Extracellular excitatory amino acids increase in the paraventricular nucleus of male rats during sexual activity: main role of N-methyl-d-aspartic acid receptors in erectile function.
The concentrations of glutamic and aspartic acids were measured in the dialysate obtained with vertical microdialysis probes implanted into the paraventricular nucleus of the hypothalamus of sexually potent male rats during sexual activity. Animals showed noncontact erections when put in the presence of, and copulated with, a receptive (ovarietomized oestrogen- and progesterone-primed) female rat. The concentrations of glutamic and aspartic acids in the paraventricular dialysate increased by 37 and 80%, respectively, above baseline values during exposure to the receptive female rat and by 55 and 127%, respectively, during copulation. No changes in the concentrations of glutamic and aspartic acids were detected in the paraventricular dialysate when sexually potent male rats were exposed to nonreceptive (ovariectomized not oestrogen- and progesterone-primed) female rats or when impotent male rats were used. The injection into the paraventricular nucleus of the excitatory amino acid receptor antagonist dizocilpine (5 micro g), a noncompetitive N-methyl-d-aspartic acid receptor antagonist, reduced noncontact erections and significantly impaired copulatory activity. The alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonist 6-cyano-7-nitro-quinoxaline-2,3-dione (5 micro g) was also able to impair copulatory activity, but to a much lower extent than dizocilpine. In contrast, (+/-)-2-amino-4-phosphono-butanoic acid, a metabotropic receptor antagonist (5 micro g), was found to be ineffective. These results confirm the involvement of the paraventricular nucleus in the control of erectile function and copulatory behaviour and show that excitatory amino acid concentration increases in the paraventricular nucleus when penile erection occurs in physiological contexts.


Outcomes at five to eight years of age for children with Hirschsprung's disease.
This study describes core outcomes of Hirschsprung's disease (HD) in a UK-wide cohort of primary school-aged children. A prospective cohort study conducted from 1 October 2010 to 30 September 2012. Outcomes data were collected from parents and clinicians when children were 5-8 years of age, and combined with data collected at birth, and 28 days and 1 year post diagnosis. All 28 UK and Irish paediatric surgical centres. Children with histologically proven HD diagnosed at <6 months of age. NETS1HD core outcomes. Data were returned for 239 (78%) of 305 children. Twelve children (5%) died prior to 5 years of age.Of the 227 surviving children, 30 (13%) had a stoma and 21 (9%) were incontinent of urine. Of the 197 children without a stoma, 155 (79%) maintained bowel movements without enemas/washouts, while 124 (63%) reported faecal incontinence. Of the 214 surviving children who had undergone a pull-through operation, 95 (44%) underwent ≥1 unplanned reoperation. 89 unplanned reoperations (27%) were major/complex.Of the 83 children with returned PedsQL scores, 37 (49%) had quality of life scores, and 31 (42%) had psychological well-being scores, that were ≥1 SD lower than the reference population mean for children without HD. This study gives a realistic picture of population outcomes of HD in primary school-aged children in the UK/Ireland. The high rates of faecal incontinence, unplanned procedures and low quality of life scores are sobering. Ensuring clinicians address the bladder, bowel and psychological problems experienced by children should be a priority.


Cloning of a human tRNA isopentenyl transferase.
A cDNA of human origin is shown to encode a tRNA isopentenyl transferase (E.C. 126.96.36.199). Expression of the gene in a Saccharomyces cerevisiae mutant lacking the endogenous tRNA isopentenyl transferase MOD5 resulted in functional complementation and reintroduction of isopentenyladenosine into tRNA. The deduced amino acid sequence contains a number of regions conserved in known tRNA isopentenyl transferases. The similarity to the S. cerevisiae MOD5 protein is 53%, and to the Escherichia coli MiaA protein 47%. The human sequence was found to contain a single C2H2 Zn-finger-like motif, which was detected also in the MOD5 protein, and several putative tRNA transferases located by BLAST searches, but not in prokaryotic homologues.


Chemopreventive effects of fermented brown rice and rice bran against 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis in female A/J mice.
The most common cause of human lung cancer is suggested to be exposure to the carcinogens in tobacco smoke. Among the multiple chemicals in tobacco smoke, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) has been regarded as one of the important agents for generation of lung cancers. Previously, our studies proved that fermented brown rice and rice bran (FBRA) has chemopreventive effects against carcinogenesis of the colon, liver, stomach, bladder and esophagus. In the present study, we examined possible chemopreventive effects of FBRA on the NNK-induced lung tumorigenesis in mice. Six-week-old female A/J mice were divided into 8 groups, and groups 1-5 were given NNK (10 mmol) by i.p. injection at week 7. Groups 2 and 3 were fed with diet containing 5 and 10% FBRA during the initiation phase, respectively. Groups 4 and 5 were fed with 5% and 10% FBRA during the post-initiation phase. Groups 1 and 6 were given control diet throughout the experiment. Groups 7 and 8 were given the diet containing 5 and 10% FBRA throughout the experiment, respectively. In both initiation (group 3) and post-initiation phase (group 5), 10% FBRA exposure significantly reduced the multiplicity of lung tumor (group 3, 2.35+/-2.13; group 5, 3.00+/-1.52; group 1, 4.08+/-1.85; p<0.006 and 0.04, respectively). Furthermore, administration of FBRA during the post-initiation phase significantly decreased the tumor size in comparison with that of control mice (0.66+/-0.32 vs. 0.77+/-0.33 mm). Treatment of 10% FBRA significantly reduced the mRNA expression levels of cytochrome P450 2A5 (Cyp2a5), which is known to be closely related to the human CYP2A6 enzyme that is involved in the mutagenic activation of NNK, in the lung but not liver tissues. A significantly reduced index of Ki67 positivity of lung tumors in group 5 was confirmed when compared with tumors of the control group (0.065+/-0.016 vs. 0.114+/-0.025). These findings suggest that FBRA has inhibitory effects on NNK-induced pulmonary tumorigenesis in A/J mice in both during initiation and post-initiation treatment, which is possibly associated with the induction of Cyp2a5 in the lung and the reduced proliferation rate of tumor cells. FBRA may be a promising chemopreventive agent for human lung cancers.


Using Best-Worst Scaling to Understand Patient Priorities: A Case Example of Papanicolaou Tests for Homeless Women.
Best-worst scaling (BWS) is a survey method for assessing individuals' priorities. It identifies the extremes-best and worst items, most and least important factors, biggest and smallest influences-among sets. In this article, we demonstrate an application of BWS in a primary care setting to illustrate its use in identifying patient priorities for services. We conducted a BWS survey in 2014 in Boston, Massachusetts, to assess the relative importance of 10 previously identified attributes of Papanicolaou (Pap) testing services among women experiencing homelessness. Women were asked to evaluate 11 sets of 5 attributes of Pap services, and identify which attribute among each set would have the biggest and smallest influence on promoting uptake. We show how frequency analysis can be used to analyze results. In all, 165 women participated, a response rate of 72%. We identified the most and least salient influences on encouraging Pap screening based on their frequency of report among our sample, with possible standardized scores ranging from+1.0 (biggest influence) to -1.0 (smallest influence). Most important was the availability of support for issues beyond health (+0.39), while least important was the availability of accommodations for personal hygiene (-0.27). BWS quantifies patient priorities in a manner that is transparent and accessible. It is easily comprehendible by patients and relatively easy to administer. Our application illustrates its use in a vulnerable population, showing that factors beyond those typically provided in health care settings are highly important to women in seeking Pap screening. This approach can be applied to other health care services where prioritization is helpful to guide decisions.


Imatinib mesylate therapy may overcome the poor prognostic significance of deletions of derivative chromosome 9 in patients with chronic myelogenous leukemia.
Deletions of derivative chromosome 9 [der(9)] can be identified by fluorescence in situ hybridization (FISH) in 10% to 15% of patients with chronic myeloid leukemia (CML). Patients with der(9) deletions have been reported to have an adverse outcome when treated with chemotherapy, interferon, and possibly imatinib mesylate. We investigated the frequency and prognostic significance of der(9) deletions among 352 patients with CML treated with imatinib mesylate at our institution, in whom a deletion status of der(9) was determined. Thirty-three patients (9%; 95% CI 0.07, 0.13) (30 in chronic phase, 3 in accelerated phase) had der(9) deletions. The rates of major (82% vs 79%, P = 0.82) and complete cytogenetic response (76% vs 66%, P = .33) with imatinib mesylate therapy were similar in patients with and without der(9) deletions, respectively. After a median follow-up of 28 months, there was no difference in overall survival (P = .30) or response duration (P = .49) in patients with and without deletions. In a multivariate analysis, der(9) deletions had no significant impact on response, survival, or response duration. We conclude that treatment with imatinib mesylate overcomes the adverse prognostic significance of der(9) deletions in patients with CML.


Blood flow and coherent vortices in the normal and aneurysmatic aortas: a fluid dynamical approach to intra-luminal thrombus formation.
Abdominal aortic aneurysms (AAAs) are frequently characterized by the development of an intra-luminal thrombus (ILT), which is known to have multiple biochemical and biomechanical implications. Development of the ILT is not well understood, and shear-stress-triggered activation of platelets could be the first step in its evolution. Vortical structures (VSs) in the flow affect platelet dynamics, which motivated the present study of a possible correlation between VS and ILT formation in AAAs. VSs educed by the λ(2)-method using computational fluid dynamics simulations of the backward-facing step problem, normal aorta, fusiform AAA and saccular AAA were investigated. Patient-specific luminal geometries were reconstructed from computed tomography scans, and Newtonian and Carreau-Yasuda models were used to capture salient rheological features of blood flow. Particularly in complex flow domains, results depended on the constitutive model. VSs developed all along the normal aorta, showing that a clear correlation between VSs and high wall shear stress (WSS) existed, and that VSs started to break up during late systole. In contrast, in the fusiform AAA, large VSs developed at sites of tortuous geometry and high WSS, occupying the entire lumen, and lasting over the entire cardiac cycle. Downward motion of VSs in the AAA was in the range of a few centimetres per cardiac cycle, and with a VS burst at that location, the release (from VSs) of shear-stress-activated platelets and their deposition to the wall was within the lower part of the diseased artery, i.e. where the thickest ILT layer is typically observed. In the saccular AAA, only one VS was found near the healthy portion of the aorta, while in the aneurysmatic bulge, no VSs occurred. We present a fluid-dynamics-motivated mechanism for platelet activation, convection and deposition in AAAs that has the potential of improving our current understanding of the pathophysiology of fluid-driven ILT growth.


