A focused ultrasound treatment system for moving targets (part I): generic system design and in-silico first-stage evaluation.
Focused ultrasound (FUS) is entering clinical routine as a treatment option. Currently, no clinically available FUS treatment system features automated respiratory motion compensation. The required quality standards make developing such a system challenging. A novel FUS treatment system with motion compensation is described, developed with the goal of clinical use. The system comprises a clinically available MR device and FUS transducer system. The controller is very generic and could use any suitable MR or FUS device. MR image sequences (echo planar imaging) are acquired for both motion observation and thermometry. Based on anatomical feature tracking, motion predictions are estimated to compensate for processing delays. FUS control parameters are computed repeatedly and sent to the hardware to steer the focus to the (estimated) target position. All involved calculations produce individually known errors, yet their impact on therapy outcome is unclear. This is solved by defining an intuitive quality measure that compares the achieved temperature to the static scenario, resulting in an overall efficiency with respect to temperature rise. To allow for extensive testing of the system over wide ranges of parameters and algorithmic choices, we replace the actual MR and FUS devices by a virtual system. It emulates the hardware and, using numerical simulations of FUS during motion, predicts the local temperature rise in the tissue resulting from the controls it receives. With a clinically available monitoring image rate of 6.67 Hz and 20 FUS control updates per second, normal respiratory motion is estimated to be compensable with an estimated efficiency of 80%. This reduces to about 70% for motion scaled by 1.5. Extensive testing (6347 simulated sonications) over wide ranges of parameters shows that the main source of error is the temporal motion prediction. A history-based motion prediction method performs better than a simple linear extrapolator. The estimated efficiency of the new treatment system is already suited for clinical applications. The simulation-based in-silico testing as a first-stage validation reduces the efforts of real-world testing. Due to the extensible modular design, the described approach might lead to faster translations from research to clinical practice.


Breastmilk donations: Bacteriological assessment, analysis of causes of non-compliance and suggestions for improvement.
A total of 1099 breastmilk donations received by the milk bank at the Amiens University Hospital from January to June 2016 were assessed for bacteriological contamination according to French regulations. This consisted in enumerating the total aerobic flora before and after heat treatment as well as the specific enumeration of coagulase-positive staphylococci. Results above the mandatory limits for at least one of these parameters were found in 25.9% of the donations, resulting in the destruction of approximately one-quarter of the volume of the donations (∼195L). This is a huge loss in both economic and health-related terms for neonates, especially for pre-terms. To identify ways to improve the bacteriological assessment results and reduce the percentage of discarded milk, an analysis of the causes was conducted. The two main causes of non-compliance were the detection of a cultivable aerobic flora after heat treatment and the presence of coagulase-positive staphylococci above the mandatory limit (11.7% and 11.2% of the tested donations, respectively). Bacillus spp. were the leading cause of post-heat-treatment non-compliance. Therefore, the implementation of better environmental control could help reduce this kind of contamination. As for samples harboring coagulase-positive staphylococci, a further detection of toxins using molecular biology techniques could help discriminate actual health-hazardous donations that have to be destroyed while enabling the use of toxin-negative donations. Nevertheless, the economic viability of this proposal needs to be further assessed because these techniques are costly. Finally, a change in breastmilk dilutions used to enumerate the total aerobic flora to better reflect the actual level of these bacteria in the milk was proposed. Indeed, the comparison of various combinations of milk dilutions led to the conclusion that the association of the 1/10 and 1/100 dilutions was the best compromise between technical ease of enumeration and ensuring the safety of the donations. Implementing these suggestions would help reduce the rate of non-compliance and give better access to safe breastmilk donations for neonates.


Drug choice, spatial distribution, HIV risk, and HIV prevalence among injection drug users in St. Petersburg, Russia.
The HIV epidemic in Russia has been driven by the unsafe injection of drugs, predominantly heroin and the ephedrine derived psychostimulants. Understanding differences in HIV risk behaviors among injectors associated with different substances has important implications for prevention programs. We examined behaviors associated with HIV risk among 900 IDUs who inject heroin, psychostimulants, or multiple substances in 2002. Study participants completed screening questionnaires that provided data on sociodemographics, drug use, place of residence and injection- and sex-related HIV risk behaviors. HIV testing was performed and prevalence was modeled using general estimating equation (GEE) analysis. Individuals were clustered by neighborhood and disaggregated into three drug use categories: Heroin Only Users, Stimulant Only Users, and Mixed Drug Users. Among Heroin Only Users, younger age, front/backloading of syringes, sharing cotton and cookers were all significant predictors of HIV infection. In contrast, sharing needles and rinse water were significant among the Stimulant Only Users. The Mixed Drug Use group was similar to the Heroin Only Users with age, front/back loading, and sharing cotton significantly associated with HIV infection. These differences became apparent only when neighborhood of residence was included in models run using GEE. The type of drug injected was associated with distinct behavioral risks. Risks specific to Stimulant Only Users appeared related to direct syringe sharing. The risks specific to the other two groups are common to the process of sharing drugs in preparation to injecting. Across the board, IDUs could profit from prevention education that emphasizes both access to clean syringes and preparing and apportioning drug with these clean syringes. However, attention to neighborhood differences might improve the intervention impact for injectors who favor different drugs.


