Nocturnin suppresses igf1 expression in bone by targeting the 3' untranslated region of igf1 mRNA.
IGF-I is an anabolic factor that mediates GH and PTH actions in bone. Expression of skeletal Igf1 differs for inbred strains of mice, and Igf expression levels correlate directly with bone mass. Previously we reported that peroxisome proliferator-activated receptor-γ2 activation in bone marrow suppressed Igf1 expression and that peroxisome proliferator-activated receptor-γ2 activation-induced Nocturnin (Noc) expression, a circadian gene with peak expression at light offset, which functions as a deadenylase. In 24-h studies we found that Igf1 mRNA exhibited a circadian rhythm in femur with the lowest Igf1 transcript levels at night when Noc transcripts were highest. Immunoprecipitation/RT-PCR analysis revealed a physical interaction between Noc protein and Igf1 transcripts. To clarify which portions of the Igf1 3' untranslated region (UTR) were necessary for regulation by Noc, we generated luciferase constructs containing various lengths of the Igf1 3'UTR. Noc did not affect the 170-bp short-form 3'UTR, but suppressed luciferase activity in constructs bearing the longer-form 3'UTR, which contains a number of potential regulatory motifs involved in mRNA degradation. C57BL/6J mice have low skeletal Igf1 mRNA compared with C3H/HeJ mice, and the Igf1 3' UTR is polymorphic between these strains. Interestingly, the activity of luciferase constructs bearing the long-form 3'UTR from C57BL/6J mice were repressed by Noc overexpression, whereas those bearing the corresponding region from C3H/HeJ were not. In summary, Noc interacts with Igf1 in a strain- and tissue-specific manner and reduces Igf1 expression by targeting the longer form of the Igf1 3'UTR. Posttranscriptional regulation of Igf1 may be critically important during skeletal acquisition and maintenance.


Impact of Advanced Age on Survival in Patients Undergoing Resection of Hepatocellular Carcinoma: Report of a Japanese Nationwide Survey.
The impact of age on survival after hepatic resection for hepatocellular carcinoma (HCC) has not been thoroughly examined. We reviewed the data of a nationwide follow-up survey to determine the outcomes of hepatectomy for HCC in elderly patients. Management of malignant diseases in elderly patients has become a global clinical issue because of the increased life expectancy worldwide. Advancements in surgical techniques and perioperative management have reduced age-related contraindications for liver surgery. In all, 12,587 patients with HCC who underwent curative hepatic resection were included in this cohort study and classified according to age group [40-59 years (n = 2991), 60-74 years (n = 7576,), and ≥75 years (n = 2020)]. Clinicopathological features, long-term survival, and cumulative incidences of death after hepatic resection were compared among the groups. The cause-specific subdistribution hazard ratios for 3 types of death depending on age were also estimated. Preoperative liver function tests showed that the prothrombin activity and platelet count were higher in the ≥75-year age group than in the other age groups. The overall survival was significantly lower in the elderly than younger patients. However, recurrence-free survival was almost identical among the 3 groups. The cumulative incidence of HCC-related or liver-related death was almost identical among the 3 groups; however, the cumulative incidence of other causes of death was significantly different. The 60-year subdistribution hazard ratio for other causes of death increased remarkably with increasing age. Elderly patients in this nationwide survey had significantly worse overall survival after hepatectomy than middle-aged and young patients. The cumulative incidence of other causes of death in elderly patients was significantly different from that of HCC-related or liver-related death among the 3 groups.


Substandard drugs: a potential crisis for public health.
Poor-quality medicines present a serious public health problem, particularly in emerging economies and developing countries, and may have a significant impact on the national clinical and economic burden. Attention has largely focused on the increasing availability of deliberately falsified drugs, but substandard medicines are also reaching patients because of poor manufacturing and quality-control practices in the production of genuine drugs (either branded or generic). Substandard medicines are widespread and represent a threat to health because they can inadvertently lead to healthcare failures, such as antibiotic resistance and the spread of disease within a community, as well as death or additional illness in individuals. This article reviews the different aspects of substandard drug formulation that can occur (for example, pharmacological variability between drug batches or between generic and originator drugs, incorrect drug quantity and presence of impurities). The possible means of addressing substandard manufacturing practices are also discussed. A concerted effort is required on the part of governments, drug manufacturers, charities and healthcare providers to ensure that only drugs of acceptable quality reach the patient.


Elders with dementia living in the community with and without caregivers: an epidemiological study.
Previous studies of dementia and family caregiving have focused on individuals seeking diagnosis and treatment, and have rarely been conducted in representative community samples. Identifying demented individuals participating in a community survey, we determined (a) the factors associated with demented elderly living alone; (b) the factors associated with the demented elderly having caregivers; (c) the factors associated with increased levels of burden among caregivers of persons with dementia. During an epidemiological survey of a mostly rural U.S. community, the authors identified 116 noninstitutionalized elderly individuals with dementia. These individuals were classified into those living alone and those living with others; both groups were further classified into those with and without identifiable family caregivers. Characteristics of both caregivers and care recipients were examined. Approximately a third of the subjects with dementia lived alone, and only half of them had caregivers. The average age of the caregivers was 67.4 years, and 73% of them were women. Almost half of the caregivers were spouses, whereas almost a third were offspring, of the demented individuals. Over two thirds of caregivers lived with the subjects. Female caregivers were significantly younger than male caregivers. Multivariate analyses revealed that subjects with dementia who were living alone were independently and significantly more likely to be women and to have dementias of shorter duration, lesser severity, and lesser functional impairment than those living with others. Demented subjects with caregivers were more likely to have greater dementia severity, functional impairment, and cognitive impairment and more current cognitive and behavioral symptoms than those without caregivers. Demented subjects whose caregivers reported higher levels of burden were more likely to be women and to have greater dementia severity, functional impairment, and cognitive impairment and more current symptoms than those whose caregivers had no/minimal burden. These results draw attention to the problems of persons with dementia living alone, particularly those without caregivers. Our data also provide epidemiological confirmation of previous clinical/volunteer studies of dementia caregiving, as well as a preliminary assessment of need in the community at large. Living arrangements and caregiver issues should be taken into account when planning services for the elderly.


Prognostic role of antibody reactivity to melanoma.
Antibody reactivity against cultured allogeneic melanoma Y-Mel 81:180 was studied in 43 patients who participated in an adjuvant trial for stage I and II melanoma. Serum samples were obtained at trial entry within 2 mo of definitive surgery. At the time of serum acquisition, all patients were free of disease by physical examination and routine radiologic and laboratory parameters. Serum antibody reactivity was tested for by protein A hemadsorption before and after acid dissociation and ultrafiltration of serum. We have previously shown that this technique for immune complex dissociation augments autologous antibody reactivity. Results of serum antibody reactivity were scored by an investigator blinded to the patient's clinical status. Of the 43 patients studied, 15 relapsed and 28 remained disease-free. At study entry, there were 25 stage I patients and 18 stage II patients. Breslow depth was 3.25 +/- 2.5 mm in relapse patients and 1.67 +/- 1.1 mm in disease-free patients. The presence and titer of antibody directed against melanoma in either native serum or serum dissociated from immune complexes was found to be associated with eventual relapse (P = 0.0001). When results were subgrouped by stage of disease, Breslow depth, and hypopigmentation, antibody reactivity was still correlated with eventual relapse. The incidence and titer of antibody reactivity against melanoma appears to be a new prognostic factor in predicting eventual disease recurrence.


Prediagnostic levels of serum beta-cryptoxanthin and retinol predict smoking-related lung cancer risk in Shanghai, China.
Higher blood levels of beta-carotene have been found to be associated with reduced risk of lung cancer, but large intervention trials have failed to demonstrate reduced lung cancer incidence after prolonged high-dose beta-carotene supplementation. Data on blood levels of specific carotenoids other than beta-carotene in relation to lung cancer are scarce. Little is known about the relationship between prediagnostic serum levels of carotenoids, retinol, and tocopherols, and risk of lung cancer especially in non-Western populations. Between January 1986 and September 1989, 18,244 men ages 45-64 years participated in a prospective study of diet and cancer in Shanghai, China. Information on tobacco smoking and other lifestyle factors was obtained through in-person interviews. A serum sample was collected from each study participant at baseline. During the first 12 years of follow-up, 209 lung cancer cases, excluding those diagnosed within 2 years of enrollment, were identified. For each cancer case, three cancer-free control subjects were randomly selected from the cohort and matched to the index case by age (within 2 years), month and year of blood sample collection, and neighborhood of residence. Serum concentrations of retinol, alpha- and gamma-tocopherols, and specific carotenoids including alpha-carotene, beta-carotene, beta-cryptoxanthin, lycopene, and lutein/zeaxanthin were determined on the 209 cases and 622 matched controls by high-performance liquid chromatography methods. A high prediagnostic serum level of beta-cryptoxanthin was significantly associated with reduced risk of lung cancer; relative to the lowest quartile, the smoking-adjusted relative risks (95% confidence intervals) for the 2nd, 3rd, and 4th quartile categories were 0.72 (0.41-1.26), 0.42 (0.21-0.84), and 0.45 (0.22-0.92), respectively (P for trend = 0.02). Increased serum levels of other specific carotenoids including alpha-carotene, beta-carotene, lycopene, and lutein/zeaxanthin were related to reduced risk of lung cancer although the inverse associations were no longer statistically significant after adjustment for smoking. A statistically significant 37% reduction in risk of lung cancer was noted in smokers with above versus below median level of total carotenoids. Serum retinol levels showed a threshold effect on lung cancer risk. Compared with the lowest quartile (<40 microg/dl), the smoking-adjusted relative risk (95% confidence interval) was 0.60 (0.39-0.92) for men in the 2nd-4th quartiles of retinol values combined; no additional decrease in risk was observed between individuals from the 2nd to 4th quartiles. There were no associations between prediagnostic serum levels of alpha- and gamma-tocopherols and lung cancer (all Ps for trend > or =0.4). The present data indicate that higher prediagnostic serum levels of total carotenoids and beta-cryptoxanthin were associated with lower smoking-related lung cancer risk in middle-aged and older men in Shanghai, China. Low level of serum retinol (with a threshold effect) is associated with increased lung cancer risk in this oriental population.


