Changes in synaptic structure underlie the developmental speeding of AMPA receptor-mediated EPSCs.
At many excitatory and inhibitory synapses throughout the nervous system, postsynaptic currents become faster as the synapse matures, primarily owing to changes in receptor subunit composition. The origin of the developmental acceleration of AMPA receptor (AMPAR)-mediated excitatory postsynaptic currents (EPSCs) remains elusive. We used patch-clamp recordings, electron microscopic immunogold localization of AMPARs, partial three-dimensional reconstruction of the neuropil and numerical simulations of glutamate diffusion and AMPAR activation to examine the factors underlying the developmental speeding of miniature EPSCs in mouse cerebellar granule cells. We found that the main developmental change that permits submillisecond transmission at mature synapses is an alteration in the glutamate concentration waveform as experienced by AMPARs. This can be accounted for by changes in the synaptic structure and surrounding neuropil, rather than by a change in AMPAR properties. Our findings raise the possibility that structural alterations could be a general mechanism underlying the change in the time course of AMPAR-mediated synaptic transmission.


Cytokine regulation of human monocyte differentiation in vitro: the tumor-cytotoxic phenotype induced by macrophage colony-stimulating factor is developmentally regulated by gamma-interferon.
In this study we continue our examination of the unique form of antibody-dependent antitumor cytotoxicity (ADCC) which develops when human monocytes are exposed to macrophage colony-stimulating factor (MCSF) in vitro. This form of ADCC is not present in fresh monocytes and emerges only as monocytes differentiate into monocyte-derived macrophages (MDM). We now report that the presence of gamma-interferon (IFN-gamma) during this period of differentiation markedly affects the development of MCSF-induced cytotoxicity. The addition of IFN-gamma on day 0 resulted in a pronounced dose-dependent inhibition of ADCC measured on day 7 (mean inhibition, 76 +/- 12%; range, 66-94%). MDM exposed to MCSF plus IFN-gamma required 3-10-fold higher effector to target cell ratios to achieve a level of cytotoxicity comparable to that of MDM cultured with MCSF alone. This inhibitory effect was attributable to an IFN-gamma-induced shift in the basic mechanism of target cell killing, away from the phagocytic form normally seen with MCSF and toward a significantly less effective extracellular form. In order to influence ADCC, IFN-gamma had to be present prior to the onset of differentiation; if it was added later it had progressively less effect, and if it was added after differentiation was complete it was inactive. The modulatory effects of IFN-gamma also extended to a number of other developmentally regulated attributes. MDM cultured with MCSF normally acquired a characteristic morphology and immunophenotype, re-entered the cell cycle, and changed functionally from accessory cells for mitogen-induced lymphocyte activation to suppressor cells. The presence of IFN-gamma prevented the emergence of each of these attributes. Despite these negative effects, MDM exposed to IFN-gamma remained viable, continued to bind and internalize MCSF, and displayed superior accessory cell function and oxidative burst activity. Taken together, our findings suggest that human monocytes are capable of following at least two distinct differentiation pathways in response to the local cytokine environment, with significant impact on the resultant macrophage phenotype in general and antitumor cytotoxicity in particular.


Pacing Strategy, Muscle Fatigue, and Technique in 1500-m Speed-Skating and Cycling Time Trials.
To evaluate pacing behavior and peripheral and central contributions to muscle fatigue in 1500-m speed-skating and cycling time trials when a faster or slower start is instructed. Nine speed skaters and 9 cyclists, all competing at regional or national level, performed two 1500-m time trials in their sport. Athletes were instructed to start faster than usual in 1 trial and slower in the other. Mean velocity was measured per 100 m. Blood lactate concentrations were measured. Maximal voluntary contraction (MVC), voluntary activation (VA), and potentiated twitch (PT) of the quadriceps muscles were measured to estimate central and peripheral contributions to muscle fatigue. In speed skating, knee, hip, and trunk angles were measured to evaluate technique. Cyclists showed a more explosive start than speed skaters in the fast-start time trial (cyclists performed first 300 m in 24.70 ± 1.73 s, speed skaters in 26.18 ± 0.79 s). Both trials resulted in reduced MVC (12.0% ± 14.5%), VA (2.4% ± 5.0%), and PT (25.4% ± 15.2%). Blood lactate concentrations after the time trial and the decrease in PT were greater in the fast-start than in the slow-start trial. Speed skaters showed higher trunk angles in the fast-start than in the slow-start trial, while knee angles remained similar. Despite similar instructions, behavioral adaptations in pacing differed between the 2 sports, resulting in equal central and peripheral contributions to muscle fatigue in both sports. This provides evidence for the importance of neurophysiological aspects in the regulation of pacing. It also stresses the notion that optimal pacing needs to be studied sport specifically, and coaches should be aware of this.


Stroke After Percutaneous Coronary Intervention in the Era of Transradial Intervention.
Periprocedural stroke is a rare but life-threatening complication of percutaneous coronary intervention (PCI). Transradial intervention (TRI) is more beneficial than transfemoral intervention for periprocedural bleeding and acute kidney injuries, but its effect on periprocedural stroke has not been fully investigated. Our study aimed to assess risk predictors of periprocedural stroke according to PCI access site. Between 2008 and 2016, 17 966 patients undergoing PCI were registered in a prospective multicenter database. Periprocedural stroke was defined as loss of neurological function caused by an ischemic or hemorrhagic event with residual symptoms lasting at least 24 hours after onset. Periprocedural stroke was observed in 42 patients (0.3%). Stroke patients were older and had a higher incidence of chronic kidney disease, peripheral artery disease, and acute coronary syndrome but were less likely to undergo TRI. Multivariable logistic regression analysis revealed TRI (odds ratio; 0.33; 95% CI, 0.16-0.71; P=0.004) was significantly associated with a lower occurrence of periprocedural stroke. Finally, propensity score-matching analysis showed that TRI was associated with a reduced risk of periprocedural stroke compared with transfemoral intervention (0.1% versus 0.4%; P=0.014). According to our sensitivity analysis, this finding was robust to the presence of an unmeasured confounder in almost all plausible scenarios. TRI was associated with a reduced risk of periprocedural stroke compared with transfemoral intervention. Increased TRI use may reduce overall PCI complications and should be recommended as the optimal access site for both urgent/emergent and elective PCIs.


Kaempferia parviflora extract increases whole-body energy expenditure in humans: roles of brown adipose tissue.
Kaempferia parviflora extract (KP) has been reported to have a preventive effect on obesity in mice, probably by increasing energy expenditure (EE). The aims of the current study were to examine the acute effects of KP ingestion on whole-body EE in humans and to analyze its relation to the activity of brown adipose tissue (BAT), a site of non-shivering thermogenesis. After an oral ingestion of an ethanol extract of KP, EE increased significantly, showing a maximal increase of 229±69 kJ/d at 60 min, while it did not change after placebo ingestion. To evaluate BAT activity, the subjects underwent fluorodeoxyglucose-positron emission tomography, and divided into two groups with high- and low-BAT activities. A similar and greater response of EE to KP ingestion was observed in the high-BAT group (351±50 kJ/d at 60 min), but not in the low activity group. Placebo ingestion did not cause any significant EE change in either group. These results indicate that a single oral ingestion of the KP extract can potentially increase whole-body EE probably through the activation of BAT in healthy men, and may be useful as an anti-obesity regimen.


Density functional study of the ground and excited state potential energy surfaces of a light-driven rotary molecular motor (3R,3'R)-(P,P)-trans-1,1',2,2',3,3',4,4'-octahydro-3,3'-dimethyl-4,4'-biphenanthrylidene.
Potential energy surfaces of the ground and the first excited singlet states of the (3R,3'R)-(P,P)-trans-1,1',2,2',3,3',4,4'-octahydro-3,3'-dimethyl-4,4'-biphenanthrylidene rotary molecular motor have been investigated along the central C(4)=C(4') double bond twisting mode starting from the (P,P)-trans and from the (P,P)-cis conformations occurring in the photoisomerization cycle of this compound. The potential energy profiles obtained with the help of the state average spin restricted ensemble-referenced Kohn-Sham (SA-REKS) method feature minima on the excited state surface, the positions of which are displaced with respect to the barriers on the ground state surface toward the isomerization products, the (M,M)-cis and the (M,M)-trans conformations, respectively. The origin of these minima is analyzed and explained. The results of the present study suggest that the experimentally observed unidirectionality of photoinduced rotation in the above compound can be corroborated by the obtained profiles of the ground and excited state potential energy surfaces.


Clinical evaluation of zirconia-based all-ceramic single crowns: an up to 12-year retrospective cohort study.
This study aims to investigate the incidence of clinical complications with tooth-supported zirconia-based all-ceramic single crowns and identify pertinent risk parameters. A retrospective cohort study (May 2004 to April 2016) utilizing clinical records of patients receiving yttrium-oxide-partially stabilized zirconia (Y-TZP)-based all-ceramic crowns placed at Tohoku University Hospital was performed. The length of time of treatment success (complication event-free) and restoration survival (including minor complication events and remaining clinically functional) were estimated using Kaplan-Meier analysis. Multilevel survival analysis was used to identify risk factors. One hundred thirty-seven crowns were evaluated (mean follow-up time, 7.0 years). A total of 21 crowns experienced at least one complication with fracture of veneering ceramic being the most common (16 crowns). Estimated success and survival rates at 5 years (96.9 and 98.5%, respectively) decreased at 10 years to 62.1 and 67.2%, respectively. The risk of complications was significantly higher for molar crowns compared to anterior crowns (p < 0.01). A significant association of complications with metal antagonist restorations was shown by univariate analysis (p < 0.01). Given the study limitations, Y-TZP single crowns placed on anterior teeth demonstrated encouraging clinical results over a period of up to 10 years. However, there is a substantial risk of complications with posterior teeth within 10 years of restoration placement. Treatment with zirconia-based all-ceramic crowns for molar teeth with metal antagonist occlusion should be undertaken with caution.


