Association between local neuroretinal function and control of adolescent type 1 diabetes.
To evaluate associations between neuroretinal function measured with multifocal electroretinogram (mfERG) and disease variables in adolescents with type 1 diabetes and no retinopathy. Fundus photographs, blood glucose (BG) concentration, HbA1c, and monocular mfERG were performed on 115 adolescent patients (mean age ± SD; 15.7 ± 1.8 years) and 30 controls (18.0 ± 2.8 years). All subjects had best-corrected visual acuity ≥ 20/20. The 45° mfERG stimulus included 103 hexagons, reversing between dark and bright according to a pseudorandom m-sequence. Amplitudes (AMPs) and implicit times (ITs) were derived from local mfERG response waveforms, and Z-scores were calculated. Retinal maps of abnormality frequencies were generated. Differences between controls and patients were evaluated using t-tests. Associations between mfERG and age, duration, and diabetes control were examined using linear regression analysis. Mean mfERG IT was significantly longer in the patients compared with that in the controls (P = 0.019), but AMP was not different (P > 0.05). In all, 26 eyes (23%) of the patients had abnormal IT and 3 eyes (3%) had abnormal AMP. IT abnormalities were essentially distributed randomly across the retina. There were too few AMP abnormalities to examine their retinal distribution. IT was positively correlated with HbA1c (P < 0.0002) but not correlated with diabetes duration, BG, or age. Higher long-term blood glucose concentration is associated with degraded neuroretinal function in adolescents with type 1 diabetes and no retinopathy. Over 20% of these patients have abnormal neuroretinal function. It will be important to determine longitudinally whether the relationship between mfERG IT and diabetes control exists within individual adolescent patients.


Homozygous GRID2 missense mutation predicts a shift in the D-serine binding domain of GluD2 in a case with generalized brain atrophy and unusual clinical features.
Spinocerebellar ataxias comprise a large and heterogeneous group of disorders that may present with isolated ataxia, or ataxia in combination with other neurologic or non-neurologic symptoms. Monoallelic or biallelic GRID2 mutations were recently reported in rare cases with cerebellar syndrome and variable degree of ataxia, ocular symptoms, hypotonia and developmental delay. We report on a consanguineous family with autosomal recessive childhood onset of slowly progressive cerebellar ataxia and delayed psychomotor development in three siblings. MRI of an adult and affected family member revealed slightly widened cerebral and cerebellar sulci, suggesting generalized brain atrophy, and mild cerebellar atrophy. Using whole exome sequencing we identified a novel homozygous missense variant [c.2128C > T, p.(Arg710Trp)] in GRID2 that segregates with the disease. The missense variant is located in a conserved region encoding the extracellular serine-binding domain of the GluD2 protein and predicts a change in conformation of the protein. The widespread supratentorial brain abnormalities, absence of oculomotor symptoms, increased peripheral muscle tone and the novel missense mutation add to the clinical and genetic variability in GRID2 associated cerebellar syndrome. The neuroradiological findings in our family indicate a generalized neurodegenerative process to be taken into account in other families segregating complex clinical features and GRID2 mutations.


Eye Tracking in the Wild: Piloting a Real-Life Assessment Paradigm for Older Adults.
Previous research showed associations between personality traits and eye movements of young adults in the laboratory. However, less is known about these associations in real life and in older age. Primarily, there seems to be no paradigm to assess eye movements of older adults in real life. The present feasibility study thus aimed to test grocery shopping as a real-life assessment paradigm with older adults. Additionally, possible links between personality traits and eye movements were explored. The sample consisted of 38 older individuals (M = 72.85 years). Participants did their grocery shopping in a supermarket while wearing an eye tracker. Three key feasibility issues were examined, that is (1) wearability of the eye tracker during grocery shopping, (2) recording, and (3) evaluation of eye movements in a real-life context. Our real-life assessment paradigm showed to be feasible to implement and acceptable to older adults. This feasibility study provides specific practical recommendations which may be useful for future studies that plan to innovatively expand the traditional methods repertoire of personality science and aging research by using eye tracking in real life.


[Mortality among Japanese migrants residing in the municipality of São Paulo, Brazil, 1990].
The mortality patterns of Japanese migrants (issei) and their descendants (nissei/sansei) resident in the City of S. Paulo, Brazil, are compared with those of their native country (Japan) and their place of adoption (S. Paulo), in 1980. The mortality data were obtained from death certificates for the issei and nissei/sansei populations and from official tabulations for deaths in Japan and S. Paulo. The population estimates were based upon the S. Paulo and Japanese censuses. The age-standardized populations were calculated according to the Jowett method. The five leading causes of death were basically the same for these populations under study. S. Paulo residents had the highest age-standardized mortality rates, except as regards deaths due to neoplasms, higher in Japan. The issei population (both sexes) presented intermediate values for deaths due to endocrine, nutritional, and metabolic diseases and diseases of the respiratory system; the female migrants also showed an intermediate rate for deaths due to diseases of the circulatory system. For the other causes, the lowest risk of dying was that registered for the issei population. The comparisons of the rates for cancers of stomach, breast, prostate, diabetes mellitus, ischaemic heart diseases, cerebrovascular diseases, homicide and suicide resulted in the detection of a possible transition experienced by the issei population, leading to the belief that the issei pattern of mortality is showing a deviation from the Japanese pattern and resembles that of S. Paulo. Since social and cultural changes are thought to be occurring among the migrants, one might argue that the role of environmental factors (including diet) is more important than the role of genetic factors in the incidence of and mortality due to these diseases.


[The effect of endoscopical intratumoral injection of OK-432 in gastric carcinoma].
Many BRMs (biological response modifiers) have been used for post-operative immunochemotherapy. And their usefulness were also reported. Nevertheless it is still unknown that which route, how much doses and which timing are the most effective to administer these drugs. We used BRMs intratumorally and preoperatively. To reconfirm the efficacy of intratumoral injection therapy randomized study was performed in gastric carcinoma. Three hundred and ninety-five cases were entered, 199 cases in group A which were treated preoperatively with OK-432 intratumorally and 196 cases in group B which were control, respectively. In the cases which had marked infiltration of lymphoid cells in tumor sites, the two year survival rate of group A was significantly better than that of group B (p less than 0.05). On the study of recurrent forms, the distal lymph node metastasis was markedly decreased in group A. The ratio of metastasis to the distal lymph nodes in group A was 5-10% lesser than that in group B on the each depth of tumor invasion. The ratio of lymph nodes metastasis was almost similar in the each group, but the number of metastatic lymph nodes was significantly reduced in high grade tumor infiltrated cases in group A (p less than 0.005). These results suggest that preoperative endoscopically intratumoral administration of OK-432 suppresses the lymph node metastasis and improves the postoperative survival rate.


Wavelength modulation spectroscopy: combined frequency and intensity laser modulation.
A theoretical model of wavelength modulation spectroscopy that uses a laser diode on a Lorentzian absorption line is presented. This theory describes the general case of a current-modulated semiconductor laser, for which a combined intensity and frequency modulation with an arbitrary phase shift occurs. On the basis of this model, the effect of several modulation parameters on the detected signals is evaluated. Experimental signals measured on an absorption line of CO2 by use of a 2-microm distributed-feedback laser are also presented and validate this analysis. These experimental results agree with the calculated signals, confirming the relevance of the model.


Elite golfers' kinematic sequence in full-swing and partial-swing shots.
The aim of this study was to investigate whether kinematic proximal-to-distal sequencing (PDS) and speed-summation are common characteristics of both partial and full-swing shots in golf players of different skill levels and genders. A total of 45 golfers participated, 11 male tournament professionals, 21 male and 13 female elite amateurs. They performed partial shots with a wedge to targets at three submaximal distances, 40, 55 and 70 m, and full-swing shots with a 5 iron and a driver for maximal distance. Pelvis, upper torso and hand movements were recorded in 3D with an electromagnetic tracking system (Polhemus Liberty) at 240 Hz and the magnitude of the resultant angular velocity vector of each segment was computed. The results showed a significant proximal-to-distal temporal relationship and a concomitant successive increase in maximum (peak) segment angular speed in every shot condition for both genders and levels of expertise. A proximal-to-distal utilization of interaction torques is indicated. Using a common PDS movement strategy in partial and full-swing golf shots appears beneficial from mechanical and control points of view and could serve the purpose of providing both high speed and accuracy.


Multidisciplinary treatment of fibromyalgia: does cognitive behavior therapy increase the response to treatment?
Multidisciplinary treatments (MTs) are usually recommended for reducing fibromyalgia (FM) symptoms and include physical exercise, drug management, education, and cognitive behavior therapy (CBT). However, there is no evidence that CBT adds efficacy to the other therapeutic components. This randomized controlled trial analyzed the response of FM patients to two MTs, with and without CBT, according to the presence of concurrent symptoms. Eighty-three women with FM were randomly assigned to MT or combined MT and CBT. The MT included medical intervention, physical training, education, and discussion of the syndrome. The CBT focused on coping with stress, modifying lifestyles, and changing pain behaviors. Demographic and clinical data, information regarding tender points, and questionnaire responses about functional capability [Fibromyalgia Impact Questionnaire (FIQ)], health status [36-item Short Form Health Survey (SF-36)], and mental health [Symptom Checklist-90-Revised (SCL-90-R)] were obtained at the beginning, at the end of the 15-week treatment, and at 6-month follow-up. Subgroups are identified in relation to treatment response. Sixty-six women (80%) completed treatment. Although the variance of the total sample had changed at posttreatment (F=2.67, P=.031), there was no significant effect for the TimexTreatment interaction (F=1.65, P=.16). Univariate tests detected a significant fall in the FIQ score. The subgroup of patients with fatigue showed a better response with MT+CBT than with MT. At 6-month follow-up, the statistical differences had been maintained. Intention-to-treat analysis ratified these results. MT improves functional capability and reduces symptom impact. CBT increases mildly the effect of MT in patients with fatigue.


Striatal Dopamine Depletion Patterns and Early Non-Motor Burden in Parkinsons Disease.
The mechanism underlying non-motor symptoms in Parkinson's disease has not yet been elucidated. In this study, we hypothesized that Parkinson patients with more non-motor symptoms have a different pattern of striatal dopamine depletion, particularly in areas other than the sensorimotor striatum, compared to those with fewer non-motor symptoms. We conducted a prospective survey of the degree of non-motor symptoms (using the Korean version of the Non-Motor Symptoms Scale; K-NMSS) in 151 patients with early-stage Parkinson's disease who had undergone a dopamine transporter PET scan as an initial diagnostic procedure. We classified the patients into two groups; high non-motor patients (HNM-PD; K-NMSS score ≥ 41) and low non-motor patients (LNM-PD). Patients in the HNM-PD group (n = 71) were older, had longer symptom duration, exhibited more severe motor deficits, and had been prescribed higher levodopa-equivalent doses at follow-up than those in the LNM-PD group. However, dopamine transporter binding to the striatal sub-regions and inter-sub-regional binding ratios were comparable between the two groups. A general linear model showed that the HNM-PD group had significantly more severe motor deficits than the LNM-PD group after controlling for age, gender, symptom duration, and dopamine transporter binding to the sensorimotor striatum. This study demonstrated that the pattern of striatal dopamine depletion does not contribute to early non-motor burden in Parkinson's disease. Our results suggest that LNM-PD patients may have a more benign course of motor symptom progression than HNM-PD patients.