International standards to document remaining autonomic function after spinal cord injury.
Experts opinions consensus. To develop a common strategy to document remaining autonomic neurologic function following spinal cord injury (SCI). The impact of a specific SCI on a person's neurologic function is generally described through use of the International Standards for the Neurological Classification of SCI. These standards document the remaining motor and sensory function that a person may have; however, they do not provide information about the status of a person's autonomic function. Based on this deficiency, the American Spinal Injury Association (ASIA) and the International Spinal Cord Society (ISCoS) commissioned a group of international experts to develop a common strategy to document the remaining autonomic neurologic function. Four subgroups were commissioned: bladder, bowel, sexual function and general autonomic function. On-line communication was followed by numerous face to face meetings. The information was then presented in a summary format at a course on Measurement in Spinal Cord Injury, held on June 24, 2006. Subsequent to this it was revised online by the committee members, posted on the websites of both ASIA and ISCoS for comment and re-revised through webcasts. Topics include an overview of autonomic anatomy, classification of cardiovascular, respiratory, sudomotor and thermoregulatory function, bladder, bowel and sexual function. This document describes a new system to document the impact of SCI on autonomic function. Based upon current knowledge of the neuroanatomy of autonomic function this paper provides a framework with which to communicate the effects of specific spinal cord injuries on cardiovascular, broncho-pulmonary, sudomotor, bladder, bowel and sexual function.


Carbohydrate, lipid, bone and inflammatory markers in HIV-positive adolescents on antiretroviral therapy and hormonal contraception.
Little is known about the cumulative effect of HIV antiretroviral therapy (ART) and hormonal contraception (HC) on metabolism and inflammation in HIV-positive women. We conducted a cross-sectional assessment of markers for carbohydrate, lipid, bone metabolism, inflammation and coagulation in HIV-positive adolescents on ART and HC (n=37) versus on ART only (n=51) in Thailand. The Wilcoxon rank-sum test was used to assess differences between groups. The median age was 19.5 years. Most adolescents (95%) were perinatally infected. All were on ART for a median of 9 years. HC used was progestin only (n=21); combined oral contraceptive (COC) tablets (n=6) for the whole study period or alternating between progestin only and COC (n=10). Prevalence of any metabolic abnormalities was 99%. Four biomarkers were significantly higher with HC vs no HC: insulin (10.3 vs 6.2 μU/mL, P=0.002), insulin resistance (1.89 vs 1.19 mass units, P=0.005), 25-OH vitamin D (33.2 vs 20.2 ng/mL, P<0.0001) and C-terminal telopeptide (690 vs 530 ng/L, P=0.011). Triglycerides and D-dimer were significantly lower with HC (103 vs 139 mg/dL, P=0.014 and 140 vs 155 ng/mL, P=0.003, respectively). There was no relationship between the type of HC or ART and the above differences. Perinatally infected HIV-positive adolescents on ART in this pilot study had a high prevalence of metabolic abnormalities. Bone turnover markers and insulin resistance were significantly higher with HC. Research on the cumulative effect of HIV, ART and HC on metabolism and inflammation in adolescents with HIV is important in order to devise strategies for preventing and mitigating long-term comorbidities.


Sporadic late onset nemaline myopathy.
To review the clinicopathologic features and outcome of sporadic late onset nemaline myopathy (SLONM). Non-HIV-related SLONM is an uncommon disease of undefined etiology. This study is based on clinical, EMG, histochemical, immunocytochemical, and electron microscopy evaluation, and long-term follow-up of 14 patients observed at the Mayo Clinic between 1975 and 2003. The disease presented between 43 and 81 years and evolved subacutely. The weakness was predominantly proximal in 11, equal proximally and distally in 3, and asymmetric in 4; dysphagia was a symptom in 6. The EMG showed myopathic features with fibrillations but the serum CK level at the time of initial examination or reevaluation was normal or below the Mayo Clinic's range of normal values for sex and age at the time of the assay. Seven patients had an associated monoclonal gammopathy. On light microscopy, the nemaline structures were best identified in 3-mum-thick frozen sections stained trichromatically or immunostained for alpha-actinin or myotilin. Electron microscopy done in 12 cases identified the rods in all and revealed additional structural abnormalities. Seven patients with monoclonal gammopathy were followed for 1 to 5 years; five died of respiratory failure. Five patients without monoclonal gammopathy were followed for 4 to 23 years and none died of the disease. Immunotherapy in eight patients was of uncertain benefit. 1) Subacutely evolving weakness after age 40, normal to low CK level, myopathic EMG with fibrillations, and often a monoclonal gammopathy are clues for the diagnosis of sporadic late onset nemaline myopathy. 2) The diagnosis is confirmed by visualizing the rods in trichrome or immunostained cryosections. 3) An associated monoclonal gammopathy heralds an unfavorable prognosis.


Upregulation of TRAF-3 by shear stress blocks CD40-mediated endothelial activation.
Atherosclerosis is an inflammatory disease of large arteries that is initiated through the activation of endothelium by proinflammatory mediators. CD40 receptor stimulation has been implicated in the pathogenesis of atherosclerosis. One of the most important atheroprotective stimuli is the viscous drag (shear stress) generated by the streaming blood acting on the endothelial monolayer. Here, we demonstrate that shear stress prevents CD40 ligand-induced endothelial cell activation, and we identify upregulation of TNF receptor-associated factor-3 (TRAF-3) as a potent CD40-inhibitory mechanism. Shear stress specifically upregulates TRAF-3 in cultured endothelial cells. Moreover, in the endothelial cells overlying human atherosclerotic plaques, TRAF-3 expression is upregulated in areas with high shear stress. Overexpression of TRAF-3 inhibits endothelial expression of proinflammatory cytokines and tissue factor and blocks DNA-binding activity of the transcription factor AP-1; it thereby prevents CD40-induced endothelial activation. Thus, upregulation of TRAF-3 represents a novel mechanism for preserving the functional integrity of the endothelial monolayer.


