7) moll-1. No recovery was observed after a 2h wash in normal saline. kappa-Bungarotoxin produced a decrease in acetylcholine-induced nicotinic responses which paralleled decreases in nicotinic synaptic potentials and currents, indicating that kappa-bungarotoxin blocked postsynaptic nicotinic receptors. This blockade appeared to be specific as resting membrane potential, input resistance and the ability to elicit an action potential in response to direct stimulation of giant interneurone 2 were unchanged following prolonged toxin exposures. Samples of alpha-bungarotoxin which were free from kappa-neurotoxin contamination were also found to be potent antagonists of cockroach neuronal nicotinic receptors. It is concluded that the cockroach receptor is the first reported example of a neuronal nicotinic receptor which is sensitive to blockade by both kappa-neurotoxins and alpha-neurotoxins.


Isolated hepatic perfusion for the treatment of patients with colorectal cancer liver metastases after irinotecan-based therapy.
Irinotecan given with 5-fluorouracil and leucovorin is currently used as first-line therapy for patients with metastatic colorectal cancer (CRC). However, the response duration is <1 year, and second-line systemic chemotherapy has limited efficacy. We analyzed the efficacy of isolated hepatic perfusion (IHP) for patients with progressive CRC liver metastases after irinotecan. Between March 1993 and February 2003, 124 patients with CRC liver metastases underwent IHP on institutional review board-approved protocols. The overall treatment mortality was 4% (5 of 124). Twenty-five patients (10 women and 15 men; mean age, 53 years) were identified who had progressive liver metastases by carcinoembryonic antigen, imaging studies, or both after irinotecan. A 1-hour hyperthermic IHP (mean hepatic temperature, 40.0 degrees C) with melphalan 1.5 mg/kg (mean total dose, 100 mg) was administered via laparotomy. Perfusion with an oxygenated extracorporeal circuit was established with inflow via a cannula in the gastroduodenal artery and common hepatic artery inflow occlusion. Outflow was via a cannula in an isolated segment of the inferior vena cava. During IHP, portal and inferior vena caval flow were shunted to the axillary vein. Patients were assessed for radiographical response, recurrence pattern, and survival. The mean number of prior irinotecan cycles in 25 patients was 6 (range, 2-14), and it was given primarily as second-line therapy. The median number of liver metastases before IHP was 10 (range, 1-50), and the median percentage of hepatic replacement by tumor was 25%. The mean operative time was 9 hours (range, 6-12 hours), and the median hospital stay was 11 days (range, 8-76 days). There was 1 complete response and there were 14 partial responses in 25 patients (60%), with a median duration of 12 months (range, 5-35 months). Disease progressed systemically in 13 of 25 patients at a median of 5 months (range, 3-16 months). The median overall survival was 12 months (range, 1-47 months), and the 2-year survival was 28%. For patients with progressive CRC liver metastases after irinotecan, IHP has good efficacy in terms of response rate and duration. Continued evaluation of IHP with melphalan as second-line therapy in this clinical setting is justified.


Sources of health insurance and characteristics of the uninsured: analysis of the March 2001 Current Population Survey.
This Issue Brief provides summary data on the insured and uninsured populations in the nation and in each state. It discusses the characteristics most closely related to an individual's health insurance status. Based on EBRI estimates from the March 2001 Current Population Survey (CPS), it represents 2000 data--the most recent available. Between 1999 and 2000, the percentage of Americans with health insurance increased: 84.1 percent of nonelderly Americans were covered by some form of health insurance in 2000, up from 83.8 percent in 1999. The percentage of nonelderly Americans without health insurance coverage declined from 16.2 percent in 1999 to 15.9 percent in 2000, continuing a trend that started between 1998 and 1999. The main reason for the decline in the number of uninsured Americans was the strong economy and low unemployment. Between 1999 and 2000, the percentage of nonelderly Americans covered by employment-based health insurance increased from 66.6 percent to 67.3 percent, continuing a longer-term trend that started between 1993 and 1994. In 2000, 34.3 million Americans received health insurance from public programs, and an additional 16.1 million purchased it directly from an insurer. More than 25 million Americans participated in Medicaid or the State Children's Health Insurance Program, and 6.1 million received their health insurance through the Tricare and CHAMPVA programs and other government programs designed to provide coverage for retired military members and their families. Even though the number and percentage of uninsured declined substantially between 1998 and 2000, more than 38 million Americans remain uninsured. While an increasing percentage of Americans were being covered by employment-based health plans, this trend may not continue because of the combined re-emergence of health care cost inflation and the weak economy. As long as the economy is strong and unemployment is low, employment-based health insurance coverage will expand and the uninsured will decline gradually. However, the combination of the current weak economy and the rising cost of providing health benefits will likely result in more Americans without health insurance coverage. Should the uninsured remain unchanged and continue to represent 15.9 percent of the nonelderly population, 40 million would be uninsured by 2005. If the uninsured represented 25 percent of the population, 63 million would be uninsured in 2005 and 65 million nonelderly Americans would be uninsured by 2010.