Molecular characterization of HIV type 1 among HIV-infected respondents in a cohort being prepared for HIV Phase III vaccine clinical trials, Western Kenya.
Kenya is one of the sub-Saharan African countries affected by HIV-1 infection and AIDS. We investigated HIV-1 genetic diversity in 130 individuals from Busia, Bungoma, and Kakamega in western Kenya as part of an HIV-1 vaccine feasibility study in preparation for Phase III efficacy clinical trials. After RNA extraction the partial gag (484 bp) and env (1297 bp) regions were amplified and directly sequenced. Phylogenetic analysis was done using MEGA version 4 and recombinants were identified using the jpHMM tool and phylogenetic analysis. HIV-1 sequences were amplified from 122 of the 130 samples, 118 (90.8%) from the gag region and 78 (60 %) from the env region and 74 samples (56.9%) from both the gag and env regions. Of these sequenced on both regions, 51.4% were subtype A, 9.4% subtype D, 1.4% subtype C, 4.1% subtype G, and 33.7% were discordant and thus possible recombinants, including A1/C, A1/D, A1/A2, and A2/C. The jpHMM tool indicated a further two samples with CD and BD breakpoints within the env gene and one within the gag gene (A1C). An additional sample had an A1D breakpoint in the gag gene, but the envelope was not amplified. HIV-1 subtype diversity in western Kenya should be considered in vaccines designed for clinical trials in this region and this genetic diversity should be continuously monitored.


Family history and risk of primary open angle glaucoma. The Baltimore Eye Survey.
Primary open angle glaucoma has been previously associated with a positive family history of glaucoma. We used data from the Baltimore Eye Survey to examine this association. A population-based prevalence survey identified 161 cases of primary open angle glaucoma among 5308 black and white residents of east Baltimore, Md, who were 40 years of age or older. Family history was ascertained by interview and included all first-degree relatives (parents, siblings, and children). Age-adjusted associations of primary open angle glaucoma with a history of glaucoma were higher in siblings (odds ratio [OR] = 3.69) than in parents (OR = 2.17) or children (OR = 1.12). Odds ratios were slightly higher in blacks than in whites, and there was evidence of selection bias, with ORs between two and three times higher for those who had prior knowledge of their glaucoma diagnosis than for those who first received their diagnosis by the study examination (history in siblings OR = 4.72 for those with prior knowledge vs 2.77 for those without). Family history is an important risk factor for primary open angle glaucoma, although clinic-based studies are likely to overstate its impact.


Pericytes and the pathogenesis of diabetic retinopathy.
Pericytes provide vascular stability and control endothelial proliferation. Pericyte loss, microaneurysms, and acellular capillaries are characteristic for the diabetic retina. Platelet-derived growth factor (PDGF)-B is involved in pericyte recruitment, and brain capillaries of mice with a genetic ablation of PDGF-B show pericyte loss and microaneurysms. We investigated the role of capillary coverage with pericytes in early diabetic retinopathy and the contribution to proliferative retinopathy using mice with a single functional allele of PDGF-B (PDGF-B(+/-) mice). As assessed by quantitative morphometry of retinal digest preparations, pericyte numbers in nondiabetic PDGF-B(+/-) mice were reduced by 30% compared with wild-type mice, together with a small but significant increase in acellular capillaries. Pericyte numbers were reduced by 40% in diabetic wild-type mice compared with nondiabetic wild-type controls. Pericyte numbers were decreased by 50% in diabetic PDGF-B(+/-) mice compared with nondiabetic wild-type littermates, and the incidence of acellular capillaries was increased 3.5-fold when compared with nondiabetic PDGF-B(+/-) mice. To investigate the effect of pericyte loss in the context of ongoing angiogenesis, we subjected mice to hypoxia-induced proliferative retinopathy. As a result, PDGF-B(+/-) mice developed twice as many new blood vessels as their wild-type littermates. We conclude that retinal capillary coverage with pericytes is crucial for the survival of endothelial cells, particularly under stress conditions such as diabetes. At high vascular endothelial growth factor levels, such as those in the retinopathy of prematurity model, pericyte deficiency leads to reduced inhibition of endothelial proliferation in vivo.


Heart Failure Incidence and Mortality in the Southern Community Cohort Study.
There is a paucity of data on heart failure (HF) incidence among low-income and minority populations. Our objective was to investigate HF incidence and post-HF survival by race and sex among low-income adults in the southeastern United States. Participants were 27 078 white and black men and women enrolled during 2002 to 2009 in the SCCS (Southern Community Cohort Study) who had no history of HF and were receiving Centers for Medicare and Medicaid Services. Incident HF diagnoses through December 31, 2010 were ascertained using International Classification of Diseases 9th Revision codes 428.x via linkage with Centers for Medicare and Medicaid Services research files. Most participants were black (68.8%), women (62.6%), and earned <$15 000/y (69.7%); mean age was 55.5 (10.4) years. Risk factors for HF were common: hypertension (62.5%), diabetes mellitus (26.5%), myocardial infarction (8.6%), and obesity (44.8%). Over a median follow-up of 5.2 years, 4341 participants were diagnosed with HF. The age-standardized incidence rates were 34.8, 37.3, 34.9, and 35.6 /1000 person-years in white women, white men, black men, and black women, respectively, remarkably higher than previously reported. Among HF cases, 952 deaths occurred over a median follow-up of 2.3 years. Men had lower survival; hazard ratios and 95% confidence intervals were 1.63 (1.27-2.08), 1.38 (1.11-1.72), and 0.90 (0.73-1.12) for white men, black men, and black women compared with white women. In this low-income population, HF incidence was higher for all race-sex groups than previously reported in other cohorts. The SCCS is a unique resource to investigate determinants of HF risk in a segment of the population underrepresented in other existing cohorts.


High-sensitivity temperature sensor using the ultrahigh order mode-enhanced Goos-Hänchen effect.
A high-sensitivity temperature sensor based on the enhanced Goos-Hänchen effect in a symmetrical metal-cladding waveguide is theoretically proposed and experimentally demonstrated. Owing to the high sensitivity of the ultrahigh-order modes, any minute variation of the refractive index and thickness in the guiding layer induced by the thermo-optic and thermal expansion effects will easily give rise to a dramatic change in the position of the reflected light. In our experiment, a series of Goos-Hänchen shifts are measured at temperatures varying from 50.0 °C to 51.2 °C with a step of 0.2 °C. The sensor exhibits a good linearity and a high resolution of approximately 5×10(-3) °C. Moreover, there is no need to employ any complicated optical equipment and servo techniques, since our transduction scheme is irrelevant to the light source fluctuation.


"Go4Life" exercise counseling, accelerometer feedback, and activity levels in older people.
Older people are more sedentary than other age groups. We sought to determine if providing an accelerometer with feedback about activity and counseling older subjects using Go4Life educational material would increase activity levels. Participants were recruited from independent living areas within assisted living facilities and the general public in the Rochester, MN area. 49 persons aged 65-95 (79.5±7.0 years) who were ambulatory but sedentary and overweight participated in this randomized controlled crossover trial for one year. After a baseline period of 2 weeks, group 1 received an accelerometer and counseling using Go4Life educational material (www.Go4Life.nia.nih.gov) for 24 weeks and accelerometer alone for the next 24 weeks. Group 2 had no intervention for the first 24 weeks and then received an accelerometer and Go4Life based counseling for 24 weeks. There were no significant baseline differences between the two groups. The intervention was not associated with a significant change in activity, body weight, % body fat, or blood parameters (p>0.05). Older (80-93) subjects were less active than younger (65-79) subjects (p=0.003). Over the course of the 48 week study, an increase in activity level was associated with a decline in % body fat (p=0.008). Increasing activity levels benefits older patients. However, providing an accelerometer and a Go4Life based exercise counseling program did not result in a 15% improvement in activity levels in this elderly population. Alternate approaches to exercise counseling may be needed in elderly people of this age range.


Evolutionary dynamism in bryophytes: Phylogenomic inferences confirm rapid radiation in the moss family Funariaceae.
Rapid diversifications of plants are primarily documented and studied in angiosperms, which are perceived as evolutionarily dynamic. Recent studies have, however, revealed that bryophytes have also undergone periods of rapid radiation. The speciose family Funariaceae, including the model taxon Physcomitrella patens, is one such lineage. Here, we infer relationships among major lineages within the Entosthodon-Physcomitrium complex from virtually complete organellar exomes (i.e., 123 genes) obtained through high throughput sequencing of genomic libraries enriched in these loci via targeted locus capture. Based on these extensive exonic data we (1) reconstructed a robust backbone topology of the Funariaceae, (2) confirmed the monophyly of Funaria and the polyphyly of Entosthodon, Physcomitrella, and Physcomitrium, and (3) argue for the occurrence of a rapid radiation within the Entosthodon-Physcomitrium complex that began 28 mya and gave rise more than half of the species diversity of the family. This diversification may have been triggered by a whole genome duplication and coincides with global Eocene cooling that continued through the Oligocene and Miocene. The Funariaceae join a growing list of bryophyte lineages whose history is marked by at least one burst of diversification, and our study thereby strengthens the view that bryophytes are evolutionarily dynamic lineages and that patterns and processes characterizing the evolution of angiosperms may be universal among land plants.


Bacterial SLH domain proteins are non-covalently anchored to the cell surface via a conserved mechanism involving wall polysaccharide pyruvylation.
Several bacterial proteins are non-covalently anchored to the cell surface via an S-layer homology (SLH) domain. Previous studies have suggested that this cell surface display mechanism involves a non-covalent interaction between the SLH domain and peptidoglycan-associated polymers. Here we report the characterization of a two-gene operon, csaAB, for cell surface anchoring, in Bacillus anthracis. Its distal open reading frame (csaB) is required for the retention of SLH-containing proteins on the cell wall. Biochemical analysis of cell wall components showed that CsaB was involved in the addition of a pyruvyl group to a peptidoglycan-associated polysaccharide fraction, and that this modification was necessary for binding of the SLH domain. The csaAB operon is present in several bacterial species that synthesize SLH-containing proteins. This observation and the presence of pyruvate in the cell wall of the corresponding bacteria suggest that the mechanism described in this study is widespread among bacteria.