Preferential expression of IgG2b in nose draining cervical lymph nodes and its putative role in mucosal tolerance induction.
Induction of intranasal tolerance prevents the body from eliciting unwanted immune responses against harmless antigens that enter the body through the nasal mucosa. To study the intrinsic capacities of the cervical, nose draining lymph nodes (CLN), which are essential for tolerance induction, genes that are differentially expressed in CLN and not in peripheral lymph nodes (PLN) were characterized. The gene that is predominantly overexpressed in CLN codes for IgG2b. This is confirmed by a higher percentage of IgG2b+ B220+ cells in CLN compared with any PLN. However, this predominance of IgG2b-positive B cells in the CLN is not specific for the lymph node itself but rather determined by the region drained by lymph nodes at the cervical site, as transplanted PLN at these locations show a comparable predominance. It was demonstrated that IgG2b, when compared with IgG1, led to differential activation of dendritic cells (DC) through Fc receptor signalling. The results point to a unique local combination of cells and factors in the nose draining CLN leading to highly specialized immune reactivity. The results point out that predominance of a distinct IgG isotype in a lymphoid environment may lead to highly specialized immune reactivity.


Low-coherence fiber-optic sensor with a large numerical aperture for topographic measurements.
We describe a compact fiber-optic setup for three-dimensional topometry. The measuring principle is based on low-coherence interferometry in combination with a confocal microscope. Integrating an optical arrangement based on compact disk optics together with fiber optics into one sensor yields a compact unit. The sensor has a numerical aperture of 0.45 and is suitable for measuring large surface slopes with high spatial resolution. Further, a depth measuring range of more than 1 mm can be achieved. The capabilities of our setup for three-dimensional measurements are demonstrated.


An undecaprenyl phosphate-aminoarabinose flippase required for polymyxin resistance in Escherichia coli.
Modification of lipid A with the 4-amino-4-deoxy-L-arabinose (L-Ara4N) moiety is required for resistance to polymyxin and cationic antimicrobial peptides in Escherichia coli and Salmonella typhimurium. An operon of seven genes (designated pmrHFIJKLM in S. typhimurium), which is regulated by the PmrA transcription factor and is also present in E. coli, is necessary for the maintenance of polymyxin resistance. We previously elucidated the roles of pmrHFIJK in the biosynthesis and attachment of L-Ara4N to lipid A and renamed these genes arn-BCADT, respectively. We now propose functions for the last two genes of the operon, pmrL and pmrM. Chromosomal inactivation of each of these genes in an E. coli pmrA(c) parent switched its phenotype from polymyxin-resistant to polymyxin-sensitive. Lipid A was no longer modified with L-Ara4N, even though the levels of the lipid-linked donor of the L-Ara4N moiety, undecaprenyl phosphate-alpha-L-Ara4N, were not reduced in the mutants. However, the undecaprenyl phosphate-alpha-L-Ara4N present in the mutants was less concentrated on the periplasmic surface of the inner membrane, as judged by 4-5-fold reduced labeling with the inner membrane-impermeable amine reagent N-hydroxysulfosuccin-imidobiotin. In an arnT mutant of the same pmrA(c) parent, which lacks the enzyme that transfers the L-Ara4N unit to lipid A but retains the same high levels of undecaprenyl phosphate-alpha-L-Ara4N as the parent, N-hydroxysulfosuccinimidobiotin labeling was not reduced. These results implicate pmrL and pmrM, but not arnT, in transporting undecaprenyl phosphate-alpha-L-Ara4N across the inner membrane. PmrM and PmrL, now renamed ArnE and ArnF because of their involvement in L-Ara4N modification of lipid A, may be subunits of an undecaprenyl phosphate-alpha-L-Ara4N flippase.


Durability of transgene expression and vector integration: recombinant SV40-derived gene therapy vectors.
Many applications of gene delivery require long-term transgene expression. In dividing cells, this result necessitates vector genome persistence, usually by integrating into cellular DNA. Since recombinant gene delivery vectors derived from tag-deleted, replication-incompetent simian virus-40 (SV40) provide for long-term transgene expression in resting and dividing cells, we tested whether such enduring transgene expression reflected integration into cellular genomes. Several lines of evidence suggested this likelihood. After transduction in vitro, continuously dividing cell lines and continuously stimulated primary cells uniformly showed transgene expression for many months. Mice whose livers were transduced in vivo, partially resected, and allowed to regenerate showed comparable levels of transgene expression in regenerated and preoperative livers. Thus, replicationincompetent SV40 vectors (rSV40) persist in vitro and in vivo despite extensive cell division. We tested the possibility that this persistence reflected integration directly. Southern blot analyses of genomic DNA from transduced 293 cells showed that vector genome incorporation into cell DNA happened within days of transduction. Episomal vector DNA was barely detectable 96 hours post-transduction. Inverted PCR, used to characterize vector integration points, showed vector DNA integrated randomly into the cell genome. The circular rSV40 genome opened at different points in each integrand. A significant proportion of the integrands did not contain the entire vector sequence, but rather only portions thereof. Quantitative Southern blot analysis showed approximately 3.05 transgene copies per cell. Therefore, recombinant SV40 gene delivery vectors integrate into the cellular DNA of both resting and dividing cells, and do so randomly and within days of transduction. This integration may explain long-term transgene expression.