Light Sensitivity Within Areas of Geographic Atrophy Secondary to Age-Related Macular Degeneration.
To investigate residual sensitivity within geographic atrophy (GA) secondary to age-related macular degeneration. Mesopic and dark-adapted (DA) cyan and red light sensitivity (Goldmann III) were investigated using fundus-controlled perimetry (microperimetry). Test points were placed within GA along an "iso-hull" with a distance of -0.645° to the atrophy boundary. The false-positive response rate was determined with suprathreshold stimuli to the optic disc (Heijl-Krakau method) and used to compute the expected sensitivity measurements for the assumption of absolute scotomata. The outermost visible retinal layer on spectral-domain optical coherence tomography at the location of each test point was determined. Thirty eyes of 36 patients (75.55 ± 7.93 years; 19 female) from the prospective natural history study Directional Spread in Geographic Atrophy (NCT02051998), with a total of 1380 threshold determinations were analyzed. The measured sensitivities were significantly (P < 0.01) higher than the expected values for absolute scotomata (mean ± standard error of +6.92 ± 0.86 dB for mesopic, +2.57 ± 0.56 dB for DA cyan, and +4.93 ± 0.74 dB for DA red testing). For mesopic testing and DA red testing, the presence of a residual outer nuclear layer had a significant effect on this discrepancy (P < 0.001). There was no effect of fixation stability or any other reliability index on this discrepancy. Measured sensitivities within the inner junctional zone of GA may not be purely explained by patient-specific false-positive response rates or other reliability indices. The marked influence of the outer retinal configuration on measured sensitivity may be indicative of residual cone function within GA at the inner junctional zone.


Breast volume and milk production during extended lactation in women.
Quantitative measurements were made of relative breast volume and milk production from 1 month of lactation until 3 months after weaning, and the storage capacity of the breasts was calculated. The increase in breast tissue volume from before conception until 1 month of lactation was maintained for the first 6 months of lactation (means+/-S.E.M.) (190.3+/-13.1 ml, number of breasts, nb = 46). During this period of exclusive breast-feeding, 24 h milk production from each breast remained relatively constant (453.6+/-201 g, nb = 48), and storage capacity was 209.9+/-11.0 ml (nb = 46). After 6 months, breast volume, milk production and storage capacity all decreased. There was a relationship between 24 h milk production and the storage capacity of the breasts, and these both appeared to be responding to infant demand for milk. At 15 months of lactation, the 24 h milk production of each breast was substantial (208.0+/-56.7 g, nb = 6), even though the breasts had returned to preconception size. This was associated with an apparent increased efficiency of the breast (milk production per unit breast tissue) after 6 months, which may have been due to redistribution of tissues within the breast. The possible causes of the decrease in breast volume are discussed.


A surgical site infection cluster: the process and outcome of an investigation--the impact of an alcohol-based surgical antisepsis product and human behavior.
The institution of a process used to successfully execute a perioperative antibiotic administration system is but 1 component of preventing postoperative infections. Continued surveillance of infections is an important part of the process of decreasing postoperative infections. We recently experienced an increase in the number of postoperative infections in our patients. Using standard infection control methods of outbreak investigation, we tracked multiple variables to search for a common cause. We describe herein the process by which Quality Improvement methodology was used to investigate and manage this surgical site infection (SSI) cluster. As part of routine surveillance for SSI, the infection control division seeks out evidence of postoperative infections. Patients were defined as having an SSI according to National Healthcare Safety Network SSI criteria. SSI data are reviewed monthly and aggregated on a quarterly basis. The SSI rate was above our usual level for 3 consecutive quarters of 2007. This increase in the infection rate led to an internal outbreak investigation, termed a "cluster investigation." This investigation comprised multiple concurrent methods including manual chart review of all cases; review of microbiological data; and inspection of operating rooms, instrument processing facilities, and storage areas. During 3 quarters, a trend emerged in our general surgical population that demonstrated that 4 surgical types had a sustained increase in SSI. The institutional antibiotic protocol was appropriate for prevention of the majority of these SSIs. As part of the investigation, direct observation of hand hygiene and surgical hand antisepsis technique was undertaken. At this time, there were 2 types of surgical hand preparation being used, at the discretion of the clinician: either a "standard" scrub with an antimicrobial soap or the application of a chlorhexidine gluconate and alcohol-based surgical hand antisepsis product. Observers noted improper use of this alcohol-based surgical hand antiseptic. This product was withdrawn from our operating rooms, and the SSI rate markedly decreased in the following 2 quarters. In conclusion, we report the results of a quality improvement process that investigated a 3-quarter increase in our SSI rate. An investigation was undertaken, and it was thought that the (mis)use of an alcohol-based hand antiseptic product was associated with the increased infection rate. Removing this product, along with reemphasizing the importance of infection control, was associated with a decrease in the infection rate to a level at or below our historical rate.


Up-regulation of CD1d expression restores the immunoregulatory function of NKT cells and prevents autoimmune diabetes in nonobese diabetic mice.
The immunoregulatory function of NKT cells is crucial for prevention of autoimmunity. The prototypical NKT cell Ag alpha-galactosylceramide is not present in mammalian cells, and little is known about the mechanism responsible for NKT cell recruitment and activation. Up-regulation of CD1d, the NKT cell restriction molecule, expressed on mononuclear cells infiltrating the target organ, could represent the physiological trigger for NKT cells to self-contain T cell immunity and to prevent autoimmune disease. Recognition of CD1d, either by itself or bound to self-ligands (selfCD1d), could drive NKT cells toward an immunoregulatory phenotype. Hence, ineffective NKT cell-mediated immunoregulation in autoimmune-prone individuals including nonobese diabetic (NOD) mice could be related to defective signals that regulate CD1d expression at time and site of autoimmunity. To test this hypothesis, we transgenically overexpressed CD1d molecules under the control of the insulin promoter within the pancreatic islets of NOD mice (insCD1d). Recognition of overexpressed CD1d molecules rescued NKT cell immunoregulatory function and prevented autoimmune diabetes in insCD1d transgenic NOD mice. Protection from diabetes was associated with a biased IL-4-secreting cytokine phenotype of NKT cells and alteration of the cytokine microenvironment in the pancreatic lymph nodes of transgenic mice. The net effect was a reduced development of the autoimmune T cell repertoire. Our findings suggest that up-regulation of CD1d expression during inflammation is critical to maintain T cell homeostasis and to prevent autoimmunity.


Numerical simulation of the optical characteristics of autostereoscopic displays that have an aspherical lens array with a slanted angle.
We developed a 3D simulation model describing the optical phenomena on a slanted lenticular surface with aspherical lenses for autostereoscopic displays and analyzed the optical behavior of the multiview autostereoscopic display under actual design conditions by using a 3D simulation model. Optical characteristics, such as 3D crosstalk and 3D luminance differences, are obtained from the simulation of the light distribution for the multiview autostereoscopic displays with slated angles of 0.0°, 9.46°, 12.59°, and 14.04°. By investigating the effect of the conic constant of an aspherical lens surface on the 3D crosstalk and the 3D luminance differences for given several design conditions, we find the optimal values of the conic constant for slanted angles of 0.0° and 9.46° in order to minimize the 3D crosstalk and the 3D luminance difference. From these results, we think that our simulation model is very useful for designing the lens array to optimize the optical characteristics of autostereoscopic displays.


A single-arm study of sublobar resection for ground-glass opacity dominant peripheral lung cancer.
The optimal mode of surgery for ground-glass opacity dominant peripheral lung cancer defined with thoracic thin-section computed tomography remains unknown. We conducted a single-arm confirmatory trial to evaluate the efficacy and safety of sublobar resection for ground-glass opacity dominant peripheral lung cancer. Lung cancer with maximum tumor diameter 2.0 cm or less and with consolidation tumor ratio 0.25 or less based on thin-section computed tomography were registered. The primary end point was 5-year relapse-free survival. The planned sample size was 330 with the expected 5-year relapse-free survival of 98%, threshold of 95%, 1-sided α of 5%, and power of 90%. The trial is registered with University Hospital Medical Information Network Clinical Trials Registry, number University Hospital Medical Information Network 000002008. Between May 2009 and April 2011, 333 patients were enrolled from 51 institutions. Median age was 62 years (interquartile range, 56-68), and 109 were smokers. Median maximum tumor diameter was 1.20 cm (1.00-1.54). Median maximum tumor diameter of consolidation was 0 (0.00-0.20). The primary end point, 5-year relapse-free survival, was estimated on 314 patients who underwent sublobar resection. Operative modes were 258 wide wedge resections and 56 segmentectomies. Median pathological surgical margin was 15 mm (0-55). The 5-year relapse-free survival was 99.7% (90% confidence interval, 98.3-99.9), which met the primary end point. There was no local relapse. Grade 3 or higher postoperative complications based on Common Terminology Criteria for Adverse Effect v3.0 were observed in 17 patients (5.4%), without any grade 4 or 5. Sublobar resection with enough surgical margin offered sufficient local control and relapse-free survival for lung cancer clinically resectable N0 staged by computed tomography with 3 or fewer peripheral lesions 2.0 cm or less amenable to sublobar resection and with a consolidation tumor ratio of 0.25 or less.


Mice with combined gene knock-outs reveal essential and partially redundant functions of amyloid precursor protein family members.
The amyloid precursor protein (APP) involved in Alzheimer's disease is a member of a larger gene family including amyloid precursor-like proteins APLP1 and APLP2. We generated and examined the phenotypes of mice lacking individual or all possible combinations of APP family members to assess potential functional redundancies within the gene family. Mice deficient for the nervous system-specific APLP1 protein showed a postnatal growth deficit as the only obvious abnormality. In contrast to this minor phenotype, APLP2(-/-)/APLP1(-/-) and APLP2(-/-)/APP(-/-) mice proved lethal early postnatally. Surprisingly, APLP1(-/-)/APP(-/-) mice were viable, apparently normal, and showed no compensatory upregulation of APLP2 expression. These data indicate redundancy between APLP2 and both other family members and corroborate a key physiological role for APLP2. This view gains further support by the observation that APLP1(-/-)/APP(-/-)/APLP2(+/-) mice display postnatal lethality. In addition, they provide genetic evidence for at least some distinct physiological roles of APP and APLP2 by demonstrating that combinations of single knock-outs with the APLP1 mutation resulted in double mutants of clearly different phenotypes, being either lethal, or viable. None of the lethal double mutants displayed, however, obvious histopathological abnormalities in the brain or any other organ examined. Moreover, cortical neurons from single or combined mutant mice showed unaltered survival rates under basal culture conditions and unaltered susceptibility to glutamate excitotoxicity in vitro.