Adherence to High-Intensity Statins Following a Myocardial Infarction Hospitalization Among Medicare Beneficiaries.
High-intensity statins are recommended following myocardial infarction. However, patients may not continue taking this medication with high adherence. To estimate the proportion of patients filling high-intensity statin prescriptions following myocardial infarction who continue taking this medication with high adherence and to analyze factors associated with continuing a high-intensity statin with high adherence after myocardial infarction. Retrospective cohort study of Medicare patients following hospitalization for myocardial infarction. Medicare beneficiaries aged 66 to 75 years (n = 29 932) and older than 75 years (n = 27 956) hospitalized for myocardial infarction between 2007 and 2012 who filled a high-intensity statin prescription (atorvastatin, 40-80 mg, and rosuvastatin, 20-40 mg) within 30 days of discharge. Beneficiaries had Medicare fee-for-service coverage including pharmacy benefits. Sociodemographic, dual Medicare/Medicaid coverage, comorbidities, not filling high-intensity statin prescriptions before their myocardial infarction (ie, new users), and cardiac rehabilitation and outpatient cardiologist visits after discharge. High adherence to high-intensity statins at 6 months and 2 years after discharge was defined by a proportion of days covered of at least 80%, down-titration was defined by switching to a low/moderate-intensity statin with a proportion of days covered of at least 80%, and low adherence was defined by a proportion of days covered less than 80% for any statin intensity without discontinuation. Discontinuation was defined by not having a statin available to take in the last 60 days of each follow-up period. Approximately half of the beneficiaries were women and fourth-fifths were white. At 6 months and 2 years after discharge among beneficiaries 66 to 75 years of age, 17 633 (58.9%) and 10 308 (41.6%) were taking high-intensity statins with high adherence, 2605 (8.7%) and 3315 (13.4%) down-titrated, 5182 (17.3%) and 4727 (19.1%) had low adherence, and 3705 (12.4%) and 4648 (18.8%) discontinued their statin, respectively. The proportion taking high-intensity statins with high adherence increased between 2007 and 2012. African American patients, Hispanic patients, and new high-intensity statin users were less likely to take high-intensity statins with high adherence, and those with dual Medicare/Medicaid coverage and more cardiologist visits after discharge and who participated in cardiac rehabilitation were more likely to take high-intensity statins with high adherence. Results were similar among beneficiaries older than 75 years of age. Many patients filling high-intensity statins following a myocardial infarction do not continue taking this medication with high adherence for 2 years postdischarge. Interventions are needed to increase high-intensity statin use and adherence after myocardial infarction.


Efficiency of hydrogen photoproduction by chloroplast-bacterial hydrogenase systems.
A comparative study of H(2) photoproduction by chloroplasts and solubilized chlorophyll was performed in the presence of hydrogenase preparations of Clostridium butyricum. The photoproduction of H(2) by chloroplasts in the absence of exogenous electron donors, and with irreversibly oxidized dithiothreitol and cysteine, is thought to be limited by a cyclic transport of electrons wherein methylviologen short-circuits the electron transport in photosystem I. The efficiency of H(2) photoproduction by chloroplasts with ascorbate and NADPH is limited by a back reaction between light-reduced methylviologen and the oxidized electron donors. The use of a combination of electron donors (dithiothreitol and ascorbate), providing anaerobiosis without damage to chloroplasts, makes it possible to avoid consumption of reduced methylviologen for the reduction of oxidized electron donors and to exclude the short-circuiting of electron transfer. Under these conditions, photoproduction of H(2) was observed to occur with a rate of 350 to 400 micromoles H(2) per milligram chlorophyll per hour. In this case, the full electron-transferring capability of photosystem I (measured by irreversible photoreduction of methyl red or O(2)) is used to produce H(2).