Long term follow-up of carpal tunnel syndrome during pregnancy: a cohort study and review of the literature.
Carpal tunnel syndrome (CTS) occurring during pregnancy is considered to have a short and benign course and very few cases required surgery, however there is no information in literature on long term follow-up. The aim of this study was a systematic review of the literature and to report 3-year follow-up after delivery in a sample of pregnant women with CTS. We enrolled 45 consecutive pregnant women with CTS (mean age 32 years). Diagnosis was based on clinical and neurographic findings. Clinical and electrophysiological severity of CTS were scored according to an ordinal scale and the self-administered Boston questionnaires on symptoms (BQ-SYMPT) and functional status (BQ-FUNCT) of the hand during pregnancy and one-year after delivery. Symptoms were evaluated again by BQ over the telephone three years after delivery. At one-year follow-up BQ-SYMPT and BQ-FUNCT scores improved in 40% of women, did not change in 46.7% and 55.6% and worsened in 13.3% and 4.4%, respectively. Clinical severity was stage 0 (i. e. without symptoms) in 26.7% of women, improved in 6.7%, unchanged in 60% and worse in 6.7%. Electrophysiological severity was stage 0 (i.e. no delay in median nerve conduction) in 17.8%, improved in 20%, unchanged in 57.8% and worse in 4.4%. Only one woman underwent surgery (5 months after delivery), three were treated with local steroid injection before delivery and 18 used a splint, 8 of whom continued to do so periodically after one year. At 3-year follow-up 51% were symptom-free and 49% had anomalous ( > 1) BQ scores, but mean BQ scores improved with respect to those at baseline and one-year follow-up. A Pubmed search identified 20 papers in which therapy and follow-up could be deduced. Almost all reported a short follow-up with disappearance of symptoms. Our study confirms that pregnancy-related CTS has a benign course: improvement of symptoms was evident at one- and 3-year follow-up, but about half the women still complained of symptoms 3 years after delivery. Only one woman underwent surgery and 11% still sometimes wore a splint at night. Despite improvement of symptoms, distal sensory conduction velocity of the median nerve improved but remained delayed in 84% of women one year after delivery.


Aspf2 From Aspergillus fumigatus Recruits Human Immune Regulators for Immune Evasion and Cell Damage.
The opportunistic fungal pathogen Aspergillus fumigatus can cause life-threatening infections, particularly in immunocompromised patients. Most pathogenic microbes control host innate immune responses at the earliest time, already before infiltrating host immune cells arrive at the site of infection. Here, we identify Aspf2 as the first A. fumigatus Factor H-binding protein. Aspf2 recruits several human plasma regulators, Factor H, factor-H-like protein 1 (FHL-1), FHR1, and plasminogen. Factor H contacts Aspf2 via two regions located in SCRs6-7 and SCR20. FHL-1 binds via SCRs6-7, and FHR1 via SCRs3-5. Factor H and FHL-1 attached to Aspf2-maintained cofactor activity and assisted in C3b inactivation. A Δaspf2 knockout strain was generated which bound Factor H with 28% and FHL-1 with 42% lower intensity. In agreement with less immune regulator acquisition, when challenged with complement-active normal human serum, Δaspf2 conidia had substantially more C3b (>57%) deposited on their surface. Consequently, Δaspf2 conidia were more efficiently phagocytosed (>20%) and killed (44%) by human neutrophils as wild-type conidia. Furthermore, Aspf2 recruited human plasminogen and, when activated by tissue-type plasminogen activator, newly generated plasmin cleaved the chromogenic substrate S2251 and degraded fibrinogen. Furthermore, plasmin attached to conidia damaged human lung epithelial cells, induced cell retraction, and caused matrix exposure. Thus, Aspf2 is a central immune evasion protein and plasminogen ligand of A. fumigatus. By blocking host innate immune attack and by disrupting human lung epithelial cell layers, Aspf2 assists in early steps of fungal infection and likely allows tissue penetration.


meso-substituted aromatic 34pi core-modified octaphyrins: syntheses, characterization and anion binding properties.
Modified octaphyrins with 34pi electrons have been synthesized and characterized following a simple synthetic methodology. An acid-catalyzed alpha,alpha coupling of tetrapyrranes containing furan, thiophene and selenophene rings resulted in the formation of the respective octaphyrins in relatively good yield. Solution studies by (1)H NMR and 2D NMR methods and single crystal Xray structural characterization reveal an almost flat structure with two heterocyclic rings inverted. Specifically, in 14 two selenophene rings (one on each biselenophene unit) are inverted while in 15 two furan rings (one on each bifuran unit) are inverted when the meso substituent are mesityl groups. On changing the mesityl substituent to m-xylyl group as in 19, the location of ring inversion shifts to pyrrole rings (one on each bipyrrole unit) indicating the dependence of structure on the meso substituents. UV/Vis studies, both in freebase and protonated forms reveal typical porphyrinic character and the aromatic nature of the octaphyrins. The Deltadelta values evaluated by (1)H NMR spectroscopy also support their aromatic nature. The protonated forms of octaphyrins bind TFA anion in a 1:2 ratio. The TFA anions are located one above and below the plane of the octaphyrin macrocycle and they are held by weak electrostatic NH-O interactions similar to that observed for protonated rubyrins. However, in the present case, there is an additional non-electrostatic CH-O interaction involving beta-CH of the inverted heterocyclic ring and the carbonyl oxygen of the TFA. Furthermore, inter molecular interactions between the Cbond;H of the meso-mesityl group and the fluorine of CF(3) group of bound TFA leads to the formation of one-dimensional supramolecular arrays with interplanar distance of 13 A between two octaphyrins.


Interaction of 6,6''-bis(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1,2,4-benzotriazin-3-yl)-2,2':6',2''-terpyridine (CyMe4-BTTP) with some trivalent ions such as lanthanide(III) ions and americium(III).
The new ligand 6,6''-bis(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1,2,4-benzotriazin-3-yl)-2,2':6',2''-terpyridine (CyMe4-BTTP) has been synthesized in 4 steps from 2,2':6',2''-terpyridine. Detailed NMR and mass spectrometry studies indicate that the ligand forms 1:2 complexes with lanthanide(III) perchlorates where the aliphatic rings are conformationally constrained whereas 1:1 complexes are formed with lanthanide(III) nitrates where the rings are conformationally mobile. An optimized structure of the 1:2 solution complex with Yb(III) was obtained from the relative magnitude of the induced paramagnetic shifts. X-Ray crystallographic structures of the ligand and of its 1:1 complex with Y(III) were also obtained. The NMR and mass spectra of [Pd(CyMe4-BTTP)]n(2n+) are consistent with a dinuclear double helical structure (n = 2). In the absence of a phase-modifier, CyMe4-BTTP in n-octanol showed a maximum distribution coefficient of Am(III) of 0.039 (±20%) and a maximum separation factor of Am(III) over Eu(III) of 12.0 from nitric acid. The metal(III) cations are extracted as the 1:1 complex from nitric acid. The generally low distribution coefficients observed compared with the BTBPs arise because the 1:1 complex of CyMe4-BTTP is considerably less hydrophobic than the 1:2 complexes formed by the BTBPs. In M(BTTP)(3+) complexes, there is a competition between the nitrate ions and the ligand for the complexation of the metal.


First laboratory results with the LINC-NIRVANA high layer wavefront sensor.
In the field of adaptive optics, multi-conjugate adaptive optics (MCAO) can greatly increase the size of the corrected field of view (FoV) and also extend sky coverage. By applying layer oriented MCAO (LO-MCAO) [4], together with multiple guide stars (up to 20) and pyramid wavefront sensors [7], LINC-NIRVANA (L-N for short) [1] will provide two AO-corrected beams to a Fizeau interferometer to achieve 10 milliarcsecond angular resolution on the Large Binocular Telescope. This paper presents first laboratory results of the AO performance achieved with the high layer wavefront sensor (HWS). This sensor, together with its associated deformable mirror (a Xinetics-349), is being operated in one of the L-N laboratories. AO reference stars, spread across a 2 arc-minute FoV and with aberrations resulting from turbulence introduced at specific layers in the atmosphere, are simulated in this lab environment. This is achieved with the Multi-Atmosphere Phase screen and Stars (MAPS) [2] unit. From the wavefront data, the approximate residual wavefront error after correction has been calculated for different turbulent layer altitudes and wind speeds. Using a somewhat undersampled CCD, the FWHM of stars in the nearly 2 arc-minute FoV has also been measured. These test results demonstrate that the high layer wavefront sensor of LINC-NIRVANA will be able to achieve uniform AO correction across a large FoV.


Donepezil impairs memory in healthy older subjects: behavioural, EEG and simultaneous EEG/fMRI biomarkers.
Rising life expectancies coupled with an increasing awareness of age-related cognitive decline have led to the unwarranted use of psychopharmaceuticals, including acetylcholinesterase inhibitors (AChEIs), by significant numbers of healthy older individuals. This trend has developed despite very limited data regarding the effectiveness of such drugs on non-clinical groups and recent work indicates that AChEIs can have negative cognitive effects in healthy populations. For the first time, we use a combination of EEG and simultaneous EEG/fMRI to examine the effects of a commonly prescribed AChEI (donepezil) on cognition in healthy older participants. The short- and long-term impact of donepezil was assessed using two double-blind, placebo-controlled trials. In both cases, we utilised cognitive (paired associates learning (CPAL)) and electrophysiological measures (resting EEG power) that have demonstrated high-sensitivity to age-related cognitive decline. Experiment 1 tested the effects of 5 mg/per day dosage on cognitive and EEG markers at 6-hour, 2-week and 4-week follow-ups. In experiment 2, the same markers were further scrutinised using simultaneous EEG/fMRI after a single 5 mg dose. Experiment 1 found significant negative effects of donepezil on CPAL and resting Alpha and Beta band power. Experiment 2 replicated these results and found additional drug-related increases in the Delta band. EEG/fMRI analyses revealed that these oscillatory differences were associated with activity differences in the left hippocampus (Delta), right frontal-parietal network (Alpha), and default-mode network (Beta). We demonstrate the utility of simple cognitive and EEG measures in evaluating drug responses after acute and chronic donepezil administration. The presentation of previously established markers of age-related cognitive decline indicates that AChEIs can impair cognitive function in healthy older individuals. To our knowledge this is the first study to identify the precise neuroanatomical origins of EEG drug markers using simultaneous EEG/fMRI. The results of this study may be useful for evaluating novel drugs for cognitive enhancement.