Polarization-independent adaptive lens with two different blue-phase liquid-crystal layers.
An adaptive microlens structure is proposed using two polymer-stabilized blue-phase liquid-crystal layers whose Kerr constant is largely mismatched. This device exhibits several favorable features, such as polarization independence, simple structure, and good parabolic phase profile. Its applications for 2D/3D switchable displays and other photonic devices are emphasized.


Usability evaluation of the progress note construction set.
The Veterans Administration (VA) Computerized Patient Record System (CPRS) is a nationally deployed software product that integrates provider order entry, progress notes, vitals, consults, discharge summaries, problem lists, medications, labs, radiology, transcribed documents, study reports, and clinical reminders. Users rapidly adopted the graphical user interface for data retrieval, but demanded options to typing for data entry. We programmed "point and click" forms that integrate with CPRS individually, but were soon overwhelmed by requests. Subsequently, we developed the Progress Note Construction Set (PNCS); a tool suite that permits subject matter experts without programming skills to create reusable "point and click" forms. In this study, we evaluate the usability of these user-constructed forms. An untrained, non-VA subject matter expert used the PNCS to create a graphical form for "skin tear" documentation. Ten VA nurses used the skin tear form to document findings for 7 standardized clinical scenarios. Following each scenario the subjects answered usability questions about the form. The subject matter expert created the skin tear form in 78 minutes. Users found the form to facilitate their data entry (p 0.0265), and to be at least as fast (p 0.0029) and as easy to use as expected (p 0.0166). Average note entry time was 3.4 minutes. The PNCS allowed a non-programmer to quickly create a usable, CPRS-integrated point and click form. Users found the subject matter expert s form fast and easy to use. The tool suite is a more scaleable form creation method because capacity is no longer limited by programmer availability.


Mandible position and activation of submental and masseter muscles during sleep.
Movement of the mandible could influence pharyngeal airway caliber because the mandible is attached to the tongue and to muscles that insert on the hyoid bone. In normal subjects and patients with obstructive sleep apnea (OSA) we measured jaw position during sleep with strain gauges, as well as masseter and submental electromyograms, airflow, esophageal pressure, oximetry, electroencephalograms, and electrooculograms. Jaws of patients with OSA were open more than those of normal subjects at end expiration and opened further at end inspiration, particularly at the termination of apneas when the masseter and submental muscles contracted. Masseter activation occurred only in patients with OSA and in a pattern similar to that of submental muscles. Jaw opening at end expiration could narrow the upper airway, whereas opening at end inspiration could reflect efforts to expand the airway with tracheal tug and with submental muscle activation and efforts to open the mouth to allow mouth breathing. Masseter contraction does not close the jaw but may serve to stabilize it.


Ibuprofen does not affect serum electrolyte concentrations after an ultradistance run.
To determine the effects of ibuprofen on serum electrolyte concentrations after a 160 km running race. Twenty nine subjects (mean (SD) age 47.9 (7.4) years) ingested 600 mg ibuprofen the day before, and 1200 mg ibuprofen during, a 160 km competitive trail running race (approximately every 4 h in 200 mg doses). Twenty five control subjects (mean (SD) age 46.8 (10.3) years) avoided ingestion of ibuprofen before or during the race. Blood was drawn on the day before the race and immediately after the race. Serum biochemical profiles were analysed by a clinical laboratory. Significant effects of treatment and time were determined with a general linear model with repeated measures. Subjects in the two groups did not differ by age, training volume, race experience, body mass index, body fat, or finishing time (25.8 (3.3) vs 25.6 (3.9) h). Body weight did not change significantly over the race (measured before, mid-race (90 km), and after). Ibuprofen ingestion did not significantly affect any of the serum markers including creatine kinase (p = 0.16). A significant decrease in serum sodium (p = 0.006), potassium (p = 0.001), chloride (p<0.001), calcium (p<0.001), albumin (p<0.001) and globulin (p<0.001) was observed after the race. Increases were seen in creatine kinase (p<0.001), creatinine (p<0.001), blood urea nitrogen (p<0.001), uric acid (p<0.001) and glucose (p<0.001) as the result of the race. These data suggest that the non-specific cyclo-oxygenase inhibitor, ibuprofen, does not alter serum electrolyte concentrations during ultradistance running. However, the stress of ultradistance running appears to be related to significant changes in certain serum markers.


Enhanced coherent terahertz Smith-Purcell superradiation excited by two electron-beams.
This paper presents the studies on the enhanced coherent THz Smith-Purcell superradiation excited by two pre-bunched electron beams that pass through the 1-D sub-wavelength holes array. The Smith-Purcell superradiation has been clearly observed. The radiation emitting out from the system has the radiation angle matching the 2nd harmonic frequency component of the pre-bunched electron beams. The results show that the two electron beams can be coupled with each other through the holes array so that the intensity of the radiated field has been enhanced about twice higher than that excited by one electron beam. Consequently superradiation at the frequency of 0.62 THz can be generated with 20A/cm(2) current density of electron beam based on above mechanism. The advantages of low injection current density and 2nd harmonic radiation promise the potential applications in the development of electron-beam driven THz sources.


Multiple Time-of-Flight/Time-of-Flight Events in a Single Laser Shot for Improved Matrix-Assisted Laser Desorption/Ionization Tandem Mass Spectrometry Quantification.
Quantitative matrix-assisted laser desorption/ionization time-of-flight (MALDI TOF) approaches have historically suffered from poor accuracy and precision mainly due to the nonuniform distribution of matrix and analyte across the target surface, matrix interferences, and ionization suppression. Tandem mass spectrometry (MS/MS) can be used to ensure chemical specificity as well as improve signal-to-noise ratios by eliminating interferences from chemical noise, alleviating some concerns about dynamic range. However, conventional MALDI TOF/TOF modalities typically only scan for a single MS/MS event per laser shot, and multiplex assays require sequential analyses. We describe here new methodology that allows for multiple TOF/TOF fragmentation events to be performed in a single laser shot. This technology allows the reference of analyte intensity to that of the internal standard in each laser shot, even when the analyte and internal standard are quite disparate in m/z, thereby improving quantification while maintaining chemical specificity and duty cycle. In the quantitative analysis of the drug enalapril in pooled human plasma with ramipril as an internal standard, a greater than 4-fold improvement in relative standard deviation (<10%) was observed as well as improved coefficients of determination (R2) and accuracy (>85% quality controls). Using this approach we have also performed simultaneous quantitative analysis of three drugs (promethazine, enalapril, and verapamil) using deuterated analogues of these drugs as internal standards.


Professor Toshio Ito: a clairvoyant in pericyte biology.
Ito cells are liver-specific pericytes which were first described as Fett Speicherung Zellen, the fat-storing cells encircling outside sinusoidal endothelial cells, in 1951 by the late professor Toshio Ito. His pioneering approaches for morphological characterization of the cells stimulate investigators to further examine their functional roles in liver homeostasis: a body of evidence has been accumulated in recent years showing that the cells play a crucial role in storage and delivery of vitamin A, regulation of sinusoidal tone and local blood supply, and tissue repair and fibrosis. It is now widely accepted that microvascular pericytes including Ito cells serve as a key player that controls angiogenesis. Furthermore, recent studies support a concept that Ito cells constitutes a bridging apparatus mediating bidirectional metabolic interactions between sinusoids and hepatocytes, utilizing prostanoids and/or gaseous mediators such as nitric oxide and carbon monoxide as signaling molecules. This article reviews researches on this liver-specific pericyte and its leading roles in recent development of pericyte biology.


Linezolid and tiamulin cross-resistance in Staphylococcus aureus mediated by point mutations in the peptidyl transferase center.
Oxazolidinone and pleuromutilin antibiotics are currently used in the treatment of staphylococcal infections. Although both antibiotics inhibit protein synthesis and have overlapping binding regions on 23S rRNA, the potential for cross-resistance between the two classes through target site mutations has not been thoroughly examined. Mutants of Staphylococcus aureus resistant to linezolid were selected and found to exhibit cross-resistance to tiamulin, a member of the pleuromutilin class of antibiotics. However, resistance was unidirectional because mutants of S. aureus selected for resistance to tiamulin did not exhibit cross-resistance to linezolid. This contrasts with the recently described PhLOPS(A) phenotype, which confers resistance to both oxazolidinones and pleuromutilins. The genotypes responsible for the phenotypes we observed were examined. Selection with tiamulin resulted in recovery of mutants with changes in the single-copy rplC gene (Gly155Arg, Ser158Leu, or Arg149Ser), whereas selection with linezolid led to recovery of mutants with changes (G2576U in 23S rRNA) in all five copies of the multicopy operon rrn. In contrast, cross-resistance to linezolid was exhibited by tiamulin-resistant mutants generated in a single-copy rrn knockout strains of Escherichia coli, illustrating that the copy number of 23S rRNA is the limiting factor in the selection of 23S rRNA tiamulin-resistant mutants. The interactions of linezolid and tiamulin with the ribosome were modeled to seek explanations for resistance to both classes in the 23S rRNA mutants and the lack of cross-resistance between tiamulin and linezolid following mutation in rplC.


Minoxidil for severe hypertension after failure of other hypotensive drugs.
Forty-four patients with severe hypertension who were resistant to treatment with more conventional hypotensive drugs or could not tolerate the side effects were treated with minoxidil, a potent peripheral vasodilator. A beta-blocking drug and a diuretic were used routinely to control, respectively, the tachycardia and fluid retention caused by minoxidil. During treatment the outpatient supine blood pressure fell from a mean of 221/134 mm Hg to 162/98 mm Hg. Eleven patients required additional or alternative hypotensive agents before blood pressure was adequately controlled. Side effects were minor, although the invariable hirsuties caused by minoxidil was unacceptable to three women. The possibility of cardiotoxic effects, raised by early studies in dogs, has not been excluded, and therefore this drug should be used only in patients with severe hypertension. In such patients minoxidil appears to be most effective.


The linear accuracy of impressions and stone dies as affected by the thickness of the impression margin.
This study compared the dimensional accuracy of impressions and dies made from a metal model simulating prepared abutments and having gingival sulci of varying widths. Measurements of the abutments, impressions, and stone dies were made using a travelling microscope, and the number of defects in each impression was recorded. The impressions and dies made from abutments with narrower sulci showed greater distortions. Analysis of variance and the Fisher PLSD post hoc test indicated significant differences between the group having a sulcular width of 0.08 mm and the groups having larger sulcular widths for the impressions and for the dies (P < .05). The large coefficient of variation occurring groups having 0.08-, 0.13-, and 0.18-mm sulcular widths demonstrated the difficulty of consistently obtaining good impressions of abutments having such narrow sulcular widths. Between 50% and 90% of abutment impressions having sulcular widths of 0.08 and 0.13 mm had defects.