The cost of illness for childhood clinical pneumonia and invasive pneumococcal disease in Nigeria.
Pneumococcal disease contributes significantly to childhood morbidity and mortality and treatment is costly. Nigeria recently introduced the pneumococcal conjugate vaccine (PCV) to prevent pneumococcal disease. The aim of this study is to estimate health provider and household costs for the treatment of pneumococcal disease in children aged <5 years (U5s), and to assess the impact of these costs on household income. We recruited U5s with clinical pneumonia, pneumococcal meningitis or pneumococcal septicaemia from a tertiary level hospital and a secondary level hospital in Kano, Nigeria. We obtained resource utilisation data from medical records to estimate costs of treatment to provider, and household expenses and income loss data from caregiver interviews to estimate costs of treatment to households. We defined catastrophic health expenditure (CHE) as household costs exceeding 25% of monthly household income and estimated the proportion of households that experienced it. We compared CHE across tertiles of household income (from the poorest to least poor). Of 480 participants recruited, 244 had outpatient pneumonia, and 236 were hospitalised with pneumonia (117), septicaemia (66) and meningitis (53). Median (IQR) provider costs were US$17 (US$14-22) for outpatients and US$272 (US$271-360) for inpatients. Median household cost was US$51 (US$40-69). Overall, 33% of households experienced CHE, while 53% and 4% of the poorest and least poor households, experienced CHE, respectively. The odds of CHE increased with admission at the secondary hospital, a diagnosis of meningitis or septicaemia, higher provider costs and caregiver having a non-salaried job. Provider costs are substantial, and households incur treatment expenses that considerably impact on their income and this is particularly so for the poorest households. Sustaining the PCV programme and ensuring high and equitable coverage to lower disease burden will reduce the economic burden of pneumococcal disease to the healthcare provider and households.


Recruiting and retaining low-income, multi-ethnic women into randomized controlled trials: successful strategies and staffing.
Developing effective recruitment and retention strategies in populations with traditionally high attrition rates is critical to the success of Randomized Controlled Trials (RCTs). Data on successful participation of women from low-income, minority populations in RCTs of behavioral interventions are limited. This is problematic given the multiplicity of Healthy People 2020 goals that target health disparities in these populations. This paper reports successful recruitment and retention methods from two separately funded NIH clinical trials of primary care-based prenatal interventions to increase breastfeeding among ethnically diverse, low-income women in urban medical centers in the Bronx, NY. It also presents the required staff effort necessary to conduct such a successful RCT, in terms of full-time equivalents (FTEs). Results include timely recruitment of 941 participants over 29 months, with 98.1% completing >¯¯1 follow-up interview. A recruitment and retention plan that maximized study staff access and availability to the participant, as well as strong study staff rapport with participants, addressed previously reported barriers in this population, optimizing follow-up rates. A qualitative assessment of the participants' study experience suggesting that high retention was due to strong rapport with participants, short interviews requiring little time commitment, and participants' perception of the study as informative, provides further evidence of our approach's effectiveness. Logistical protocol procedures and staff management strategies relating to successful recruitment/retention are provided to propose a practical, cost-effective and translational recruitment-retention plan for other researchers to adopt.


Towards an international pediatric liver tumor consensus classification: proceedings of the Los Angeles COG liver tumors symposium.
Liver tumors are rare in children, and their diagnoses may be challenging particularly because of the lack of a current consensus classification system. Systematic central histopathological review of these tumors performed as part of the pediatric collaborative therapeutic protocols has allowed the identification of histologic subtypes with distinct clinical associations. As a result, histopathology has been incorporated within the Children's Oncology Group (COG) protocols, and only in the United States, as a risk-stratification parameter and for patient management. Therefore, the COG Liver Tumor Committee sponsored an International Pathology Symposium in March 2011 to discuss the histopathology and classification of pediatric liver tumors, and hepatoblastoma in particular, and work towards an International Pediatric Liver Tumors Consensus Classification that would be required for international collaborative projects. Twenty-two pathologists and experts in pediatric liver tumors, including those serving as central reviewers for the COG, European Société Internationale d'Oncologie Pédiatrique, Gesellschaft für Pädiatrische Onkologie und Hämatologie, and Japanese Study Group for Pediatric Liver Tumors protocols, as well as pediatric oncologists and surgeons specialized in this field, reviewed more than 50 pediatric liver tumor cases and discussed classic and newly reported entities, as well as criteria for their classification. This symposium represented the first collaborative step to develop a classification that may lead to a common treatment-stratification system incorporating tumor histopathology. A standardized, clinically meaningful classification will also be necessary to allow the integration of new biological parameters and to move towards clinical algorithms based on patient characteristics and tumor genetics, which should improve future patient management and outcome.