TWEAK and cIAP1 regulate myoblast fusion through the noncanonical NF-κB signaling pathway.
The fusion of mononucleated muscle progenitor cells (myoblasts) into multinucleated muscle fibers is a critical aspect of muscle development and regeneration. We identified the noncanonical nuclear factor κB (NF-κB) pathway as a signaling axis that drives the recruitment of myoblasts into new muscle fibers. Loss of cellular inhibitor of apoptosis 1 (cIAP1) protein led to constitutive activation of the noncanonical NF-κB pathway and an increase in the number of nuclei per myotube. Knockdown of essential mediators of NF-κB signaling, such as p100, RelB, inhibitor of κB kinase α, and NF-κB-inducing kinase, attenuated myoblast fusion in wild-type myoblasts. In contrast, the extent of myoblast fusion was increased when the activity of the noncanonical NF-κB pathway was enhanced by increasing the abundance of p52 and RelB or decreasing the abundance of tumor necrosis factor (TNF) receptor-associated factor 3, an inhibitor of this pathway. Low concentrations of the cytokine TNF-like weak inducer of apoptosis (TWEAK), which preferentially activates the noncanonical NF-κB pathway, also increased myoblast fusion, without causing atrophy or impairing myogenesis. These results identify roles for TWEAK, cIAP1, and noncanonical NF-κB signaling in the regulation of myoblast fusion and highlight a role for cytokine signaling during adult skeletal myogenesis.


Crystal structure of human plasma platelet-activating factor acetylhydrolase: structural implication to lipoprotein binding and catalysis.
Human plasma platelet-activating factor (PAF) acetylhydrolase functions by reducing PAF levels as a general anti-inflammatory scavenger and is linked to anaphylactic shock, asthma, and allergic reactions. The enzyme has also been implicated in hydrolytic activities of other pro-inflammatory agents, such as sn-2 oxidatively fragmented phospholipids. This plasma enzyme is tightly bound to low and high density lipoprotein particles and is also referred to as lipoprotein-associated phospholipase A2. The crystal structure of this enzyme has been solved from x-ray diffraction data collected to a resolution of 1.5 angstroms. It has a classic lipase alpha/beta-hydrolase fold, and it contains a catalytic triad of Ser273, His351, and Asp296. Two clusters of hydrophobic residues define the probable interface-binding region, and a prediction is given of how the enzyme is bound to lipoproteins. Additionally, an acidic patch of 10 carboxylate residues and a neighboring basic patch of three residues are suggested to play a role in high density lipoprotein/low density lipoprotein partitioning. A crystal structure is also presented of PAF acetylhydrolase reacted with the organophosphate compound paraoxon via its active site Ser273. The resulting diethyl phosphoryl complex was used to model the tetrahedral intermediate of the substrate PAF to the active site. The model of interface binding begins to explain the known specificity of lipoprotein-bound substrates and how the active site can be both close to the hydrophobic-hydrophilic interface and at the same time be accessible to the aqueous phase.


Removing adsorbed heavy metal ions from sand surfaces via applying interfacial properties of rhamnolipid.
In this study, the interfacial properties of biosurfactant rhamnolipid were investigated and were applied to remove adsorbed heavy metal ions from sand surfaces with flushing operations. The surface tension-lowering activity, micelle charge characteristic, and foaming ability of rhamnolipid were identified first. For rhamnolipid in water, the negatively charged characteristic of micelles or aggregates was confirmed and the foaming ability at concentrations higher than 40 mg/L was evaluated. By using the rhamnolipid solutions in a batch washing approach, the potential of applying the interfacial properties of rhamnolipid to remove adsorbed copper ions from sand surfaces was then demonstrated. In rhamnolipid solution flushing operations for sand-packed medium, higher efficiency was found for the removal of adsorbed copper ions with residual type than with inner-sphere interaction type, implying the important role of interaction type between the copper ion and the sand surface in the removal efficiency. In addition, the channeling effect of rhamnolipid solution flow in the sand-packed medium was clearly observed in the solution flushing operations and was responsible for the low removal efficiency with low contact areas between solution and sand. By using rhamnolipid solution with foam to flush the sand-packed medium, one could find that the channeling effect of the solution flow was reduced and became less pronounced with the increase in the rhamnolipid concentration, or with the enhanced foaming ability. With the reduced channeling effect in the flushing operations, the removal efficiency for adsorbed copper ions was significantly improved. The results suggested that the foam-enhanced rhamnolipid solution flushing operation was efficient in terms of surfactant usage and operation time.


Incidence of oxygen toxicity during the treatment of dysbarism.
Oxygen (O2) toxicity may result from exposure to partial pressures of O2 above 0.6ATA. Potential toxic exposure for divers occurs during the treatment of dysbarism. In the recompression chamber, PO2 may range from 0.9ATA to 3.3ATA depending upon the treatment table employed. This retrospective study examines the nature and incidence of O2 toxicity in 998 patients who underwent recompression treatment at our facility from 1983 through 2001. Only patients evaluated for diving related injury were considered for this study. Of 1189 charts reviewed, 998 patients received recompression and were entered into this study. The total number of treatment exposures was determined as was the total number of O2 toxicity events characterized as either pulmonary or CNS, and patients were divided into male/female analysis. Overall incidence as well as the incidence for both toxicity types was determined, and their occurrence in both male and female patients was ascertained. 2166 recompressions were undertaken, 449 female and 1717 male. The peak PO2 for these treatments ranged from 2.6ATA to 2.9ATA. 155 O2 toxicity events occurred in 152 patients, 49 females and 103 males. Three patients, 2 females and 1 male, had mixed events. Incidence of an O2 toxic event = 7.0 per 100 recompressions. Incidence of pulmonary toxicity overall = 5.0 per 100 recompressions, while CNS events = 2.0 per 100 recompressions with overall seizure rate = 0.6 per 100 recompressions. In females, pulmonary toxicity rate = 6.9 per 100 recompressions, CNS toxicity rate = 4.4 per 100 recompressions with seizures occurring at 1.3 per 100 recompressions. In males, pulmonary toxicity rate = 4.6 per 100 recompressions, CNS toxicity rate = 1.4 per 100 recompressions, and seizures at 0.4 per 100 recompressions.


Plasmid-mediated AmpC-type beta-lactamase isolated from Klebsiella pneumoniae confers resistance to broad-spectrum beta-lactams, including moxalactam.
Klebsiella pneumoniae NU2936 was isolated from a patient and was found to produce a plasmid-encoded beta-lactamase (MOX-1) which conferred resistance to broad spectrum beta-lactams, including moxalactam, flomoxef, ceftizoxime, cefotaxime, and ceftazidime. Resistance could be transferred from K. pneumoniae NU2936 to Escherichia coli CSH2 by conjugation with a transfer frequency of 5 x 10(-7). The structural gene of MOX-1 (blaMOX-1) was cloned and expressed in E. coli HB101. The MIC of moxalactam for E. coli HB101 producing MOX-1 was > 512 micrograms/ml. The apparent molecular mass and pI of this enzyme were calculated to be 38 kDa and 8.9, respectively. Hg2+ and Cu2+ failed to block enzyme activity, and the presence of EDTA in the reaction buffer did not reduce the enzyme activity. However, clavulanate and cloxacillin, serine beta-lactamase inhibitors, inhibited the enzyme activity competitively (Kis = 5.60 and 0.35 microM, respectively). The kinetic study of MOX-1 suggested that it effectively hydrolyzed broad-spectrum beta-lactams. A hybridization study confirmed that blaMOX-1 is encoded on a large resident plasmid (pRMOX1; 180 kb) of strain NU2936. By deletion analysis, the functional region was localized within a 1.2-kb region of the plasmid. By amino acid sequencing, 18 of 33 amino acid residues at the N terminus of MOX-1 were found to be identical to those of Pseudomonas aeruginosa AmpC. These findings suggest that MOX-1 is a plasmid-mediated AmpC-type beta-lactamase that provides enteric bacteria resistance to broad-spectrum beta-lactams, including moxalactam.


Bridging Three Orders of Magnitude: Multiple Scattered Waves Sense Fractal Microscopic Structures via Dispersion.
Wave scattering provides profound insight into the structure of matter. Typically, the ability to sense microstructure is determined by the ratio of scatterer size to probing wavelength. Here, we address the question of whether macroscopic waves can report back the presence and distribution of microscopic scatterers despite several orders of magnitude difference in scale between wavelength and scatterer size. In our analysis, monosized hard scatterers 5 μm in radius are immersed in lossless gelatin phantoms to investigate the effect of multiple reflections on the propagation of shear waves with millimeter wavelength. Steady-state monochromatic waves are imaged in situ via magnetic resonance imaging, enabling quantification of the phase velocity at a voxel size big enough to contain thousands of individual scatterers, but small enough to resolve the wavelength. We show in theory, experiments, and simulations that the resulting coherent superposition of multiple reflections gives rise to power-law dispersion at the macroscopic scale if the scatterer distribution exhibits apparent fractality over an effective length scale that is comparable to the probing wavelength. Since apparent fractality is naturally present in any random medium, microstructure can thereby leave its fingerprint on the macroscopically quantifiable power-law exponent. Our results are generic to wave phenomena and carry great potential for sensing microstructure that exhibits intrinsic fractality, such as, for instance, vasculature.


The alar contour graft: correction and prevention of alar rim deformities in rhinoplasty.
One of the most common problems affecting both the primary and secondary rhinoplasty patient is deformity of the alar rim. Typically, this deformity is caused by congenital malpositioning, hypoplasia, or surgical weakening of the lateral crura, with the potential for both functional and aesthetic ramifications. Successful correction and prevention of alar rim deformities requires precise preoperative diagnosis and planning. Multiple techniques of varying complexity have been described to treat this common and challenging problem. Over the past 6 years (1994 through 2000), the authors have employed a simple technique in 123 patients for alar retraction that involves the nonanatomic insertion of an autogenous cartilage buttress into an alar-vestibular pocket. Among the 53 patients who underwent primary rhinoplasty in this study, 91 percent experienced correction or prevention of alar notching or collapse. However, correction was achieved for only 73 percent of the patients who underwent secondary rhinoplasty; many of whom had alar retraction secondary to scarring or lining loss. In patients with moderate or significant lining loss or scarring, a lateral crural strut graft is recommended. The alar contour graft provides the foundation in the patient undergoing primary or secondary rhinoplasty for the reestablishment of a normally functioning external nasal valve and an aesthetically pleasing alar contour. This article discusses the anatomic and aesthetic considerations of alar rim deformities and the indications and the surgical technique for the alar contour graft.