Capitated assertive community treatment program savings: system implications.
In a California county of one million people, 500 clients, 4% of all those served in 1994, were found to use 38% of publicly funded mental health services. A controlled experiment was designed to test whether a capitated Assertive Community Treatment (ACT) program could produce outcomes that were equivalent or better than "usual services" for a subset of very-high-utilizing clients while reducing costs. Results showed that major challenges in using an ACT program for cost reduction were successfully met. Costs over all 4 years were substantially lower for the experimental group than for a randomly assigned comparison group.


Infrared spectroscopy of hydrated amino acids in the gas phase: protonated and lithiated valine.
We report here infrared spectra of protonated and lithiated valine with varying degrees of hydration in the gas phase and interpret them with the help of DFT calculations at the B3LYP/6-31++G** level. In both the protonated and lithiated species our results clearly indicate that the solvation process is driven first by solvation of the charge site and subsequently by formation of a second solvation shell. The infrared spectra of Val x Li+ (H2O)4 and Val x H+ (H2O)4 are strikingly similar in the region of the spectrum corresponding to hydrogen-bonded stretches of donor water molecules, suggesting that in both cases similar extended water structures are formed once the charge site is solvated. In the case of the lithiated species, our spectra are consistent with a conformation change of the amino acid backbone from syn to anti accompanied by a change in the lithium binding from a NO coordination to OO coordination configuration upon addition of the third water molecule. This change in the mode of metal ion binding was also observed previously by Williams and Lemoff [J. Am. Soc. Mass Spectrom. 2004, 15, 1014-1024] using blackbody infrared radiative dissociation (BIRD). In contrast to the zwitterion formation inferred from results of the BIRD experiments upon addition of a third water molecule, our spectra, which are a more direct probe of structure, show no evidence for zwitterion formation with the addition of up to four water molecules.


Dabigatran etexilate--a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity.
Dabigatran etexilate is an oral, reversible direct thrombin inhibitor that is approved in the EU and several other countries for the prevention of venous thromboembolism after elective hip and knee replacement, and is in advanced clinical development for other thromboembolic disorders. Dabigatran has a predictable pharmacokinetic profile, allowing for a fixed-dose regimen without the need for routine coagulation monitoring. In certain clinical situations such as serious bleeding into critical organs (e.g. intracerebral bleeding), potential overdose and emergency surgery, clinicians will need to make an assessment of the anticoagulant status of a patient receiving dabigatran before deciding on future management strategies. If available, thrombin clotting time (TT), ecarin clotting time (ECT) and TT determined by Hemoclot thrombin inhibitor assay are sensitive tests to evaluate the anticoagulant effects of dabigatran. Prothrombin time (INR) is less sensitive than other assays and cannot be recommended. The activated partial thromboplastin time (aPTT) can provide a useful qualitative assessment of anticoagulant activity but is less sensitive at supratherapeutic dabigatran levels. There are limited data for activated clotting time (ACT). Overall, the aPTT and TT are the most accessible qualitative methods for determining the presence or absence of anticoagulant effect. Although there is no specific antidote to antagonise the anticoagulant effect of dabigatran, due to its short duration of effect drug discontinuation is usually sufficient to reverse any excessive anticoagulant activity. In case of potential overdose, the feasibility of early administration of activated charcoal and subsequent charcoal filtration are undergoing preclinical evaluation. Dabigatran can also be dialysed in patients with renal impairment. In instances of life-threatening bleeding, where conventional measures have failed or are unavailable, other non-specific prohaemostatic agents such as recombinant activated factor VII and prothrombin complex concentrates can be considered.


Therapeutic targeting of microenvironment in follicular lymphoma.
Immune and nonimmune microenvironmental factors play a critical role in the progression, transformation, and resistance to therapy in follicular lymphoma (FL). A recent increase in our understanding of the role of microenvironment in FL biology has led to the development of novel therapeutic strategies targeting the nonimmune and immune microenvironment. These include immunomodulatory drugs, immune checkpoint inhibitors, immnunoconjugates, and small-molecule inhibitors with an impact on the microenvironment in addition to direct antitumor activity. These agents are now at different stages of clinical development, ranging from early clinical trials in relapsed disease to phase 3 studies in the upfront setting, including combinations with other agents such as monoclonal antibodies and chemotherapy. It is important to recognize that, although the current upfront therapy of FL is associated with favorable outcomes in the majority of patients, a significant proportion experience early disease progression and develop treatment resistance and transformation to aggressive lymphoma. Although the development of "chemo-free" combinations using drugs targeting the microenvironment offers a promising approach to minimize toxicity, the identification of patients at risk of relapse and the use of biomarkers allowing the personalization of therapy will likely play a major role in the development of maintenance strategies. Against this landscape of currently available therapy options, this chapter discusses the clinical status of therapies targeting the microenvironment in FL.


Can group-based reassuring information alter low back pain behavior? A cluster-randomized controlled trial.
Low back pain (LBP) is common in the population and multifactorial in nature, often involving negative consequences. Reassuring information to improve coping is recommended for reducing the negative consequences of LBP. Adding a simple non-threatening explanation for the pain (temporary muscular dysfunction) has been successful at altering beliefs and behavior when delivered with other intervention elements. This study investigates the isolated effect of this specific information on future occupational behavior outcomes when delivered to the workforce. A cluster-randomized controlled trial. Publically employed workers (n = 505) from 11 Danish municipality centers were randomized at center-level (cluster) to either intervention (two 1-hour group-based talks at the workplace) or control. The talks provided reassuring information together with a simple non-threatening explanation for LBP-the 'functional-disturbance'-model. Data collections took place monthly over a 1-year period using text message tracking (SMS). Primary outcomes were self-reported days of cutting down usual activities and work participation. Secondary outcomes were self-reported back beliefs, work ability, number of healthcare visits, bothersomeness, restricted activity, use of pain medication, and sadness/depression. There was no between-group difference in the development of LBP during follow-up. Cumulative logistic regression analyses showed no between-group difference on days of cutting down activities, but increased odds for more days of work participation in the intervention group (OR = 1.83 95% CI: 1.08-3.12). Furthermore, the intervention group was more likely to report: higher work ability, reduced visits to healthcare professionals, lower bothersomeness, lower levels of sadness/depression, and positive back beliefs. Reassuring information involving a simple non-threatening explanation for LBP significantly increased the odds for days of work participation and higher work ability among workers who went on to experience LBP during the 12-month follow-up. Our results confirm the potential for public-health education for LBP, and add to the discussion of simple versus multidisciplinary interventions.


Preventive effect of ilioinguinal nerve block on postoperative pain after cesarean section.
Cesarean section is a major operation that can be the predictor of postoperative pain and discomfort and, therefore, providing the effective postoperative analgesia is an important factor to facilitate sooner movement of the patient, better care of infants. The aim of this study was to determine the preventive effect of ilioinguinal nerve block on pain after cesarean section. In a randomized clinical trial study, 80 female candidates for cesarean section under general anesthesia were selected and divided into two groups. In the first group, ilioinguinal nerve was blocked and in the control group, ilioinguinal nerve block was not done. Finally, postoperative pain was compared between the two groups. The mean pain intensity at 6 and 24 h after operation had no significant difference between two groups but in the rest of the times, it was different between two groups. Furthermore, in sitting position, except for 6 h, the pain intensity at the rest of the time had a significant difference between two groups. The pain intensity in 12 h after operation had a significant difference while in 24 h after operation; there was no difference between two groups. Doing repeated measures, ANOVA also indicated that the process of changes in the pain intensity in three positions of rest, sitting and walking had no significant difference up to 24 h after operation (P < 0.001). Control of pain after cesarean as one of the most common factors for abdominal surgery will lead to decrease the staying of the patient in hospital, reduce morbidity and lower use of narcotics and analgesics after surgery.


Sequence differences in the IQ motifs of CaV1.1 and CaV1.2 strongly impact calmodulin binding and calcium-dependent inactivation.
The proximal C terminus of the cardiac L-type calcium channel (Ca(V)1.2) contains structural elements important for the binding of calmodulin (CaM) and calcium-dependent inactivation, and exhibits extensive sequence conservation with the corresponding region of the skeletal L-type channel (Ca(V)1.1). However, there are several Ca(V)1.1 residues that are both identical in six species and are non-conservatively changed from the corresponding Ca(V)1.2 residues, including three of the "IQ motif." To investigate the functional significance of these residue differences, we used native gel electrophoresis and expression in intact myotubes to compare the binding of CaM to extended regions (up to 300 residues) of the C termini of Ca(V)1.1 and Ca(V)1.2. We found that in the presence of Ca(2+) (either millimolar or that in resting myotubes), CaM bound strongly to C termini of Ca(V)1.2 but not of Ca(V)1.1. Furthermore, replacement of two residues (Tyr(1657) and Lys(1662)) within the IQ motif of a C-terminal Ca(V)1.2 construct with the divergent residues of Ca(V)1.1 (His(1532) and Met(1537)) led to a weakening of CaM binding (native gels), whereas the reciprocal substitution in Ca(V)1.1 caused a gain of CaM binding. In full-length Ca(V)1.2, substitution of these same two divergent residues with those of Ca(V)1.1 (Y1657H, K1662M) eliminated calcium-dependent inactivation of the heterologously expressed channel. Thus, our results reveal that a conserved difference between the IQ motifs of Ca(V)1.2 and Ca(V)1.1 has a profound effect on both CaM binding and calcium-dependent inactivation.


Radiographic recommendations for the primary dentition: comparison of general dentists and pediatric dentists.
A survey which included brief case histories and intraoral photos of four primary dentitions ranging from healthy to severely carious was mailed to a random sample of 2000 general dentists and 1000 pediatric dentists. Radiographic options were listed, from which the dentist was to indicate all films needed for each child's examination. Surveys were received from 1273 (43%) dentists, including 713 (36%) general dentists and 560 (56%) pediatric dentists. The pediatric dentists recommended significantly more diagnostic radiographs than did the general dentists across all four primary dentition cases. This trend was apparent in the absence of clinically visible caries. When radiographs were recommended, bite-wing radiographs were the most frequently ordered films. The most frequently ordered combination among all respondents was bite-wing radiographs plus anterior periapical films. The results suggest that, frequently, neither general dentists nor pediatric dentists prescribe radiographs for the primary dentition patient that conform to the USDHHS guidelines for radiographic examination (1987).