Long-term regulation of arterial pressure, glomerular filtration and renal sodium reabsorption by angiotensin II in dogs.
1. This study was designed to quantify the role of angiotensin II in determining the chronic relationships between arterial pressure, renal haemodynamics and sodium excretion. 2. In six control dogs sodium balance was achieved during chronic increases in sodium intake from 5 to 495 mmol/day with small increases in arterial pressure (7mmHg), moderate increases in glomerular filtration rate (19%) and decreases in filtration fraction. Similar increases in sodium intake in dogs whose circulating levels of angiotensin II were fixed, due to a constant intravenous infusion of 4.85 pmol of angiotensin II min-1 kg-1, caused large increases in arterial pressure (42%), glomerular filtration rate (31%), filtration fraction and calculated renal sodium reabsorption above control. In six dogs whose angiotensin II formation was blocked by SQ 14 225, sodium balance at intakes of 5-80 mmol/day occurred at reduced arterial pressure, glomerular filtration rate, filtration fraction and sodium reabsorption although plasma aldosterone concentration was not substantially different from that in control dogs. At sodium intakes above 240 mmoL/day arterial pressure was not altered by SQ 14 225. 3. These data indicate that during chronic variations in sodium intake angiotensin II plays a major role, independently of changes in plasma aldosterone concentration, in allowing sodium balance without large fluctuations in glomerular filtration rate or arterial pressure. The mechanism whereby angiotensin II conserves sodium chronically is through increased sodium reabsorption, since steady-state sodium reabsorption was increased by angiotensin II and decreased by SQ 14 225.


Funding and Service Delivery in Rural and Urban Local US Health Departments in 2010 and 2016.
Objectives. To investigate differences in funding and service delivery between rural and urban local health departments (LHDs) in the United States.Methods. In this repeated cross-sectional study, we examined rural-urban differences in funding and service provision among LHDs over time using 2010 and 2016 National Association of County and City Health Officials data.Results. Local revenue among urban LHDs (41.2%) was higher than that in large rural (31.3%) and small rural LHDs (31.2%; P < .05). Small (20.9%) and large rural LHDs (19.8%) reported greater reliance on revenue from Center for Medicare and Medicaid Services than urban LHDs (11.5%; P < .05). All experienced decreases in clinical revenue between 2010 and 2016. Urban LHDs provided less primary care services in 2016; rural LHDs provided more mental health and substance abuse services (P < .05).Conclusions. Urban LHDs generated more revenues from local sources, and rural LHDs generated more from the Center for Medicare and Medicaid Services and clinical services. Rural LHDs tended to provide more clinical services. Given rural LHDs' reliance on clinical revenue, decreases in clinical services could have disproportionate effects on them.Public Health Implications. Differences in financing and service delivery by rurality have an impact on the communities. Rural LHDs rely more heavily on state and federal dollars, which are vulnerable to changes in state and national health policy.