Association of anticholinergic burden with cognitive and functional status in a cohort of hospitalized elderly: comparison of the anticholinergic cognitive burden scale and anticholinergic risk scale: results from the REPOSI study.
Drugs with anticholinergic effects are associated with adverse events such as delirium and falls as well as cognitive decline and loss of independence. The aim of the study was to evaluate the association between anticholinergic burden and both cognitive and functional status, according to the hypothesis that the cumulative anticholinergic burden, as measured by the Anticholinergic Cognitive Burden (ACB) Scale and Anticholinergic Risk Scale (ARS), increases the risk of cognitive decline and impairs activities of daily living. This cross-sectional, prospective study (3-month telephone follow-up) was conducted in 66 Italian internal medicine and geriatric wards participating in the Registry of Polytherapies SIMI (Società Italiana di Medicina Interna) (REPOSI) study during 2010. The sample included 1,380 inpatients aged 65 years or older. Cognitive status was rated with the Short Blessed Test (SBT) and physical function with the Barthel Index. Each patient's anticholinergic burden was evaluated using the ACB and ARS scores. The mean SBT score for patients treated with anticholinergic drugs was higher than that for patients receiving no anticholinergic medications as also indicated by the ACB scale, even after adjustment for age, sex, education, stroke and transient ischaemic attack [9.2 (95 % CI 8.6-9.9) vs. 8.5 (95 % CI 7.8-9.2); p = 0.05]. There was a dose-response relationship between total ACB score and cognitive impairment. Patients identified by the ARS had more severe cognitive and physical impairment than patients identified by the ACB scale, and the dose-response relationship between this score and ability to perform activities of daily living was clear. No correlation was found with length of hospital stay. Drugs with anticholinergic properties identified by the ACB scale and ARS are associated with worse cognitive and functional performance in elderly patients. The ACB scale might permit a rapid identification of drugs potentially associated with cognitive impairment in a dose-response pattern, but the ARS is better at rating activities of daily living.


Cytotoxic and cytostatic effects of the streptococcal preparation OK-432 and its subcellular fractions on human ovarian tumor cells.
Previous studies have indicated that OK-432 is a potent biologic response modifier (BRM) and that it augments immune responses to tumor cells. We studied the direct effect of OK-432 on tumor cells. Established and freshly derived human ovarian carcinoma lines were examined for their susceptibility to OK-432 or its subcellular fractions in direct cytotoxicity, cytostatic activity, and inhibition of metabolic activity. OK-432 was cytotoxic to 13 of 15 freshly derived ovarian carcinoma lines in a 24-hour chromium-51 (51Cr) release assay. The optimal effect was noticed at OK-432 concentrations between 0.1 and 1.0 Klinishe Einhert (KE) per milliliter. The cytostatic effect on two established lines and one fresh line correlated with the cytotoxic activity. In all three lines, however, the metabolic activities (DNA, RNA, and protein synthesis) were inhibited by OK-432, suggesting that cell lysis by OK-432 may not be directly correlated with the inhibition of metabolic activities. Several subcellular fractions were derived from OK-432 and only the cytoplasmic and protoplast membrane fractions showed cytotoxic activity against the OK-432-sensitive tumor cell lines, although the cytotoxicity obtained was greatly less than the whole microorganism OK-432. The direct binding of 14C-OK-432 to tumor cells was examined. Binding took place rapidly after 1 hour of incubation and reached a maximum activity at 37 degrees C. Binding in all three lines ranged between 1.7 and 2.7 pg/cell. These results demonstrate the direct cytotoxic effect of OK-432 and some subcellular fractions on human ovarian carcinoma lines. These results also show that the BRM OK-432 may exert its effect by both potentiating the antitumor response and directly inhibiting tumor cell growth.


Effect of Chaplaincy Visits in an Elder Care Setting: A Pilot Analysis of Existing Data.
Religion is a consistent, positive predictor of health in older adults. Studies focused on religion and spirituality as a coping mechanism find significant positive effects on the lives of older adults. This study investigated how an older person's living situation influences his or her access to spiritual and religious resources and, consequently, his or her health. Utilizing existing data, this pilot project examined the relationship between visits from a chaplain and the mood, pain level, functional ability, and/or discharge status of elders residing in the rehabilitation unit of one long-term care facility. Samples of patients who did and did not have chaplaincy visits were matched based on their level of frailty. Analytic comparisons revealed no significantly different outcomes in terms of mood, pain level, functional ability, or discharge status for patients visited by a chaplain. The outcomes suggest future hypotheses and offer a model for outcomes-based chaplaincy research.


Differential geometry of the ruled surfaces optically generated by mirror-scanning devices. I. Intrinsic and extrinsic properties of the scan field.
Rectilinear propagation of light rays in homogeneous isotropic media makes it possible for optical generation of ruled surfaces as the ray is deflected by a rotatable mirror. Scan patterns on a plane or curved surface are merely curves on the ruled surface. Based on this understanding, structures of the scan fields produced by mirror-scanning devices of different configurations are investigated in terms of differential geometry. Expressions of the first and second fundamental coefficients and the first and second Gauss differential forms are given for an investigation of the intrinsic properties of the optically generated ruled surfaces. The Plücker ruled conoid is then generalized for mathematical modeling of the scan fields produced by single-mirror scanning devices of different configurations. Part II will be devoted to a study of multi-mirror scanning systems for optical generation of well-known ruled surfaces such as helicoids and hyperbolic paraboloids.


Effective risk assessment tools for osteoporosis in the Indian menopausal female.
This study was designed to assess the effectiveness of self-administered osteoporosis risk score sheet, body mass index (BMI), and bone mineral density (BMD) (ultrasound) in screening females with low bone mass, and how the results of the tools correlate with each other. The study was conducted on 536 postmenopausal women, who attended public awareness camps on Midlife Women Health held at the Menopause Research Unit, MGMCH, Sitapura, Jaipur. At these camps, in addition to several informational sessions on issues related to menopause, ultrasonic measurement of BMD was conducted on each participant. A broad questionnaire to identify midlife health problems was developed, and osteoporosis specific score sheet was designed to be self-administered. Patients were required to complete the osteoporosis specific risk score sheet and women health questionnaire (WHQ). BMI was determined. Statistical analysis was carried out to find the correlation between various variables. Sensitivity and specificity of the each risk score ascertained and cutoff risk score for identifying osteopenia was derived by comparing area under curve of each risk score on drawing receiver operational curve (ROC). Sensitivity of risk score system was calculated to be 78.33% with 95% confidence interval being 73.24-82.86% and specificity was 27.12% with 95% confidence interval being 21.56-33.27%, keeping the cutoff point at nine. There was statistically significant inverse relationship between risk score and BMD values with Pearson correlation coefficient of (-) 0.22 and positive relationship between BMD and BMI with correlation coefficient of 0.192. By noting down the risk factors and BMI, we can screen out the women who require further evaluation and management, thus, it is an effective tool, particularly in developing countries like India, where most of the patients cannot afford expensive DEXA scans, although considered as the gold standard for BMD assessment. With the help of such scoring systems, health resources can be judiciously utilized.


Numerical Estimation in Children With Autism.
Number skills are often reported anecdotally and in the mass media as a relative strength for individuals with autism, yet there are remarkably few research studies addressing this issue. This study, therefore, sought to examine autistic children's number estimation skills and whether variation in these skills can explain at least in part strengths and weaknesses in children's mathematical achievement. Thirty-two cognitively able children with autism (range = 8-13 years) and 32 typical children of similar age and ability were administered a standardized test of mathematical achievement and two estimation tasks, one psychophysical nonsymbolic estimation (numerosity discrimination) task and one symbolic estimation (numberline) task. Children with autism performed worse than typical children on the numerosity task, on the numberline task, which required mapping numerical values onto space, and on the test of mathematical achievement. These findings question the widespread belief that mathematical skills are generally enhanced in autism. For both groups of children, variation in performance on the numberline task was also uniquely related to their academic achievement, over and above variation in intellectual ability; better number-to-space mapping skills went hand-in-hand with better arithmetic skills. Future research should further determine the extent and underlying causes of some autistic children's difficulties with regards to number.


Erythrocyte protoporphyrin fluorescence as a potential marker of diabetes.
Protoporphyrin (PpIX), a porphyrin derivative, is the intermediate metabolic precursor of the heme molecule. Abnormal metabolism of total erythrocyte PpIX has been observed in diseases such as cancer, lead poisoning, psoriasis, iron deficiency anemia and acute porphyries. Diabetes mellitus (DM) is a complex metabolic syndrome in which hyperglycemia is the primary clinical manifestation and contributes to the diabetic complications. The aim of this study was to evaluate the utility of fluorescence spectroscopy of erythrocyte PpIX for monitoring the early stages of diabetes. A total of 14 male C 57BL mice, 6 weeks old, were divided into two groups: diabetic and non-diabetic. Diabetes was induced by intraperitoneal injection of streptozotocin (SZT). Blood cells were cultured with standard and 50 mM supplemented RPMI medium. Blood smears were prepared and stained for qualitative morphology analysis under optical microscopy. Blood porphyrin autofluorescence was analyzed by fluorescence spectroscopy. Characteristic PpIX emission spectra were obtained by exciting the samples at 405 nm. Average blood glucose was lower in the control group than in the diabetic group (156.50 +/- 8.11 mg/dL vs. 371.10 +/- 14.43 mg/dL, P < 0.05). Both diabetic and glucose-cultured erythroblasts showed a significant decrease (around 30.5% and 40%, respectively) in the emission band intensity at 635 nm. Our results indicate that the erythrocyte PpIX profile could be used as a biological monitor for diabetes.


High-fat diet disrupts metabolism in two generations of rats in a parent-of-origin specific manner.
Experimental and epidemiological evidence demonstrate that ancestral diet might contribute towards offspring health. This suggests that nutrition may be able to modify genetic or epigenetic information carried by germ cells (GCs). To examine if a parental high fat diet (HFD) influences metabolic health in two generations of offspring, GC-eGFP Sprague Dawley rats were weaned onto HFD (45% fat) or Control Diet (CD; 10% fat). At 19 weeks, founders (F0) were bred with controls, establishing the F1 generation. HFD resulted in 9.7% and 14.7% increased weight gain in male and female F0 respectively. F1 offspring of HFD mothers and F1 daughters of HFD-fed fathers had increased weight gain compared to controls. F1 rats were bred with controls at 19 weeks to generate F2 offspring. F2 male offspring derived from HFD-fed maternal grandfathers exhibited increased adiposity, plasma leptin and luteinising hormone to testosterone ratio. Despite transmission via the founding male germline, we did not find significant changes in the F0 intra-testicular GC transcriptome. Thus, HFD consumption by maternal grandfathers results in a disrupted metabolic and reproductive hormone phenotype in grandsons in the absence of detectable changes in the intra-testicular GC transcriptome.