Absence of auditory 'global interference' in autism.
There has been considerable recent interest in the cognitive style of individuals with Autism Spectrum Disorder (ASD). One theory, that of weak central coherence, concerns an inability to combine stimulus details into a coherent whole. Here we test this theory in the case of sound patterns, using a new definition of the details (local structure) and the coherent whole (global structure). Thirteen individuals with a diagnosis of autism or Asperger's syndrome and 15 control participants were administered auditory tests, where they were required to match local pitch direction changes between two auditory sequences. When the other local features of the sequence pairs were altered (the actual pitches and relative time points of pitch direction change), the control participants obtained lower scores compared with when these details were left unchanged. This can be attributed to interference from the global structure, defined as the combination of the local auditory details. In contrast, the participants with ASD did not obtain lower scores in the presence of such mismatches. This was attributed to the absence of interference from an auditory coherent whole. The results are consistent with the presence of abnormal interactions between local and global auditory perception in ASD.


Night work, light exposure and melatonin on work days and days off.
We aimed to examine the effects of night work on salivary melatonin concentration during and subsequent to night work and the mediating role of light. We included 254 day workers and 87 night workers who were followed during 322 work days and 301 days off work. Each day was defined as the 24 hour period starting from the beginning of a night shift or from waking in the mornings with day work and days off. Light levels were recorded and synchronized with diary information (start and end of sleep and work). On average, participants provided four saliva samples per day, and these were analyzed for melatonin concentration by liquid chromatography tandem mass spectrometry (LC-MS/MS). Differences between day and night workers on work days and days off were assessed with multilevel regression models with melatonin concentration as the primary outcome. All models were stratified or adjusted by time of day. For light exposure, we estimated the total, direct and indirect effects of night work on melatonin concentrations obtaining 95% confidence intervals through bootstrapping. On work days, night workers showed 15% lower salivary melatonin concentrations compared with day workers (-15.0%; 95% CI: -31.4%; 5.2%). During the night, light exposure mediated a melatonin suppression of approximately 6% (-5.9%, 95% CI: -10.2%; -1.5%). No mediating effect of light was seen during the day time. On days off, we observed no difference in melatonin concentrations between day and night workers. These findings are in accordance with a transient and partly light-mediated effect of night work on melatonin production.


Protective effect of melatonin against oxidative stress on adhesion formation in the rat cecum and uterine horn model.
This experimental study was designed to evaluate the degree of adhesion formation and peritoneal tissue levels of malondialdehyde (MDA), reduced glutathione (GSH) and nitric oxide (NO) and the effect of melatonin on these metabolites in a postoperative intraperitoneal adhesion formation model in rats. Thirty adult female Wistar albino rats were subjected to standardized lesions by cecal and uterine horn abrasion and were randomly divided into three groups. Control rats were treated with 5% ethanol. Melatonin treated rats received 4 mg/kg melatonin before closure and for 10 consecutive days intraperitoneally after surgery. Rats in the sham operation group underwent a surgical procedure similar to the other groups however the peritoneal abrasion was not performed. On postoperative day 10 relaparatomy was performed. After the assessment of the adhesions, the rats in each group were sacrificed and peritoneal tissues were harvested to determine the tissue levels of MDA, GSH and NO activity. Adhesion formation scores in the melatonin group were significantly lower than that of control and sham group (p<0.01 and p<0.02, respectively). Tissue levels of MDA and NO were significantly lower in the melatonin treated rats when compared with control and sham groups. The levels of GSH in the melatonin treated rats were significantly higher than those of control and sham groups (p<0.01). The results demonstrate that in this experimental model, intraperitoneal administration of melatonin decreases the extent of peritoneal adhesions and causes a decrease in MDA and NO and an increase in GSH levels.


A novel approach for prediction of vitamin d status using support vector regression.
Epidemiological evidence suggests that vitamin D deficiency is linked to various chronic diseases. However direct measurement of serum 25-hydroxyvitamin D (25(OH)D) concentration, the accepted biomarker of vitamin D status, may not be feasible in large epidemiological studies. An alternative approach is to estimate vitamin D status using a predictive model based on parameters derived from questionnaire data. In previous studies, models developed using Multiple Linear Regression (MLR) have explained a limited proportion of the variance and predicted values have correlated only modestly with measured values. Here, a new modelling approach, nonlinear radial basis function support vector regression (RBF SVR), was used in prediction of serum 25(OH)D concentration. Predicted scores were compared with those from a MLR model. Determinants of serum 25(OH)D in Caucasian adults (n = 494) that had been previously identified were modelled using MLR and RBF SVR to develop a 25(OH)D prediction score and then validated in an independent dataset. The correlation between actual and predicted serum 25(OH)D concentrations was analysed with a Pearson correlation coefficient. Better correlation was observed between predicted scores and measured 25(OH)D concentrations using the RBF SVR model in comparison with MLR (Pearson correlation coefficient: 0.74 for RBF SVR; 0.51 for MLR). The RBF SVR model was more accurately able to identify individuals with lower 25(OH)D levels (<75 nmol/L). Using identical determinants, the RBF SVR model provided improved prediction of serum 25(OH)D concentrations and vitamin D deficiency compared with a MLR model, in this dataset.


The combined effect of individual and neighborhood socioeconomic status on cancer survival rates.
This population-based study investigated the relationship between individual and neighborhood socioeconomic status (SES) and mortality rates for major cancers in Taiwan. A population-based follow-up study was conducted with 20,488 cancer patients diagnosed in 2002. Each patient was traced to death or for 5 years. The individual income-related insurance payment amount was used as a proxy measure of individual SES for patients. Neighborhood SES was defined by income, and neighborhoods were grouped as living in advantaged or disadvantaged areas. The Cox proportional hazards model was used to compare the death-free survival rates between the different SES groups after adjusting for possible confounding and risk factors. After adjusting for patient characteristics (age, gender, Charlson Comorbidity Index Score, urbanization, and area of residence), tumor extent, treatment modalities (operation and adjuvant therapy), and hospital characteristics (ownership and teaching level), colorectal cancer, and head and neck cancer patients under 65 years old with low individual SES in disadvantaged neighborhoods conferred a 1.5 to 2-fold higher risk of mortality, compared with patients with high individual SES in advantaged neighborhoods. A cross-level interaction effect was found in lung cancer and breast cancer. Lung cancer and breast cancer patients less than 65 years old with low SES in advantaged neighborhoods carried the highest risk of mortality. Prostate cancer patients aged 65 and above with low SES in disadvantaged neighborhoods incurred the highest risk of mortality. There was no association between SES and mortality for cervical cancer and pancreatic cancer. Our findings indicate that cancer patients with low individual SES have the highest risk of mortality even under a universal health-care system. Public health strategies and welfare policies must continue to focus on this vulnerable group.


Self-reported history of sexually transmissible infections (STIs) and STI-related utilization of the German health care system by men who have sex with men: data from a large convenience sample.
In Germany, testing and treatment of sexually transmissible infections (STIs) services are not provided by one medical discipline, but rather dispersed among many different providers. Common STIs like gonorrhoea or Chlamydia infection are not routinely reported. Although men who have sex with men (MSM) are particularly vulnerable to STIs, respective health care utilization among MSM is largely unknown. A sexual behaviour survey among MSM was conducted in 2006. Questions on self-reported sexual behaviour, STI-related health care consultation and barriers to access, coverage of vaccination against hepatitis, screening for asymptomatic STIs, self-reported history of STIs, and partner notification were analysed. Analysis was stratified by HIV-serostatus (3,511 HIV-negative/unknown versus 874 positive). General Practitioners, particularly gay doctors, were preferred for STI-related health care. Low threshold testing in sex-associated venues was acceptable for most respondents. Shame and fear of homophobic reactions were the main barriers for STI-testing. More than half of the respondents reported vaccination against hepatitis A/B. HIV-positive MSM reported screening offers for STIs three to seven times more often than HIV-negative or untested MSM. Unlike testing for syphilis or hepatitis C, screening for asymptomatic pharyngeal and rectal infections was rarely offered. STIs in the previous twelve months were reported by 7.1% of HIV-negative/untested, and 34.7% of HIV-positive respondents. Self-reported histories of STIs in MSM convenience samples differ significantly by HIV-serostatus. Higher rates of STIs among HIV-positive MSM may partly be explained by more testing. Communication between health care providers and their clients about sexuality, sexual practices, and sexual risks should be improved. A comprehensive STI screening policy for MSM is needed.


Snow tussocks, chaos, and the evolution of mast seeding.
One hitherto intractable problem in studying mast seeding (synchronous intermittent heavy flowering by a population of perennial plants) is determining the relative roles of weather, plant reserves, and evolutionary selective pressures such as predator satiation. We parameterize a mechanistic resource-based model for mast seeding in Chionochloa pallens (Poaceae) using a long-term individually structured data set. Each plant's energy reserves were reconstructed using annual inputs (growing degree days), outputs (flowering), and a novel regression technique. This allowed the estimation of the parameters that control internal plant resource dynamics, and thereby allowed different models for masting to be tested against each other. Models based only on plant size, season degree days, and/or climatic cues (warm January temperatures) fail to reproduce the pattern of autocovariation in individual flowering and the high levels of flowering synchrony seen in the field. This shows that resource-matching or simple cue-based models cannot account for this example of mast seeding. In contrast, the resource-based model pulsed by a simple climate cue accurately describes both individual-level and population-level aspects of the data. The fitted resource-based model, in the absence of environmental forcing, has chaotic (but often statistically periodic) dynamics. Environmental forcing synchronizes individual reproduction, and the models predict highly variable seed production in close agreement with the data. An evolutionary model shows that the chaotic internal resource dynamics, as predicted by the fitted model, is selectively advantageous provided that adult mortality is low and seeds survive for more than 1 yr, both of which are true for C. pallens. Highly variable masting and chaotic dynamics appear to be advantageous in this case because they reduce seed losses to specialist seed predators, while balancing the costs of missed reproductive events.