Correlation between cell-mediated immunity and degree of infection in subjects living in an endemic area of schistosomiasis.
Cell-mediated immunity to Schistosoma mansoni antigens, unrelated antigens and mitogens was evaluated in 50 subjects with the same degree of exposure to infection living in an endemic area of schistosomiasis. The degree of infection, assessed by the number of eggs/g of stool, was variable in this population (0-5604), suggesting differences in susceptibility to infection. Absence of lymphoproliferative response was observed in 56% of this group, despite having a response to purified protein derivative of tuberculin (PPD) and tetanus toxoid (TT) antigens and to pokeweed mitogen. The 50 subjects were divided into two groups, according to their degree of infection. The lymphoproliferative responses to schistosomula and adult worm antigens in the group with a low degree of infection (< 400 eggs/g of stool) were higher than the ones documented in patients with a high degree of infection (> 400 eggs/g of stool), and these differences were statistically significant (p < 0.001). An inverse correlation between the lymphocyte proliferation in response to S. mansoni antigens and the degree of infection was also observed (p = 0.02), indicating that subjects with a lower degree of infection have a higher lymphoproliferative response to schistosomula and adult worm antigens. No differences in the lymphocyte reactivity to other antigens (PPD and TT) were detected in these groups. An impairment of interferon-gamma in vitro production was observed when the lymphocytes from these subjects were stimulated with S. mansoni adult worm antigen, although they produced gamma interferon in response to phytohemagglutinin.


Salmonella enterica Serovar Typhi conceals the invasion-associated type three secretion system from the innate immune system by gene regulation.
Delivery of microbial products into the mammalian cell cytosol by bacterial secretion systems is a strong stimulus for triggering pro-inflammatory host responses. Here we show that Salmonella enterica serovar Typhi (S. Typhi), the causative agent of typhoid fever, tightly regulates expression of the invasion-associated type III secretion system (T3SS-1) and thus fails to activate these innate immune signaling pathways. The S. Typhi regulatory protein TviA rapidly repressed T3SS-1 expression, thereby preventing RAC1-dependent, RIP2-dependent activation of NF-κB in epithelial cells. Heterologous expression of TviA in S. enterica serovar Typhimurium (S. Typhimurium) suppressed T3SS-1-dependent inflammatory responses generated early after infection in animal models of gastroenteritis. These results suggest that S. Typhi reduces intestinal inflammation by limiting the induction of pathogen-induced processes through regulation of virulence gene expression.


Heavy metals in soil, vegetables and fruits in the endemic upper gastrointestinal cancer region of Turkey.
The environmental exposure to heavy metals is a well-known risk factor for cancer. We investigated levels of seven different heavy metals, (Co, Cd, Pb, Zn, Mn, Ni and Cu) in soil, fruit and vegetable samples of Van region in Eastern Turkey where upper gastrointestinal (GI) cancers are endemic. Heavy metal contents of the samples were determined by flame atomic absorption spectrometer. Four heavy metals (Cd, Pb, Cu and Co) were present in 2- to 50-fold higher concentrations whereas zinc levels were present in 40-fold lower concentrations in soil. The fruit and vegetable samples were found to contain 3.5- to 340-fold higher amounts of the six heavy metals (Co, Cd, Pb, Mn, Ni and Cu) tested. The volcanic soil, fruit and vegetable samples contain potentially carcinogenic heavy metals in such a high levels that these elements could be related to the high prevalence of upper GI cancer rates in Van region.


Computational models of the neural control of breathing.
The ongoing process of breathing underlies the gas exchange essential for mammalian life. Each respiratory cycle ensues from the activity of rhythmic neural circuits in the brainstem, shaped by various modulatory signals, including mechanoreceptor feedback sensitive to lung inflation and chemoreceptor feedback dependent on gas composition in blood and tissues. This paper reviews a variety of computational models designed to reproduce experimental findings related to the neural control of breathing and generate predictions for future experimental testing. The review starts from the description of the core respiratory network in the brainstem, representing the central pattern generator (CPG) responsible for producing rhythmic respiratory activity, and progresses to encompass additional complexities needed to simulate different metabolic challenges, closed-loop feedback control including the lungs, and interactions between the respiratory and autonomic nervous systems. The integrated models considered in this review share a common framework including a distributed CPG core network responsible for generating the baseline three-phase pattern of rhythmic neural activity underlying normal breathing. WIREs Syst Biol Med 2017, 9:e1371. doi: 10.1002/wsbm.1371 For further resources related to this article, please visit the WIREs website.