Criminogenic Needs, Substance Use, and Offending among Rural Stimulant Users.
There is a need to understand the determinants of both substance use and criminal activity in rural areas in order to design appropriate treatment interventions for these linked problems. The present study drew on a predominant model used to assess and treat offenders -- the Risk-Need-Responsivity (RNR) model -- to examine risk factors for substance use and criminal activity in a rural drug using sample. This study extends the RNR model's focus on offenders to assessing rural-dwelling individuals using stimulants (N=462). We examined substance use and criminal justice outcomes at 6-month (91%) and 3-year (79%) follow-ups, and used Generalized Estimating Equations to examine the extent to which RNR criminogenic need factors at baseline predicted outcomes at follow-ups. Substance use and criminal justice outcomes improved at six months, and even more at three years, post-baseline. As expected, higher risk was associated with poorer outcomes. Antisocial personality patterns and procriminal attitudes at baseline predicted poorer legal and drug outcomes measured at subsequent follow-ups. In contrast, less connection to antisocial others and fewer work difficulties predicted lower alcohol problem severity, but more frequent alcohol use. Engagement in social-recreational activities was associated with fewer subsequent arrests and less severe alcohol and drug problems. The RNR model's criminogenic need factors predicted drug use and crime-related outcomes among rural residents. Services adapted to rural settings that target these factors, such as telehealth and other technology-based resources, may hasten improvement on both types of outcomes among drug users.


Ability of guanine nucleotide derivatives to bind and activate bovine transducin.
Several guanine nucleotide analogs, in one series of which a hydrogen on the 2-amino group is replaced with the p-n-butylphenyl group (BuPGNP derivatives), were used to probe the GTP binding domain of bovine transducin. The order of apparent binding affinities in a series of nucleoside 5'-triphosphates was GTP gamma S greater than GTP approximately BuPGTP greater than dGTP approximately ITP much greater than ATP, values which were 30-100 times higher than affinities of the corresponding 5'-diphosphates. A derivative bearing a 6-aminohexylamino group on the gamma-phosphate, BuPGTP X C6, had a 60-fold lower affinity compared to BuPGTP. In contrast, the p-n-butylphenyl substituent on the 2-amino group had little effect on the binding affinity relative to GTP. Substitutions at the 2-amino group had little effect on either the hydrolysis of the derivatives by the GTPase activity associated with the alpha-subunit of transducin or the activation of cGMP phosphodesterase. The results indicate that the GTP binding domain of transducin is similar in tertiary structure to the corresponding domain of EF-Tu. The 5'-phosphates of GTP are oriented in the binding site of transducin so that the bulky C6 group of BuPGTP X C6 dramatically interferes with binding. The 2-amino group on the guanine ring is probably located at the periphery of the binding site, with the p-n-butylphenyl substituent of BuPGTP facing outward and only weakly interacting with the protein. BuPGTP should be an excellent parent compound for development of novel probes of G-protein interactions with other cellular proteins involved in receptor signal transduction.


A Novel, Modified Human Butyrylcholinesterase Catalytically Degrades the Chemical Warfare Nerve Agent, Sarin.
Chemical warfare nerve agents (CWNAs) present a global threat to both military and civilian populations. The acute toxicity of CWNAs stems from their ability to effectively inhibit acetylcholinesterase (AChE). This inhibition can lead to uncontrolled cholinergic cellular signaling, resulting in cholinergic crisis and, ultimately, death. Although the current FDA-approved standard of care is moderately effective when administered early, development of novel treatment strategies is necessary. Butyrylcholinesterase (BChE) is an enzyme which displays a high degree of structural homology to AChE. Unlike AChE, the roles of BChE are uncertain and possibilities are still being explored. However, BChE appears to primarily serve as a bioscavenger of toxic esters due to its ability to accommodate a wide variety of substrates within its active site. Like AChE, BChE is also readily inhibited by CWNAs. Due to its high affinity for binding CWNAs, and that null-BChE yields no apparent health effects, exogenous BChE has been explored as a candidate therapeutic for CWNA intoxication. Despite years of research, minimal strides have been made to develop a catalytic bioscavenger. Furthermore, BChE is only in early clinical trials as a stoichiometric bioscavenger of CWNAs, and large quantities must be administered to treat CWNA toxicity. Here, we describe previously unidentified mutations to residues within and adjacent to the acyl binding pocket (positions 282-285 were mutagenized from YGTP to NHML) of BChE that confer catalytic degradation of the CWNA, sarin. These mutations, along with corresponding future efforts, may finally lead to a novel therapeutic to combat CWNA intoxication.


Brillouin optical time domain analyzer sensors assisted by advanced image denoising techniques.
We have experimentally analyzed and compared the performance of Brillouin optical time-domain analyzer (BOTDA) sensors assisted by non-local means (NLM) and wavelet denoising (WD) techniques in terms of measurement accuracy and experimental spatial resolution, respectively. Degradation of the measurement accuracy and experimental spatial resolution after denoising by NLM and WD are observed, which originate from the fact that higher signal-to-noise ratio (SNR) improvement is achieved at the expense of sacrificing the details of BOTDA data, and smaller data sampling point number (SPN) gives rise to insufficient redundant information for denoising. The two parameters degrade to different extents depending on the amount of SNR improvement and SPN adopted in data acquisition. Compared with WD, NLM relies more on the features of the raw data, which makes its performance highly dependent on the level of neighbouring data similarity. Also, for the first time we propose and demonstrate a BOTDA assisted by advanced Block-Matching and 3D filtering (BM3D) denoising technique, which minimizes the degradation of the two parameters even under higher SNR improvement and smaller SPN. BM3D takes the advantage of NLM and WD and utilizes the spatial-domain non-local principle to enhance the denoising in the transform domain, thus it shows the least degradation of measurement accuracy/experimental spatial resolution after denoising. Thus the BOTDA assisted by BM3D maintains the best measurement accuracy/experimental spatial resolution compared with those by NLM and WD. We also show that BM3D has the advantage of temperature independent performance, unlike NLM where the accuracy is affected by the temperature value. We believe BM3D would be an excellent denoising technique for state-of-the-art BOTDA sensors. In addition, this work is also valuable for practical applications of image denoising techniques in BOTDA sensors with respect to the appropriate choice of image denoising techniques, design of SNR improvement and the adoption of SPN to maintain optimal measurement accuracy/experimental spatial resolution/data acquisition speed.