Breed, Coat Color, and Hair Length as Risk Factors for Hyperthyroidism in Cats.
Hyperthyroidism is very common in older cats, but the etiopathogenesis is poorly understood. Decreased risk of hyperthyroidism has been reported in certain colorpoint breeds, and this observation previously has been hypothesized to result from relatively greater tyrosine availability for thyroid hormone production because of limited ability to convert tyrosine to melanin pigment. However, studies investigating a potential link between coat pigmentation and risk of hyperthyroidism are limited. To identify associations between coat phenotype and hyperthyroidism by investigation of breed, coat color, and hair length as risk factors for the disease. Data were used from 4,705 cats aged ≥10 years, referred to a single veterinary teaching hospital (2006-2014) in the United Kingdom. Retrospective, epidemiological, cross-sectional study using Bayesian multivariable logistic regression to assess risk factors for hyperthyroidism. Burmese (odds ratio [OR], 0.01; 0.00-0.23; P = .004), Tonkinese (OR, 0.05; 0.00-0.95; P = .046), Persian (OR, 0.21; 0.10-0.44; P < .001), Siamese (OR, 0.27; 0.12-0.61; P = .002), Abyssinian (OR, 0.04; 0.00-0.74; P = .031), and British shorthair (OR, 0.47; 0.28-0.79; P = .004) breeds had decreased risk of hyperthyroidism compared to domestic shorthairs. Longhaired, nonpurebred cats (OR, 1.30; 1.03-1.64; P = .028) were at increased risk of hyperthyroidism. Coat color/pattern was not associated with hyperthyroidism in nonpurebred cats. We identified decreased risk of hyperthyroidism in the Tonkinese, Abyssinian, and British shorthair breeds, identified an association between risk of hyperthyroidism and hair length, and confirmed decreased risk in Burmese, Siamese, and Persian breeds. Additional studies are warranted to further investigate these findings.


Integrating NOE and RDC using sum-of-squares relaxation for protein structure determination.
We revisit the problem of protein structure determination from geometrical restraints from NMR, using convex optimization. It is well-known that the NP-hard distance geometry problem of determining atomic positions from pairwise distance restraints can be relaxed into a convex semidefinite program (SDP). However, often the NOE distance restraints are too imprecise and sparse for accurate structure determination. Residual dipolar coupling (RDC) measurements provide additional geometric information on the angles between atom-pair directions and axes of the principal-axis-frame. The optimization problem involving RDC is highly non-convex and requires a good initialization even within the simulated annealing framework. In this paper, we model the protein backbone as an articulated structure composed of rigid units. Determining the rotation of each rigid unit gives the full protein structure. We propose solving the non-convex optimization problems using the sum-of-squares (SOS) hierarchy, a hierarchy of convex relaxations with increasing complexity and approximation power. Unlike classical global optimization approaches, SOS optimization returns a certificate of optimality if the global optimum is found. Based on the SOS method, we proposed two algorithms-RDC-SOS and RDC-NOE-SOS, that have polynomial time complexity in the number of amino-acid residues and run efficiently on a standard desktop. In many instances, the proposed methods exactly recover the solution to the original non-convex optimization problem. To the best of our knowledge this is the first time SOS relaxation is introduced to solve non-convex optimization problems in structural biology. We further introduce a statistical tool, the Cramér-Rao bound (CRB), to provide an information theoretic bound on the highest resolution one can hope to achieve when determining protein structure from noisy measurements using any unbiased estimator. Our simulation results show that when the RDC measurements are corrupted by Gaussian noise of realistic variance, both SOS based algorithms attain the CRB. We successfully apply our method in a divide-and-conquer fashion to determine the structure of ubiquitin from experimental NOE and RDC measurements obtained in two alignment media, achieving more accurate and faster reconstructions compared to the current state of the art.


Dynamics of CD8+ T cell priming by dendritic cells in intact lymph nodes.
The cellular dynamics underlying activation of CD8+ T cells by dendritic cells (DCs) in the lymph node are not known. Here we have tracked the behavior of T cells and DCs by subjecting intact lymph nodes to real-time two-photon microscopy. We show that DCs scan at least 500 different T cells per hour in the absence of antigen. Antigen-bearing DCs are highly efficient in recruiting peptide-specific T cells and can engage more than ten T cells simultaneously. The duration of these interactions is of the order of hours, not minutes. The overall avidity of the interaction influences the probability that T cells will be stably captured by DCs, providing a possible basis for T cell competition. Taken together, our results identify the cellular behaviors that promote an efficient CD8+ T cell response in the lymph node.


Patterns of growth hormone-releasing factor and somatostatin secretion into the hypophysial-portal circulation of the rat.
The interrelation between the secretion of two hypophysiotropic peptides, growth hormone-releasing factor (GRF) and somatostatin (SRIF), in the generation of episodic growth hormone (GH) secretion was inferred from direct measurements of immunoreactive GRF and immunoreactive SRIF concentrations in the hypophysial-portal plasma of the rat. Secretion of immunoreactive GRF was found to be episodic, with maximal concentrations present during periods of expected GH secretory episodes. Secretion of immunoreactive GRF was accompanied by a moderate reduction in portal plasma levels of immunoreactive SRIF. Passive immunoneutralization of SRIF was associated with increased concentrations of immunoreactive GRF in hypophysial-portal plasma. On the basis of these observations, it appears that each GH secretory episode is initiated by pulsatile secretion of immunoreactive GRF into the portal circulation, which is preceded by or is concurrent with a moderate reduction of inhibitory tone provided by portal immunoreactive SRIF. These experiments provide direct insights into central and adenohypophysial mechanisms by which GRF and SRIF interact to generate episodic secretion of GH.


18F-FDG Metabolic Tumor Volume: Association with Short- and Long-Term Feeding Tube Use in Head and Neck IMRT.
The purpose of this study was to investigate whether the metabolic tumor volume (MTV) of head and neck primary tumors may be a significant prognostic factor for feeding tube (FT) use and FT dependence. Seventy-nine patients with evaluable primary tumors, pre-therapy FDG-PET scans, treated with definitive intensity-modulated radiotherapy (IMRT) (± concurrent chemotherapy) for head and neck mucosal cancers were included. MTV was quantified and recorded for the primary lesion using a minimum standardized uptake value (SUV) threshold of 2.0. Patients were recommended prophylactic FT and followed up by a dietician for at least eight weeks of post-radiotherapy. Associations between MTV, dose to swallowing organs at risk, FT use, and FT dependence were analyzed. MTV was positively correlated with gross tumor volume (GTV) (r = 0.7357; p < 0.0001). MTVs larger than 17 cc were associated with higher rates of FT use (87.8% vs. 69.5%, p = 0.0067) and FT dependence at six weeks (76.7% vs. 41.7%, p = 0.0024) and six months (25.0% vs. 8.7%, p = 0.0088). Increasing MTV was associated with increasing mean dose to the oral cavity (p = < 0.0001), tongue base (p = 0.0009), and superior (SPCM) (p = 0.0001) and middle pharyngeal constrictor muscles (MPCM) (p = 0.0005). Increasing MTV was associated with increasing maximum dose to oral cavity (p = 0.0028), tongue base (p = 0.0056), SPCM (p = 0.0037), and MPCM (p = 0.0085). Pre-treatment MTV is a reproducible parameter that can be generated at or prior to a pre-treatment Multidisciplinary Tumor Board and may expedite decisions regarding placement of prophylactic FTs. Prospective evaluation in larger series is required to determine whether MTV is a more useful prognostic variable for FT use than clinical T-classification.


When the going gets tough: behavioural type-dependent space use in the sleepy lizard changes as the season dries.
Understanding space use remains a major challenge for animal ecology, with implications for species interactions, disease spread, and conservation. Behavioural type (BT) may shape the space use of individuals within animal populations. Bolder or more aggressive individuals tend to be more exploratory and disperse further. Yet, to date we have limited knowledge on how space use other than dispersal depends on BT. To address this question we studied BT-dependent space-use patterns of sleepy lizards (Tiliqua rugosa) in southern Australia. We combined high-resolution global positioning system (GPS) tracking of 72 free-ranging lizards with repeated behavioural assays, and with a survey of the spatial distributions of their food and refuge resources. Bayesian generalized linear mixed models (GLMM) showed that lizards responded to the spatial distribution of resources at the neighbourhood scale and to the intensity of space use by other conspecifics (showing apparent conspecific avoidance). BT (especially aggressiveness) affected space use by lizards and their response to ecological and social factors, in a seasonally dependent manner. Many of these effects and interactions were stronger later in the season when food became scarce and environmental conditions got tougher. For example, refuge and food availability became more important later in the season and unaggressive lizards were more responsive to these predictors. These findings highlight a commonly overlooked source of heterogeneity in animal space use and improve our mechanistic understanding of processes leading to behaviourally driven disease dynamics and social structure.


Asian monsoon transport of pollution to the stratosphere.
Transport of air from the troposphere to the stratosphere occurs primarily in the tropics, associated with the ascending branch of the Brewer-Dobson circulation. Here, we identify the transport of air masses from the surface, through the Asian monsoon, and deep into the stratosphere, using satellite observations of hydrogen cyanide (HCN), a tropospheric pollutant produced in biomass burning. A key factor in this identification is that HCN has a strong sink from contact with the ocean; much of the air in the tropical upper troposphere is relatively depleted in HCN, and hence, broad tropical upwelling cannot be the main source for the stratosphere. The monsoon circulation provides an effective pathway for pollution from Asia, India, and Indonesia to enter the global stratosphere.


Development and characterization of a mouse with profound biotinidase deficiency: a biotin-responsive neurocutaneous disorder.
Biotinidase deficiency is the primary enzymatic defect in biotin-responsive, late-onset multiple carboxylase deficiency. Untreated children with profound biotinidase deficiency usually exhibit neurological symptoms including lethargy, hypotonia, seizures, developmental delay, sensorineural hearing loss and optic atrophy; and cutaneous symptoms including skin rash, conjunctivitis and alopecia. Although the clinical features of the disorder markedly improve or are prevented with biotin supplementation, some symptoms, once they occur, such as developmental delay, hearing loss and optic atrophy, are usually irreversible. To prevent development of symptoms, the disorder is screened for in the newborn period in essentially all states and in many countries. In order to better understand many aspects of the pathophysiology of the disorder, we have developed a transgenic biotinidase-deficient mouse. The mouse has a null mutation that results in no detectable serum biotinidase activity or cross-reacting material to antibody prepared against biotinidase. When fed a biotin-deficient diet these mice develop neurological and cutaneous symptoms, carboxylase deficiency, mild hyperammonemia, and exhibit increased urinary excretion of 3-hydroxyisovaleric acid and biotin and biotin metabolites. The clinical features are reversed with biotin supplementation. This biotinidase-deficient animal can be used to study systematically many aspects of the disorder and the role of biotinidase, biotin and biocytin in normal and in enzyme-deficient states.