Dynamics of Skeletal Status under Optimized Management during Subsequent Pregnancy in Three Women with a History of Pregnancy- and Lactation-Associated Osteoporosis Carrying pathogenic Variants in WNT1 and LRP5.
Pregnancy- and lactation-associated osteoporosis (PLO) is a rare but clinically highly relevant condition, characterized by reduced bone mineral density (BMD) and acute onset of severe pain due to symptomatic bone marrow edema of the hip or vertebral and/or insufficiency fractures, among others. Previous reports showed a high frequency of hereditary bone disorders unmasked by PLO, predisposing for more severe forms. To date, no data on the risk for additional fractures during subsequent pregnancy in women with PLO and genetic bone disorder have been available. To address this question, we retrospectively analyzed the clinical, biochemical, and densitometric course of three women with a history of PLO and detected variants in WNT1 or LRP5 and subsequent pregnancies. Calcium homeostasis and bone turnover were optimized by basic treatment, and timely initiation of weaning was recommended. Teriparatide treatment for 12 months under strict contraception was initiated in one woman after the diagnosis of PLO. In none of the women did additional fractures or symptomatic bone marrow edemas occur, and BMD by dual-energy X-ray absorptiometry as bone microarchitecture by high-resolution peripheral quantitative computed tomography remained stable. In conclusion, this report expands the understanding of this rare but severe condition and helps to improve clinical counseling and management. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.


Treatment-related mortality in relapsed childhood acute lymphoblastic leukemia.
Treatment of relapsed childhood acute lymphoblastic leukemia (ALL) is particularly challenging due to the high treatment intensity needed to induce and sustain a second remission. To improve results, it is important to understand how treatment-related toxicity impacts survival. In this retrospective population-based study, we described the causes of death and estimated the risk for treatment-related mortality in patients with first relapse of childhood ALL in the Nordic Society of Paediatric Haematology and Oncology ALL-92 and ALL-2000 trials. Among the 483 patients who received relapse treatment with curative intent, we identified 52 patients (10.8%) who died of treatment-related causes. Twelve of these died before achieving second remission and 40 died in second remission. Infections were the cause of death in 38 patients (73.1%), predominantly bacterial infections during the chemotherapy phases of the relapse treatment. Viral infections were more common following hematopoietic stem cell transplantation (HSCT) in second remission. Independent risk factors for treatment-related mortality were as follows: high-risk stratification at relapse (hazard ratio [HR] 2.2; 95% confidence interval [CI] 1.3-3.9; P < 0.01), unfavorable cytogenetic aberrations (HR 3.4; 95% CI 1.3-9.2; P = 0.01), and HSCT (HR 4.64; 95% CI 2.17-9.92; P < 0.001). In contrast to previous findings, we did not observe any statistically significant sex or age differences. Interestingly, none of the 17 patients with Down syndrome died of treatment-related causes. Fatal treatment complications contribute significantly to the poor overall survival after relapse. Implementation of novel therapies with reduced toxicity and aggressive supportive care management are important to improve survival in relapsed childhood ALL.


Preventive Effects of Vitamin D on Seasonal Influenza A in Infants: A Multicenter, Randomized, Open, Controlled Clinical Trial.
This study aimed to evaluate the clinical efficacy and safety of vitamin D for preventing influenza A in 400 infants in a multicenter, randomized, open, controlled clinical trial. The infants were randomized into low-dose and high-dose vitamin D groups, and serum calcium, inorganic phosphorus and 25-hydroxyvitamin D levels were detected thrice in 4 months. Infants infected with influenza A were monitored for symptoms including fever, cough and wheezing. Pathogen levels and safety of vitamin D treatment were also evaluated. Of 121 cases in total, 78 and 43 cases of influenza A infection occurred in the low-dose and high-dose vitamin D groups, respectively. There was a significant difference between the groups (χ = 14.6324, P = 0.0001). Among the cases of influenza infection, the median durations for fever, cough and wheezing were shorter in the high-dose vitamin D group than in the low-dose vitamin D group. The viral loads showed a downward trend in both groups and were significantly different between the groups at the second and third detections. Additionally, the incidences of adverse events and severe adverse events were very low and not significantly different between the 2 groups. High-dose vitamin D (1200 IU) is suitable for the prevention of seasonal influenza as evidenced by rapid relief from symptoms, rapid decrease in viral loads and disease recovery. In addition, high-dose vitamin D is probably safe for infants.