Diabetes mellitus attenuates the pressure response against hypotensive stress by impairing the sympathetic regulation of the baroreflex afferent arc.
Patients with diabetes mellitus (DM) often show arterial pressure (AP) lability associated with cardiovascular autonomic neuropathy. Because the arterial baroreflex tightly regulates AP via sympathetic nerve activity (SNA), we investigated the systematic baroreflex function, considering the control theory in DM by open-loop analysis. We used Zucker diabetic fatty (ZDF) rats as a type 2 DM model. Under general anesthesia, we isolated the carotid sinuses from the systemic circulation, changed intracarotid sinus pressure (CSP), and recorded SNA and AP responses. We compared CSP-AP (total loop), CSP-SNA (afferent arc), and SNA-AP (efferent arc) relationships between ZDF lean ( n = 8) and ZDF fatty rats ( n = 6). Although the total loop gain of baroreflex (ΔAP/ΔCSP) at the operating point did not differ between the two groups, the average gain in the lower CSP range was markedly reduced in ZDF fatty rats (0.03 ± 0.01 vs. 0.87 ± 0.10 mmHg/mmHg, P < 0.001). The afferent arc showed the same trend as the total loop, with a response threshold of 139.8 ± 1.0 mmHg in ZDF fatty rats. There were no significant differences in the gain of efferent arc between the two groups. Simulation experiments indicated a markedly higher AP fall and lower total loop gain of baroreflex in ZDF fatty rats than in ZDF lean rats against hypotensive stress because the efferent arc intersected with the afferent arc in the SNA unresponsive range. Thus, we concluded that impaired baroreflex sympathetic regulation in the lower AP range attenuates the pressure response against hypotensive stress and may partially contribute to AP lability in DM. NEW & NOTEWORTHY In this study, we investigated the open-loop baroreflex function, considering the control theory in type 2 diabetes mellitus model rats to address the systematic mechanism of arterial pressure (AP) lability in diabetes mellitus. The unresponsiveness of baroreflex sympathetic regulation in the lower AP range was observed in type 2 diabetic rats. It may attenuate the baroreflex pressure-stabilizing function and induce greater AP fall against hypotensive stress.


Arsenic availability from chromated copper arsenate (CCA)-treated wood.
Lumber used to construct raised garden beds is often treated with chromated copper arsenate (CCA). This project aimed to determine (i) how far As, Cu, and Cr had diffused away from CCA-treated wood surfaces in raised garden beds under realistic conditions, (ii) the uptake of these elements by crops, and (iii) the effect of CCA solution on soil bacteria. This study showed that As, Cu, and Cr diffuse into soil from CCA-treated wood used to construct raised garden beds. To determine crop uptake of these elements, contaminated soil 0 to 2 cm from the treated wood was obtained from two different beds (40-50 mg kg(-1) As); control soil was collected 1.5 m away from the treated wood (<3-10 mg kg(-1) As). Four replicates of carrot (Daucus carota var. sativus Hoffm. cv. Thumbelina), spinach (Spinacia oleracea L. cv. Indian Summer), bush bean (Phaseolus vulgaris L. cv. Provider), and buckwheat (Fagopyrum esculentum Moench cv. Common) were grown in pots containing these soils in a greenhouse. After harvest, plant materials were dried, ground, digested, and analyzed for As by inductively coupled plasma-hydride generation (ICP-HG). Concentrations of As in all crops grown in contaminated soils were higher than those from control soils. The levels of As in the crops remained well below the recommended limit for As set by the United States Public Health Service (2.6 mg kg(-1) fresh wt.). To determine if bacteria in soils 0 to 2 cm from the treated wood had higher resistance to Type C chromated copper arsenate (CCA-C) solution than those from reference soils, dilution plates were set up using quarter-strength tryptic soy agar (TSA) media and 0 to 22.94 g L(-1) (0-1.25% v/v) CCA-C working solution. The microorganisms from soils adjacent to treated wood had greater growth on the CCA-amended media than those from reference soils outside the bed.


Value-Based Pricing Alternatives for Personalised Drugs: Implications of Asymmetric Information and Competition.
The market for new drugs is changing: personalised drugs will increase the heterogeneity in patients' responses and, possibly, costs. In this context, price regulation will play an increasingly important role. In this article, we argue that personalised medicine opens new scenarios in the relationship between value-based prices, regulation and industry listing strategies. Our focus is on the role of asymmetry of information and competition. We show that, if the firm has more information than the payer on the heterogeneity in patients' responses and it adopts a profit-maximising listing strategy, the outcome may be independent of the choice of the type of value-based price. In this case, the information advantage that the manufacturer has prevents the payer from using marginal value-based prices to extract part of the surplus. However, in a dynamic setting where competition by a new entrant is possible, the choice of the type of value-based price may matter. We suggest that more research should be devoted to the dynamic analysis of price regulation for personalised medicines.


The effect of glucosamine and/or chondroitin sulfate on the progression of knee osteoarthritis: a report from the glucosamine/chondroitin arthritis intervention trial.
Osteoarthritis (OA) of the knee causes significant morbidity and current medical treatment is limited to symptom relief, while therapies able to slow structural damage remain elusive. This study was undertaken to evaluate the effect of glucosamine and chondroitin sulfate (CS), alone or in combination, as well as celecoxib and placebo on progressive loss of joint space width (JSW) in patients with knee OA. A 24-month, double-blind, placebo-controlled study, conducted at 9 sites in the United States as part of the Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT), enrolled 572 patients with knee OA who satisfied radiographic criteria (Kellgren/Lawrence [K/L] grade 2 or grade 3 changes and JSW of at least 2 mm at baseline). Patients with primarily lateral compartment narrowing at any time point were excluded. Patients who had been randomized to 1 of the 5 groups in the GAIT continued to receive glucosamine 500 mg 3 times daily, CS 400 mg 3 times daily, the combination of glucosamine and CS, celecoxib 200 mg daily, or placebo over 24 months. The minimum medial tibiofemoral JSW was measured at baseline, 12 months, and 24 months. The primary outcome measure was the mean change in JSW from baseline. The mean JSW loss at 2 years in knees with OA in the placebo group, adjusted for design and clinical factors, was 0.166 mm. No statistically significant difference in mean JSW loss was observed in any treatment group compared with the placebo group. Treatment effects on K/L grade 2 knees, but not on K/L grade 3 knees, showed a trend toward improvement relative to the placebo group. The power of the study was diminished by the limited sample size, variance of JSW measurement, and a smaller than expected loss in JSW. At 2 years, no treatment achieved a predefined threshold of clinically important difference in JSW loss as compared with placebo. However, knees with K/L grade 2 radiographic OA appeared to have the greatest potential for modification by these treatments.


Magnetic targeting to enhance microbubble delivery in an occluded microarterial bifurcation.
Ultrasound and microbubbles have been shown to accelerate the breakdown of blood clots both in vitro and in vivo. Clinical translation of this technology is still limited, however, in part by inefficient microbubble delivery to the thrombus. This study examines the obstacles to delivery posed by fluid dynamic conditions in occluded vasculature and investigates whether magnetic targeting can improve microbubble delivery. A 2D computational fluid dynamic model of a fully occluded Y-shaped microarterial bifurcation was developed to determine: (i) the fluid dynamic field in the vessel with inlet velocities from 1-100 mm s-1 (corresponding to Reynolds numbers 0.25-25); (ii) the transport dynamics of fibrinolytic drugs; and (iii) the flow behavior of microbubbles with diameters in the clinically-relevant range (0.6-5 µm). In vitro experiments were carried out in a custom-built microfluidic device. The flow field was characterized using tracer particles, and fibrinolytic drug transport was assessed using fluorescence microscopy. Lipid-shelled magnetic microbubbles were fluorescently labelled to determine their spatial distribution within the microvascular model. In both the simulations and experiments, the formation of laminar vortices and an abrupt reduction of fluid velocity were observed in the occluded branch of the bifurcation, severely limiting drug transport towards the occlusion. In the absence of a magnetic field, no microbubbles reached the occlusion, remaining trapped in the first vortex, within 350 µm from the bifurcation center. The number of microbubbles trapped within the vortex decreased as the inlet velocity increased, but was independent of microbubble size. Application of a magnetic field (magnetic flux density of 76 mT, magnetic flux density gradient of 10.90 T m-1 at the centre of the bifurcation) enabled delivery of microbubbles to the occlusion and the number of microbubbles delivered increased with bubble size and with decreasing inlet velocity.


Independent mechanisms for bright and dark image features in a stereo correspondence task.
A pioneering study by J. M. Harris and A. J. Parker (1995) found that disparity judgments using random-dot stereograms were better for stimuli composed of mixed bright and dark dots than when the dots were all bright or all dark. They attribute this to an improvement in stereo correspondence. This result is hard to explain within current models of how stereo correspondence is achieved. However, their experiment varied task difficulty by adding disparity noise. We wondered if this might challenge mechanisms subsequent to the solution of the correspondence problem rather than mechanisms that solve the correspondence problem itself. If so, this would avoid the need to modify current models of stereo correspondence. We therefore repeated Harris and Parker's experiment using interocular decorrelation to vary task difficulty. This technique is believed to probe stereo correspondence more specifically. We observed the efficiency increase reported by Harris and Parker for mixed-polarity dots both using their original technique of disparity noise and using interocular decorrelation. We show that this effect cannot be accounted for by the stereo energy or by simple modifications of it. Our results confirm Harris and Parker's original conclusion that mixed-polarity dots specifically benefit stereo correspondence and point up the challenge to current models of this process.