Mechanisms responsible for the failure of protamine to inactivate low-molecular-weight heparin.
Protamine is unable to completely reverse the anticoagulant effect of the low-molecular-weight heparins (LMWH), a fact of clinical importance given the rapid increase in use of LMWH in clinical practice. This investigation sought to determine the mechanism by which LMWH were able to resist protamine-mediated inactivation. Affinity fractionation of LMWH by passage through a protamine column, with subsequent determination of molecular mass and sulphate charge density, demonstrated that the protamine-resistant fraction in LMWH is an ultra-low-molecular-weight fraction with low sulphate charge density. This group of molecules was not found in unfractionated heparin, even when species of similar molecular mass were compared. We then determined that different commercially available LMWH varied in their ability to be neutralized by protamine, and that this variability correlated with the total sulphate content of the LMWH. We conclude that reduced sulphate charge, not molecular mass, is the principle reason that protamine is unable to fully inactivate LMWH. Furthermore, different LMWH vary in their ability to be neutralized by protamine, suggesting that product-specific recommendations for neutralization might be developed.


The decoupled mind: mind-wandering disrupts cortical phase-locking to perceptual events.
The mind flows in a "stream of consciousness," which often neglects immediate sensory input in favor of focusing on intrinsic, self-generated thoughts or images. Although considerable research has documented the disruptive influences of task-unrelated thought for perceptual processing and task performance, the brain dynamics associated with these phenomena are not well understood. Here we investigate the possibility, suggested by several convergent lines of research, that task-unrelated thought is associated with a reduction in the trial-to-trial phase consistency of the oscillatory neural signal in response to perceptual input. Using an experience sampling paradigm coupled with continuous high-density electroencephalography, we observed that task-unrelated thought was associated with a reduction of the P1 ERP, replicating prior observations that mind-wandering is accompanied by a reduction of the brain-evoked response to sensory input. Time-frequency analysis of the oscillatory neural response revealed a decrease in theta-band cortical phase-locking, which peaked over parietal scalp regions. Furthermore, we observed that task-unrelated thought impacted the oscillatory mode of the brain during the initiation of a task-relevant action, such that more cortical processing was required to meet task demands. Together, these findings document that the attenuation of perceptual processing that occurs during task-unrelated thought is associated with a reduction in the temporal fidelity with which the brain responds to a stimulus and suggest that increased neural processing may be required to recouple attention to a task. More generally, these data provide novel confirmatory evidence for the mechanisms through which attentional states facilitate the neural processing of sensory input.


Simulating and evaluating local interventions to improve cardiovascular health.
Numerous local interventions for cardiovascular disease are available, but resources to deliver them are limited. Identifying the most effective interventions is challenging because cardiovascular risks develop through causal pathways and gradual accumulations that defy simple calculation. We created a simulation model for evaluating multiple approaches to preventing and managing cardiovascular risks. The model incorporates data from many sources to represent all US adults who have never had a cardiovascular event. It simulates trajectories for the leading direct and indirect risk factors from 1990 to 2040 and evaluates 19 interventions. The main outcomes are first-time cardiovascular events and consequent deaths, as well as total consequence costs, which combine medical expenditures and productivity costs associated with cardiovascular events and risk factors. We used sensitivity analyses to examine the significance of uncertain parameters. A base case scenario shows that population turnover and aging strongly influence the future trajectories of several risk factors. At least 15 of 19 interventions are potentially cost saving and could reduce deaths from first cardiovascular events by approximately 20% and total consequence costs by 26%. Some interventions act quickly to reduce deaths, while others more gradually reduce costs related to risk factors. Although the model is still evolving, the simulated experiments reported here can inform policy and spending decisions.


A VapBC toxin-antitoxin module is a posttranscriptional regulator of metabolic flux in mycobacteria.
The largest family of toxin-antitoxin (TA) modules are encoded by the vapBC operons, but their roles in bacterial physiology remain enigmatic. Microarray analysis in Mycobacterium smegmatis overexpressing VapC/VapBC revealed a high percentage of downregulated genes with annotated roles in carbon transport and metabolism, suggesting that VapC was targeting specific metabolic mRNA transcripts. To validate this hypothesis, purified VapC was used to identify the RNA cleavage site in vitro. VapC had RNase activity that was sequence specific, cleaving single-stranded RNA substrates at AUAU and AUAA in vitro and in vivo (viz., MSMEG_2121 to MSMEG_2124). A bioinformatic analysis of these regions suggested that an RNA hairpin 3' of the AUA(U/A) motif is also required for efficient cleavage. VapC-mediated regulation in vivo was demonstrated by showing that MSMEG_2124 (dhaF) and MSMEG_2121 (dhaM) were upregulated in a ΔvapBC mutant growing on glycerol. The ΔvapBC mutant had a specific rate of glycerol consumption that was 2.4-fold higher than that of the wild type during exponential growth. This increased rate of glycerol consumption was not used for generating bacterial biomass, suggesting that metabolism by the ΔvapBC mutant was uncoupled from growth. These data suggest a model in which VapC regulates the rate of glycerol utilization to match the anabolic demands of the cell, allowing for fine-tuning of the catabolic rate at a posttranscriptional level.