Induction of cancer-associated fibroblast-like cells by carbon nanotubes dictates its tumorigenicity.
Tumor microenvironment has been recognized as a key determinant of tumor formation and metastasis, but how tumor microenvironment is affected by nanomaterials is essentially unknown. Here, we investigated whether carbon nanotubes (CNTs), a widely used nanomaterial with known carcinogenic potential, can affect cancer-associated fibroblasts (CAFs), which are a key component of tumor microenvironment that provides necessary support for tumor growth. We show for the first time that single-walled CNT and to a lesser extent multi-walled and its COOH-functionalized form induced CAF-like cells, which are non-tumorigenic in animals, but promote tumor growth of human lung carcinoma and CNT-transformed lung epithelial cells. The mechanism by which CNT-induced CAF-like cells promote tumor growth involved the acquisition of cancer stem cells (CSCs) in cancer population. Gene knockdown experiments showed that an expression of podoplanin on CAF-like cells is essential for their effects, indicating the functional role of CAF-like cells and podoplanin in CNT tumorigenic process. Our findings unveil a novel mechanism of CNT-induced carcinogenesis through the induction of CAF-like cells that support CSCs and drive tumor formation. Our results also suggest the potential utility of podoplanin as a mechanism-based biomarker for rapid screening of carcinogenicity of CNTs and related nanomaterials for their safer design.


Appendicular skeletal status and hip fracture in the elderly: 14-year prospective data.
Fourteen-year follow-up of 535 elderly people included in a British survey in 1973 revealed 23 incident hip fractures. The relationship between appendicular bone mass, assessed in the initial survey by metacarpal morphometry, and fracture risk was analyzed. There was an increased risk of hip fracture with declining metacarpal cortical index at baseline. The risk increase, however, was not statistically significant. It remained similar after adjustment was made for the reported prevalence of falls. These prospective data suggest that osteoporosis may contribute less to the risk of hip fracture in the very elderly than in younger individuals.


Automated assessment of keratocyte density in stromal images from the ConfoScan 4 confocal microscope.
Purpose. To develop a program to determine cell densities in images from the ConfoScan 4 (Nidek, Inc., Freemont, CA) confocal microscope and compare the densities with those determined in images obtained by the Tandem Scanning confocal microscope (Tandem Scanning Corp., Reston, VA). Methods. A program was developed that used image-processing routines to identify stromal cell nuclei in images from the ConfoScan 4 confocal microscope. Cell selection parameters were set to match cell densities from the program with those determined manually in 15 normal corneas of 15 volunteers. The program was tested on scans from 16 other normal volunteers and 17 volunteers 3 years after LASIK. Cell densities were compared to densities determined by manual assessment and to those in scans by the Tandem Scanning confocal microscope in the same corneas. Results. The difference in cell density between the automatic and manual assessment was -539 +/- 3005 cells/mm(3) (mean +/- SD, P = 0.11) in the 16 test corneas. Densities estimated from the ConfoScan 4 agreed with those from the Tandem Scanning confocal microscope in all regions of the stroma except in the anterior 10%, where the ConfoScan 4 indicated a 30% lower density. Conclusions. Differences in anterior stromal cell density between the ConfoScan 4 and the Tandem Scanning confocal microscope can be explained by the different optical designs. The lower spatial resolution of the ConfoScan 4 limits its ability to resolve thin layers. The adaptation of our earlier cell-counting program to the ConfoScan 4 provides a timesaving, objective, and reproducible means of determining stromal cell densities in images from the ConfoScan 4.


Do regular high protein diets have potential health risks on kidney function in athletes?
Excess protein and amino acid intake have been recognized as hazardous potential implications for kidney function, leading to progressive impairment of this organ. It has been suggested in the literature, without clear evidence, that high protein intake by athletes has no harmful consequences on renal function. This study investigated body-builders (BB) and other well-trained athletes (OA) with high and medium protein intake, respectively, in order to shed light on this issue. The athletes underwent a 7-day nutrition record analysis as well as blood sample and urine collection to determine the potential renal consequences of a high protein intake. The data revealed that despite higher plasma concentration of uric acid and calcium, Group BB had renal clearances of creatinine, urea, and albumin that were within the normal range. The nitrogen balance for both groups became positive when daily protein intake exceeded 1.26 g.kg but there were no correlations between protein intake and creatinine clearance, albumin excretion rate, and calcium excretion rate. To conclude, it appears that protein intake under 2. 8 g.kg does not impair renal function in well-trained athletes as indicated by the measures of renal function used in this study