Complex DNA Damage Induced by High Linear Energy Transfer Alpha-Particles and Protons Triggers a Specific Cellular DNA Damage Response.
To investigate the precise mechanism of recognition and processing of ionizing radiation (IR)-induced complex DNA damage (CDD), where two or more DNA lesions are in close proximity, in cellular DNA which is packaged with histones to form chromatin. HeLa and oropharyngeal squamous cell carcinoma (UMSCC74A and UMSCC6) cells were irradiated with high linear energy transfer (LET) α-particles or protons, versus low-LET protons and X rays. At various time points after irradiation, site-specific histone post-translational modifications were analyzed by quantitative Western blotting; DNA damage and repair were measured by different versions of the comet assay; and cell survival was determined using clonogenic assays. Site-specific histone post-translational modifications after low- and high-LET radiation, particularly proton irradiation, were screened, aiming to identify those responsive to CDD. We demonstrate that histone H2B ubiquitylated on lysine 120 (H2Bub) is specifically induced several hours after irradiation in response to high-LET α-particles and protons but not by low-LET protons or X rays/γ-radiation. This is associated with increased levels of CDD, which contributes to decreased cell survival. We further discovered that modulation of H2Bub is under the control of two E3 ubiquitin ligases, MSL2 and RNF20/RNF40 complex, whose depletion leads to defective processing and further persistence of CDD, and to additional decreased cell survival after irradiation. This study demonstrates that the signaling and repair of CDD, particularly induced by high-LET IR is co-ordinated through the specific induction of H2Bub catalyzed by MSL2 and RNF20/40, a mechanism that contributes significantly to cell survival after irradiation.


Uniformity in measuring adherence to reporting guidelines: the example of TRIPOD for assessing completeness of reporting of prediction model studies.
To promote uniformity in measuring adherence to the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) statement, a reporting guideline for diagnostic and prognostic prediction model studies, and thereby facilitate comparability of future studies assessing its impact, we transformed the original 22 TRIPOD items into an adherence assessment form and defined adherence scoring rules. TRIPOD specific challenges encountered were the existence of different types of prediction model studies and possible combinations of these within publications. More general issues included dealing with multiple reporting elements, reference to information in another publication, and non-applicability of items. We recommend our adherence assessment form to be used by anyone (eg, researchers, reviewers, editors) evaluating adherence to TRIPOD, to make these assessments comparable. In general, when developing a form to assess adherence to a reporting guideline, we recommend formulating specific adherence elements (if needed multiple per reporting guideline item) using unambiguous wording and the consideration of issues of applicability in advance.


Implications of resource constraints and high workload on speaking up about threats to patient safety: a qualitative study of surgical teams in Ghana.
Although under-resourcing of healthcare facilities and high workload is known to undermine patient safety, there is a dearth of evidence about how these factors affect employee voice and silence about unsafe care. We address this gap in the literature by exploring how resource constraints and high workload influence the willingness of staff to speak up about threats to patient safety in surgical departments in Ghana. Semistructured interviews with a purposeful sample of 91 multidisciplinary professionals drawn from a range of specialities, ranks and surgical teams in two teaching hospitals in Ghana. Conservation of Resources theory was used as a theoretical frame for the study. Data were processed and analysed thematically with the aid of NVivo 12. Endemic resource constraints and excessive workload generate stress that undermines employee willingness to speak up about unsafe care. The preoccupation with managing scarce resources predisposes managers in surgical units to ignore or downplay concerns raised and not to instigate appropriate remedial actions. Resource constraints lead to rationing and improvising in order to work around problems with inadequate infrastructure and malfunctioning equipment, which in turn creates unsupportive environments for staff to air legitimate concerns. Faced with high workloads, silence was used as a coping strategy by staff to preserve energy and avoid having to take on the burden of additional work. Under-resourcing and high workload contribute significantly towards undermining employee voice about unsafe care. We highlight the central role that adequate funding and resourcing play in creating safe environments and that supporting 'hearer' courage may be as important as supporting speaking up in the first place.


[FSGS collapsing variant during anabolic steroid abuse: Case Report].
Anabolic Androgenic Steroids (AAS) is an hormone family whose use has considerably increased among body-builders during the last decades. The AAS abuse, especially associated with other drugs or nutritional supplements and protein loads, may cause a variety of pathologies to several organs with a mechanism related to dosage, timing and substance. The kidney is the main metabolizer of these drugs and it can be acutely or chronically damaged with ESKD. The literature reports some cases of Focal Segmental Glomerulosclerosis (FSGS) in body-builders who abused of AAS. However, the link is not well understood and limited to some case-studies. In this paper, we report the case of a young body-builder who developed a FSGS collapsing variant with ESKD after prolonged abuse of AAS and a strongly hyperproteic diet and other dietary supplements. The patient underwent a genetic test because of the rapid and irreversibile onset of ESKD. The test showed a gene mutation of ACTN4, predisposing and causal of some genetic forms of FSGS. It was a very complex case, caused by several factors. The mutant protein of ACTN4 gene makes most vulnerable the cytoskeleton of the podocytes to external disturbances. That would explain why in those patients where the mutation has occurred, only those patients subject to "unfavorable environmental conditions", like the abuse of AAS, can develop a disease.


Effectiveness of STOPP/START criteria in primary prevention of polypharmacy and under-treatment in older patients.
STOPP/START criteria appear to be a useful tool to curb inappropriate prescribing (IP), which encompasses errors of both, over and under-treatment. This study aimed to find out whether application of STOPP/START reduces the IP effectively in primary care. This prospective cross-sectional study was conducted in two family health centers (FHCs) in Istanbul. All older adults who applied to FHCs between 01-07-2018 and 01-07-2020 were enrolled. The potential inappropriate medications (PIMs) and potential prescription omissions (PPOs) were identified according to STOPP/START version 2 criteria. Mean drug consumptions before and after STOPP/START were compared using Student's t-test. Among 1023 participants there were 626 females and 397 males. The mean age was 73.33±7.30 years. The number of the patients seen at FHCs was 657 (64.2%) while 366 (35.8%) of them were visited at home. Of the patients, 383 (37.8) were 75 years old or older and 631 (62.2%) of them were under 75. Overall number of drugs consumed per patient was 5.49±3.93 while it was 6.01±3.71 and 4.55±4.138 for outpatients and home patients respectively (p<0.001). By application of STOPP criteria, among the 5616 medications consumed by the overall patients, 881(%15.6) of them were found to be potentially inappropriate. 424 (41.4%) patients were using at least one PIM. This ratio was 354 (53.8%) in outpatients and 70 (19%) in home patients. START criteria identified 380 (%7.4) PPOs. There were 246 (24.0%) patients at least with one PPO; 155 (42.3%) of whom were home patients and 91 (13.8%) were outpatients. Regarding the age groups; PIM ratio was 35.5% in patients under 75 and 52.1% over 75 whereas PPO ratio was 22.5% under 75 and 26.8% over 75. This study supports the data reporting the effectiveness of STOPP/START criteria in primary care units in implementing appropriate prescription criteria.


Educating physicians for the twenty-first century.
The author reviews the fundamental changes that have taken place in the U.S. health care system since 1935, predicts what that system will be like in the early part of the next century, and discusses the implications for academic medicine. Specifically, he maintains that physicians being trained today will practice within the context of large organizations, with payment for care being either by employment-based insurance or by some form of government-subsidized insurance. Care will be delivered across diffuse networks, and most physicians will be paid according to capitation or salary schemes. The role of technology will be high and will revolutionize the health care system, which will be focused on prevention and maintenance of function rather than cure. The success of the system will be measured by its cost-effectiveness and by how well it works to maintain the mental, social, and physical functions of its participants. Finally, the obligation of the physician will be not only to individual patients but also to the populations and communities from which patients come. Training physicians to meet these obligations and to function effectively in the revolutionized system will involve changes in medical education to more appropriately socialize students into the next century's medical culture. The author reviews in detail the various elements of the medical culture that must be addressed by medical education, gives examples of the kinds of changes that must be made, and describes efforts at his school to reinforce across the curriculum the population-based model of clinical practice.


Apathy: a separate syndrome from depression in dementia? A critical review.
Apathy and depression are the most prevalent neuropsychiatric symptoms in Alzheimer's disease and mild cognitive impairment. Despite much research on apathy and depression in dementia, the nosological position of apathy as a separate syndrome from depression remains debated. This literature review provides a critical analysis of the areas of clinical manifestation, symptomatology, assessment, prevalence and neuropathology. Evidence does not provide a clear view of the nosological position of apathy in dementia for symptoms and neuropathology. However, the ambiguity of the evidence may be attributed in large part to a lack of clarity in definition and etiology, clinical criteria and assessment overlap. Given the evidence, it is concluded that the argument in favor of apathy as a separate syndrome from depression in dementia is persuasive. Reaching a consensus on the definition and nosological position of apathy within dementia is vital to provide patients and caregivers with the support they require, increase understanding of risk factors, and enable comparisons across research and practice.


Sequencing metabolically labeled transcripts in single cells reveals mRNA turnover strategies.
The regulation of messenger RNA levels in mammalian cells can be achieved by the modulation of synthesis and degradation rates. Metabolic RNA-labeling experiments in bulk have quantified these rates using relatively homogeneous cell populations. However, to determine these rates during complex dynamical processes, for instance during cellular differentiation, single-cell resolution is required. Therefore, we developed a method that simultaneously quantifies metabolically labeled and preexisting unlabeled transcripts in thousands of individual cells. We determined synthesis and degradation rates during the cell cycle and during differentiation of intestinal stem cells, revealing major regulatory strategies. These strategies have distinct consequences for controlling the dynamic range and precision of gene expression. These findings advance our understanding of how individual cells in heterogeneous populations shape their gene expression dynamics.