Caffeine occupancy of human cerebral A1 adenosine receptors: in vivo quantification with 18F-CPFPX and PET.
Caffeine is the neuroactive agent in coffee and tea and is a broadly consumed stimulant. It is a nonselective antagonist of the neuromodulator adenosine and, if applied in commonly consumed doses, evokes its stimulating effects through the blockade of adenosine receptors. (18)F-8-cyclopentyl-3-(3-fluoropropyl)-1-propylxanthine ((18)F-CPFPX) has been established as a highly selective and affine PET ligand for the A(1) adenosine receptor (A(1)AR). The objective of the present study was to visualize and quantify the in vivo occupancy of the human cerebral A(1)AR by caffeine using (18)F-CPFPX and PET. Fifteen subjects (age range, 24-68 y) underwent a 140-min bolus-plus-constant-infusion PET experiment after at least 36 h of caffeine abstinence. Metabolite-corrected blood data were used to calculate steady-state distribution volumes (V(T)) during the baseline condition of the scan between 70 and 90 min. Subsequently, subjects received a 10-min infusion of varying concentrations (0.5-4.3 mg/kg of body weight) of caffeine at 90 min. Occupancy V(T) of the A(1)AR was thereafter estimated using data acquired between 120 and 140 min. Occupancy levels were calculated using the Lassen plot, from which the inhibitory concentrations of 50% were derived. Plasma levels of caffeine were determined at regular intervals. One subject received an intravenous vehicle as a placebo. Caffeine displaced 5%-44% of (18)F-CPFPX binding in a concentration-dependent manner. There was no change of radioligand binding after the administration of placebo. Half-maximal displacement was achieved at a plasma caffeine concentration of 67 μM, which corresponds to 450 mg in a 70-kg subject or approximately 4.5 cups of coffee. Given a biologic half-life of about 5 h, caffeine might therefore occupy up to 50% of the cerebral A(1)AR when caffeinated beverages are repeatedly consumed during a day. Furthermore, the present study provides evidence that (18)F-CPFPX PET is suitable for studying the cerebral actions of caffeine, the most popular neurostimulant worldwide.


Short exposure to high levels of fluoride induces stage-dependent structural changes in ameloblasts and enamel mineralization.
We tested the hypothesis that the sensitivity of forming dental enamel to fluoride (F-) is ameloblast developmental stage-dependent and that enamel mineralization disturbances at the surface of fluorotic enamel are caused by damage to late-secretory- and transitional-stage ameloblasts. Four-day-old hamsters received a single intraperitoneal dose of 2.5-20 mg NaF/kg body weight and were examined, 24 h later, by histology and histochemistry. A single dose of >or=5 mg of NaF/kg induced the formation of a hyper- followed by a hypomineralized band in the secretory enamel, without changing the ameloblast structure. At 10 mg of NaF/kg, cystic lesions became apparent under isolated populations of distorted late-secretory- and transitional-stage ameloblasts. Staining with von Kossa stain showed that the enamel under these lesions was hypermineralized. At 20 mg of NaF/kg, cystic lesions containing necrotic cells were also found in the early stages of secretory amelogenesis and were also accompanied with hypermineralization of the enamel surface. We concluded that the sensitivity to F- is ameloblast developmental stage-dependent. Groups of transitional ameloblasts are most sensitive, followed by those at early secretory stages. These data suggest that a F-induced increase in cell death in the transitional-stage ameloblasts accompanies the formation of cystic lesions, which may explain the formation of enamel pits seen clinically in erupted teeth.


Minimally Invasive Combined Nd:YAG and Er:YAG Laser-Assisted Uvulopalatoplasty for Treatment of Obstructive Sleep Apnea.
Objective: In this article, efficacy of minimally invasive outpatient laser-assisted uvulopalatoplasty (LAUP) procedure (NightLase® LAUP) to reduce apnea-hypopnea index (AHI) in patients with obstructive sleep apnea (OSA) is evaluated. Background: OSA is a serious condition, but its treatment is often not effective or is poorly accepted by patients. Newer modes of therapy that are more effective and also more accepted by patients need to be developed. The latest treatment approaches involve a minimally invasive LAUP procedure. This procedure involves thermal processing of the relaxed soft palate and surrounding tissues using neodimium-doped yttrium aluminum garnet (Nd:YAG) and erbium-doped yttrium aluminum garnet (Er:YAG) lasers, resulting in favorable collagen shrinkage and development of new collagen fibers. Procedure has previously been reported to safely and effectively reduce snoring, as well as increase the volume of the oropharyngeal airway, and is well accepted by patients. Materials and methods: The efficacy of the minimally invasive LAUP procedure, combining Nd:YAG laser (λ = 1064 nm) and Er:YAG laser (λ = 2940 nm) applied to the soft palate for treatment of OSA on 27 patients with different severities of OSA was evaluated based on AHI measurements before and after only three 20-min sessions in an outpatient setting over a period of 45-60 days. Results: A decrease in AHI for all the patients with different severities of OSA tested in this study was achieved, with 66.3% average improvement (32-100%). Fifty percent or more improvement was achieved in 78% (21) of all patients. Conclusions: Based on our observations, the NightLase® LAUP treatment of OSA represents an effective and safe therapeutic method. Further research and longer term prospective trials are needed to improve the evidence base for the potential integration of this treatment method into the current guidelines for treatment of OSA.


MAZ-dependent termination between closely spaced human complement genes.
The zinc finger protein MAZ, originally identified as a factor that binds to the c-myc P2 promoter, is associated with transcriptional termination. As shown in these studies, a termination sequence between the closely spaced human complement genes C2 and Factor B contains a protein binding site which interacts with three different proteins in vitro. Binding of one of these factors, MAZ, correlates with activity of the C2 termination sequence in vivo. Cloned MAZ was used to obtain a consensus binding site, G5AG5. This allowed identification of new sites, between the closely spaced human genes g11 and C4 and within an intron of the mouse IgM-D gene, where termination is known to occur and regulate the expression of IgD. The g11 and IgM MAZ sites lie within sequences that have activity in a termination assay and, furthermore, mutation of C2 or g11 MAZ sites severely reduces termination activity. MAZ bends DNA, and inherently bent DNA is highly active as a terminator, suggesting that MAZ-induced bending is important for C2 and g11 termination. We propose that MAZ sites exist in promoters which require protection against transcriptional interference, such as those of closely spaced genes, to cause efficient termination. The MAZ consensus sequence will facilitate the identification of further sites.


Fenretinide mediated retinoic acid receptor signalling and inhibition of ceramide biosynthesis regulates adipogenesis, lipid accumulation, mitochondrial function and nutrient stress signalling in adipocytes and adipose tissue.
Fenretinide (FEN) is a synthetic retinoid that inhibits obesity and insulin resistance in high-fat diet (HFD)-fed mice and completely prevents 3T3-L1 pre-adipocyte differentiation. The aim of this study was to determine the mechanism(s) of FEN action in 3T3-L1 adipocytes and in mice. We used the 3T3-L1 model of adipogenesis, fully differentiated 3T3-L1 adipocytes and adipose tissue from HFD-induced obese mice to investigate the mechanisms of FEN action. We measured expression of adipogenic and retinoid genes by qPCR and activation of nutrient-signalling pathways by western blotting. Global lipid and metabolite analysis was performed and specific ceramide lipid species measured by liquid chromatography-mass spectrometry. We provide direct evidence that FEN inhibits 3T3-L1 adipogenesis via RA-receptor (RAR)-dependent signaling. However, RARα antagonism did not prevent FEN-induced decreases in lipid levels in mature 3T3-L1 adipocytes, suggesting an RAR-independent mechanism. Lipidomics analysis revealed that FEN increased dihydroceramide lipid species 5- to 16-fold in adipocytes, indicating an inhibition of the final step of ceramide biosynthesis. A similar blockade in adipose tissue from FEN-treated obese mice was associated with a complete normalisation of impaired mitochondrial β-oxidation and tricarboxylic acid cycle flux. The FEN catabolite, 4-oxo-N-(4-hydroxyphenyl)retinamide (4-OXO), also decreased lipid accumulation without affecting adipogenesis. FEN and 4-OXO (but not RA) treatment additionally led to the activation of p38-MAPK, peIF2α and autophagy markers in adipocytes. Overall our data reveals FEN utilises both RAR-dependent and -independent pathways to regulate adipocyte biology, both of which may be required for FEN to prevent obesity and insulin resistance in vivo.


A systematic review and meta-analysis to revise the Fenton growth chart for preterm infants.
The aim of this study was to revise the 2003 Fenton Preterm Growth Chart, specifically to: a) harmonize the preterm growth chart with the new World Health Organization (WHO) Growth Standard, b) smooth the data between the preterm and WHO estimates, informed by the Preterm Multicentre Growth (PreM Growth) study while maintaining data integrity from 22 to 36 and at 50 weeks, and to c) re-scale the chart x-axis to actual age (rather than completed weeks) to support growth monitoring. Systematic review, meta-analysis, and growth chart development. We systematically searched published and unpublished literature to find population-based preterm size at birth measurement (weight, length, and/or head circumference) references, from developed countries with: Corrected gestational ages through infant assessment and/or statistical correction; Data percentiles as low as 24 weeks gestational age or lower; Sample with greater than 500 infants less than 30 weeks. Growth curves for males and females were produced using cubic splines to 50 weeks post menstrual age. LMS parameters (skew, median, and standard deviation) were calculated. Six large population-based surveys of size at preterm birth representing 3,986,456 births (34,639 births < 30 weeks) from countries Germany, United States, Italy, Australia, Scotland, and Canada were combined in meta-analyses. Smooth growth chart curves were developed, while ensuring close agreement with the data between 24 and 36 weeks and at 50 weeks. The revised sex-specific actual-age growth charts are based on the recommended growth goal for preterm infants, the fetus, followed by the term infant. These preterm growth charts, with the disjunction between these datasets smoothing informed by the international PreM Growth study, may support an improved transition of preterm infant growth monitoring to the WHO growth charts.


Dairy products and physical stature: a systematic review and meta-analysis of controlled trials.
The positive relationship between per capita availability of dairy products and average height found in historical studies (for instance in nineteenth century Bavaria, Prussia and France; Baten, 2009) does not necessarily indicate a causal relationship. Historical studies usually apply non-experimental methods that may produce substantial bias. Modern experimental controlled studies may provide high quality evidence supporting a causal relationship between consumption of dairy products and physical growth. This paper provides a systematic review and meta-analysis of controlled trials investigating the effect of supplementing usual diet with dairy products on physical growth. Twelve studies provided sufficient, independent data for meta-analysis. Seven studies were conducted since the 1990s. The other studies were conducted between 1926 and 1980. Studies were conducted in Europe, USA, China, Northern Vietnam, Kenya, Indonesia and India. Many studies had some internal validity problems such as lack of randomisation or dissimilarity of groups at baseline regarding height and age, which affects the quality of evidence. Meta-analysis and sensitivity analysis showed that the most likely effect of dairy products supplementation is 0.4 cm per annum additional growth per ca 245 ml of milk daily. Meta-regression analysis indicated that milk might have more effect on growth than other dairy products while lower height-for-age and being a teenager increased the effect of supplementation. In conclusion, there is moderate quality evidence that dairy products supplementation stimulate linear growth supporting hypotheses that changing levels of consumption of dairy products in the 19th and 20th centuries contributed to trends in height.