Increasing power for voxel-wise genome-wide association studies: the random field theory, least square kernel machines and fast permutation procedures.
Imaging traits are thought to have more direct links to genetic variation than diagnostic measures based on cognitive or clinical assessments and provide a powerful substrate to examine the influence of genetics on human brains. Although imaging genetics has attracted growing attention and interest, most brain-wide genome-wide association studies focus on voxel-wise single-locus approaches, without taking advantage of the spatial information in images or combining the effect of multiple genetic variants. In this paper we present a fast implementation of voxel- and cluster-wise inferences based on the random field theory to fully use the spatial information in images. The approach is combined with a multi-locus model based on least square kernel machines to associate the joint effect of several single nucleotide polymorphisms (SNP) with imaging traits. A fast permutation procedure is also proposed which significantly reduces the number of permutations needed relative to the standard empirical method and provides accurate small p-value estimates based on parametric tail approximation. We explored the relation between 448,294 single nucleotide polymorphisms and 18,043 genes in 31,662 voxels of the entire brain across 740 elderly subjects from the Alzheimer's disease neuroimaging initiative (ADNI). Structural MRI scans were analyzed using tensor-based morphometry (TBM) to compute 3D maps of regional brain volume differences compared to an average template image based on healthy elderly subjects. We find method to be more sensitive compared with voxel-wise single-locus approaches. A number of genes were identified as having significant associations with volumetric changes. The most associated gene was GRIN2B, which encodes the N-methyl-d-aspartate (NMDA) glutamate receptor NR2B subunit and affects both the parietal and temporal lobes in human brains. Its role in Alzheimer's disease has been widely acknowledged and studied, suggesting the validity of the approach. The various advantages over existing approaches indicate a great potential offered by this novel framework to detect genetic influences on human brains.


Vital confocal microscopy in bone.
We wished to exploit confocal microscopy for high spatial and temporal resolution vital microscopy in bone. To this end, we evolved implants with glass windows supported in titanium, which were placed in the medial proximal tibial plateau of the rabbit, and special small, self-focussing objectives (dry 10/0.25, water immersion 20/0.45, and oil immersion 45/0.65 and 120/1.0) which mated and matched to the conical window entrance section of the metal components. At intervals of up to 21 months after implant healing, these lenses were used to study live tissue using two genera of confocal microscope: multiple aperture disc, tandem scanning, microscopes for observation in reflection, and video rate confocal laser scanning microscopes for recording, mainly in the fluorescence mode. The latter allowed the study of a variety of intravenously administered substances, including fluorescein, fluorescein-dextrans, fluorescent microspheres, acridine orange, DASPMI, calcein, and tetracycline. We were able to remove blood, stain cells with fluorescent markers, and replace them into the circulation. Calcein and tetracycline bind to the mineral front in bone: this labelling was studied in progress. We observed that both substances partition and remain for long periods (at least days) in adipocytes. Further characterisation of the system used both confocal fluorescence and scanning electron microscopy methods in the study of retrieved implants. These studies showed that the subimplant cortical bone remodelled to a less compact structure with a rich microvasculature extremely close to bone. The points of attachment of bone to glass were found to involve coarse fibres, with the matrix containing large numbers of large cells: some of this tissue was cartilage and some immature bone. An amorphous, mineralised matrix was in immediate contact with glass. The results provide further confirmation of the general utility of high-scan speed confocal methodology in physiology.


Monolithic polarization diversity coherent receiver based on 120-degree optical hybrids on silicon.
We present a monolithic polarization diversity coherent receiver by employing 120-degree optical hybrids on a silicon photonic integrated circuit (PIC). This PIC monolithically integrates silicon inverse tapers for fiber coupling, silicon polarization splitters, germanium high-speed photo detectors, and 120-degree optical hybrids based on 3x3 multimode interferometers (MMI). We demonstrate that 112-Gb/s polarization-division-multiplexed quadrature phase-shift keyed signals are detected in the wavelength range of 1530-1580 nm with comparable performance to commercial receivers.


Legal Regulation of Sodium Consumption to Reduce Chronic Conditions.
In the United States, tens of thousands of Americans die each year of heart disease, stroke, or other chronic conditions tied to hypertension from long-term overconsumption of sodium compounds. Major strides to lower dietary sodium have been made over decades, but the goal of reducing Americans' daily consumption is elusive. The Food and Drug Administration (FDA) has been urged to consider stronger regulatory limits on sodium, especially in processed and prepared foods. Still, FDA categorizes salt (and many other sodium compounds) as "generally recognized as safe," meaning they can be added to foods when ingested in reasonable amounts. Legal reforms or actions at each level of government offer traditional and new routes to improving chronic disease outcomes. However, using law as a public health tool must be assessed carefully, given potential trade-offs and unproven efficacy.


Time keeping and working memory development in early adolescence: a 4-year follow-up.
In this longitudinal study, we examined time keeping in relation to working memory (WM) development. School-aged children completed two tasks of WM updating and a time monitoring task in which they indicated the passing of time every 5 min while watching a film. Children completed these tasks first when they were 8 to 12 years old and then 4 years later when they were 12 to 16 years old. Time keeping in early adolescence showed a different pattern of outcome measures than 4 years earlier, with reduced clock checking and increased timing error. However, relative changes in WM development moderated these adverse effects. Adolescents with greater relative gains in WM development were better calibrated than participants with less developing WM functions. We discuss these findings in relation to individual and developmental differences in executive control functions and socioemotionally driven reward seeking.


Inter-strain differences of serotonergic inhibitory pain control in inbred mice.
Descending inhibitory pain control contributes to the endogenous defense against chronic pain and involves noradrenergic and serotonergic systems. The clinical efficacy of antidepressants suggests that serotonin may be particularly relevant for neuropathic pain conditions. Serotonergic signaling is regulated by synthesis, metabolisms, reuptake and receptors. To address the complexity, we used inbred mouse strains, C57BL/6J, 129 Sv, DBA/2J and Balb/c, which differ in brain serotonin levels. Serotonin analysis after nerve injury revealed inter-strain differences in the adaptation of descending serotonergic fibers. Upregulation of spinal cord and midbrain serotonin was apparent only in 129 Sv mice and was associated with attenuated nerve injury evoked hyperalgesia and allodynia in this strain. The increase of dorsal horn serotonin was blocked by hemisectioning of descending fibers but not by rhizotomy of primary afferents indicating a midbrain source. Para-chlorophenylalanine-mediated serotonin depletion in spinal cord and midbrain intensified pain hypersensitivity in the nerve injury model. In contrast, chronic inflammation of the hindpaw did not evoke equivalent changes in serotonin levels in the spinal cord and midbrain and nociceptive thresholds dropped in a parallel manner in all strains. The results suggest that chronic nerve injury evoked hypernociception may be contributed by genetic differences of descending serotonergic inhibitory control.


Clustering and assembly dynamics of a one-dimensional microphase former.
Both ordered and disordered microphases ubiquitously form in suspensions of particles that interact through competing short-range attraction and long-range repulsion (SALR). While ordered microphases are more appealing materials targets, understanding the rich structural and dynamical properties of their disordered counterparts is essential to controlling their mesoscale assembly. Here, we study the disordered regime of a one-dimensional (1D) SALR model, whose simplicity enables detailed analysis by transfer matrices and Monte Carlo simulations. We first characterize the signature of the clustering process on macroscopic observables, and then assess the equilibration dynamics of various simulation algorithms. We notably find that cluster moves markedly accelerate the mixing time, but that event chains are of limited help in the clustering regime. These insights will inspire further study of three-dimensional microphase formers.


Variability in lipid profile in patients with acute myocardial infarction from two tertiary care hospitals in Pakistan.
To investigate changes in total cholesterol, high density lipoprotein (HDL)-cholesterol, low density lipoprotein (LDL)-cholesterol and triglycerides in serum of Pakistani patients with AMI due to age, gender, body mass index (BMI), diabetes, hypertension, and smoking, and also find out the prevalence of hypercholesterolemia, hypertriglyceridemia, "low HDL-cholesterol" and "isolated low-HDL cholesterol" in them. Serum samples from 451 consecutive AMI patients (250 from National Institute of Cardiovascular Diseases, Karachi and 201 from Armed Forces Institute of Cardiology, Rawalpindi) were analyzed for total cholesterol, HDL-cholesterol and triglycerides using kit methods. LDL-cholesterol was determined using the Friedewald formula. Mean serum concentrations of total cholesterol, HDL-cholesterol, LDL-cholesterol and triglycerides in AMI patients were found to be 181 +/- 50 mg/dl, 35.7 +/- 11.3 mg/dl, 110 +/- 47 mg/dl and 177 +/- 127 mg/dl, respectively. Mean levels of total cholesterol and HDL-cholesterol were not significantly affected by age, gender, BMI, diabetes mellitus, hypertension and smoking. Mean LDL-cholesterol concentration, however, was found to be significantly increased in diabetes mellitus (p=0.047), while age, gender, BMI, hypertension and smoking had no significant effect on the levels of this lipoprotein. Mean levels of triglycerides were significantly decreased in older patients (>50 years) compared to younger (<50 years) ones (p=0.019). Gender, BMI, diabetes mellitus, hypertension and smoking, however, had no effect on triglyceride levels The frequencies of hypercholesterolemia, hypertriglyceridemia, "low HDL-cholesterol" and "isolated low-HDL-cholesterol" were found to be 30.6%, 30.1%, 48.6% and 34.1%, respectively. High prevalence of hypertriglyceridemia and low HDL-cholesterol (which constitute a component of metabolic syndrome) in Pakistani AMI patients is suggestive that these two lipid abnormalities could be playing a major role in the development of atherosclerosis in Pakistani population.