Menopausal hormone therapy and subsequent risk of specific invasive breast cancer subtypes in the California Teachers Study.
Although it is well established that combined estrogen-progestin therapy (EPT) increases breast cancer risk, questions remain regarding the effect of different formulations of hormones, whether certain women are at particularly high risk, and whether risk varies by tumor subtype. We investigated hormone therapy (HT) use in relation to breast cancer risk in the California Teachers Study cohort; after a mean follow-up of 9.8 years, 2,857 invasive breast cancers were diagnosed. Compared with women who had never used HT, women who reported 15 or more years of estrogen therapy (ET) use had a 19% greater risk of breast cancer (95% confidence interval, 1.03-1.37), whereas women using EPT for 15 or more years had an 83% greater risk (95% confidence interval, 1.48-2.26). Breast cancer risk was highest among women using continuous combined EPT regimens. Risks associated with EPT and ET use were increased with duration of HT use for women with a body mass index (BMI) of <29.9 kg/m(2) but not for women with BMI of >or=30 kg/m(2). Elevated risks associated with EPT and ET use were confined to tumors that were positive for both estrogen and progesterone receptors and those that were HER2+ but were slightly diminished for HER2- tumors. Breast cancer risks increased with longer duration of ET and EPT use, and risks were highest for continuous-combined EPT use. Furthermore, risks varied by BMI and tumor subtype. These findings underscore the need for personalized risk-benefit discussions with women contemplating HT use.


Lowering the overall charge on TMPyP4 improves its selectivity for G-quadruplex DNA.
Ligands that stabilize non-canonical DNA structures called G-quadruplexes (GQs) might have applications in medicine as anti-cancer agents, due to the involvement of GQ DNA in a variety of cancer-related biological processes. Five derivatives of 5,10,15,20-tetrakis(N-methyl-4-pyridyl)porphyrin (TMPyP4), where a N-methylpyridyl group was replaced with phenyl (4P3), 4-aminophenyl (PN3M), 4-phenylamidoproline (PL3M), or 4-carboxyphenyl (PC3M and P2C2M) were investigated for their interactions with human telomeric DNA (Tel22) using fluorescence resonance energy transfer (FRET) assay, and UV-visible and circular dichroism spectroscopies in K+ buffer. The molecules are cationic or zwitterionic with an overall charge of 3+ (4P3, PN3M, and PL3M), 2+ (PC3M) or neutral (P2C2M). All porphyrins except P2C2M stabilize human telomeric DNA in FRET assays by ∼20 °C at 5 eq CD melting experiments suggest that 4P3 is the most stabilizing ligand with a stabilization temperature of 16.8 °C at 4 eq. Importantly, 4P3, PC3M and PL3M demonstrate excellent selectivity for quadruplexes, far superior to that of TMPyP4. Binding constants, determined using UV-vis titrations, correlate with charge: triply cationic 4P3, PN3M and PL3M display Ka of 5-9 μM-1, doubly cationic PC3M displays Ka of 1 μM-1, and neutral P2C2M displays weak-to-no binding. UV-vis data suggest that binding interactions are driven by electrostatic attractions and that the binding mode may be base-stacking (or end-stacking) judging by the high values of red shift (15-20 nm) and hypochromicity (40-50%). We conclude that lowering the charge on TMPyP4 to 3+ can achieve the desired balance between stabilizing ability, affinity, and high selectivity required for an excellent quadruplex ligand.


Impacts of CA9 gene polymorphisms and environmental factors on oral-cancer susceptibility and clinicopathologic characteristics in Taiwan.
In Taiwan, oral cancer has causally been associated with environmental carcinogens. Carbonic anhydrase 9 (CA9) is reportedly overexpressed in several types of carcinomas and is generally considered a marker of malignancy. The current study explored the combined effect of CA9 gene polymorphisms and exposure to environmental carcinogens on the susceptibility of developing oral squamous cell carcinoma (OSCC) and the clinicopathological characteristics of the tumors. Four single-nucleotide polymorphisms (SNPs) of the CA9 gene from 462 patients with oral cancer and 519 non-cancer controls were analyzed by a real-time polymerase chain reaction (PCR). While the studied SNPs (CA9 rs2071676, rs3829078, rs1048638 and +376 Del) were not associated with susceptibility to oral cancer, the GAA haplotype of 3 CA9 SNPs (rs2071676, rs3829078, and rs1048638) was related to a higher risk of oral cancer. Moreover, the four CA9 SNPs combined with betel quid chewing and/or tobacco consumption could robustly elevate susceptibility to oral cancer. Finally, patients with oral cancer who had at least one G allele of CA9 rs2071676 were at higher risk for developing lymph-node metastasis (p = 0.022), compared to those patients homozygous for AA. Our results suggest that the haplotype of rs2071676, rs3829078, and rs1048638 combined has potential predictive significance in oral carcinogenesis. Gene-environment interactions of CA9 polymorphisms, smoking, and betel-quid chewing might alter oral cancer susceptibility and metastasis.


Autologous bone marrow-derived stem cells in amyotrophic lateral sclerosis: a pilot study.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with no effective treatment. Stem cell therapy may be one of the promising treatment options for such patients. To assess the feasibility, efficacy and safety of autologous bone marrow-derived stem cells in patients of ALS. We conducted an open-label pilot study of autologous bone marrow-derived stem cells in patients with ALS attending the Neurology Clinic of a tertiary care referral centre. Ten patients with ALS with mean revised ALS Functional Rating Scale (ALSFRS-R) score of 30.2 (± 10.58) at baseline received intrathecal autologous bone marrow-derived stem cells. Primary end point was improvement in the ALSFRS-R score at 90, 180, 270 and 365 days post therapy. Secondary endpoints included ALSFRS-R subscores, time to 4-point deterioration, median survival and reported adverse events. Paired t-test was used to compare changes in ALSFRS-R from baseline and Kaplan-Meier analysis was used for survival calculations. There was no significant deterioration in ALSFRS-R composite score from baseline at one-year follow-up (P=0.090). The median survival post procedure was 18.0 months and median time to 4-point deterioration was 16.7 months. No significant adverse events were reported. Autologous bone marrow-derived stem cell therapy is safe and feasible in patients of ALS. Short-term follow-up of ALSFRS-R scores suggests a trend towards stabilization of disease. However, the benefit needs to be confirmed in the long-term follow-up period.


Health care management of adults with Down syndrome.
The family physician's holistic approach to patients forms the basis of good health care for adults with Down syndrome. Patients with Down syndrome are likely to have a variety of illnesses, including thyroid disease, diabetes, depression, obsessive-compulsive disorder, hearing loss, atlantoaxial subluxation and Alzheimer's disease. In addition to routine health screening, patients with Down syndrome should be screened for sleep apnea, hypothyroidism, signs and symptoms of spinal cord compression and dementia. Patients with Down syndrome may have an unusual presentation of an ordinary illness or condition, and behavior changes or a loss of function may be the only indication of medical illnesses. Plans for long-term living arrangements, estate planning and custody arrangements should be discussed with the parents or guardians. Because of improvements in health care and better education, and because more people with this condition are being raised at home, most adults with Down syndrome can expect to function well enough to live in a group home and hold a meaningful job.


Brain size is not correlated with forelimb dexterity in fissiped carnivores (Carnivora): A comparative test of the principle of proper mass.
To test the hypothesis that brain size and forelimb dexterity are positively correlated, the relative brain size of 41 species of fissiped (terrestrial) carnivores (Order: Carnivora) was examined with respect to their forelimb use during feeding. With the use of a newly derived dexterity index, the forelimb dexterity executed by each of the species was calculated as a single, continuous variable which was then regressed against the residuals of brain size. To account for confounding effects of phylogenetic inertia, the analysis was performed with independent contrasts analysis using a speciational model of evolutionary change (i.e. equal branch lengths). The results suggest that relative brain size and isocortex size are not correlated with the dexterity of the proximal or distal segments or a combination of the two (total forelimb dexterity). The presence of species with widely different brain sizes and similar dexterities, and vice versa, suggests that an increase in the amount of neural substrate might not be necessary for the production of finely coordinated forelimb movements. It is suggested that this outcome is representative of the plasticity of both mammalian brain size and behavior and that variations in brain size and forelimb dexterity could be linked to disparate ecological and phylogenetic factors which act in concert to promote or constrain neural development and behavior in different species.


Interactive indirect illumination using adaptive multiresolution splatting.
Global illumination provides a visual richness not achievable with the direct illumination models used by most interactive applications. To generate global effects, numerous approximations attempt to reduce global illumination costs to levels feasible in interactive contexts. One such approximation, reflective shadow maps, samples a shadow map to identify secondary light sources whose contributions are splatted into eye space. This splatting introduces significant overdraw that is usually reduced by artificially shrinking each splat's radius of influence. This paper introduces a new multiresolution approach for interactively splatting indirect illumination. Instead of reducing GPU fill rate by reducing splat size, we reduce fill rate by rendering splats into a multiresolution buffer. This takes advantage of the low-frequency nature of diffuse and glossy indirect lighting, allowing rendering of indirect contributions at low resolution where lighting changes slowly and at high-resolution near discontinuities. Because this multiresolution rendering occurs on a per-splat basis, we can significantly reduce fill rate without arbitrarily clipping splat contributions below a given threshold-those regions simply are rendered at a coarse resolution.