Dural marginal zone lymphoma with massive amyloid deposition: rare low-grade primary central nervous system B-cell lymphoma. Case report.
The authors report the case of a 63-year-old woman who presented with a primary dural extranodal marginal zone lymphoma (MZL) associated with massive kappa light chain amyloidosis of the meninges. Extranodal MZL is a low-grade B-cell lymphoma that may show variable degrees of plasmacytic differentiation. Like solitary plasmacytoma of soft tissue, which can also be associated with amyloid, extranodal MZL generally responds well to local therapy and has a good prognosis. It is important to distinguish these entities from high-grade primary central nervous system (CNS) B-cell lymphomas and more aggressive and/or widespread, potentially amyloidogenic conditions such as multiple myeloma, lympho-plasmacytoid lymphoma, and chronic lymphocytic leukemia/small lymphocytic lymphoma. To the authors' knowledge this is the first reported case of dural MZL associated with massive meningeal amyloid deposition. Extranodal MZL is a rare low-grade primary CNS B-cell lymphoma that may be associated with amyloidosis. It should be considered in the differential diagnosis of CNS lymphoproliferative lesions and CNS amyloidosis.


Type of Findings Generated by the Occupational Therapy Workforce Research Worldwide: Scoping Review and Content Analysis.
Occupational therapists are needed to meet the health and occupational needs of the global population, but we know little about the type of findings generated by occupational therapy workforce research conducted worldwide. We aim to synthesize these findings and their range of content to inform future investigations. A scoping review with content analysis was used. Six scientific databases, websites of official institutions, snowballing, and key informants were used for searches. Two independent reviewers took selection decisions against the eligibility criteria published a priori in the review protocol. Of the 1246 unique references detected, 57 papers were included for the last 25 years. A total of 18 papers addressed issues of attractiveness and retention, often in Australia, and 14 addressed the issues of supply, demand, and distribution, often in the US. Only these two categories generated subtopics. Many workforce issues were rarely addressed as a main topic (e.g., race/ethnic representation). Cross-national, cross-regional, or cross-professional studies generated more actionable findings. Overall, we found few discernable trends, minimal evidence of research programs, and various gaps in content coverage or in the use of contemporary research approaches. There is a need for a coordinated strengthening of the occupational therapy workforce research worldwide.


Punish or Protect? How Close Relationships Shape Responses to Moral Violations.
People have fundamental tendencies to punish immoral actors and treat close others altruistically. What happens when these tendencies collide-do people punish or protect close others who behave immorally? Across 10 studies (N = 2,847), we show that people consistently anticipate protecting close others who commit moral infractions, particularly highly severe acts of theft and sexual harassment. This tendency emerged regardless of gender, political orientation, moral foundations, and disgust sensitivity and was driven by concerns about self-interest, loyalty, and harm. We further find that people justify this tendency by planning to discipline close others on their own. We also identify a psychological mechanism that mitigates the tendency to protect close others who have committed severe (but not mild) moral infractions: self-distancing. These findings highlight the role that relational closeness plays in shaping people's responses to moral violations, underscoring the need to consider relational closeness in future moral psychology work.


Back-scattered detection yields viable signals in many conditions.
Precision position-sensing is required for many microscopy techniques. One promising method, back-scattered detection (BSD), is incredibly sensitive, allowing for position measurements at the level of tens of picometers in three dimensions. In BSD the position of a micron-sized bead is measured by back-scattering a focused laser beam off the bead and imaging the resulting interference pattern onto a detector. Since the detection system geometry is confined to one side of the objective, the technique is compatible with platforms that have restricted optical access (e.g. magnetic tweezers, atomic force microscopy, and microfluidics). However, general adoption of BSD may be limited according to a recent theory [Volpe et al., J. Appl. Phys. 102, 084701, 2007] that predicts diminished signals under certain conditions. We directly measured the BSD response while varying the experimental conditions, including bead radius, numerical aperture, and relative index. Contrary to the proposed theory, we find that all experimental conditions tested produced a viable signal for atomic-scale measurements.


Extracellular Signal-Regulated Kinase 1/2 Regulates Mouse Kidney Injury Molecule-1 Expression Physiologically and Following Ischemic and Septic Renal Injury.
The upregulation of kidney injury molecule-1 (KIM-1) has been extensively studied in various renal diseases and following acute injury; however, the initial mechanisms controlling KIM-1 expression remain limited. In this study, KIM-1 expression was examined in mouse renal cell cultures and in two different models of acute kidney injury (AKI), ischemia reperfusion (IR)-induced and lipopolysaccharide (LPS)-induced sepsis. KIM-1 mRNA increased in both AKI models, and pharmacological inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) signaling attenuated injury-induced KIM-1 expression in the renal cortex. Toll-like receptor 4 knockout (TLR4KO) mice exhibited reduced ERK1/2 phosphorylation and attenuated KIM-1 mRNA after LPS exposure. TLR4KO mice were not protected from IR-induced ERK1/2 phosphorylation and upregulation of KIM-1 mRNA. Following renal IR injury, phosphorylation of signal transducer and activator of transcription 3 (STAT3) at serine 727 and tyrosine 705 increased downstream from ERK1/2 activation. Because phosphorylated STAT3 is a transcriptional upregulator of KIM-1 and inhibition of ERK1/2 attenuated increases in STAT3 phosphorylation, we suggest an ERK1/2-STAT3-KIM-1 pathway following renal injury. Finally, ERK1/2 inhibition in naive mice decreased KIM-1 mRNA and nuclear STAT3 phosphorylation in the cortex, indicating homeostatic regulation of KIM-1. These findings reveal renal ERK1/2 as an important initial regulator of KIM-1 expression in IR and septic AKI and at a physiologic level.Visual Abstract.Proposed mechanism of IR, LPS, and ROS-induced renal damage that initiates ERK1/2 and STAT3 phosphorylation. STAT3 then binds to the KIM-1 promoter and increases KIM-1 mRNA. By preventing ERK1/2 phosphorylation following renal injury, STAT3 phosphorylation is decreased, leading to less phosphorylated STAT3 within the nucleus, and subsequently less KIM-1 mRNA increases post injury.