The "motion silencing" illusion results from global motion and crowding.
Suchow and Alvarez (2011) recently devised a striking illusion, where objects changing in color, luminance, size, or shape appear to stop changing when they move. They refer to the illusion as "motion silencing of awareness to visual change." Here we present evidence that the illusion results from two perceptual processes: global motion and crowding. We adapted Suchow and Alvarez's stimulus to three concentric rings of dots, a central ring of "target dots" flanked on either side by similarly moving flanker dots. Subjects had to identify in which of two presentations the target dots were continuously changing (sinusoidally) in size, as distinct from the other interval in which size was constant. The results show: (a) Motion silencing depends on target speed, with a threshold around 0.2 rotations per second (corresponding to about 10°/s linear motion). (b) Silencing depends on both target-flanker spacing and eccentricity, with critical spacing about half eccentricity, consistent with Bouma's law. (c) The critical spacing was independent of stimulus size, again consistent with Bouma's law. (d) Critical spacing depended strongly on contrast polarity. All results imply that the "motion silencing" illusion may result from crowding.


Organelle selection determines agonist-specific Ca2+ signals in pancreatic acinar and beta cells.
How different extracellular stimuli can evoke different spatiotemporal Ca2+ signals is uncertain. We have elucidated a novel paradigm whereby different agonists use different Ca2+-storing organelles ("organelle selection") to evoke unique responses. Some agonists select the endoplasmic reticulum (ER), and others select lysosome-related (acidic) organelles, evoking spatial Ca2+ responses that mirror the organellar distribution. In pancreatic acinar cells, acetylcholine and bombesin exclusively select the ER Ca2+ store, whereas cholecystokinin additionally recruits a lysosome-related organelle. Similarly, in a pancreatic beta cell line MIN6, acetylcholine selects only the ER, whereas glucose mobilizes Ca2+ from a lysosome-related organelle. We also show that the key to organelle selection is the agonist-specific coupling messenger(s) such that the ER is selected by recruitment of inositol 1,4,5-trisphosphate (or cADP-ribose), whereas lysosome-related organelles are selected by NAADP.


Chanzyme TRPM7 protects against cardiovascular inflammation and fibrosis.
Transient Receptor Potential Melastatin 7 (TRPM7) cation channel is a chanzyme (channel + kinase) that influences cellular Mg2+ homeostasis and vascular signalling. However, the pathophysiological significance of TRPM7 in the cardiovascular system is unclear. The aim of this study was to investigate the role of this chanzyme in the cardiovascular system focusing on inflammation and fibrosis. TRPM7-deficient mice with deletion of the kinase domain (TRPM7+/Δkinase) were studied and molecular mechanisms investigated in TRPM7+/Δkinase bone marrow-derived macrophages (BMDM) and co-culture systems with cardiac fibroblasts. TRPM7-deficient mice had significant cardiac hypertrophy, fibrosis, and inflammation. Cardiac collagen and fibronectin content, expression of pro-inflammatory mediators (SMAD3, TGFβ) and cytokines [interleukin (IL)-6, IL-10, IL-12, tumour necrosis factor-α] and phosphorylation of the pro-inflammatory signalling molecule Stat1, were increased in TRPM7+/Δkinase mice. These processes were associated with infiltration of inflammatory cells (F4/80+CD206+ cardiac macrophages) and increased galectin-3 expression. Cardiac [Mg2+]i, but not [Ca2+]i, was reduced in TRPM7+/Δkinase mice. Calpain, a downstream TRPM7 target, was upregulated (increased expression and activation) in TRPM7+/Δkinase hearts. Vascular functional and inflammatory responses, assessed in vivo by intra-vital microscopy, demonstrated impaired neutrophil rolling, increased neutrophil: endothelial attachment and transmigration of leucocytes in TRPM7+/Δkinase mice. TRPM7+/Δkinase BMDMs had increased levels of galectin-3, IL-10, and IL-6. In co-culture systems, TRPM7+/Δkinase macrophages increased expression of fibronectin, proliferating cell nuclear antigen, and TGFβ in cardiac fibroblasts from wild-type mice, effects ameliorated by MgCl2 treatment. We identify a novel anti-inflammatory and anti-fibrotic role for TRPM7 and suggest that its protective effects are mediated, in part, through Mg2+-sensitive processes.


The role of membrane-bound ankyrin-repeat protein ACD6 in programmed cell death and plant defense.
Programmed cell death (PCD) is a common defense response in plants against pathogen infection. The recently cloned ACD6 gene was identified in an Arabidopsis mutant, accelerated cell death 6 (acd6), that undergoes PCD in the absence of a pathogen challenge. ACD6 is a founding member of a large family of genes that encode proteins with a short amino-terminal region, nine ankyrin repeats in the middle, and five putative transmembrane domains in the carboxyl-terminal region. Characterization of the original gain-of-function acd6 mutant and a transferred-DNA knockout mutant acd6-T showed that ACD6 is an activator of the defense pathway against bacterial pathogens and plays a role in PCD through regulation of the defense signal salicylic acid (SA). SA mediates not only downstream pathogenesis-related (PR) genes, which encode proteins with antimicrobial activities, but also ACD6, forming a feedback signal amplification loop.


Circulating tumour cells detected by a novel adenovirus-mediated system may be a potent therapeutic marker in gynaecological cancers.
Recently developed detection system for circulating tumour cells (CTCs) using a telomerase-specific replicative adenovirus generated nonspecific green fluorescent protein (GFP) signals because of the co-presence of white blood cells (WBCs) nonspecifically infected by viruses. Here, we established a unique detection system for CTCs that completely excludes nonspecific signals. Blood obtained from the patients was subjected to haemolytic processes to eliminate red blood cells. The cell pellets were then infected with OBP-401, fixed, incubated with fluorescence-labelled anti-CD45 antibody to mark white blood WBCs, and examined on slides under a microscope. Preparatory experiments with cancer cells artificially added to healthy donor samples confirmed that CD45 labelling could distinguish GFP-positive cancer cells from WBCs. In 53 patients with gynaecological cancers, CTCs were detected in 21 patients (39.6%) when CD45-positive cells were excluded as WBCs among GFP-positive cells. No CTCs were detected in samples from healthy volunteers. There was no significant correlation between CTC counts and known clinicopathological factors. The CTCs rapidly vanished after surgery or chemotherapy in most patients whose treatments were effective. In contrast, the persistence of CTCs even after treatments was tightly associated with poor response to the treatments (P<0.005). The presence of CTCs in our system may potentially be a novel therapeutic marker in gynaecological cancers.


alpha2-Heremans-Schmid glycoprotein gene polymorphisms are associated with adipocyte insulin action.
The aim of this study was to investigate the effect of single-nucleotide polymorphisms (SNPs) in the gene encoding the human alpha(2)-Heremans-Schmid glycoprotein (AHSG) on obesity and insulin action in adipocytes. We screened 24 individuals for SNPs in AHSG. Six haplotype-tagging SNPs were genotyped in 188 lean and 176 obese otherwise healthy women for whom common blood chemistry phenotypes were also available. Adipocyte lipolysis and lipogenesis phenotypes were quantified in a subset of 117 lean and 174 obese women. The -469T>G SNP, which is located in the 5' region of AHSG, was associated with insulin-mediated inhibition of lipolysis and stimulation of lipogenesis, as well as basal and 8-bromocyclic AMP-stimulated lipolysis. Three AHSG SNPs were associated with circulating levels of cholesterol. None of the six genotyped SNPs or inferred haplotypes were associated with BMI, calculated percent body fat, waist circumference, circulating levels of glucose or insulin, or homeostasis model assessment of insulin resistance, which was used as an estimate of in vivo insulin sensitivity. Our results are in agreement with a threshold model of susceptibility for insulin resistance and type 2 diabetes, in which specific genetic loci regulate intermediate molecular phenotypes. When an individual's set of susceptibility alleles at such loci exceeds a threshold, clinical disease occurs. Lipolysis in adipocytes appears to be a phenotype that is particularly sensitive to variation in AHSG.


Epidemiology of Viral Hepatitis and Liver Diseases in Nepal.
Geographical and ethnic diversity in Nepal has led to interesting epidemiology of viral hepatitis and liver diseases. Before the epidemic of Biratnagar that occurred in April to June 2014, Kathmandu was the only known endemic region for hepatitis E virus infection (HEV), where at least four previous epidemics have been documented since 1973. Due to rapid urbanization with still low socioeconomic condition, other major cities are appreciated to be at increasing risk of outbreaks. Characteristics of HEV epidemics and genetic changes of HEV during last decade have been studied. While hepatitis A virus infection was only common during childhood till recent years, it is re-emerging as an important etiology of acute hepatitis in young adults. Nepal is classified as low endemic region for hepatitis B virus infection (HBV) with overall seroprevalence of 1.1%. But, some ethnic groups and geographical areas have high prevalence rates. Despite low endemicity, HBV accounts for majority of cases of hepatocellular carcinoma and liver cirrhosis in the country. Similarly, though hepatitis C virus (HCV) is present in only 0.4% of general population, high seroprevalence was found among intravenous drug abusers many of them with HIV coinfection. Apart from hepatitis viruses, alcohol use also contributes significantly to liver cirrhosis and chronic liver failure. A unique form of hepatic venous outflow obstruction called 'hepatic vena cava syndrome' has been identified as an important etiology of liver cirrhosis and hepatocellular carcinoma. Shrestha A. Epidemiology of Viral Hepatitis and Liver Diseases in Nepal. Euroasian J Hepato-Gastroenterol 2015;5(1):40-42.


Pilot prospective evaluation of 99mTc-MDP scintigraphy, 18F NaF PET/CT, 18F FDG PET/CT and whole-body MRI for detection of skeletal metastases.
The aim of this study was to compare 99mTc-MDP bone scanning, 18F NaF PET/CT, 18F FDG PET/CT, and whole-body MRI (WBMRI) for detection of known osseous metastases. This prospective pilot trial (September 2007-April 2009) enrolled 10 participants (5 men, 5 women, 47-81 years old) diagnosed with cancer and known osseous metastases. 18F NaF PET/CT, 18F FDG PET/CT, and WBMRI were performed within 1 month for each participant. The image quality and evaluation of extent of disease were superior by 18F NaF PET/CT compared to 99mTc-MDP scintigraphy in all patients with skeletal lesions and compared to 18F FDG PET/CT in 3 of the patients with skeletal metastases. 18F NaF PET/CT showed osseous metastases where 18F FDG PET/CT was negative in another 3 participants. Extraskeletal metastases were identified by 18F FDG PET/CT in 6 participants. WBMRI with the combination of iterative decomposition of water and fat with echo asymmetry and least-squares estimation, short tau inversion recovery, and diffusion-weighted imaging pulse sequences showed fewer lesions than 18F NaF PET/CT in 5 patients, same number of lesions in 2 patients, and more lesions in 1 patient. WBMRI showed fewer lesions than 18F FDG in 3 patients and same lesions in 6 patients. Our pilot phase prospective trial demonstrated superior image quality and evaluation of skeletal disease extent with 18F NaF PET/CT compared to 99mTc-MDP scintigraphy and 18F FDG PET/CT, as well as the feasibility of multisequence WBMRI. In addition, 18F FDG PET/CT provided valuable soft-tissue information that can change disease management. Further evaluation of these findings using the recently introduced PET/MRI scanners is warranted.