Thoracic periaortic adipose tissue in relation to cardiovascular risk in type 2 diabetes mellitus.
To evaluate thoracic periaortic adipose tissue (TAT) burden in patients with type 2 diabetes mellitus (DM) in comparison with controls and in relation to cardiovascular risk factors. A total of 93 patients with type 2 DM (mean (standard deviation; SD) age: 56.7 (11.2) years, 71.0 % were men) and 85 nondiabetic control subjects (mean (SD) age: 54.6 (10.9) years, 58.8 % were men) who were admitted to Mevlana University hospital between January 2011 and June 2013 and underwent multidetector computed tomography for any reason were included in this retrospective cohort study. Patient and control groups were compared in terms of demographic characteristics, anthropometrics, and laboratory findings. TAT volume was evaluated in both groups, while correlates of TAT were determined via linear regression analysis among patients. In patients with type 2 DM, TAT volume (40.1 (23.9) versus 16.9 (7.7) cm(3), p < 0.001), fasting blood glucose (p < 0.001), total cholesterol (p < 0.001), triglyceride (p = 0.017), and low-density lipoprotein (LDL) cholesterol (p = 0.034) levels were significantly higher compared with the control group. Strong positive correlation of TAT was noted with body mass index (r = 0.339, p = 0.001) and serum levels for fasting blood glucose (r = 0.343, p < 0.001), hemoglobin A1c (HbA1c; r = 0.615, p < 0.001), total cholesterol (r = 0.269, p = 0.009), and LDL cholesterol (r = 0.258, p = 0.013). In stepwise regression analysis, Hba1c emerged as a significant predictor of TAT (b = 0.610, p < 0.001), contributing to 19 % of its variability. In conclusion, our findings indicate significantly higher values for TAT in diabetics than controls, being associated positively with body weight, poor glycemic control, and dyslipidemia and strongly predicted by HbA1c levels in diabetic patients, while not differing with respect to gender, smoking status, and concomitant hypertension.


Unique competitive effects of lianas and trees in a tropical forest understory.
Lianas are an important component of tropical forests, contributing up to 25% of the woody stems and 35% of woody species diversity. Lianas invest less in structural support but more in leaves compared to trees of similar biomass. These physiological and morphological differences suggest that lianas may interact with neighboring plants in ways that are different from similarly sized trees. However, the vast majority of past liana competition studies have failed to identify the unique competitive effects of lianas by controlling for the amount of biomass removed. We assessed liana competition in the forest understory over the course of 3 years by removing liana biomass and an equal amount of tree biomass in 40 plots at 10 sites in a secondary tropical moist forest in central Panama. We found that growth of understory trees and lianas, as well as planted seedlings, was limited due to competitive effects from both lianas and trees, though the competitive impacts varied by species, season, and size of neighbors. The removal of trees resulted in greater survival of planted seedlings compared to the removal of lianas, apparently related to a greater release from competition for light. In contrast, lianas had a species-specific negative effect on drought-tolerant Dipteryx oleifera seedlings during the dry season, potentially due to competition for water. We conclude that, at local scales, lianas and trees have unique and differential effects on understory dynamics, with lianas potentially competing more strongly during the dry season, and trees competing more strongly for light.


Three-dimensional structure of the tetragonal crystal form of egg-white avidin in its functional complex with biotin at 2.7 A resolution.
The three-dimensional structure of hen egg-white avidin, crystallized in a tetragonal crystal form, has been solved at 2.7 A resolution by molecular replacement methods. After refinement the crystallographic R-factor is 16.8%, for the 7255 reflections in the 10.0 to 2.7 A resolution range. The asymmetric unit contains two avidin polypeptide chains (M(r) 2 x 15,600), which build up the functional tetramer through a crystallographic 2-fold axis parallel to the c unit cell direction. The avidin tetramer has almost exact 222 molecular symmetry; the three possible dimers display quite distinct packing interfaces. Each protomer is organized in an eight-stranded antiparallel orthogonal beta-barrel, with extended loop regions. The avidin binding site within each promoter is located in a deep pocket, at the center of the barrel, displaying both hydrophobic and polar residues for recognition of the tightly bound vitamin. Two Trp residues, Trp70 and Trp97, and Phe79 are in close contact with biotin. Moreover, the binding pocket is partly closed in its outer rim by residue Trp110 of a neighboring subunit. Once bound, biotin is almost completely buried in the protein core, with the exception of the valeryl side-chain carboxylate group which is exposed to solvent, hydrogen bonds to residues Ala39, Thr40 and Ser75, and triggers the formation of a network of hydrogen bonded water molecules. Modeling of synthetic biotin analogues allows us to rationalize functional data available for the binding of these compounds, and to analyze them in terms of biotin recognition mechanism. Hen egg-white avidin shows clear structural homology to streptavidin, from Streptomyces avidinii, but significant deviations can be observed in some regions.


Flares assessed weekly in patients with rheumatoid arthritis or axial spondyloarthritis and relationship with physical activity measured using a connected activity tracker: a 3-month study.
The evolution of rheumatoid arthritis (RA) and axial spondyloarthritis (axSpA) is marked by flares, although their frequency is unclear. Flares may impact physical activity. Activity can be assessed objectively using activity trackers. The objective was to assess longitudinally the frequency of flares and the association between flares and objective physical activity. This prospective observational study (ActConnect) included patients with definite clinician-confirmed RA or axSpA, owning a smartphone. During 3 months, physical activity was assessed continuously by number of steps/day, using an activity tracker, and disease flares were self-assessed weekly using a specific flare question and, if relevant, the duration of the flare. The relationship between flares and physical activity for each week (time point) was assessed by linear mixed models. In all, 170/178 patients (91 patients with RA and 79 patients with axSpA; 1553 time points) were analysed: mean age was 45.5±12.4 years, mean disease duration was 10.3±8.7 years, 60 (35.3%) were men and 90 (52.9%) received biologics. The disease was well-controlled (mean Disease Activity Score 28: 2.3±1.2; mean Bath Ankylosing Spondylitis Disease Activity Index score: 3.3±2.1). Patients self-reported flares in 28.2%±28.1% of the weekly assessments. Most flares (78.9%±31.4%) lasted ≤3 days. Persistent flares lasting more than 3 days were independently associated with less weekly physical activity (p=0.03), leading to a relative decrease of 12%-21% and an absolute decrease ranging from 836 to 1462 steps/day. Flares were frequent but usually of short duration in these stable patients with RA and axSpA. Persistent flares were related to a moderate decrease in physical activity, confirming objectively the functional impact of patient-reported flares.


Effect of Passive, Active and Combined Warm up on Lower Limb Muscle Performance and Dynamic Stability in Recreational Sports Players.
Warm up is an activity that is done before a sports activity. The warm up can be done actively and passively. The preferred mode is active warm up in athletes. There are inconclusive effects of passive warm up compared with an active warm up on short term muscle performance. The cumulative effect of passive and active warm up on muscle performance and dynamic stability is not known. To find out the effects of passive, active and combined warm up on lower limb muscle performance and dynamic stability in recreational sports players. A randomized crossover study was done on 19 recreational lower limb dominant sports players. Three different warm ups were included in the study passive, active and combined. Active warm up included series of activities like cycling, leg press, jump squats, squat jumps while passive warm up included application of moist heat for a period of 20 minutes on lower limb muscles. Combined warm up included both passive and active warm up. Six different sequences were made from these three warm ups. Subjects were screened and allotted into different groups based on the six warm up sequences after sequence randomization with 48 hours wash out period. After every warm up session Vertical Jump Test (VJT) and Star Excursion Balance Test (SEBT) was performed and results were recorded. Study duration was one year and six months. There was no difference noticed in both the outcome measures. Mean and SD values for passive, active and combined warm up are 47.62±9.64, 48.50±10.16 and 48.87±10.70 respectively in Vertical Jump Test (VJT) and 85.43±8.61, 85.17±8.60 and 85.17±8.38 respectively for SEBT. The p-value for mean difference between passive-active, active-combined, combined-passive are 0.67, 1.00, 0.51 respectively, for VJT and 1.00, 1.00, 1.00 respectively for SEBT. All warm ups are equally effective in short term sports performance.


Individual music therapy for mental health care clients with low therapy motivation: multicentre randomised controlled trial.
Music therapy (MT) has been shown to be efficacious for mental health care clients with various disorders such as schizophrenia, depression and substance abuse. Referral to MT in clinical practice is often based on other factors than diagnosis. We aimed to examine the effectiveness of resource-oriented MT for mental health care clients with low motivation for other therapies. This was a pragmatic parallel trial. In specialised centres in Norway, Austria and Australia, 144 adults with non-organic mental disorders and low therapy motivation were randomised to 3 months of biweekly individual, resource-oriented MT plus treatment as usual (TAU) or TAU alone. TAU was typically intensive (71% were inpatients) and included the best combination of therapies available for each participant, excluding MT. Blinded assessments of the Scale for the Assessment of Negative Symptoms (SANS) and 15 secondary outcomes were collected before randomisation and after 1, 3 and 9 months. Changes were analysed on an intention-to-treat basis using generalised estimating equations in longitudinal linear models, controlling for diagnosis, site and time point. MT was superior to TAU for total negative symptoms (SANS, d = 0.54, p < 0.001) as well as functioning, clinical global impressions, social avoidance through music, and vitality (all p < 0.01). Individual MT as conducted in routine practice is an effective addition to usual care for mental health care clients with low motivation.


Genetic variability of the forkhead box O3 and prostate cancer risk in the European Prospective Investigation on Cancer.
Forkhead box O3 (FOXO3) has a wide range of functions: it promotes tumor suppression, cell cycle arrest, repair of damaged DNA, detoxification of reactive oxygen species, apoptosis and plays a pivotal role in promoting longevity. FOXO3 is a key downstream target of the PI3K-Akt pathway in response to cellular stimulation by growth factors or insulin and has been proposed as a bridge between ageing and tumor suppression. Three SNPs in the FOXO3 gene (rs3800231, rs9400239 and rs479744) that have been shown to be strongly and consistently associated with longevity, were examined in relation to PC risk in a case control study of 1571 incident PC cases and 1840 controls nested within the European Prospective Investigation into Cancer and Nutrition (EPIC). There was no statistically significant association between the SNPs and PC risk regardless of the model of inheritance (dominant, codominant and recessive). The associations were not modified by disease aggressiveness, circulating levels of steroid sex hormones, or IGFs or BMI. We conclude that polymorphisms in the FOXO3 gene that are associated with longevity are not major risk factors for PC risk, in this population of Caucasian men.