The Effect of Gestational and Lactational Age on the Human Milk Metabolome.
Human milk is the ideal nutrition source for healthy infants during the first six months of life and a detailed characterisation of the composition of milk from mothers that deliver prematurely (<37 weeks gestation), and of how human milk changes during lactation, would benefit our understanding of the nutritional requirements of premature infants. Individual milk samples from mothers delivering prematurely and at term were collected. The human milk metabolome, established by nuclear magnetic resonance (NMR) spectroscopy, was influenced by gestational and lactation age. Metabolite profiling identified that levels of valine, leucine, betaine, and creatinine were increased in colostrum from term mothers compared with mature milk, while those of glutamate, caprylate, and caprate were increased in mature term milk compared with colostrum. Levels of oligosaccharides, citrate, and creatinine were increased in pre-term colostrum, while those of caprylate, caprate, valine, leucine, glutamate, and pantothenate increased with time postpartum. There were differences between pre-term and full-term milk in the levels of carnitine, caprylate, caprate, pantothenate, urea, lactose, oligosaccharides, citrate, phosphocholine, choline, and formate. These findings suggest that the metabolome of pre-term milk changes within 5-7 weeks postpartum to resemble that of term milk, independent of time of gestation at pre-mature delivery.


Complete genomic screen in late-onset familial Alzheimer disease. Evidence for a new locus on chromosome 12.
Four genetic loci have been identified as contributing to Alzheimer disease (AD), including the amyloid precursor protein gene, the presenilin 1 gene, the presenilin 2 gene, and the apolipoprotein E gene, but do not account for all the genetic risk for AD. To identify additional genetic risk factors for late-onset AD. A complete genomic screen was performed (N=280 markers). Critical values for chromosomal regional follow-up were a P value of .05 or less for affected relative pair analysis or sibpair analysis, a parametric lod score of 1.0 or greater, or both. Regional follow-up included analysis of additional markers and a second data set. Clinic populations in the continental United States. From a series of multiplex families affected with late-onset (> or =60 years) AD ascertained during the last 14 years (National Insititute of Neurological Disorders and Stroke-Alzheimer's Disease and Related Disorders Association diagnostic criteria) and for which DNA has been obtained, a subset of 16 families (135 total family members, 52 of whom were patients with AD) was used for the genomic screen. A second subset of 38 families (216 total family members, 89 of whom were patients with AD) was used for the follow-up analysis. Linkage analysis results generated using both genetic model-dependent (lod score) and model-independent methods. Fifteen chromosomal regions warranted initial follow-up. Follow-up analyses revealed 4 regions of continued interest on chromosomes 4, 6, 12, and 20, with the strongest results observed forchromosome 12. Peak 2-point affecteds-only lod scores (n=54) were 1.3, 1.6, 2.7, and 2.2 and affected relative pairs P values (n=54) were .04, .03, .14, and .04 for D12S373, D12S1057, D12S1042, and D12S390, respectively. Sibpair analysis (n=54) resulted in maximum lod scores (MLSs) of 1.5, 2.6, 3.2, and 2.3 for these markers, with a peak multipoint MLS of 3.5. A priori stratification by APOE genotype identified 27 families that had at least 1 member with AD whose genotype did not contain an APOE*4 allele. Analysis of these 27 families resulted in MLSs of 1.0, 2.4, 3.7, and 3.3 and a peak multipoint MLS of 3.9. A complete genomic screen in families affected with late-onset AD identified 4 regions of interest after follow-up. Chromosome 12 gave the strongest and most consistent results with a peak multipoint MLS of 3.5, suggesting that this region contains a new susceptibility gene for AD. Additional analyses are necessary to identify the chromosome 12 susceptibility gene for AD and to follow up the regions of interest on chromosomes 4, 6, and 20.


A Novel Population of Phytophthora, Similar to P. infestans, Attacks Wild Solanum Species in Ecuador.
ABSTRACT Twenty-six isolates of a Phytophthora population from two wild solanaceous species, Solanum tetrapetalum (n 11) and S. brevifolium (n = 15), were characterized morphologically, with genetic and phenotypic markers, and for pathogenicity on potato and tomato. Based on morphology, ribosomal internal transcribed spacer region 2 (ITS2) sequence, and pathogenicity, all isolates closely resembled P. infestans and were tentatively placed in that species. Nonetheless, this population of Phytophthora is novel. Its primary host is neither potato nor tomato, and all isolates had three restriction fragment length polymorphism (RFLP) bands (probe RG57) and a mitochondrial DNA haplotype that have not been reported for P. infestans. All the isolates were the A2 mating type when tested with a P. infestans A1 isolate. The A2 mating type has not been found among isolates of P. infestans from potato or tomato in Ecuador. Geographical substructing of the Ecuadorian A2 population was detected. The three isolates from the village of Nono, identical to the others in all other aspects, differed by three RFLP bands; those from Nono lacked bands 10 and 16, but possessed band 19. Most of the Ecuadorian A2 isolates were nonpathogenic on potato and tomato, but a few caused very small lesions with sparse sporulation on necrotic tissue. Cluster analysis of multilocus genotypes (RFLP, mating type, and two allozymes) dissociated this A2 population from genotypes representing clonally propagated populations of P. infestans worldwide. The current hypotheses for the historical global movements of P. infestans do not satisfactorily explain the origin or possible time of introduction into Ecuador of this A2 population. Assuming the population is P. infestans, its presence in Ecuador suggests either a hitherto unreported migration of the pathogen or an indigenous population that had not previously been detected.