Hydraulic performance of a full-scale peat and ash biofilter in treatment of industrial landfill leachate.
The purpose of this study was to evaluate the hydraulic performance of a full-scale on-site vertical-flow biofilter, consisting of a mixture of peat and carbon-containing ash, and a 500 m(3) equalization pond prior to the filter-system. The treatment plant was constructed to clean up leachate from an industrial mono-landfill that contained shredder residues of end-of-life vehicles and white goods. With the limited storage capacity of the equalization pond, peak loading rates exceeded up to five to six times the designed daily hydraulic load limit of the biofilter system. Such relatively short overloading events did not negatively affect the purification efficiency. To provide the designed annual irrigation rate on the biofilter of 97 m(3) day(- 1) (or 133 mm day(-1)), with large seasonal variations in precipitation, a relatively large pond would be needed. Calculations showed that a storage volume of about 23 000 m(3) would be sufficient for annual leachate volumes up to about 35 000 m(3). A combination of sprinkler and drip irrigation with straw insulation of the latter made it possible to run the plant continuously even when the ambient air temperature was below zero for more than a month at a time. The grain size distribution of the biofilter medium was noticeably changed after 4 years of usage due to the loading of suspended solids from the leachate and decomposition of the peat, causing reduced hydraulic conductivity.


Urinary concentrations of 2,4-dichlorophenol and 2,5-dichlorophenol in the U.S. population (National Health and Nutrition Examination Survey, 2003-2010): trends and predictors.
2,4-Dichlorophenol (2,4-DCP), 2,5-dichlorophenol (2,5-DCP), and their precursors are widely used in industry and in consumer products. Urinary concentrations of these dichlorophenols (DCPs) have been measured as part of four National Health and Nutrition Examination Survey (NHANES) cycles in order to assess the exposure to these compounds or their precursors among the general U.S. population. We identified predictors and evaluated trends in DCP concentrations according to race/ethnicity, age, sex, family income, and housing type. We used analysis of covariance to examine associations of various demographic parameters and survey cycle with urinary concentrations of DCPs during NHANES 2003-2010. We also conducted weighted logistic regressions to estimate associations of DCP concentrations above the 95th percentile with housing type, race/ethnicity, and income. We detected DCPs in at least 81% of participants. Geometric mean (GM) urinary concentrations were higher for 2,5-DCP (6.1-12.9 μg/L) than 2,4-DCP (0.8-1.0 μg/L) throughout 2003-2010. Adjusted GM concentrations of the DCPs among children (6-11 years of age) and adults > 60 years of age were higher than among adolescents and other adults. Adjusted GM concentrations among non-Hispanic whites were lower than among non-Hispanic blacks and Mexican Americans, although differences according to race/ethnicity were less pronounced among participants in high-income households. Among non-Hispanic blacks and Mexican Americans, adjusted GM concentrations were lowest among high-income participants relative to other income groups, with a monotonic decrease with increasing income among Mexican Americans. Type of housing and race/ethnicity were significant predictors of DCP urinary concentrations above the 95th percentile. Furthermore, urinary DCP concentrations have showed a downward trend since 2003. Exposure to DCPs and their precursors was prevalent in the general U.S. population in 2003-2010. We identified age and race/ethnicity, family income, and housing type as predictors of exposure to these compounds.


Suppression of dextran sulfate sodium-induced colitis in mice by radon inhalation.
The enhanced release of reactive oxygen species from activated neutrophils plays important role in the pathogenesis of inflammatory bowel disease. We previously reported that radon inhalation activates antioxidative functions in various organs of mice. In this study, we examined the protective effects of radon inhalation on dextran sulfate sodium- (DSS) induced colitis in mice which were subjected to DSS for 7 days. Mice were continuously treated with air only (sham) or radon at a concentration of 2000 Bq/m³ from a day before DSS administration to the end of colitis induction. In the results, radon inhalation suppressed the elevation of the disease activity index score and histological damage score induced by DSS. Based on the changes in tumor necrosis factor-alpha in plasma and myeloperoxidase activity in the colon, it was shown that radon inhalation suppressed DSS-induced colonic inflammation. Moreover, radon inhalation suppressed lipid peroxidation of the colon induced by DSS. The antioxidant level (superoxide dismutase and total glutathione) in the colon after DSS administration was significantly higher in mice treated with radon than with the sham. These results suggested that radon inhalation suppressed DSS-induced colitis through the enhancement of antioxidative functions in the colon.


Ocular surface extracellular DNA and nuclease activity imbalance: a new paradigm for inflammation in dry eye disease.
We determined whether nucleases are deficient in the tear fluid of dry eye disease (DED) patients, and whether this causes extracellular DNA (eDNA) and neutrophil extracellular trap (NET) accumulation in the precorneal tear film, thus causing ocular surface inflammation. Exfoliated cells adhered to Schirmer test strips were collected on glass slides, and immunofluorescence confocal microscopy was used to evaluate neutrophils, eDNA, NETs, and their molecular components. Similar experiments were performed with mucoid films collected from the inferior conjunctival fornix or bulbar conjunctiva. We used quantitative PCR to evaluate eDNA signaling pathways and inflammatory cytokine expression. We also determined the amount of ocular surface eDNA and evaluated tear fluid nuclease activity. eDNA, NETs, and neutrophils were present on the ocular surface in DED patients and abundant in mucoid films. NETs consisted of eDNA, histones, cathelicidin, and neutrophil elastase. Tear fluid nuclease activity was decreased significantly in DED patients, whereas the amount of eDNA on the ocular surface was increased significantly. Expression of genes downstream of eDNA signaling, such as TLR9, MyD88, and type I interferon, as well as the inflammatory cytokines interleukin-6 and tumor necrosis factor-α, was significantly increased in DED patients. Extracellular DNA production and clearance mechanisms are dysregulated in DED. Nuclease deficiency in tear fluid allows eDNA and NETs to accumulate in precorneal tear film, and results in ocular surface inflammation. These findings point to novel therapeutic interventions in severe DED based on clearance of eDNA, NETs, and other molecular components from the ocular surface.


Alternative mental health clinical placements: Knowledge transfer and benefits for nursing practice outside mental healthcare settings.
To explore whether nursing student's experiences at Recovery Camp have impacted their current nursing practices. Recently, there has been a move towards more holistic models of nursing care, which seek to break down barriers of stigmatisation and embrace the tenets of self-determination, to acknowledge people with lived experiences of mental illness and their ability to manage their recovery. In that regard, future health professionals such as nursing students will need to be educated in a manner that recognises the importance of lived experience. In this paper, we propose that Recovery Camp, an alternative clinical placement setting model, enhances clinical practice in multiple domains and is beneficial for both nursing practitioners and people with lived experiences of mental illness, as well as offering an effective nontraditional alternative to conventional clinical placement opportunities. This study employed a phenomenological research design, involving individual semi-structured telephone interviews. The Standards for Reporting Qualitative Research (SRQR) checklist was adhered to. Three main themes were identified from the analysis: (a) engagement, (b) understanding mental health and (c) holistic care. "I definitely look at people with mental health conditions in a different light." At Recovery Camp, participants felt that they had greater opportunities for engagement with people with lived experiences, and through this engagement, their preconceptions of mental illness began to change. Recovery Camp may have facilitated the transfer of knowledge that is more person-centred among nursing students, consequently impacting their current nursing practices. Nurses should be equipped with mental health skills regardless of their career trajectory. While Recovery Camp represents a promising approach to facilitate knowledge transfer, further investigation will be required to determine which other factors are instrumental. This approach may have wider implications for nursing education.


A computerized asthma-specific quality of life: a novel tool for reflecting asthma control and predicting exacerbation.
Proper assessment of health-related quality of life is essential to achieve and maintain a controlled status in asthmatic patients. We developed our own computerized asthma-specific quality-of-life (cA-QOL) questionnaire based on in-depth interviews with adult asthmatic patients. In this study, we evaluated this cA-QOL in terms of the Asthma Control Test (ACT) score and Global Initiative for Asthma (GINA) guidelines as well as asthma exacerbation, and compared it with the asthma-related quality-of-life questionnaire (AQLQ). We conducted a multicenter, prospective, observational study in 133 adult asthmatic patients recruited from 5 university hospitals in South Korea, who were randomized into 2 groups according to the operating order of the cA-QOL and AQLQ. At every visit (3-month interval), physicians evaluated asthma control status with monitoring spirometry. The self-administered cA-QOL, AQLQ(S) and ACT were completed. The cA-QOL scores correlated significantly with ACT and AQLQ(S) scores (r = 0.814, p < 0.001; r = 0.900, p < 0.001). The cA-QOL score was significantly lower where the ACT score was <19, in the patients with an uncontrolled asthma status according to the GINA guidelines and in those with asthma exacerbation (p < 0.001, respectively). A multivariate analysis showed that this cA-QOL was a significant parameter associated with an uncontrolled asthma status and asthma exacerbation (p < 0.001, p = 0.045, p = 0.019, respectively). The cA-QOL is a valid tool for reflecting current asthma control status and for assessment to predict the future risk of asthma exacerbation in adult asthmatics.


Microcomputed tomography assessment of lipopolysaccharide-induced acute lung injury in rat.
High-resolution microcomputed tomography (micro-CT) is an extremely flexible and accurate technique for three-dimensional examination of biological tissues. The aim was to evaluate the feasibility of micro-CT as a noninvasive tool for analyzing the lung structure during lipopolysaccharide (LPS)-induced acute lung injury (ALI) in rats. ALI was induced in rats by intratracheal instillation of LPS (2 mg/kg) in 0.3 ml saline, and the control treatment consisted of intratracheal instillation of an equal volume of normal saline. Morphological changes were assessed by using micro-CT and a light microscope at 24 and 48 hours after LPS instillation. Total volume is the sum of all pixels marked as the whole lung and total air volume (Air V) is the sum volume of all air in the lung. The saline groups exhibited no major histological abnormalities, whereas the LPS groups exhibited patchy areas of haemorrhage and thickened alveolar walls with inflammatory cell infiltration at 24 and 48 hours. The LPS groups had significantly smaller Air V and percent total air volume (Air V/TV) compared with those of the saline groups at 24 and 48 hours. Air V/TV was strongly negatively correlated with the lung injury score (r = -0.641, P = .004). Micro-CT is a feasible tool for evaluating the lung structure and lung injury progression during LPS-induced ALI.