Tissue-engineered small intestine and stomach form from autologous tissue in a preclinical large animal model.
Tissue-engineered small intestine, stomach, large intestine, esophagus, and gastroesophageal (GE) junction have been successfully formed from syngeneic cells, and employed as a rescue therapy in a small animal model. The purpose of this study is to determine if engineered intestine and stomach could be generated in an autologous, preclinical large animal model, and to identify if the tissue-engineered intestine retained features of an intact stem cell niche. A short segment of jejunum or stomach was resected from 6-wk-old Yorkshire swine. Organoid units, multicellular clusters with predominantly epithelial content, were generated and loaded onto biodegradable scaffold tubes. The constructs were then implanted intraperitoneally in the autologous host. Seven wk later, all implants were harvested and analyzed using histology and immunohistochemistry techniques. Autologous engineered small intestine and stomach formed. Tissue-engineered intestinal architecture replicated that of native intestine. Histology revealed tissue-engineered small intestinal mucosa composed of a columnar epithelium with all differentiated intestinal cell types adjacent to an innervated muscularis mucosae. Intestinal subepithelial myofibroblasts, specialized cells that participate in the stem cell niche formation, were identified. Moreover, cells positive for the putative intestinal stem cell marker, doublecortin and CaM kinase-like-1 (DCAMKL-1) expression were identified at the base of the crypts. Finally, tissue-engineered stomach also formed with antral-type mucosa (mucus cells and surface foveolar cells) and a muscularis. We successfully generated tissue-engineered intestine with correct architecture, including features of an intact stem cell niche, in the pig model. To our knowledge, this is the first demonstration in which tissue-engineered intestine was successfully generated in an autologous manner in an animal model, which may better emulate a human host and the intended therapeutic pathway for humans.


Naturally induced secretions of the potato cyst nematode co-stimulate the proliferation of both tobacco leaf protoplasts and human peripheral blood mononuclear cells.
Naturally induced secretions from infective juveniles of the potato cyst nematode Globodera rostochiensis co-stimulate the proliferation of tobacco leaf protoplasts in the presence of the synthetic phytohormones alpha-naphthaleneacetic acid (NAA) and 6-benzylaminopurine (BAP). With the use of a protoplast-based bioassay, a low-molecular-weight peptide(s) (< 3 kDa) was shown to be responsible for the observed effect. This mitogenic oligopeptide(s) is functionally dissimilar to auxin and cytokinin and, in addition, it does not change the sensitivity of the protoplasts toward these phytohormones. In combination with the mitogen phytohemagglutinin (PHA), cyst nematode secretions also co-stimulated mitogenesis in human peripheral blood mononuclear cells (PBMC). The stimulation of plant cells isolated from nontarget tissue--these nematodes normally invade the roots of potato plants--suggests the activation of a general signal transduction mechanism(s) by an oligopeptide(s) secreted by the nematode. Whether a similar oligopeptide-induced mechanism underlies human PBMC activation remains to be investigated. Reactivation of the cell cycle is a crucial event in feeding cell formation by cyst nematodes. The secretion of a mitogenic low-molecular-weight peptide(s) by infective juveniles of the potato cyst nematode could contribute to the redifferentiation of plant cells into such a feeding cell.


Intracellular Mycoplasma genitalium infection of human vaginal and cervical epithelial cells elicits distinct patterns of inflammatory cytokine secretion and provides a possible survival niche against macrophage-mediated killing.
Mycoplasma genitalium is an emerging sexually transmitted pathogen that has been associated with significant reproductive tract inflammatory syndromes in women. In addition, the strong association between severity of M. genitalium infection and Human Immunodeficiency Virus type 1 (HIV-1) shedding from the cervix suggests that innate responses to M. genitalium may influence pathogenesis of other sexually transmitted infections. Epithelial cells (ECs) of the reproductive mucosa are the first cells contacted by sexually transmitted pathogens. Therefore, we first characterized the dynamics of intracellular and extracellular localization and resultant innate immune responses from human vaginal, ecto- and endocervical ECs to M. genitalium type strain G37 and a low-pass contemporary isolate, M2300. Both M. genitalium strains rapidly attached to vaginal and cervical ECs by 2 h post-infection (PI). By 3 h PI, M. genitalium organisms also were found in intracellular membrane-bound vacuoles of which approximately 60% were adjacent to the nucleus. Egress of M. genitalium from infected ECs into the culture supernatant was observed but, after invasion, viable intracellular titers were significantly higher than extracellular titers at 24 and 48 h PI. All of the tested cell types responded by secreting significant levels of pro-inflammatory cytokines and chemokines in a pattern consistent with recruitment and stimulation of monocytes and macrophages. Based on the elaborated cytokines, we next investigated the cellular interaction of M. genitalium with human monocyte-derived macrophages and characterized the resultant cytokine responses. Macrophages rapidly phagocytosed M. genitalium resulting in a loss of bacterial viability and a potent pro-inflammatory response that included significant secretion of IL-6 and other cytokines associated with enhanced HIV-1 replication. The macrophage-stimulating capacity of M. genitalium was independent of bacterial viability but was sensitive to heat denaturation and proteinase-K digestion suggesting that M. genitalium protein components are the predominant mediators of inflammation. Collectively, the data indicated that human genital ECs were susceptible and immunologically responsive to M. genitalium infection that likely induced cellular immune responses. Although macrophage phagocytosis was an effective method for M. genitalium killing, intracellular localization within vaginal and cervical ECs may provide M. genitalium a survival niche and protection from cellular immune responses thereby facilitating the establishment and maintenance of reproductive tract infection.


Measurement of birefringence of low-loss, high-reflectance coating of m-axis sapphire.
The birefringence of a low-loss, high-reflectance coating applied to an 8-cm-diameter sapphire crystal grown in the m-axis direction has been mapped. By monitoring the transmission of a high-finesse Fabry-Perot cavity as a function of the polarization of the input light, we find an upper limit for the magnitude of the birefringence of 2.5 x 10(-4) rad and an upper limit in the variation in direction of the birefringence of 10 deg. These values are sufficiently small to allow consideration of m-axis sapphire as a substrate material for the optics of the advanced detector at the Laser Interferometer Gravitational Wave Observatory.


Normative database for corneal backscatter analysis by in vivo confocal microscopy.
To ascertain the sex and age relatedness, diurnal variation, and repeatability of backscatter measurement in the normal human cornea. Seven corneal backscatter variants were measured by in vivo confocal microscopy (IVCM) in both normal eyes (n = 314) of 157 healthy subjects. These subjects were assigned to one or more of three groups. The sex and age relatedness of corneal backscatter were assessed in group 1 (n = 300), which comprised 75 men and 75 women evenly distributed over five age categories. To assess diurnal variation, eyes in group 2 (n = 40) were measured four times a day, at 3-hour intervals. The eyes in group 3 (n = 50) were examined four times a year to determine intersession repeatability. Intrasession repeatability was determined by performing all IVCM examinations in duplicate. Linear mixed models were used to assess the effects of sex, age, and time of measurement on corneal backscatter. Mean corneal backscatter was 3.5% higher in men (P = 0.003). From the age of 50 years, backscatter increased significantly in the anterior stroma (P = 0.0003). A small but statistically significant diurnal variation was found in all seven backscatter variants (P < 0.01). The test-retest coefficient of variation of mean corneal backscatter was 5.3%, comprising intra- and intersession repeatability. Sex and time of measurement significantly affect corneal backscatter measured by IVCM, whereas age affects only backscatter in the anterior stroma. All three factors should be taken into account when conducting scientific research. For ophthalmic practice, the authors suggest ignoring these factors and propose a generalized normal range and minimum detectable change for each backscatter variant.


Post-hospital syndrome in adults with asthma: a case-crossover study.
Post-hospital syndrome refers to the period of generalized risk of adverse health outcomes among patients who are recently discharged from hospital. This period is associated with a short-term increased risk of readmission which may not be related to the original condition. While the majority of studies of post-hospital syndrome have focused on all-cause readmissions, whether and to what extent such a phenomenon exists within discrete medical conditions is not yet known. To investigate whether the risk of admission due to asthma is increased in individuals who are discharged following any-cause hospital admission. Using administrative health data for the period 1997 to 2007 from the province of British Columbia, Canada, we created a cohort of adults with asthma. Using a case-crossover design, we assessed the association between discharge from a hospital (exposure) within 30 days before an asthma-related hospitalization (the outcome), using two 30-day control periods within the same subject. Conditional logistic regression was performed to calculate the relative risk (RR) of the outcome in association with exposure. We performed several sensitivity and subgroup analyses. The final cohort included 3,852 patients experiencing 6,333 instances of the outcome. Mean age at the time of the outcome was 43.7 (SD 14.2), 69.0% of such outcomes belonged to females. The RR of the outcome within the next 30 days of a previous any-cause discharge was 1.40 (95% CI 1.22 - 1.59). However, the association was mainly caused by discharge from asthma-related admission [RR = 1.99 (95% CI 1.65 - 2.39)]. The RR associated with non-asthma-related discharge was 0.88 (95% CI 0.74 - 1.04) and was not statistically significant. Similar results were obtained in a range of sensitivity analyses. Our results indicate that in patients with asthma, the 30-day risk of asthma-related admission is increased after an episode of asthma-related hospitalization, but not after an episode of non-asthma-related hospitalization.


Identification of a major growth factor for AIDS-Kaposi's sarcoma cells as oncostatin M.
Conditioned medium from human T cell leukemia virus type 2 (HTLV-II)-infected T cells supports the growth and long-term culture of cells derived from acquired immunodeficiency syndrome (AIDS)-associated Kaposi's sarcoma lesions (AIDS-KS cells). A protein of 30 kilodaltons was purified from conditioned medium that supports the growth of AIDS-KS cells. The amino-terminal sequence of this protein was identical to the amino-terminal sequence of Oncostatin M, a glycoprotein that inhibits the growth of a variety of cancer cells. Oncostatin M from conditioned medium stimulated a twofold increase in the growth of AIDS-KS cells at a concentration of less than 1 nanogram of the protein per milliliter of medium.