Structural and ultrastructural features of boar seminal vesicles.
The morphological features of boar seminal vesicles were examined by light and transmission microscopy. Boar seminal vesicles consist of glandular tissue arranged in multiple lobules containing a system of ramified secretory tubules. The secretory tubules are composed of a mucosa formed by an epithelium and an underlying lamina propria and, are surrounded by a muscular layer. The epithelium is made up of columnar cells and occasional basal cells. Mast cells are frequently found among epithelial cells. Three types of columnar cells, considered different stages of the secretory cell cycle, are present: principal cells, clear cells and dense cells. Principal cells are functionally differentiated cells characterised by abundant mitochondria, great development of the rough endoplasmic reticulum and presence of secretory granules in their cytoplasm. The apical surface of many principal cells shows apical blebs filled with PAS-positive material. No acid mucosubstances are detected. Microvilli cover the apical surface except in the apical blebs. Dense cells, arranged between principal cells, are also functional differentiated cells but with signs of cellular degeneration. Clear cells are an initial differentiated stage of columnar cells and are characterised by the presence of a poorly developed rough endoplasmic reticulum and by the absence of secretory granules. Proliferating cells are present among columnar cells. Basal cells contain scarce cytoplasm, few organelles and no secretory granules. The lack of mitotic activity in these cells suggests that they do not act as precursors of columnar cells.


Hypoxia-induced genetic instability--a calculated mechanism underlying tumor progression.
The cause of human cancers is imputed to the genetic alterations at nucleotide and chromosomal levels of ill-fated cells. It has long been recognized that genetic instability-the hallmark of human cancers-is responsible for the cellular changes that confer progressive transformation on cancerous cells. How cancer cells acquire genetic instability, however, is unclear. We propose that tumor development is a result of expansion and progression-two complementary aspects that collaborate with the tumor microenvironment-hypoxia in particular, on genetic alterations through the induction of genetic instability. In this article, we review the recent literature regarding how hypoxia functionally impairs various DNA repair pathways resulting in genetic instability and discuss the biomedical implications in cancer biology and treatment.


Biosensors-Publication Trends and Knowledge Domain Visualization.
The number of scholarly publications on the topic of biosensors has increased rapidly; as a result, it is no longer easy to build an informed overview of the developments solely by manual means. Furthermore, with many new research results being continually published, it is useful to form an up-to-date understanding of the recent trends or emergent directions in the field. This paper utilizes bibliometric methods to provide an overview of the developments in the topic based on scholarly publications. The results indicate an increasing interest in the topic of biosensor(s) with newly emerging sub-topics. The US is identified as the country with highest total contribution to this area, but as a collective, EU countries top the list of total contributions. An examination of trends over the years indicates that in recent years, China-based authors have been more productive in this area. If research contribution per capita is considered, Singapore takes the top position, followed by Sweden, Switzerland and Denmark. While the number of publications on biosensors seems to have declined in recent years in the PubMed database, this is not the case in the Web of Science database. However, there remains an indication that the rate of growth in the more recent years is slowing. This paper also presents a comparison of the developments in publications on biosensors with the full set of publications in two of the main journals in the field. In more recent publications, synthetic biology, smartphone, fluorescent biosensor, and point-of-care testing are among the terms that have received more attention. The study also identifies the top authors and journals in the field, and concludes with a summary and suggestions for follow up research.


Influence of DMSO on Carbon K ultrasoft X-rays induced chromosome aberrations in V79 Chinese hamster cells.
Ultrasoft X-rays have been shown to be very efficient in inducing chromosomal aberrations in mammalian cells. The present study was aimed to evaluate the modifying effects of DMSO (a potent scavenger of free radicals) on the frequencies of chromosome aberrations induced by soft X-rays. Confluent held G1 Chinese hamster cells (V79) were irradiated with Carbon K ultrasoft X-rays in the presence and absence of 1M DMSO and frequencies of chromosome aberrations in the first division cells were determined. DMSO reduced the frequencies of exchange types of aberrations (dicentrics and centric rings) by a factor of 2.1-3.5. The results indicate that free radicals induced by ultrasoft X-rays contribute to a great extent to the induction of chromosome aberrations. The possible implications of these results in interpreting the mechanisms involved in the high efficiency of ultrasoft X-rays in the induction of chromosome aberrations are discussed.


Systems analysis identifies miR-29b regulation of invasiveness in melanoma.
In many cancers, microRNAs (miRs) contribute to metastatic progression by modulating phenotypic reprogramming processes such as epithelial-mesenchymal plasticity. This can be driven by miRs targeting multiple mRNA transcripts, inducing regulated changes across large sets of genes. The miR-target databases TargetScan and DIANA-microT predict putative relationships by examining sequence complementarity between miRs and mRNAs. However, it remains a challenge to identify which miR-mRNA interactions are active at endogenous expression levels, and of biological consequence. We developed a workflow to integrate TargetScan and DIANA-microT predictions into the analysis of data-driven associations calculated from transcript abundance (RNASeq) data, specifically the mutual information and Pearson's correlation metrics. We use this workflow to identify putative relationships of miR-mediated mRNA repression with strong support from both lines of evidence. Applying this approach systematically to a large, published collection of unique melanoma cell lines - the Ludwig Melbourne melanoma (LM-MEL) cell line panel - we identified putative miR-mRNA interactions that may contribute to invasiveness. This guided the selection of interactions of interest for further in vitro validation studies. Several miR-mRNA regulatory relationships supported by TargetScan and DIANA-microT demonstrated differential activity across cell lines of varying matrigel invasiveness. Strong negative statistical associations for these putative regulatory relationships were consistent with target mRNA inhibition by the miR, and suggest that differential activity of such miR-mRNA relationships contribute to differences in melanoma invasiveness. Many of these relationships were reflected across the skin cutaneous melanoma TCGA dataset, indicating that these observations also show graded activity across clinical samples. Several of these miRs are implicated in cancer progression (miR-211, -340, -125b, -221, and -29b). The specific role for miR-29b-3p in melanoma has not been well studied. We experimentally validated the predicted miR-29b-3p regulation of LAMC1 and PPIC and LASP1, and show that dysregulation of miR-29b-3p or these mRNA targets can influence cellular invasiveness in vitro. This analytic strategy provides a comprehensive, systems-level approach to identify miR-mRNA regulation in high-throughput cancer data, identifies novel putative interactions with functional phenotypic relevance, and can be used to direct experimental resources for subsequent experimental validation. Computational scripts are available: http://github.com/uomsystemsbiology/LMMEL-miR-miner.


How and why do women's groups (WGs) improve the quality of maternal and child health (MCH) care? A systematic review of the literature.
This systematic review was undertaken to assist the implementation of the WOmen's action for Mums and Bubs (WOMB) project which explores Aboriginal and Torres Strait Islander community women's group (WG) action to improve maternal and child health (MCH) outcomes. There is now considerable international evidence that WGs improve MCH outcomes, and we were interested in understanding how and why this occurs. The following questions guided the review: (1) What are the characteristics, contextual influences and group processes associated with the MCH outcomes of WGs? (2) What are the theoretical and conceptual approaches to WGs? (3) What are the implications likely to inform Aboriginal and Torres Strait Islander WGs? We systematically searched electronic databases (MEDLINE (Ovid); CINAHL (Ebsco); Informit health suite, Scopus, Emcare (Ovid) and the Cochrane Library and Informit), online search registers and grey literature using the terms mother, child, group, participatory and community and their variations during all time periods to January 2021. The inclusion criteria were: (1) Population: studies involving community WGs in any country. (2) Intervention: a program/intervention involving any aspect of community WGs planning, acting, learning and reviewing MCH improvements. (3) Outcome: studies with WGs reported a component of: (i) MCH outcomes; or (ii) improvements in the quality of MCH care or (iii) improvements in socioemotional well-being of mothers and/or children. (4) Context: the primary focus of initiatives must be in community-based or primary health care settings. (5) Process: includes some description of the process of WGs or any factors influencing the process. (6) Language: English. (7) Study design: all types of quantitative and qualitative study designs involving primary research and data collection.Data were extracted under 14 headings and a narrative synthesis identified group characteristics and analysed the conceptual approach to community participation, the use of theory and group processes. An Australian typology of community participation, concepts from Aboriginal and Torres Strait Islander group work and an adapted framework of Cohen and Uphoff were used to synthesise results. Risk of bias was assessed using Joanna Briggs Institute Critical Appraisal Tools. Thirty-five (35) documents were included with studies conducted in 19 countries. Fifteen WGs used participatory learning and action cycles and the remainder used cultural learning, community development or group health education. Group activities, structure and who facilitated groups was usually identified. Intergroup relationships and decision-making were less often described as were important concepts from an Aboriginal or Torres Strait Islander perspective (the primacy of culture, relationships and respect). All but two documents used an explicit theoretical approach. Using the typology of community participation, WGs were identified as predominantly developmental (22), instrumental (10), empowerment (2) and one was unclear. A framework to categorise links between contextual factors operating at micro, meso and macro levels, group processes and MCH improvements is required. Currently, despite a wealth of information about WGs, it was difficult to determine the methods through which they achieved their outcomes. This review adds to existing systematic reviews about the functioning of WGs in MCH improvement in that it covers WGs in both high-income and low-income settings, identifies the theory underpinning the WGs and classifies the conceptual approach to participation. It also introduces an Australian Indigenous perspective into analysis of WGs used to improve MCH. CRD42019126533.


Human cytomegalovirus UL18 utilizes US6 for evading the NK and T-cell responses.
Human cytomegalovirus (HCMV) US6 glycoprotein inhibits TAP function, resulting in down-regulation of MHC class I molecules at the cell surface. Cells lacking MHC class I molecules are susceptible to NK cell lysis. HCMV expresses UL18, a MHC class I homolog that functions as a surrogate to prevent host cell lysis. Despite a high level of sequence and structural homology between UL18 and MHC class I molecules, surface expression of MHC class I, but not UL18, is down regulated by US6. Here, we describe a mechanism of action by which HCMV UL18 avoids attack by the self-derived TAP inhibitor US6. UL18 abrogates US6 inhibition of ATP binding by TAP and, thereby, restores TAP-mediated peptide translocation. In addition, UL18 together with US6 interferes with the physical association between MHC class I molecules and TAP that is required for optimal peptide loading. Thus, regardless of the recovery of TAP function, surface expression of MHC class I molecules remains decreased. UL18 represents a unique immune evasion protein that has evolved to evade both the NK and the T cell immune responses.