A murine model of CML blast crisis induced by cooperation between BCR/ABL and NUP98/HOXA9.
Constitutive activation of tyrosine kinases, such as the BCR/ABL fusion associated with t(9;22)(q34;q22), is a hallmark of chronic myeloid leukemia (CML) syndromes in humans. Expression of BCR/ABL is both necessary and sufficient to cause a chronic myeloproliferative syndrome in murine bone marrow transplantation models, and absolutely depends on kinase activity. Progression of CML to acute leukemia (blast crisis) in humans has been associated with acquisition of secondary chromosomal translocations, including the t(7;11)(p15;p15) resulting in the NUP98/HOXA9 fusion protein. We demonstrate that BCR/ABL cooperates with NUP98/HOXA9 to cause blast crisis in a murine model. The phenotype depends both on expression of BCR/ABL and NUP98/HOXA9, but tumors retain sensitivity to the ABL inhibitor STI571 in vitro and in vivo. This paradigm is applicable to other constitutively activated tyrosine kinases such as TEL/PDGFbetaR. These experiments document cooperative effects between constitutively activated tyrosine kinases, which confer proliferative and survival properties to hematopoietic cells, with mutations that impair differentiation, such as the NUP98/HOXA9, giving rise to the acute myeloid leukemia (AML) phenotype. Furthermore, these data indicate that despite acquisition of additional mutations, CML blast crisis cells retain their dependence on BCR/ABL for proliferation and survival.


Epizootiologic investigations of selected abortive agents in free-ranging Alpine ibex (Capra ibex ibex) in Switzerland.
In the early 2000s, several colonies of Alpine ibex (Capra ibex ibex) in Switzerland ceased growing or began to decrease. Reproductive problems due to infections with abortive agents might have negatively affected recruitment. We assessed the presence of selected agents of abortion in Alpine ibex by serologic, molecular, and culture techniques and evaluated whether infection with these agents might have affected population densities. Blood and fecal samples were collected from 651 ibex in 14 colonies throughout the Swiss Alps between 2006 and 2008. All samples were negative for Salmonella spp., Neospora caninum, and Bovine Herpesvirus-1. Antibodies to Coxiella burnetii, Leptospira spp., Chlamydophila abortus, Toxoplasma gondii, and Bovine Viral Diarrhea virus were detected in at least one ibex. Positive serologic results for Brucella spp. likely were false. Overall, 73 samples (11.2%) were antibody-positive for at least one abortive agent. Prevalence was highest for Leptospira spp. (7.9%, 95% CI=5.0-11.7). The low prevalences and the absence of significant differences between colonies with opposite population trends suggest these pathogens do not play a significant role in the population dynamics of Swiss ibex. Alpine ibex do not seem to be a reservoir for these abortive agents or an important source of infection for domestic livestock in Switzerland. Finally, although interactions on summer pastures occur frequently, spillover from infected livestock to free-ranging ibex apparently is uncommon.


Structure of the hirugen and hirulog 1 complexes of alpha-thrombin.
The isomorphous structures of the hirugen (N-acetylhirudin 53'-64' with sulfato-Tyr63') and hirulog 1 (D-Phe-Pro-Arg-Pro-(Gly)4 desulfato-Tyr63'-hirugen) complexes of human alpha-thrombin have been determined and refined at 2.2 A resolution to crystallographic R-factors of 0.167 and 0.163, respectively. The binding of hirugen to thrombin is similar to that of the binding of the C-terminal dodecapeptide of hirudin, including that of the terminal 3(10) helical turn. The sulfato Tyr63', which, as a result of sulfation, increases the binding affinity by an order of magnitude, is involved in an extended hydrogen bonding network utilizing all three sulfato oxygen atoms. The hirugen-thrombin complex is the first thrombin structure determined to have an unobstructed active site; this site is practically identical in positioning of catalytic residues and in its hydrogen bonding pattern with that of other serine proteinases. Hirulog 1, which is a poor thrombin substrate, is cleaved at the Arg3'-Pro4' bond in the crystal structure. The Arg3' of hirulog 1 occupies the specificity site, the D-Phe-Pro-Arg tripeptide is positioned like that of D-Phe-Pro-Arg chloromethylketone in the active site and the Pro4'(Gly)4 spacer to hirugen is disordered in the structure, as is the 3(10) turn of hirugen. The latter must be related to the simultaneous absence both of sulfation and of the last residue of hirudin (Gln65'). In addition, the autolysis loop of thrombin (Lys145-Gly150) is disordered in both structures. Changes in circular dichroism upon hirugen binding are therefore most likely the result of the flexibility associated with this loop.


Habitat discrimination by gravid Anopheles gambiae sensu lato--a push-pull system.
The non-random distribution of anopheline larvae in natural habitats suggests that gravid females discriminate between habitats of different quality. Whilst physical and chemical cues used by Culex and Aedes vector mosquitoes for selecting an oviposition site have been extensively studied, those for Anopheles remain poorly explored. Here the habitat selection by Anopheles gambiae sensu lato (s.l.), the principal African malaria vector, was investigated when presented with a choice of two infusions made from rabbit food pellets, or soil. Natural colonization and larval survival was evaluated in artificial ponds filled randomly with either infusion. Dual-choice, egg-count bioassays evaluated the responses of caged gravid females to (1) two- to six-day old infusions versus lake water; (2) autoclaved versus non-autoclaved soil infusions; and assessed (3) the olfactory memory of gravid females conditioned in pellet infusion as larvae. Wild Anopheles exclusively colonized ponds with soil infusion and avoided those with pellet infusion. When the individual infusions were tested in comparison with lake water, caged An. gambiae sensu stricto (s.s.) showed a dose response: females increasingly avoided the pellet infusion with increasing infusion age (six-day versus lake water: odds ratio (OR) 0.22; 95% confidence interval (CI) 0.1-0.5) and showed increasing preference to lay eggs as soil infusion age increased (six-day versus lake water: OR 2.1; 95% CI 1.4-3.3). Larvae survived in soil infusions equally well as in lake water but died in pellet infusions. Anopheles gambiae s.s. preferred to lay eggs in the non-autoclaved soil (OR 2.6; 95% CI 1.8-3.7) compared with autoclaved soil. There was no change in the avoidance of pellet infusion by individuals reared in the infusion compared with those reared in lake water. Wild and caged An. gambiae s.l. females discriminate between potential aquatic habitats for oviposition. These choices benefit the survival of the offspring. Although the study was not designed to distinguish between stimuli that acted over a distance or on contact, it could be demonstrated that the choice of habitat is mediated by chemical cues based on both preference and avoidance. These cues, if identified, might be developed for 'push-pull' strategies to improve malaria vector monitoring and control.


Similarity relations for the interaction parameters in radiation transport.
It is possible to alter the interaction parameters characterizing neutral particle radiation transport without significantly altering the spatial distribution of the particle fluence rate. Practical mathematical relations specifying the constraints that such an alteration must satisfy are known as similarity relations. Similarity relations are derived in this work from integrated versions of the single energy neutral particle transport equation. The application of these relations in accelerating Monte Carlo deep penetration simulations is described and assessed. Computational reductions may exceed a factor of 10 in highly scattering media in which the scattering is highly forward peaked, such as applies to the propagation of red and near IR light through soft tissues.


Hospitalizations for severe lower respiratory tract infections.
Hospitalization for lower respiratory tract infections (LRTIs) among children have been well characterized. We characterized hospitalizations for severe LRTI among children. We analyzed claims data from commercial and Medicaid insurance enrollees (MarketScan) ages 0 to 18 years from 2007 to 2011. LRTI hospitalizations were identified by the first 2 listed International Classification of Diseases, Ninth Revision discharge codes; those with ICU admission and/or receiving mechanical ventilation were defined as severe LRTI. Underlying conditions were determined from out- and inpatient discharge codes in the preceding year. We report insurance specific and combined rates that used both commercial and Medicaid rates and adjusted for age and insurance status. During 2007-2011, we identified 16797 and 12053 severe LRTI hospitalizations among commercial and Medicaid enrollees, respectively. The rates of severe LRTI hospitalizations per 100000 person-years were highest in children aged <1 year (commercial: 244; Medicaid: 372, respectively), and decreased with age. Among commercial enrollees, ≥ 1 condition increased the risk for severe LRTI (1 condition: adjusted relative risk, 2.68; 95% confidence interval, 2.58-2.78; 3 conditions: adjusted relative risk, 4.85; 95% confidence interval, 4.65-5.07) compared with children with no medical conditions. Using commercial/Medicaid combined rates, an estimated 31289 hospitalizations for severe LRTI occurred each year in children in the United States. Among children, the burden of hospitalization for severe LRTI is greatest among children aged <1 year. Children with underlying medical conditions are at greatest risk for severe LRTI hospitalization.


Independence of interrupted coarsening on initial system order: ion-beam nanopatterning of amorphous versus crystalline silicon targets.
Interrupted coarsening (IC) has recently been identified as an important feature for the dynamics of the typical length-scale in pattern-forming systems on surfaces. In practice, it can be beneficial to improve pattern ordering since it combines a certain degree of defect suppression with a limited increase in the typical pattern wavelength. However, little is known about its robustness with respect to changes in the preparation of the initial system for cases with potential applications. Working in the context of nano-scale pattern formation by ion-beam sputtering (IBS), we prove that IC properties do not depend on sample preparation. Specifically, interface dynamics under IBS is quantitatively compared on virgin amorphous and crystalline silicon surfaces, using 1 keV Ar(+) ions at normal incidence where nanodot pattern formation is triggered by concurrent co-deposition of Fe atoms during processing. Atomic force microscopy shows that dot patterns with similar spatial order and dynamics are obtained in both cases, underscoring the key dynamical role of the amorphous surface layer produced by irradiation. Both systems have been quantitatively described by an effective interface equation. We employ a new procedure based on the linear growth of the initial surface correlations to accurately estimate the equation coefficients. Such a method improves the predictive power of the interface equation with respect to previous studies and leads to a better description of the experimental pattern and its dynamical features.


The proprioceptive representation of eye position in monkey primary somatosensory cortex.
The cerebral cortex must have access to an eye position signal, as humans can report passive changes in eye position in total darkness, and visual responses in many cortical areas are modulated by eye position. The source of this signal is unknown. Here we demonstrate a representation of eye position in monkey primary somatosensory cortex, in the representation of the trigeminal nerve, near cells with a tactile representation of the contralateral brow. The neurons have eye position signals that increase monotonically with increasing orbital eccentricity from near the center of gaze, with directionally selectivity tuned in a Gaussian manner. All directions of eye position are represented in a single hemisphere. The signal is proprioceptive, because it can be obliterated by anesthetizing the contralateral orbit. It is not related to foveal or peripheral visual stimulation, and it represents the position of the eye in the head and not the angle of gaze in space.