Homologous and Heterologous Covid-19 Booster Vaccinations.
Although the three vaccines against coronavirus disease 2019 (Covid-19) that have received emergency use authorization in the United States are highly effective, breakthrough infections are occurring. Data are needed on the serial use of homologous boosters (same as the primary vaccine) and heterologous boosters (different from the primary vaccine) in fully vaccinated recipients. In this phase 1-2, open-label clinical trial conducted at 10 sites in the United States, adults who had completed a Covid-19 vaccine regimen at least 12 weeks earlier and had no reported history of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection received a booster injection with one of three vaccines: mRNA-1273 (Moderna) at a dose of 100 μg, Ad26.COV2.S (Johnson & Johnson-Janssen) at a dose of 5×1010 virus particles, or BNT162b2 (Pfizer-BioNTech) at a dose of 30 μg. The primary end points were safety, reactogenicity, and humoral immunogenicity on trial days 15 and 29. Of the 458 participants who were enrolled in the trial, 154 received mRNA-1273, 150 received Ad26.COV2.S, and 153 received BNT162b2 as booster vaccines; 1 participant did not receive the assigned vaccine. Reactogenicity was similar to that reported for the primary series. More than half the recipients reported having injection-site pain, malaise, headache, or myalgia. For all combinations, antibody neutralizing titers against a SARS-CoV-2 D614G pseudovirus increased by a factor of 4 to 73, and binding titers increased by a factor of 5 to 55. Homologous boosters increased neutralizing antibody titers by a factor of 4 to 20, whereas heterologous boosters increased titers by a factor of 6 to 73. Spike-specific T-cell responses increased in all but the homologous Ad26.COV2.S-boosted subgroup. CD8+ T-cell levels were more durable in the Ad26.COV2.S-primed recipients, and heterologous boosting with the Ad26.COV2.S vaccine substantially increased spike-specific CD8+ T cells in the mRNA vaccine recipients. Homologous and heterologous booster vaccines had an acceptable safety profile and were immunogenic in adults who had completed a primary Covid-19 vaccine regimen at least 12 weeks earlier. (Funded by the National Institute of Allergy and Infectious Diseases; DMID 21-0012 ClinicalTrials.gov number, NCT04889209.).


Signet-ring cell carcinoma of the ampulla of Vater.
Carcinomas of the ampulla of Vater are uncommon, and signet-ring cell carcinoma is rare. We report a case of signet-ring cell carcinoma of the ampulla of Vater with obstructive jaundice in a 53-year-old man. Abdominal ultrasonography and abdominal computed tomographic scan revealed dilatation of the common bile duct, intrahepatic duct, and main pancreatic duct, with the obstruction level in the distal common bile duct near the ampulla of Vater. Duodenoscopy displayed an ampullary tumor protruding from the papilla of Vater with an erythematous and sloughing surface. Endoscopic biopsy of the tumor showed a signet-ring cell carcinoma. The patient received percutaneous transhepatic cholangiographic drainage, and the jaundice gradually improved. A Whipple operation including pancreatoduodenectomy and hemigastrectomy was performed. Pathological examination confirmed signet-ring cell carcinoma of the ampulla of Vater with direct invasion of the periampullary duodenum and distal common bile duct. No gastric lesion or nodal metastasis was found. The postoperative course was uneventful. The patient was alive with no recurrent disease during a follow-up period of 25 months.


Chlorhexidine versus saline in reducing the risk of catheter associated urinary tract infection: A cost-effectiveness analysis.
Catheter associated urinary tract infections are one of the most common infections acquired in hospital. A recent randomised control study demonstrated the benefit of using chlorhexidine (0.1%) for meatal cleaning prior to urinary catheter insertion, by reducing both catheter associated asymptomatic bacteriuria and infection. These findings raise the important question of whether a decision to switch from saline to chlorhexidine was likely to be cost-effective. The aim of this paper was to evaluate the cost-effectiveness of adopting routine use of chlorhexidine for meatal cleaning prior to urinary catheter insertion METHODS: The outcomes of this cost-effectiveness study are changes to health service costs in $AUD and changes to quality adjusted life years from a decision to adopt 0.1% chlorhexidine for meatal cleaning prior to urinary catheter insertion as compared to saline. Effectiveness outcomes for this study were taken from a 32 week stepped wedge randomised controlled study conducted in three Australian hospitals. The changes in health costs from switching from saline to 0.1% chlorhexidine per 100,000 catheterisations would save hospitals AUD$387,909 per 100,000 catherisations, prevent 70 cases of catheter associated urinary tract infections, release 282 bed days and provide a small improvement in health benefits of 1.43 quality adjusted life years. Using a maximum willingness to pay for a marginal quality adjusted life year threshold of AUD$28,000 per 100,000 catherisations, suggests that adopting chlorhexidine would be cost effective and potentially cost-saving. The findings from our work provide evidence to health system administrators and those responsible for drafting catheter associated urinary tract infections prevention guidelines that investing in switching from saline to chlorhexidine is not only clinically effective but also a sensible decision in the context of allocating finite healthcare resources.


Mechanism of cell death induced by the novel enzyme-prodrug combination, nitroreductase/CB1954, and identification of synergism with 5-fluorouracil.
Virus-directed enzyme prodrug therapy (VDEPT) utilising the bacterial enzyme nitroreductase delivered by a replication-defective adenovirus vector to activate the prodrug CB1954 is a promising strategy currently undergoing clinical trials in patients with a range of cancers. An understanding of the mechanism of tumour cell death induced by activated CB1954 will facilitate this clinical development. Here, we report that activated CB1954 kills cells predominantly by caspase-dependent apoptosis. This may have important implications for the generation of immune-mediated bystander effects. Further, the use of a replication-defective adenovirus vector to deliver nitroreductase may negatively affect cellular apoptotic pathways stimulated by activated CB1954. Finally, examination of nitroreductase/CB1954 in combination with conventional chemotherapy reveals a synergistic interaction with 5-fluorouracil. These data will facilitate the further development and future clinical trial design of this novel therapy.


Learning to Detect Deception from Evasive Answers and Inconsistencies across Repeated Interviews: A Study with Lay Respondents and Police Officers.
Previous research has shown that inconsistencies across repeated interviews do not indicate deception because liars deliberately tend to repeat the same story. However, when a strategic interview approach that makes it difficult for liars to use the repeat strategy is used, both consistency and evasive answers differ significantly between truth tellers and liars, and statistical software (binary logistic regression analyses) can reach high classification rates (Masip et al., 2016b). Yet, if the interview procedure is to be used in applied settings the decision process will be made by humans, not statistical software. To address this issue, in the current study, 475 college students (Experiment 1) and 142 police officers (Experiment 2) were instructed to code and use consistency, evasive answers, or a combination or both before judging the veracity of Masip et al.'s (2016b) interview transcripts. Accuracy rates were high (60% to over 90%). Evasive answers yielded higher rates than consistency, and the combination of both these cues produced the highest accuracy rates in identifying both truthful and deceptive statements. Uninstructed participants performed fairly well (around 75% accuracy), apparently because they spontaneously used consistency and evasive answers. The pattern of results was the same among students, all officers, and veteran officers only, and shows that inconsistencies between interviews and evasive answers reveal deception when a strategic interview approach that hinders the repeat strategy is used.


Calcarea carbonica induces apoptosis in cancer cells in p53-dependent manner via an immuno-modulatory circuit.
Complementary medicines, including homeopathy, are used by many patients with cancer, usually alongside with conventional treatment. However, the molecular mechanisms underneath the anti-cancer effect, if any, of these medicines have still remained unexplored. To this end we attempted to evaluate the efficacy of calcarea carbonica, a homeopathic medicine, as an anti-cancer agent and to delineate the detail molecular mechanism(s) underlying calcerea carbonica-induced tumor regression. To investigate and delineate the underlying mechanisms of calcarea carbonica-induced tumor regression, Trypan blue dye-exclusion test, flow cytometric, Western blot and reverse transcriptase-PCR techniques were employed. Further, siRNA transfections and inhibitor studies were used to validate the involvement of p53 pathway in calcarea carbonica-induced apoptosis in cancer cells. Interestingly, although calcarea carbonica administration to Ehrlich's ascites carcinoma (EAC)- and Sarcoma-180 (S-180)-bearing Swiss albino mice resulted in 30-35% tumor cell apoptosis, it failed to induce any significant cell death in ex vivo conditions. These results prompted us to examine whether calcarea carbonica employs the immuno-modulatory circuit in asserting its anti-tumor effects. Calcarea carbonica prevented tumor-induced loss of effector T cell repertoire, reversed type-2 cytokine bias and attenuated tumor-induced inhibition of T cell proliferation in tumor-bearing host. To confirm the role of immune system in calcarea carbonica-induced cancer cell death, a battery of cancer cells were co-cultured with calcarea carbonica-primed T cells. Our results indicated a "two-step" mechanism of the induction of apoptosis in tumor cells by calcarea carbonica i.e., (1) activation of the immune system of the host; and (2) induction of cancer cell apoptosis via immuno-modulatory circuit in p53-dependent manner by down-regulating Bcl-2:Bax ratio. Bax up-regulation resulted in mitochondrial transmembrane potential loss and cytochrome c release followed by activation of caspase cascade. Knocking out of p53 by RNA-interference inhibited calcarea carbonica-induced apoptosis thereby confirming the contribution of p53. These observations delineate the significance of immuno-modulatory circuit during calcarea carbonica-mediated tumor apoptosis. The molecular mechanism identified may serve as a platform for involving calcarea carbonica into immunotherapeutic strategies for effective tumor regression.


Stage-Related Defense Response Induction in Tomato Plants by Nesidiocoris tenuis.
The beneficial effects of direct predation by zoophytophagous biological control agents (BCAs), such as the mirid bug Nesidiocoris tenuis, are well-known. However, the benefits of zoophytophagous BCAs' relation with host plants, via induction of plant defensive responses, have not been investigated until recently. To date, only the females of certain zoophytophagous BCAs have been demonstrated to induce defensive plant responses in tomato plants. The aim of this work was to determine whether nymphs, adult females, and adult males of N. tenuis are able to induce defense responses in tomato plants. Compared to undamaged tomato plants (i.e., not exposed to the mirid), plants on which young or mature nymphs, or adult males or females of N. tenuis fed and developed were less attractive to the whitefly Bemisia tabaci, but were more attractive to the parasitoid Encarsia formosa. Female-exposed plants were more repellent to B. tabaci and more attractive to E. formosa than were male-exposed plants. When comparing young- and mature-nymph-exposed plants, the same level of repellence was obtained for B. tabaci, but mature-nymph-exposed plants were more attractive to E. formosa. The repellent effect is attributed to the signaling pathway of abscisic acid, which is upregulated in N. tenuis-exposed plants, whereas the parasitoid attraction was attributed to the activation of the jasmonic acid signaling pathway. Our results demonstrate that all motile stages of N. tenuis can trigger defensive responses in tomato plants, although these responses may be slightly different depending on the stage considered.