Prospective memory impairments in schizophrenic patients.
Memory impairment is one of the most pervasive cognitive dysfunctions in schizophrenic patients. The aim of the current study was to conduct the most comprehensive assessment of how prospective memory (PM) is affected in schizophrenia in comparison with healthy controls. In this study, 30 first-episode schizophrenic patients who fulfilled the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders based on the diagnostic interview were recruited from eight regional psychiatric clinics in Iran. All participants were males (age 27-42). Moreover, 28 healthy controls were recruited from the same social-class as the patients. The Prospective and Retrospective Memory Questionnaire (PRMQ), PM tasks, and the Virtual Week Board Game were administered. Moreover, clinical symptoms were rated using the positive and negative symptoms scale. The results showed that in all of the memory types, the group with dominant positive symptoms was superior to the group with dominant negative symptoms. In addition, the results showed that in all of the memory types, the control group had superiority to the schizophrenic group. The most considerable differences between groups were in time-based PM tasks, irregular event-based virtual week tasks, and retrospective tasks (PRMQ). The current study confirmed that schizophrenic patients have severe PM deficits.


Detection of breast cancer-derived exosomes using the horseradish peroxidase-mimicking DNAzyme as an aptasensor.
Exosomes are membrane-enclosed phospholipid extracellular vesicles with a variety of tumor antigens which can be applied in the diagnosis and treatment of cancer due to the high secretion on the surface of cancer cells. Until now, many research studies on exosomes have been reported, but convenient and low-cost detection methods still need to be developed. Recently, we have developed a sensitive, simple and low-cost colorimetric aptasensor by designing a hairpin-like structure, which combined the highly specific MUC1 aptamer with a hemin/G-quadruplex for the detection of breast cancer exosomes. The hemin/G-quadruplex toward H2O2 reduction was used to generate an evidently strong colorimetric response owing to acting as a HRP-mimicking DNAzyme. The aptasensor is regarded as an "on-off" type switch, which strictly controls the process of reaction responding to the existence or not of exosomes. In our study, associated exosome detection limits are 3.94 × 105 particles per mL, which showed a higher sensitivity compared to commercial ELISA. Our method not only exhibited the advantages of being convenient and time-saving, with few instruments used, but also the signal generated using this method can be easily observed by the naked eye. Furthermore, the proposed strategy can well differentiate breast cancer patients from healthy individuals, demonstrating potential application in the analysis of clinical specimens.


Compensation by the muscle limits the metabolic consequences of lipodystrophy in PPAR gamma hypomorphic mice.
Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a nuclear receptor, which controls adipocyte differentiation. We targeted with homologous recombination the PPAR gamma 2-specific exon B, resulting in a white adipose tissue knockdown of PPAR gamma. Although homozygous (PPAR gamma hyp/hyp) mice are born with similar weight as the WT mice, the PPAR gamma hyp/hyp animals become growth retarded and develop severe lipodystrophy and hyperlipidemia. Almost half of these PPAR gamma hyp/hyp mice die before adulthood, whereas the surviving PPAR gamma hyp/hyp animals overcome the growth retardation, yet remain lipodystrophic. In contrast to most lipodystrophic models, the adult PPAR gamma hyp/hyp mice only have mild glucose intolerance and do not have a fatty liver. These metabolic consequences of the lipodystrophy are relatively benign because of the induction of a compensatory gene expression program in the muscle that enables efficient oxidation of excess lipids. The PPAR gamma hyp/hyp mice unequivocally demonstrate that PPAR gamma is the master regulator of adipogenesis in vivo and establish that lipid and glucose homeostasis can be relatively well maintained in the absence of white adipose tissue.


Impact of 2.45 GHz microwave radiation on the testicular inflammatory pathway biomarkers in young rats: The role of gallic acid.
The aim of this study was to investigate electromagnetic radiation (EMR) transmitted by wireless devices (2.45 GHz), which may cause physiopathological or ultrastructural changes, in the testes of rats. We addressed if the supplemental gallic acid (GA) may reduce these adverse effects. Six-week-old male Sprague Dawley rats were used in this study. Forty eight rats were equally divided into four groups, which were named: Sham, EMR only (EMR, 3 h day-1 for 30 days), EMR + GA (30 mg/kg/daily), and GA (30 mg/kg/daily) groups. Malondialdehyde (MDA) and total oxidant status (TOS) levels increased (p = 0.001 for both) in EMR only group. TOS and oxidative stress index (OSI) levels decreased in GA treated group significantly (p = 0.001 and p = 0.045, respectively). Total antioxidant status (TAS) activities decreased in EMR only group and increased in GA treatment group (p = 0.001 and p = 0.029, respectively). Testosterone and vascular endothelial growth factor (VEGF) levels decreased in EMR only group, but this was not statistically significant. Testosterone and VEGF levels increased in EMR+GA group, compared with EMR only group (p = 0.002), and also increased in GA group compared with the control and EMR only group (p = 0.044 and p = 0.032, respectively). Prostaglandin E2 (PGE2 ) and calcitonin gene releated peptide (CGRP) staining increased in tubules of the testes in EMR only group (p < 0.001 for both) and decreased in tubules of the testes in EMR+GA group (p < 0.001 for all parameters). In EMR only group, most of the tubules contained less spermatozoa, and the spermatozoon counts decreased in tubules of the testes. All these findings and the regenerative reaction, characterized by mitotic activity, increased in seminiferous tubules cells of the testes in EMR+GA group (p < 0.001). Long term EMR exposure resulted in testicular physiopathology via oxidative damage and inflammation. GA may have ameliorative effects on the prepubertal rat testes physiopathology. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1771-1784, 2016.


Continuing to Confront COPD International Patient Survey: Economic Impact of COPD in 12 Countries.
The Continuing to Confront COPD International Patient Survey estimated the prevalence and burden of COPD across 12 countries. Using data from this survey we evaluated the economic impact of COPD. This cross-sectional, population-based survey questioned 4,343 subjects aged 40 years and older, fulfilling a case definition of COPD based on self-reported physician diagnosis or symptomatology. Direct cost measures were based on exacerbations of COPD (treated and those requiring emergency department visits and/or hospitalisation), contacts with healthcare professionals, and COPD medications. Indirect costs were calculated from work loss values using the Work Productivity and Activity Impairment scale. Combined direct and indirect costs estimated the total societal costs per patient. The annual direct costs of COPD ranged from $504 (South Korea) to $9,981 (USA), with inpatient hospitalisations (5 countries) and home oxygen therapy (3 countries) being the key drivers of direct costs. The proportion of patients completely prevented from working due to their COPD ranged from 6% (Italy) to 52% (USA and UK) with 8 countries reporting this to be ≥20%. Total societal costs per patient varied widely from $1,721 (Russia) to $30,826 (USA) but a consistent pattern across countries showed greater costs among those with increased burden of COPD (symptoms, health status and more severe disease) and a greater number of comorbidities. The economic burden of COPD is considerable across countries, and requires targeted resources to optimise COPD management encompassing the control of symptoms, prevention of exacerbations and effective treatment of comorbidities. Strategies to allow COPD patients to remain in work are important for addressing the substantial wider societal costs.


The mechanism of DNA damage induced by Roundup 360 PLUS, glyphosate and AMPA in human peripheral blood mononuclear cells - genotoxic risk assessement.
Glyphosate is the most heavily applied among pesticides in the world, and thus human exposure to this substance continues to increase. WHO changed classification of glyphosate to probably cancerogenic to humans, thus there is urgent need to assess in detail genotoxic mechanism of its action. We have assessed the effect of glyphosate, its formulation (Roundup 360 PLUS) and its main metabolite (aminomethylphosphonic acid, AMPA) in the concentration range from 1 to 1000 μM on DNA damage in human peripheral blood mononuclear cells (PBMCs). The cells were incubated for 24 h. The compounds studied and formulation induced DNA single and double strand-breaks and caused purines and pyrimidines oxidation. None of compounds examined was capable of creating adducts with DNA, while those substances increased ROS (including •OH) level in PBMCs. Roundup 360 PLUS caused damage to DNA even at 5 μM, while glyphosate and particularly AMPA induced DNA lesions from the concentration of 250 μM and 500 μM, respectively. DNA damage induced by glyphosate and its derivatives increased in order: AMPA, glyphosate, Roundup 360 PLUS. We may conclude that observed changes were not associated with direct interaction of xenobiotics studied with DNA, but the most probably they occurred through ROS-mediated effects.


Evolution of integrated causal structures in animats exposed to environments of increasing complexity.
Natural selection favors the evolution of brains that can capture fitness-relevant features of the environment's causal structure. We investigated the evolution of small, adaptive logic-gate networks ("animats") in task environments where falling blocks of different sizes have to be caught or avoided in a 'Tetris-like' game. Solving these tasks requires the integration of sensor inputs and memory. Evolved networks were evaluated using measures of information integration, including the number of evolved concepts and the total amount of integrated conceptual information. The results show that, over the course of the animats' adaptation, i) the number of concepts grows; ii) integrated conceptual information increases; iii) this increase depends on the complexity of the environment, especially on the requirement for sequential memory. These results suggest that the need to capture the causal structure of a rich environment, given limited sensors and internal mechanisms, is an important driving force for organisms to develop highly integrated networks ("brains") with many concepts, leading to an increase in their internal complexity.