Self-administration of intravenous C1-inhibitor therapy for hereditary angioedema and associated quality of life benefits.
Hereditary angioedema (HAE) is often debilitating with a serious effect on quality of life (QOL). Treatment of acute HAE attacks is usually with C1 esterase inhibitor (C1-INH) concentrates; however, treatment can be delayed by patients' travel time for attending emergency units. We assessed the impact of self-administered home therapy with intravenous C1-INH concentrate on QOL in patients with HAE. Nine patients experiencing frequent or severe debilitating HAE attacks were offered self-administration of C1-INH concentrate. QOL was assessed prior to and following home therapy using the Dermatology Life Quality Index (DLQI) and 36-Item Short Form Survey (SF-36) questionnaires. Seven patients were recruited into the study. QOL was assessed at baseline and after 3 to 48 months of home therapy. The mean DLQI score fell from 12.6 +/- 4.65 to 2.7 +/- 1.38 (P < 0.001). Mean SF-36 scores for the individual and combined components also improved significantly. No serious complications were documented during a follow-up period of 27 to 72 months. Self-administration of C1-INH improved QOL on both physical and psychological parameters. Patients were able to resume a normal life without restrictions caused by the condition.


[Cholecalciferol supplementation improves secondary hyperparathyroidism control in hemodialysis patients].
Introduction: Vitamin D deficiency is common among hemodialysis (HD) patients and is an important component in the pathogenesis of secondary hyperparathyroidism (SHPT). We herein report our experience on the impact of cholecalciferol supplementation on PTH levels in a group of HD patients. Patients and methods: We selected 122 HD patients. The main selection criteria were 25- hydroxyvitamin D (25(OH)D) levels ≤30 ng/mL and SHPT defined as PTH levels >300 pg/mL or PTH levels between 150-300 pg/mL during therapy with cinacalcet or paricalcitol. 82 patients agreed to receive cholecalciferol at the fixed dose of 25,000 IU per week orally for 12 months, while the remaining 40 represented the control group. The main endopoints of the study were the reduction in PTH levels ≥30% compared to baseline values and the increase of 25(OH)D levels to values >30 ng/mL. Results: At follow-up PTH levels decreased in the supplemented group from 476 ±293 to 296 ± 207 pg/mL (p<0.001), 25(OH)D levels increased from 10.3 ± 5.7 to 33.5 ± 11.2 ng/mL (p<0.001), serum calcium increased from 8.6 ± 0.5 to 8.8 ± 0.6 mg/dL (p<0.05) while serum phosphorus did not change. In this group the mean doses of paricalcitol were significantly reduced, from 8.7 ± 4.0 to 6.1 ± 3.9 µg/week (p<0.001). Moreover, in this group there were a significant increase of hemoglobin levels, from 11.6 ± 1.3 to 12.2 ± 1.1 g/dL (p <0.01) and a significant reduction of erythropoietin doses (p<0.05). In the control group the 25(OH)D and PTH levels did not change, while cinacalcet doses increased from 21 ±14 to 43 ± 17 mg/d (p<0.01). Conclusions: Vitamin deficiency is very common in HD patients. Cholecalciferol treatment significantly increased serum 25(OH)D levels, significantly decreased PTH levels and paricalcitol doses, concurrently entailing a better control of anemia.


Methodology of light response curves: application of chlorophyll fluorescence to microphytobenthic biofilms.
The light response curve methodology for microphytobenthic biofilms was studied by comparing the two most usual approaches used in pulse amplitude modulated (PAM) fluorometry. The non-sequential light curve (N-SLC) method is characterized by independent measures of the photosynthetic activity across a light gradient whereas the rapid light curve (RLC) method consists of successive measures on the same sample exposed to a stepwise increase of light intensities. Experiments were carried out on experimental microphytobenthic biofilms prepared from natural assemblages and acclimated to dark conditions. In preliminary experiments, N-SLCs were constructed from fluorescence induction curves performed at 12 different photon flux densities (PFDs). A minimum of 50 s of illumination was necessary to reach a stable light response curve; shorter illumination times resulted in underestimating the physiological parameters (α the light utilization coefficient in light-limited conditions and rETRmax the maximum rate of photosynthesis efficiency) of the light response curve. For the comparison between N-SLCs and RLCs, the same time of illumination (50 s) was used for each light step of RLCs so that N-SLCs differed from RLCs only by the way the amount of light was delivered, i.e., a light dose accumulation for RLC. The experimental results showed the difference between the two photobiological response curves. In the lower range of PFDs, RLCs exhibited a larger value of α; in this light-limited part of the response curve the incremental increase of PFDs limited the development of NPQ and resulted in a better optimization of electron transport rate for RLC. In the higher range of PFDs, the trend was reversed and the RLC showed a lower value of rETRmax than the N-SLC did; this is attributed to the light dose accumulation which likely led to a more efficient dispersion of energy, as illustrated by a higher non-photochemical quenching (NPQ). In conclusion, these results confirm that parameters derived from both methods differ in their value and do not bear the same physiological information.


Laboratory informatics capacity for effective antimicrobial resistance surveillance in resource-limited settings.
Antimicrobial resistance (AMR) is a major threat to human health globally. Surveillance is a key activity to determine AMR burden, impacts, and trends and to monitor effects of interventions. Surveillance systems require efficient capture and onward sharing of high-quality laboratory data. Substantial investment is being made to improve laboratory capacity, particularly in low-income and middle-income countries (LMICs) with high disease burdens. However, building capacity for effective laboratory data management remains an under-resourced area, which, unless addressed, will limit progress towards comprehensive AMR surveillance in LMICs. The lack of a fit-for-purpose and open-source laboratory information management system software is of particular concern. In this Personal View, we summarise the technical requirements for microbiology laboratory data management, provide a snapshot of laboratory data management in LMIC laboratories, and describe the key steps required to improve the situation. Without action to improve information technology infrastructure and data management systems in microbiology laboratories, the ongoing efforts to develop capacity for AMR surveillance in LMICs might not realise their full potential.


Missense mutations that alter the DNA-binding domain of the MtrR protein occur frequently in rectal isolates of Neisseria gonorrhoeae that are resistant to faecal lipids.
Resistance of Neisseria gonorrhoeae to structurally diverse hydrophobic agents (HAs) has been associated with missense or deletion mutations in the mtrR (multiple transferable resistance Regulator) gene of laboratory-derived strains but their prevalence in clinical isolates was heretofore unknown. Since faecal lipids provide strong selective pressure for the emergence of variants resistant to HAs (HAR), the nucleotide sequence of the mtrR gene from rectal isolates of N. gonorrhoeae, which displayed different levels of HAR, was determined. Compared to the mtrR gene possessed by the HA-sensitive strain FA19, each clinical isolate contained mutations in the coding and/or promoter regions of their mtrR gene. A missense mutation in codon 45 (Gly-45 to Asp) was the most common mutation found in the strains studied and impacted the structure of the helix-turn-helix domain of the MtrR protein thought to be important in DNA-binding activity. Two clinical isolates bearing a missense mutation in codon 45 also contained a single basepair deletion in a 13 bp inverted sequence positioned within the mtrR promoter region. Introduction of mtrR sequences amplified from the clinical isolates into strain FA19 revealed that acquisition of the single basepair deletion was correlated with high level HAR while mutations in the mtrR-coding region provided for an intermediate level of HAR.


Predictive systems ecology.
Human societies, and their well-being, depend to a significant extent on the state of the ecosystems that surround them. These ecosystems are changing rapidly usually in response to anthropogenic changes in the environment. To determine the likely impact of environmental change on ecosystems and the best ways to manage them, it would be desirable to be able to predict their future states. We present a proposal to develop the paradigm of predictive systems ecology, explicitly to understand and predict the properties and behaviour of ecological systems. We discuss the necessary and desirable features of predictive systems ecology models. There are places where predictive systems ecology is already being practised and we summarize a range of terrestrial and marine examples. Significant challenges remain but we suggest that ecology would benefit both as a scientific discipline and increase its impact in society if it were to embrace the need to become more predictive.


Postnatal retention in HIV care: insight from the Swiss HIV Cohort Study over a 15-year observational period.
The aim of this study was to quantify loss to follow-up (LTFU) in HIV care after delivery and to identify risk factors for LTFU, and implications for HIV disease progression and subsequent pregnancies. We used data on pregnancies within the Swiss HIV Cohort Study from 1996 to 2011. A delayed clinical visit was defined as > 180 days and LTFU as no visit for > 365 days after delivery. Logistic regression analysis was used to identify risk factors for LTFU. A total of 695 pregnancies in 580 women were included in the study, of which 115 (17%) were subsequent pregnancies. Median maternal age was 32 years (IQR 28-36 years) and 104 (15%) women reported any history of injecting drug use (IDU). Overall, 233 of 695 (34%) women had a delayed visit in the year after delivery and 84 (12%) women were lost to follow-up. Being lost to follow-up was significantly associated with a history of IDU [adjusted odds ratio (aOR) 2.79; 95% confidence interval (CI) 1.32-5.88; P = 0.007] and not achieving an undetectable HIV viral load (VL) at delivery (aOR 2.42; 95% CI 1.21-4.85; P = 0.017) after adjusting for maternal age, ethnicity and being on antiretroviral therapy (ART) at conception. Forty-three of 84 (55%) women returned to care after LTFU. Half of them (20 of 41) with available CD4 had a CD4 count < 350 cells/μL and 15% (six of 41) a CD4 count < 200 cells/μL at their return. A history of IDU and detectable HIV VL at delivery were associated with LTFU. Effective strategies are warranted to retain women in care beyond pregnancy and to avoid CD4 cell count decline. ART continuation should be advised especially if a subsequent pregnancy is planned.


Interaction of DJ-1 with Daxx inhibits apoptosis signal-regulating kinase 1 activity and cell death.
Investigations into the cellular and molecular biology of genes that cause inherited forms of Parkinson's disease, as well as the downstream pathways that they trigger, shed considerable light on our understanding the fundamental determinants of life and death in dopaminergic neurons. Homozygous deletion or missense mutation in DJ-1 results in autosomal recessively inherited Parkinson's disease, suggesting that wild-type DJ-1 has a favorable role in maintaining these neurons. Here, we show that DJ-1 protects against oxidative stress-induced cell death, but that its relatively modest ability to quench reactive oxygen species is insufficient to account for its more robust cytoprotective effect. To elucidate the mechanism of this cell-preserving function, we have screened out the death protein Daxx as a DJ-1-interacting partner. We demonstrate that wild-type DJ-1 sequesters Daxx in the nucleus, prevents it from gaining access to the cytoplasm, from binding to and activating its effector kinase apoptosis signal-regulating kinase 1, and therefore, from triggering the ensuing death pathway. All these steps are impaired by the disease-causing L166P mutant isoform of DJ-1. These findings suggest that the regulated sequestration of Daxx in the nucleus and keeping apoptosis signal-regulating kinase 1 activation in check is a critical mechanism by which DJ-1 exerts its cytoprotective function.