Evaluation of the Ages and Stages Questionnaires in identifying children with neurosensory disability in the Magpie Trial follow-up study.
To evaluate performance of the Ages and Stages Questionnaires (full ASQ), and a shortened version (short ASQ), in detecting children with severe neurosensory disability in the Magpie Trial follow-up study. All children, born to women in the Magpie Trial and selected for follow-up, with a completed full 30 items and/or short 9-items ASQ were included in this analysis. Sensitivity and specificity, corrected for verification bias, were computed to assess detection ability. Of the 2046 children who completed a full ASQ, 406 (19.8%) failed the assessment, 54 of whom had confirmed neurosensory disability. Adjusted sensitivity and specificity (95% confidence intervals) were 87.4% (62.9-96.6%), and 82.3% (80.5-83.9%), respectively. Two of the five domains in the full ASQ (Fine Motor and Problem Solving) contributed little to detection ability. Sensitivity and specificity for the short ASQ were 69.2% and 95.7%, respectively. Sensitivity of the full ASQ for severe neurosensory disability is generally good, and does not appear to be much reduced by restricting questions to three out of the five domains. The short ASQ reported here reduced performance, although this might be improved by a different choice of questions or scoring system.


Smoking restrictions in bars and bartender smoking in the US, 1992-2007.
The present work is an analysis of whether adoption of state clean indoor air laws (SCIALs) covering bars reduces the proportion of bartenders who smoke primarily by reducing smoking among people already employed as bartenders when restrictions are adopted or by changing the composition of the bartender workforce with respect to smoking behaviours. Logistic regressions were estimated for a variety of smoking outcomes, controlling for individual demographic characteristics, state economic characteristics, and state, year, and month fixed effects, using data on 1380 bartenders from the 1992-2007 Tobacco Use Supplement to the Current Population Survey combined with data on SCIALs from ImpacTeen. State restrictions on smoking in bars are negatively associated with whether a bartender smokes, with a 1-point increase in restrictiveness (on a scale of 0-3) associated with a 5.3% reduction in the odds of smoking. Bar SCIALs are positively associated with the likelihood a bartender reports never having smoked cigarettes but not with the likelihood a bartender reports having been a former smoker. State clean indoor air laws covering bars appear to reduce smoking among bartenders primarily by changing the composition of the bartender workforce with respect to smoking rather than by reducing smoking among people already employed as bartenders when restrictions are adopted. Such laws may nonetheless be an important public health tool for reducing secondhand smoke.


Determinants of virulence of influenza A virus.
Influenza A viruses cause yearly seasonal epidemics and occasional global pandemics in humans. In the last century, four human influenza A virus pandemics have occurred. Occasionally, influenza A viruses that circulate in other species cross the species barrier and infect humans. Virus reassortment (i.e. mixing of gene segments of multiple viruses) and the accumulation of mutations contribute to the emergence of new influenza A virus variants. Fortunately, most of these variants do not have the ability to spread among humans and subsequently cause a pandemic. In this review, we focus on the threat of animal influenza A viruses which have shown the ability to infect humans. In addition, genetic factors which could alter the virulence of influenza A viruses are discussed. The identification and characterisation of these factors may provide insights into genetic traits which change virulence and help us to understand which genetic determinants are of importance for the pandemic potential of animal influenza A viruses.


Type and course of symptoms demonstrated in the terminal and dying phases by people with dementia in nursing homes.
In all, 39 % of people living in Swiss nursing homes suffer from dementia. Detailed data about type and course of symptoms displayed by these patients in their terminal phase are lacking. This descriptive, retrospective study analysed 65 nursing documents from deceased people with dementia in four nursing homes in the canton of Zurich, Switzerland. Difficulties with mobility (81 %), pain (71 %) and sleep disturbance (63 %) were the most frequent of the 10 identified symptoms. Towards the end of life, difficulties with mobility, sleep disturbance, agitation and other neuropsychiatric symptoms, such as episodes of depression, decreased (decrescent pattern), while pain, feeding problems, breathing abnormalities, apathy and anxiety increased (crescent pattern). Courses of pain were documented in 17 % of the nursing records. In addition, 76 % of the residents had been visited on a daily basis by next of kin in their last 7 days, compared with only one third of residents previously. Furthermore, daily communication between healthcare professionals and next of kin tripled during this period. The documented prevalence of a high and increasing level of pain towards the end of life, combined with the lack of documented courses of pain, shows potential for improvement in pain relief and pain identification for patients with dementia in their terminal phase. The increasing number of visits by next of kin and the increasingly intensive contact between healthcare professionals and next of kin in the last 7 days are a strong indicator that the end of life can be predicted relatively well by the involved participants and appropriate reactions follow.


Pseudomonas aeruginosa enhances production of a non-alginate exopolysaccharide during long-term colonization of the cystic fibrosis lung.
The gram-negative opportunistic pathogen Pseudomonas aeruginosa is the primary cause of chronic respiratory infections in individuals with the heritable disease cystic fibrosis (CF). These infections can last for decades, during which time P. aeruginosa has been proposed to acquire beneficial traits via adaptive evolution. Because CF lacks an animal model that can acquire chronic P. aeruginosa infections, identifying genes important for long-term in vivo fitness remains difficult. However, since clonal, chronological samples can be obtained from chronically infected individuals, traits undergoing adaptive evolution can be identified. Recently we identified 24 P. aeruginosa gene expression traits undergoing parallel evolution in vivo in multiple individuals, suggesting they are beneficial to the bacterium. The goal of this study was to determine if these genes impact P. aeruginosa phenotypes important for survival in the CF lung. By using a gain-of-function genetic screen, we found that 4 genes and 2 operons undergoing parallel evolution in vivo promote P. aeruginosa biofilm formation. These genes/operons promote biofilm formation by increasing levels of the non-alginate exopolysaccharide Psl. One of these genes, phaF, enhances Psl production via a post-transcriptional mechanism, while the other 5 genes/operons do not act on either psl transcription or translation. Together, these data demonstrate that P. aeruginosa has evolved at least two pathways to over-produce a non-alginate exopolysaccharide during long-term colonization of the CF lung. More broadly, this approach allowed us to attribute a biological significance to genes with unknown function, demonstrating the power of using evolution as a guide for targeted genetic studies.


Six1 transcription factor is critical for coordination of epithelial, mesenchymal and vascular morphogenesis in the mammalian lung.
Six1 is a member of the six-homeodomain family of transcription factors. Six1 is expressed in multiple embryonic cell types and plays important roles in proliferation, differentiation and survival of precursor cells of different organs, yet its function during lung development was hitherto unknown. Herein we show that Six1(-/-) lungs are severely hypoplastic with greatly reduced epithelial branching and increased mesenchymal cellularity. Six1 is expressed at the distal epithelial tips of branching tubules as well as in the surrounding distal mesenchyme. Six1(-/-) lung epithelial cells show increased expression of differentiation markers, but loss of progenitor cell markers. Six1 overexpression in MLE15 lung epithelial cells in vitro inhibited cell differentiation, but increases the expression of progenitor cell markers. In addition, Six1(-/-) embryos and newborn mice exhibit mesenchymal overproliferation, decreased Fgf10 expression and severe defects in the smooth muscle component of the bronchi and major pulmonary vessels. These defects lead to rupture of major vessels in mutant lungs after birth. Treatment of Six1(-/-) epithelial explants in culture with recombinant Fgf10 protein restores epithelial branching. As Shh expression is abnormally increased in Six1(-/-) lungs, we also treated mutant mesenchymal explants with recombinant Shh protein and found that these explants were competent to respond to Shh and continued to grow in culture. Furthermore, inhibition of Shh signaling with cyclopamine stimulated Six1(-/-) lungs to grow and branch in culture. This study provides the first evidence for the requirement of Six1 in coordinating Shh-Fgf10 signaling in embryonic lung to ensure proper levels of proliferation and differentiation along the proximodistal axis of epithelial, mesenchymal and endothelial cells. These findings uncover novel and essential functions for Six1 as a critical coordinator of Shh-Fgf10 signaling during embryonic lung development. We propose that Six1 is hence critical for coordination of proper lung epithelial, mesenchymal and vascular development.


Self-mixing interference in a diode laser: experimental observations and theoretical analysis.
The experimental results of an investigation of self-mixing effects or backscatter modulation in diode lasers coupled with a simple theoretical analysis are presented. The laser is used to send light, either in free space or through an optical fiber, to a movable target from which the optical backscatter is detected and fed back into the laser. In the experiment three significant conclusions are drawn: (1) self-mixing interference is not dependent on the coherence length of the laser, (2) the interference is not dependent on the use of a single-mode or multimode laser as the source, and (3) the interference is independent of the type of fiber employed, i.e., whether it is single mode or multimode. A comparison of this kind of interference with that in a conventional interferometer shows that self-mixing interference has the same phase sensitivity as that of the conventional arrangement, the modulation depth of the interference is comparable with that of a conventional interferometer, and the direction of the phase movement can be obtained from the interference signal. The above factors have implications for the optical sensing of a wide range of physical parameters. Several applications of the method are discussed that highlight the significant advantages of simplicity, compactness, and robustness as well as the self-aligning and self-detecting abilities of fiber-based self-mixing interferometry when compared with the use of conventional interference methods.


A master equation for power laws.
We propose a new mechanism for generating power laws. Starting from a random walk, we first outline a simple derivation of the Fokker-Planck equation. By analogy, starting from a certain Markov chain, we derive a master equation for power laws that describes how the number of cascades changes over time (cascades are consecutive transitions that end when the initial state is reached). The partial differential equation has a closed form solution which gives an explicit dependence of the number of cascades on their size and on time. Furthermore, the power law solution has a natural cut-off, a feature often seen in empirical data. This is due to the finite size a cascade can have in a finite time horizon. The derivation of the equation provides a justification for an exponent equal to 2, which agrees well with several empirical distributions, including Richardson's Law on the size and frequency of deadly conflicts. Nevertheless, the equation can be solved for any exponent value. In addition, we propose an urn model where the number of consecutive ball extractions follows a power law. In all cases, the power law is manifest over the entire range of cascade sizes, as shown through log-log plots in the frequency and rank distributions.