Docosahexaenoic Acid.
Docosahexaenoic acid (DHA) is a long-chain, highly unsaturated omega-3 (n-3) fatty acid. It has a structure that gives it unique physical and functional properties. DHA is metabolically related to other n-3 fatty acids: it can be synthesised from the plant essential fatty acid α-linolenic acid (ALA). However, this pathway does not appear to be very efficient in many individuals, although the conversion of ALA to DHA is much better in young women than in young men. Furthermore, young infants may be more efficient converters of ALA to DHA than many adults, although the conversion rate is variable among infants. Many factors have been identified that affect the rate of conversion. The implication of poor conversion is that preformed DHA needs to be consumed. DHA is found in fairly high amounts in seafood, especially fatty fish, and in various forms of n-3 supplements. The amount of DHA in seafood and in supplements varies. Breast milk contains DHA. DHA is found esterified into complex lipids within the bloodstream, in adipose stores and in cell membranes. Its concentration in different compartments varies greatly. The brain and eye have high DHA contents compared to other organs. DHA is especially concentrated in the grey matter of the brain and in the rod outer segments of the retina. In the brain DHA is involved in neuronal signalling, while in the eye it is involved in the quality of vision. DHA is accumulated in the brain and eye late in pregnancy and in early infancy. A lower DHA content is linked to poorer cognitive development and visual function. DHA affects cell and tissue physiology and function through numerous mechanisms, including alterations in membrane structure and function, in membrane protein function, in cellular signalling and in lipid mediator production.


Assessing the gain of biological data integration in gene networks inference.
A current challenge in gene annotation is to define the gene function in the context of the network of relationships instead of using single genes. The inference of gene networks (GNs) has emerged as an approach to better understand the biology of the system and to study how several components of this network interact with each other and keep their functions stable. However, in general there is no sufficient data to accurately recover the GNs from their expression levels leading to the curse of dimensionality, in which the number of variables is higher than samples. One way to mitigate this problem is to integrate biological data instead of using only the expression profiles in the inference process. Nowadays, the use of several biological information in inference methods had a significant increase in order to better recover the connections between genes and reduce the false positives. What makes this strategy so interesting is the possibility of confirming the known connections through the included biological data, and the possibility of discovering new relationships between genes when observed the expression data. Although several works in data integration have increased the performance of the network inference methods, the real contribution of adding each type of biological information in the obtained improvement is not clear. We propose a methodology to include biological information into an inference algorithm in order to assess its prediction gain by using biological information and expression profile together. We also evaluated and compared the gain of adding four types of biological information: (a) protein-protein interaction, (b) Rosetta stone fusion proteins, (c) KEGG and (d) KEGG+GO. This work presents a first comparison of the gain in the use of prior biological information in the inference of GNs by considering the eukaryote (P. falciparum) organism. Our results indicates that information based on direct interaction can produce a higher improvement in the gain than data about a less specific relationship as GO or KEGG. Also, as expected, the results show that the use of biological information is a very important approach for the improvement of the inference. We also compared the gain in the inference of the global network and only the hubs. The results indicates that the use of biological information can improve the identification of the most connected proteins.


Does Degenerative Lumbar Spine Disease Influence Femoroacetabular Flexion in Patients Undergoing Total Hip Arthroplasty?
Sitting pelvic tilt dictates the proximity of the rim of the acetabulum to the proximal femur and, therefore, the risk of impingement in patients undergoing total hip arthroplasty (THA). Sitting position is achieved through a combination of lumbar spine segmental motions and/or femoroacetabular articular motion in the lumbar-pelvic-femoral complex. Multilevel degenerative disc disease (DDD) may limit spine flexion and therefore increase femoroacetabular flexion in patients having THAs, but this has not been well characterized. Therefore, we measured standing and sitting lumbar-pelvic-femoral alignment in patients with radiographic signs of DDD and in patients with no radiographic signs of spine arthrosis. We asked: (1) Is there a difference in standing and sitting lumbar-pelvic-femoral alignment before surgery among patients undergoing THA who have no radiographic signs of spine arthrosis compared with those with preexisting lumbar DDD? (2) Do patients with lumbar DDD experience less spine flexion moving from a standing to a sitting position and therefore compensate with more femoroacetabular flexion compared with patients who have no radiographic signs of arthrosis? Three hundred twenty-five patients undergoing primary THA had preoperative low-dose EOS spine-to-ankle lateral radiographs in standing and sitting positions. Eighty-three patients were excluded from this study for scoliosis (39 patients), spondylolysis (15 patients), not having five lumbar vertebrae (7 patients), surgical or disease fusion (11 patients), or poor image quality attributable to high BMI (11 patients). In the remaining 242 of 325 patients (75%), two observers categorized the lumbar spine as either without radiographic arthrosis or having DDD based on defined radiographic criteria. Sacral slope, lumbar lordosis, and proximal femur angles were measured, and these angles were used to calculate lumbar spine flexion and femoroacetabular flexion in standing and sitting positions. Patients were aligned in a standardized sitting position so that their femurs were parallel to the floor to achieve approximately 90° of apparent hip flexion. After controlling for age, sex, and BMI, we found patients with DDD spines had a mean of 5° more posterior pelvic tilt (95% CI, -2° to -8° lower sacral slope angles; p < 0.01) and 7° less lumbar lordosis (95% CI, -10° to -3°; p < 0.01) in the standing position compared with patients without radiographic arthrosis. However, in the sitting position, patients with DDD spines had 4° less posterior pelvic tilt (95% CI, 1°-7° higher sacral slope angles; p = 0.02). From standing to sitting position, patients with DDD spines experienced 10° less spine flexion (95% CI, -14° to -7°; p < 0.01) and 10° more femoroacetabular flexion (95% CI, 6° to 14°; p < 0.01). Most patients undergoing THA sit in a similar range of pelvic tilt, with a small mean difference in pelvic tilt between patients with DDD spines and those without radiographic arthrosis. However, in general, the mechanism by which patients with DDD of the lumbar spine achieve sitting differs from those without spine arthrosis with less spine flexion and more femoroacetabular flexion. When planning THA, it may be important to consider which patients sit with less posterior pelvic tilt and those who rotate their pelvises forward to achieve a sitting position, as both mechanisms will limit or reduce the functional anteversion of the acetabular component in a patient with a THA. Our study provides some additional perspective on normal relationships between pelvic tilt and femoroacetabular flexion, but further research might better characterize this relationship in outliers and the possible implications for posterior instability after THA.


Use of meixner functions in estimation of Volterra kernels of nonlinear systems with delay.
Volterra series representation of nonlinear systems is a mathematical analysis tool that has been successfully applied in many areas of biological sciences, especially in the area of modeling of hemodynamic response. In this study, we explored the possibility of using discrete time Meixner basis functions (MBFs) in estimating Volterra kernels of nonlinear systems. The problem of estimation of Volterra kernels can be formulated as a multiple regression problem and solved using least squares estimation. By expanding system kernels with some suitable basis functions, it is possible to reduce the number of parameters to be estimated and obtain better kernel estimates. Thus far, Laguerre basis functions have been widely used in this framework. However, research in signal processing indicates that when the kernels have a slow initial onset or delay, Meixner functions, which can be made to have a slow start, are more suitable in terms of providing a more accurate approximation to the kernels. We, therefore, compared the performance of Meixner functions, in kernel estimation, to that of Laguerre functions in some test cases that we constructed and in a real experimental case where we studied photoreceptor responses of photoreceptor cells of adult fruitflies (Drosophila melanogaster). Our results indicate that when there is a slow initial onset or delay, MBF expansion provides better kernel estimates.


Fine-Scale Human Population Structure in Southern Africa Reflects Ecogeographic Boundaries.
Recent genetic studies have established that the KhoeSan populations of southern Africa are distinct from all other African populations and have remained largely isolated during human prehistory until ∼2000 years ago. Dozens of different KhoeSan groups exist, belonging to three different language families, but very little is known about their population history. We examine new genome-wide polymorphism data and whole mitochondrial genomes for >100 South Africans from the ≠Khomani San and Nama populations of the Northern Cape, analyzed in conjunction with 19 additional southern African populations. Our analyses reveal fine-scale population structure in and around the Kalahari Desert. Surprisingly, this structure does not always correspond to linguistic or subsistence categories as previously suggested, but rather reflects the role of geographic barriers and the ecology of the greater Kalahari Basin. Regardless of subsistence strategy, the indigenous Khoe-speaking Nama pastoralists and the N|u-speaking ≠Khomani (formerly hunter-gatherers) share ancestry with other Khoe-speaking forager populations that form a rim around the Kalahari Desert. We reconstruct earlier migration patterns and estimate that the southern Kalahari populations were among the last to experience gene flow from Bantu speakers, ∼14 generations ago. We conclude that local adoption of pastoralism, at least by the Nama, appears to have been primarily a cultural process with limited genetic impact from eastern Africa.


Aspirin in Alzheimer's disease (AD2000): a randomised open-label trial.
Cardiovascular risk factors and a history of vascular disease can increase the risk of Alzheimer's disease (AD). AD is less common in aspirin users than non-users, and there are plausible biological mechanisms whereby aspirin might slow the progression of either vascular or Alzheimer-type pathology. We assessed the benefits of aspirin in patients with AD. 310 community-resident patients who had AD and who had no potential indication or definite contraindication for aspirin were randomly assigned to receive open-label aspirin (n=156; one 75-mg enteric-coated tablet per day, to continue indefinitely) or to avoid aspirin (n=154). Primary outcome measures were cognition (assessed with the mini-mental state examination [MMSE]) and functional ability (assessed with the Bristol activities of daily living scale [BADLS]). Secondary outcomes were time to formal domiciliary or institutional care, progress of disability, behavioural symptoms, caregiver wellbeing, and care time. Patients were assessed at 12-week intervals in the first year and once each year thereafter. Analysis of the primary outcome measures was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN96337233. Patients had a median age of 75 years; 156 patients had mild AD, 154 had moderate AD, and 18 had concomitant vascular dementia. Over the 3 years after randomisation, in patients who took aspirin, mean MMSE score was 0.10 points higher (95% CI -0.37 to 0.57; p=0.7) and mean BADLS score was 0.62 points lower (-1.37 to 0.13; p=0.11) than in patients assigned to aspirin avoidance. There were no obvious differences between the groups in any other outcome measurements. 13 (8%) patients on aspirin and two (1%) patients in the control group had bleeds that led to admission to hospital (relative risk=4.4, 95% CI 1.5-12.8; p=0.007); three (2%) patients in the aspirin group had fatal cerebral bleeds. Although aspirin is commonly used in dementia, in patients with typical AD 2 years of treatment with low-dose aspirin has no worthwhile benefit and increases the risk of serious bleeds.