A phase III, randomized, double-blind, placebo-controlled, study of iseganan for the reduction of stomatitis in patients receiving stomatotoxic chemotherapy.
The invasion and colonization of oral cavity mucosal tissues by microflora may contribute to the pathophysiology of ulcerative oral mucositis (UOM). Iseganan is an analog of protegrin-1, a naturally occurring peptide with broad-spectrum microbicidal activity. A randomized, double-blind, placebo-controlled study was conducted to evaluate the efficacy and safety of iseganan in preventing UOM after stomatotoxic therapy. Patients received an oral rinse, consisting of iseganan 9mg or placebo, to be swished/swallowed six times daily, starting with stomatotoxic therapy and continuing up to 21 days. Patients were assessed for stomatitis and UOM, and administered a questionnaire evaluating mouth pain and difficulty swallowing thrice weekly. The primary study efficacy endpoint was the proportion of patients who did not have peak stomatitis NCI-CTC grade >or=2. Between November 2001 and June 2002, 502 patients were randomized to receive iseganan (251) or placebo (251). Equivalent numbers of patients in both cohorts received bone marrow or peripheral blood allogeneic or autologous stem cell transplantation (SCT). Forty-three percent and 37% of iseganan and placebo patients, respectively, did not have peak stomatitis grade =2 (P = 0.182). There was no significant difference between the cohorts in stomatitis severity, incidence of UOM, peak mouth pain, peak difficulty swallowing, amount of opiate analgesics used, or adverse event type or incidence. A major impact of Iseganan on reducing stomatitis, UOM, or its clinical sequelae in patients receiving stomatotoxic therapy was not detected on this study.


Health-related quality of life outcomes improve after multilevel surgery in ambulatory children with cerebral palsy.
Studies evaluating multilevel surgery to treat spastic deformity and functional deficits in cerebral palsy (CP) usually focus on data from instrumented gait analysis and clinical examination without examining functional and health-related quality of life (HRQOL) outcomes. Recently, outcome measures for well-being in children with a variety of musculoskeletal disorders have also been validated specifically for CP. Therefore, this study aimed to investigate the impact of multilevel surgery on the function and HRQOL in a group of ambulatory children with CP. In a multicenter prospective trial, 57 ambulatory children with CP, mean age 9.5 years, underwent multilevel soft tissue surgery to correct sagittal imbalance. Validated clinical outcome measures for HRQOL were administered preoperatively and postoperatively with an average follow-up time of 15.2 months. The functional and psychosocial components of the Pediatric Outcomes Data Collection Instrument (PODCI), Pediatric Quality of Life Questionnaire (PedsQL), and the Functional Assessment Questionnaire Walking Score were used. Significant improvements in outcome scores occurred postoperatively in the following: PedsQL parent-total (17.6%; P < 0.001) and parent-physical sections (25.0%; P < 0.001), the Functional Assessment Questionnaire Walking Score (15.3%; P < 0.001), and the PODCI sections for transfers and basic mobility (15.8%; P < 0.001), sports and physical function (23.9%; P = 0.012), and global (12.9%; P < 0.001). Improvements also occurred in the PedsQL child-total (8.4%; P = 0.104) and child-physical sections (8.6%; P = 0.189), but these were not statistically significant. There were no significant changes in the PODCI parent-derived pain (-3.2%; P = 0.504) and happiness sections (1.9%; P = 0.645). Multilevel surgery in ambulatory patients with CP improves function and HRQOL. However, improved functional well-being does not imply improved psychosocial well-being, and patients and their families should be counseled accordingly.


Andropause. Testosterone replacement therapy for aging men.
To review the rationale for treating symptomatic aging men whose testosterone levels are mildly reduced or low-normal with testosterone replacement therapy. Large-scale multicentre prospective studies on the value of treating andropausal men with hormone therapy do not exist because the whole area of hormone therapy is barely 10 years old. Evidence presented is based on physiologic studies, particularly studies in which treatment has been assessed. These were largely uncontrolled open studies. Studies to date report positive responses to testosterone treatment with very few serious side effects. Physicians should consider hypoandrogenism if male patients complain of loss of libido, erectile dysfunction, weakness, fatigue, lethargy, loss of motivation, or mood swings. Less obvious associations with reduced levels of testosterone are anemia and osteoporosis. The main cause of reduced testosterone production is primary gonadal insufficiency, but secondary causes, such as hypothalamic-pituitary disease, should be considered. Evidence shows that most men treated with testosterone will feel better about themselves and their lives. Andropause is a term of convenience describing a complex of symptoms in aging men who have low testosterone levels. Physicians should be aware of its existence, should consider ordering tests for men who have symptoms, and should treat carefully selected patients whose serum testosterone levels are low.


Potent monoclonal antibodies against Clostridium difficile toxin A elicited by DNA immunization.
Recent studies have demonstrated that DNA immunization is effective in eliciting antigen-specific antibody responses against a wide range of infectious disease targets. The polyclonal antibodies elicited by DNA vaccination exhibit high sensitivity to conformational epitopes and high avidity. However, there have been limited reports in literature on the production of monoclonal antibodies (mAb) by DNA immunization. Here, by using Clostridium difficile (C. diff) toxin A as a model antigen, we demonstrated that DNA immunization was effective in producing a panel of mAb that are protective against toxin A challenge and can also be used as sensitive reagents to detect toxin A from various testing samples. The immunoglobulin (Ig) gene usage for such mAb was also investigated. Further studies should be conducted to fully establish DNA immunization as a unique platform to produce mAb in various hosts.


Reactions of Hexadehydro-Diels-Alder (HDDA)-Derived Benzynes with Thioamides: Synthesis of Dihydrobenzothiazino-Heterocyclics.
Reaction of thioamides (e.g., II) with benzynes generated by the hexadehydro-Diels-Alder (HDDA) cycloisomerization (e.g., I) produces dihydrobenzothiazines (e.g., III). It is postulated that the reaction proceeds via benzothietene (cf. IV) and o-thiolatoaryliminium (cf. V) intermediates and that the latter undergoes intramolecular 1,3-hydrogen atom migration to produce the penultimate isomeric iminium zwitterions VI.


Methanol extract of Lonicera caerulea var. emphyllocalyx fruit has anti-motility and anti-biofilm activity against enteropathogenic Escherichia coli.
Foodborne diseases have become a worldwide problem that threatens public health and welfare. Enteropathogenic Escherichia coli (EPEC) is one of major pathogens of moderate to severe diarrhea. The increased prevalence of EPEC strains that produce extended spectrum β-lactamase (ESBL) has deepened the problem. The fruit of Lonicera caerulea var. emphyllocalyx (LCE) has been used as a traditional food preservative and medicine in northern temperate zones such as Hokkaido Island, Japan. In this study, we investigated the antibacterial effect of LCE fruit extract (LCEE) against EPEC. The antibacterial activities of LCEE were examined by bacterial growth, time-kill curve, soft-agar motility, electron microscopy, and 96 well-microplate biofilm assays. We also investigated the bacterial mRNA expression of biofilm-associated genes (fliC, csgA, and fimA) by quantitative real-time PCR assays. LCEE was found to suppress the growth, time-kill curve, and spread of EPEC. It also reduced the biofilm formation in a dose-dependent manner. Morphological analysis using transmission and scanning electron microscopy revealed that LCEE diminished the function of flagella resulting in reduced motility and biofilm formation. The mRNA expression of all three biofilm associated genes was downregulated under LCEE treatment. Extracts of the fruit of LCE inhibit the motility and biofilm formation of EPEC as a result of the inhibition of flagella development and function. We propose LCEE as a therapeutic candidate for the effective therapy of EPEC-associated infectious diseases.


Characteristics of martial art injuries in a defined Canadian population: a descriptive epidemiological study.
The martial arts have emerged as common activities in the Canadian population, yet few studies have investigated the occurrence of associated injuries on a population basis. We performed such an investigation and suggest potential opportunities for prevention. The data source was 14 years (1993 to 2006) of records from the Kingston sites of the Canadian Hospital Injury Reporting and Prevention Program (CHIRPP). 920 cases were identified. Incidence rates were initially estimated using census data as denominators. We then imputed annual injury rates per 10000 using a range of published estimates of martial arts participation available from a national survey. Rates of injury in males and females were 2300 and 1033 per 10000 (0.3% participation) and 575 and 258 per 10000 (1.2% participation). Injuries were most frequently reported in karate (33%) and taekwondo (14%). The most common mechanisms of injury were falls, throws and jumps (33%). Fractures (20%) were the most frequently reported type of injury and the lower limb was the most common site of injury (41%). Results provide a foundation for potential interventions with a focus on falls, the use of weapons, participation in tournaments, as well as head and neck trauma.


Targeted metagenomics and ecology of globally important uncultured eukaryotic phytoplankton.
Among eukaryotes, four major phytoplankton lineages are responsible for marine photosynthesis; prymnesiophytes, alveolates, stramenopiles, and prasinophytes. Contributions by individual taxa, however, are not well known, and genomes have been analyzed from only the latter two lineages. Tiny "picoplanktonic" members of the prymnesiophyte lineage have long been inferred to be ecologically important but remain poorly characterized. Here, we examine pico-prymnesiophyte evolutionary history and ecology using cultivation-independent methods. 18S rRNA gene analysis showed pico-prymnesiophytes belonged to broadly distributed uncultivated taxa. Therefore, we used targeted metagenomics to analyze uncultured pico-prymnesiophytes sorted by flow cytometry from subtropical North Atlantic waters. The data reveal a composite nuclear-encoded gene repertoire with strong green-lineage affiliations, which contrasts with the evolutionary history indicated by the plastid genome. Measured pico-prymnesiophyte growth rates were rapid in this region, resulting in primary production contributions similar to the cyanobacterium Prochlorococcus. On average, pico-prymnesiophytes formed 25% of global picophytoplankton biomass, with differing contributions in five biogeographical provinces spanning tropical to subpolar systems. Elements likely contributing to success include high gene density and genes potentially involved in defense and nutrient uptake. Our findings have implications reaching beyond pico-prymnesiophytes, to the prasinophytes and stramenopiles. For example, prevalence of putative Ni-containing superoxide dismutases (SODs), instead of Fe-containing SODs, seems to be a common adaptation among eukaryotic phytoplankton for reducing Fe quotas in low-Fe modern oceans. Moreover, highly mosaic gene repertoires, although compositionally distinct for each major eukaryotic lineage, now seem to be an underlying facet of successful marine phytoplankton.