Nitrogen cycling microbiomes are structured by plant mycorrhizal associations with consequences for nitrogen oxide fluxes in forests.
Volatile nitrogen oxides (N2 O, NO, NO2 , HONO, …) can negatively impact climate, air quality, and human health. Using soils collected from temperate forests across the eastern United States, we show microbial communities involved in nitrogen (N) cycling are structured, in large part, by the composition of overstory trees, leading to predictable N-cycling syndromes, with consequences for emissions of volatile nitrogen oxides to air. Trees associating with arbuscular mycorrhizal (AM) fungi promote soil microbial communities with higher N-cycle potential and activity, relative to microbial communities in soils dominated by trees associating with ectomycorrhizal (ECM) fungi. Metagenomic analysis and gene expression studies reveal a 5 and 3.5 times greater estimated N-cycle gene and transcript copy numbers, respectively, in AM relative to ECM soil. Furthermore, we observe a 60% linear decrease in volatile reactive nitrogen gas flux (NOy ≡ NO, NO2 , HONO) as ECM tree abundance increases. Compared to oxic conditions, gas flux potential of N2 O and NO increase significantly under anoxic conditions for AM soil (30- and 120-fold increase), but not ECM soil-likely owing to small concentrations of available substrate ( NO 3 - ) in ECM soil. Linear mixed effects modeling shows that ECM tree abundance, microbial process rates, and geographic location are primarily responsible for variation in peak potential NOy flux. Given that nearly all tree species associate with either AM or ECM fungi, our results indicate that the consequences of tree species shifts associated with global change may have predictable consequences for soil N cycling.


T-cell receptor-induced phosphorylation of the zeta chain is efficiently promoted by ZAP-70 but not Syk.
Engagement of the T-cell receptor (TCR) results in the activation of Lck/Fyn and ZAP-70/Syk tyrosine kinases. Lck-mediated tyrosine phosphorylation of signaling motifs (ITAMs) in the CD3-zeta subunits of the TCR is an initial step in the transduction of signaling cascades. However, zeta phosphorylation is also promoted by ZAP-70, as TCR-induced zeta phosphorylation is defective in ZAP-70-deficient T cells. We show that this defect is corrected by stable expression of ZAP-70, but not Syk, in primary and transformed T cells. Indeed, these proteins are differentially coupled to the TCR with a 5- to 10-fold higher association of ZAP-70 with zeta as compared to Syk. Low-level Syk-zeta binding is associated with significantly less Lck coupled to the TCR. Moreover, diminished coupling of Lck to zeta correlates with a poor phosphorylation of the positive regulatory tyr352 residue of Syk. Thus, recruitment of Lck into the TCR complex with subsequent zeta chain phosphorylation is promoted by ZAP-70 but not Syk. Importantly, the presence of ZAP-70 positively regulates the TCR-induced tyrosine phosphorylation of Syk. The interplay between Syk and ZAP-70 in thymocytes, certain T cells, and B-chronic lymphocytic leukemia cells, in which they are coexpressed, will therefore modulate the amplitude of antigen-mediated receptor signaling.


Avian Bornaviruses in North American Gulls.
Avian bornaviruses, recently described members of the family Bornaviridae, have been isolated from captive parrots and passerines as well as wild waterfowl in which they may cause lethal neurologic disease. We report detection of avian bornavirus RNA in the brains of apparently healthy gulls. We tested 439 gull brain samples from 18 states, primarily in the northeastern US, using a reverse-transcriptase PCR assay with primers designed to detect a conserved region of the bornavirus M gene. Nine birds yielded a PCR product of appropriate size. Sequencing of PCR products indicated that the virus was closely related to aquatic bird bornavirus 1 (ABBV-1). Viral RNA was detected in Herring Gulls (Larus argentatus), Ring-billed Gulls (Larus delawarensis), and Laughing Gulls (Leucophaeus atricilla). Eight of the nine positive birds came from the New York/New Jersey area. One positive Herring Gull came from New Hampshire. Histopathologic examination of one well-preserved brain from a Herring Gull from Union County New Jersey, showed a lymphocytic encephalitis similar to that observed in bornavirus-infected parrots and geese. Bornavirus N protein was confirmed in two Herring Gull brains by immunohistochemistry. Thus ABBV-1 can infect gulls and cause encephalitic brain lesions similar to those observed in other birds.


Public health importance of human leptospirosis in the South Pacific: a five-year study in New Caledonia.
A retrospective study of 192 cases of human leptospirosis in New Caledonia (South Pacific) diagnosed between 1989 and 1993 showed that the disease was endemic throughout the territory. The annual incidence rate was 30 per 100,000 population, and the disease was more frequent in males (67.5%). Cases occurred mainly in March each year. Forty isolates were obtained (20.8%) and identified as belonging to serovars icterohaemorrhagiae (28), pomona (6), pyrogenes (3), ballum (2), and javanica (1). Most cases (54.7%) presented as influenza-like illnesses, while classical Weil's syndrome (fever, jaundice, and renal involvement) occurred in only 15.6% of the patients. Severe ocular complications were found in 3.6% of the patients. Local differences in climate, environment and socioeconomic conditions determined the epidemiologic features. These data emphasize the potential public health importance of leptospirosis in the other insular states in the South Pacific.


Determining the number of factors to retain in an exploratory factor analysis using comparison data of known factorial structure.
Exploratory factor analysis (EFA) is used routinely in the development and validation of assessment instruments. One of the most significant challenges when one is performing EFA is determining how many factors to retain. Parallel analysis (PA) is an effective stopping rule that compares the eigenvalues of randomly generated data with those for the actual data. PA takes into account sampling error, and at present it is widely considered the best available method. We introduce a variant of PA that goes even further by reproducing the observed correlation matrix rather than generating random data. Comparison data (CD) with known factorial structure are first generated using 1 factor, and then the number of factors is increased until the reproduction of the observed eigenvalues fails to improve significantly. We evaluated the performance of PA, CD with known factorial structure, and 7 other techniques in a simulation study spanning a wide range of challenging data conditions. In terms of accuracy and robustness across data conditions, the CD technique outperformed all other methods, including a nontrivial superiority to PA. We provide program code to implement the CD technique, which requires no more specialized knowledge or skills than performing PA.


Atom type preferences, structural diversity, and property profiles of known drugs, leads, and nondrugs: a comparative assessment.
A new characterization of known drug, lead, and representative nondrug databases was performed taking into account several properties at the atomic and molecular levels. This characterization included atom type preferences, intrinsic structural diversity (Atom Type Diversity, ATD), and other well-known physicochemical properties, as an approach for rapid assessment of druglikeness for small molecule libraries. To characterize ATD, an elaborate united atom classification, UALOGP (United Atom Log P), with 148 atom types, was developed along with associated atomic physicochemical parameters. This classification also enabled an analysis of atom type and physicochemical property distributions (for calculated log P, molar refractivity, molecular weight, total atom count, and ATD) of drug, lead, and nondrug databases, a reassessment of the Ro5 (Rule of Five) and GVW (Ghose−Viswanadhan−Wendoloski) criteria, and development of new criteria and ranges more accurately reflecting the chemical space occupied by small molecule drugs. A relative druglikeness parameter was defined for atom types in drugs, identifying the most preferred types. The present work demonstrates that drug molecules are constitutionally more diverse relative to nondrugs, while being less diverse than leads.


Accelerated hydrolysis method to estimate the amino acid content of wheat (Triticum durum Desf.) flour using microwave irradiation.
The technique of microwave-assisted acid hydrolysis was applied to wholegrain wheat (Triticum durum Desf. cv. Balcali 2000) flour in order to speed the preparation of samples for analysis. The resultant hydrolysates were chromatographed and quantified in an automated amino acid analyzer. The effect of different hydrolysis temperatures, times and sample weights was examined using flour dispersed in 6 N HCl. Within the range of values tested, the highest amino acid recoveries were generally obtained by setting the hydrolysis parameters to 150 °C, 3 h and 200 mg sample weight. These conditions struck an optimal balance between liberating amino acid residues from the wheat matrix and limiting their subsequent degradation or transformation. Compared to the traditional 24 h reflux method, the hydrolysates were prepared in dramatically less time, yet afforded comparable ninhydrin color yields. Under optimal hydrolysis conditions, the total amino acid recovery corresponded to at least 85.1% of the total protein content, indicating the efficient extraction of amino acids from the flour matrix. The findings suggest that this microwave-assisted method can be used to rapidly profile the amino acids of numerous wheat grain samples, and can be extended to the grain analysis of other cereal crops.


Perfluorinated acid isomer profiling in water and quantitative assessment of manufacturing source.
A method for isomer profiling of perfluorinated compounds (PFCs) in water was developed and applied to quantitatively assess the contributions from electrochemical (ECF) and telomer manufacturing processes around source regions of North America, Asia, and Europe. With the exception of 3 sites in Japan, over 80% of total perfluorooctanoate (PFOA, C(7)F(15)COO(-)) was from ECF, with the balance attributable to strictly linear (presumably telomer) manufacturing source(s). Comparing PFOA isomer profiles in samples from China, with PFOA obtained from a local Chinese manufacturer, indicated <3% difference in overall branched isomer content; thus, exclusive contribution from local ECF production cannot be ruled out. In Tokyo Bay, ECF, linear-telomer, and isopropyl-telomer sources contributed to 33%, 53%, and 14% of total PFOA, respectively. Perfluorooctane sulfonate (PFOS, C(8)F(17)SO(3)(-)) isomer profiles were enriched in branched content (i.e., >50% branched) in the Mississippi River but in all other locations were similar or only slightly enriched in branched content relative to historical ECF PFOS. Isomer profiles of other PFCs are also reported. Overall, these data suggest that, with the exception of Tokyo Bay, ECF manufacturing has contributed to the bulk of contamination around these source regions, but other sources are significant, and remote sites should be monitored.