Psychological reactions to terrorist attacks: findings from the National Study of Americans' Reactions to September 11.
The terrorist attacks of September 11, 2001, represent an unprecedented exposure to trauma in the United States. To assess psychological symptom levels in the United States following the events of September 11 and to examine the association between postattack symptoms and a variety of indices of exposure to the events. Web-based epidemiological survey of a nationally representative cross-sectional sample using the Posttraumatic Stress Disorder (PTSD) Checklist and the Brief Symptom Inventory, administered 1 to 2 months following the attacks. Sample of 2273 adults, including oversamples of the New York, NY, and Washington, DC, metropolitan areas. Self-reports of the symptoms of PTSD and of clinically significant nonspecific psychological distress; adult reports of symptoms of distress among children living in their households. The prevalence of probable PTSD was significantly higher in the New York City metropolitan area (11.2%) than in Washington, DC (2.7%), other major metropolitan areas (3.6%), and the rest of the country (4.0%). A broader measure of clinically significant psychological distress suggests that overall distress levels across the country, however, were within expected ranges for a general community sample. In multivariate models, sex, age, direct exposure to the attacks, and the amount of time spent viewing TV coverage of the attacks on September 11 and the few days afterward were associated with PTSD symptom levels; sex, the number of hours of television coverage viewed, and an index of the content of that coverage were associated with the broader distress measure. More than 60% of adults in New York City households with children reported that 1 or more children were upset by the attacks. One to 2 months following the events of September 11, probable PTSD was associated with direct exposure to the terrorist attacks among adults, and the prevalence in the New York City metropolitan area was substantially higher than elsewhere in the country. However, overall distress levels in the country were within normal ranges. Further research should document the course of symptoms and recovery among adults following exposure to the events of September 11 and further specify the types and severity of distress in children.


Can Sulfate Be the First Dominant Aqueous Sulfur Species Formed in the Oxidation of Pyrite by Acidithiobacillus ferrooxidans?
According to the literature, pyrite (FeS2) oxidation has been previously determined to involve thiosulfate as the first aqueous intermediate sulfur product, which is further oxidized to sulfate. In the present study, pyrite oxidation by Acidithiobacillus ferrooxidans was studied using electrochemical and metabolic approaches in an effort to extend existing knowledge on the oxidation mechanism. Due to the small surface area, the reaction rate of a compact pyrite electrode in the form of polycrystalline pyrite aggregate in A. ferrooxidans suspension was very slow at a spontaneously formed high redox potential. The slow rate made it possible to investigate the oxidation process in detail over a term of 100 days. Using electrochemical parameters from polarization curves and levels of released iron, the number of exchanged electrons per pyrite molecule was estimated. The values close to 14 and 2 electrons were determined for the oxidation with and without bacteria, respectively. These results indicated that sulfate was the dominant first aqueous sulfur species formed in the presence of bacteria and elemental sulfur was predominantly formed without bacteria. The stoichiometric calculations are consistent with high iron-oxidizing activities of bacteria that continually keep the released iron in the ferric form, resulting in a high redox potential. The sulfur entity of pyrite was oxidized to sulfate by Fe3+ without intermediate thiosulfate under these conditions. Cell attachment on the corroded pyrite electrode surface was documented although pyrite surface corrosion by Fe3+ was evident without bacterial participation. Attached cells may be important in initiating the oxidation of the pyrite surface to release iron from the mineral. During the active phase of oxidation of a pyrite concentrate sample, the ATP levels in attached and planktonic bacteria were consistent with previously established ATP content of iron-oxidizing cells. No significant upregulation of three essential genes involved in energy metabolism of sulfur compounds was observed in the planktonic cells, which represented the dominant biomass in the pyrite culture. The study demonstrated the formation of sulfate as the first dissolved sulfur species with iron-oxidizing bacteria under high redox potential conditions. Minor aqueous sulfur intermediates may be formed but as a result of side reactions.


Lanthanide upconversion within microstructured optical fibers: improved detection limits for sensing and the demonstration of a new tool for nanocrystal characterization.
We investigate a powerful new sensing platform based on the excitation of upconversion luminescence from NaYF(4):Yb/Er nanocrystals loaded in solution within a suspended-core microstructured optical fiber. We demonstrate a substantial improvement in the detection limit that can be achieved in a suspended-core fiber sensor for solution-based measurements using these nanocrystals as an alternative to more traditional fluorophores, with sensing of concentrations as low as 660 fM demonstrated compared with the 10 pM obtained using quantum dots. This nanocrystal loaded suspended core fiber platform also forms the basis for a novel and robust nanoscale spectrometry device capable of capturing power-dependent spectra over a large dynamic range from 10(3) W cm(-2) to 10(6) W cm(-2) using a laser diode. This serves as a useful tool to study the multiple energy levels of rare earth luminescent nano-materials, allowing the two sharp emission bands to be studied in detail over a large dynamic range of excitation powers. Thus, in addition to demonstrating a highly sensitive dip sensor, we have devised a powerful new approach for characterizing upconversion nanoparticles.


Metabolic inhibition increases activity of connexin-32 hemichannels permeable to Ca2+ in transfected HeLa cells.
Numerous cell types express functional connexin (Cx) hemichannels (HCs), and membrane depolarization and/or exposure to a divalent cation-free bathing solution (DCFS) have been shown to promote HC opening. However, little is known about conditions that can promote HC opening in the absence of strong depolarization and when extracellular divalent cation concentrations remain at physiological levels. Here the effects of metabolic inhibition (MI), an in vitro model of ischemia, on the activity of mouse Cx32 HCs were examined. In HeLa cells stably transfected with mouse Cx32 (HeLa-Cx32), MI induced an increase in cellular permeability to ethidium (Etd). The increase in Etd uptake was directly related to an increase in levels of Cx32 HCs present at the cell surface. Moreover, MI increased membrane currents in HeLa-Cx32 cells. Underlying these currents were channels exhibiting a unitary conductance of approximately 90 pS, consistent with Cx32 HCs. These currents and Etd uptake were blocked by HC inhibitors. The increase in Cx32 HC activity was preceded by a rapid reduction in mitochondrial membrane potential and a rise in free intracellular Ca(2+) concentration ([Ca(2+)](i)). The increase in free [Ca(2+)](i) was prevented by HC blockade or exposure to extracellular DCFS and was virtually absent in parental HeLa cells. Moreover, inhibition of Cx32 HCs expressed by HeLa cells in low-confluence cultures drastically reduced cell death induced by oxygen-glucose deprivation, which is a more physiological model of ischemia-reperfusion. Thus HC blockade could reduce the increase in free [Ca(2+)](i) and cell death induced by ischemia-like conditions in cells expressing Cx32 HCs.


Discovery of Potent and Highly Selective A2B Adenosine Receptor Antagonist Chemotypes.
Three novel families of A2B adenosine receptor antagonists were identified in the context of the structural exploration of the 3,4-dihydropyrimidin-2(1H)-one chemotype. The most appealing series contain imidazole, 1,2,4-triazole, or benzimidazole rings fused to the 2,3-positions of the parent diazinone core. The optimization process enabled identification of a highly potent (3.49 nM) A2B ligand that exhibits complete selectivity toward A1, A2A, and A3 receptors. The results of functional cAMP experiments confirmed the antagonistic behavior of representative ligands. The main SAR trends identified within the series were substantiated by a molecular modeling study based on a receptor-driven docking model constructed on the basis of the crystal structure of the human A2A receptor.


Serological analysis of hemorrhagic fever with renal syndrome (HFRS) patients in Far Eastern Russia and identification of the causative hantavirus genotype.
Hemorrhagic fever with renal syndrome (HFRS) is endemic in East Asia and Europe. The disease is caused by several viruses belonging to the genus Hantavirus, including the Hantaan virus (HTNV), Seoul virus (SEOV), Dobrava Belgrade virus (DOBV), and Puumala virus (PUUV). Recently, HTNV-related viruses, Amur (AMR) and Far East (FE) genotypes were identified as causative agents of HFRS in Far Eastern Russia. To investigate the epidemiology of HFRS and virus transmission, we collected sera from 17 acute and 32 convalescent patients who were clinically diagnosed with HFRS in the Khabarovsk region of Far Eastern Russia, and detected anti-hantavirus antibodies using an ELISA that can differentiate the infected virus serotype using truncated hantavirus nucleocapsid protein antigen. Sixteen of the 17 acute phase patients had antibodies to hantavirus, and all the positive sera had higher optical densities for HTNV-specific antigen than for SEOV-, DOBV-, or PUUV-specific antigens. The partial M segment of the viral genome was amplified from blood clots from three acute patients by PCR. The nucleotide sequences had closer identities to the FE genotype (>96%) than to the prototype HTNV (88 to 89%) or AMR genotype (81 to 83%). A phylogenetic analysis found that the virus sequences from the patients clustered with the FE type, and were distinct from the AMR type. Thirty-one of 32 convalescent patient sera had antibodies to HTNV-specific antigen. These data suggest that our ELISA system can detect HTNV-specific antibodies to the FE type, which may be responsible for most of the HFRS in Khabarovsk.


Dietary Protein and Potassium, Diet-Dependent Net Acid Load, and Risk of Incident Kidney Stones.
Protein and potassium intake and the resulting diet-dependent net acid load may affect kidney stone formation. It is not known whether protein type or net acid load is associated with risk of kidney stones. We prospectively examined intakes of protein (dairy, nondairy animal, and vegetable), potassium, and animal protein-to-potassium ratio (an estimate of net acid load) and risk of incident kidney stones in the Health Professionals Follow-Up Study (n=42,919), the Nurses' Health Study I (n=60,128), and the Nurses' Health Study II (n=90,629). Multivariable models were adjusted for age, body mass index, diet, and other factors. We also analyzed cross-sectional associations with 24-hour urine (n=6129). During 3,108,264 person-years of follow-up, there were 6308 incident kidney stones. Dairy protein was associated with lower risk in the Nurses' Health Study II (hazard ratio for highest versus lowest quintile, 0.84; 95% confidence interval, 0.73 to 0.96; P value for trend <0.01). The hazard ratios for nondairy animal protein were 1.15 (95% confidence interval, 0.97 to 1.36; P value for trend =0.04) in the Health Professionals Follow-Up Study and 1.20 (95% confidence interval, 0.99 to 1.46; P value for trend =0.06) in the Nurses' Health Study I. Potassium intake was associated with lower risk in all three cohorts (hazard ratios from 0.44 [95% confidence interval, 0.36 to 0.53] to 0.67 [95% confidence interval, 0.57 to 0.78]; P values for trend <0.001). Animal protein-to-potassium ratio was associated with higher risk (P value for trend =0.004), even after adjustment for animal protein and potassium. Higher dietary potassium was associated with higher urine citrate, pH, and volume (P values for trend <0.002). Kidney stone risk may vary by protein type. Diets high in potassium or with a relative abundance of potassium compared with animal protein could represent a means of stone prevention.