The Role of Genetics in Advancing Precision Medicine for Alzheimer's Disease-A Narrative Review.
Alzheimer's disease (AD) is the most common type of dementia, which has a substantial genetic component. AD affects predominantly older people. Accordingly, the prevalence of dementia has been rising as the population ages. To date, there are no effective interventions that can cure or halt the progression of AD. The only available treatments are the management of certain symptoms and consequences of dementia. The current state-of-the-art medical care for AD comprises three simple principles: prevent the preventable, achieve early diagnosis, and manage the manageable symptoms. This review provides a summary of the current state of knowledge of risk factors for AD, biological diagnostic testing, and prospects for treatment. Special emphasis is given to recent advances in genetics of AD and the way genomic data may support prevention, early intervention, and development of effective pharmacological treatments. Mutations in the APP, PSEN1, and PSEN2 genes cause early onset Alzheimer's disease (EOAD) that follows a Mendelian inheritance pattern. For late onset Alzheimer's disease (LOAD), APOE4 was identified as a major risk allele more than two decades ago. Population-based genome-wide association studies of late onset AD have now additionally identified common variants at roughly 30 genetic loci. Furthermore, rare variants (allele frequency <1%) that influence the risk for LOAD have been identified in several genes. These genetic advances have broadened our insights into the biological underpinnings of AD. Moreover, the known genetic risk variants could be used to identify presymptomatic individuals at risk for AD and support diagnostic assessment of symptomatic subjects. Genetic knowledge may also facilitate precision medicine. The goal of precision medicine is to use biological knowledge and other health information to predict individual disease risk, understand disease etiology, identify disease subcategories, improve diagnosis, and provide personalized treatment strategies. We discuss the potential role of genetics in advancing precision medicine for AD along with its ethical challenges. We outline strategies to implement genomics into translational clinical research that will not only improve accuracy of dementia diagnosis, thus enabling more personalized treatment strategies, but may also speed up the discovery of novel drugs and interventions.


A dual-learning paradigm can simultaneously train multiple characteristics of walking.
Impairments in human motor patterns are complex: what is often observed as a single global deficit (e.g., limping when walking) is actually the sum of several distinct abnormalities. Motor adaptation can be useful to teach patients more normal motor patterns, yet conventional training paradigms focus on individual features of a movement, leaving others unaddressed. It is known that under certain conditions, distinct movement components can be simultaneously adapted without interference. These previous "dual-learning" studies focused solely on short, planar reaching movements, yet it is unknown whether these findings can generalize to a more complex behavior like walking. Here we asked whether a dual-learning paradigm, incorporating two distinct motor adaptation tasks, can be used to simultaneously train multiple components of the walking pattern. We developed a joint-angle learning task that provided biased visual feedback of sagittal joint angles to increase peak knee or hip flexion during the swing phase of walking. Healthy, young participants performed this task independently or concurrently with another locomotor adaptation task, split-belt treadmill adaptation, where subjects adapted their step length symmetry. We found that participants were able to successfully adapt both components of the walking pattern simultaneously, without interference, and at the same rate as adapting either component independently. This leads us to the interesting possibility that combining rehabilitation modalities within a single training session could be used to help alleviate multiple deficits at once in patients with complex gait impairments.


Identification of Pt-based catalysts for propane dehydrogenation via a probability analysis.
The intrinsic errors due to functionals are always a concern on the reliability of the predicted catalytic performance by density functional theory. This paper describes a probability-based computational screening study, which has successfully identified an optimal bimetallic alloy (Pt3In) for the propane dehydrogenation reaction (PDH). Considering DFT uncertainty, Pt3In was found to have an activity comparable to that of pure Pt and Pt3Sn. Meanwhile, Pt3In shows a considerable improvement in the propylene selectivity compared with pure Pt. After a complete and progressive potential energy, free energy and microkinetic analysis, Pt3In was discovered to show a great balance between activity and selectivity and reach a maximum propylene formation performance. The first dehydrogenation step was found to be the rate-controlling step on most of the facets. Apart from separating Pt atoms and covering the low coordinated step Pt atoms, the role of In can also be attributed to an apparently increasing electron transfer from In to Pt. The adsorption energies of propylene that play a key role in selectivity and activity were correlated with the d-band center, which can be used to tune a more precise PtIn ratio for the PDH reaction in the future.


Ultrasensitive Detection of Methylmercaptan Gas Using Layered Manganese Oxide Nanosheets with a Quartz Crystal Microbalance Sensor.
Methylmercaptan (MM) is a marker of periodontal disease; however, the required sensitivity for MM is parts per billion, which has been challenging to realize with a simple sensor. Here, we report the capability to detect MM at concentrations as low as 20 ppb using layered manganese oxide nanosheets with a quartz crystal microbalance sensor. The sensing capabilities of the manganese oxide nanosheets are promoted by adsorbed water present on and between the nanosheets. The strong adsorption of MM to the sensor, which is necessary for the high sensitivity, leads to significant hysteresis in the response on cycling due to irreversible adsorption. However, the sensor can be readily reset by heating to 80 °C, which leads to highly reproducible response to MM vapor at low concentrations. A key aspect of this sensor design is the high selectivity toward MM in comparison to other compounds such as ethanol, ammonia, acetaldehyde, acetic acid, toluene, and pyridine. This layered nanosheets design for high-sensitivity sensors, demonstrated here for dilute MM, holds significant promise for addressing needs to identify sulfur compounds associated for environmental protection and medical diagnostics.


Microstructural Integrity of Hippocampal Subregions Is Impaired after Mild Traumatic Brain Injury.
Mild traumatic brain injury (mTBI) affects a large number of individuals and diffusion tensor imaging can be used to investigate microstructural integrity of brain tissue after mTBI. However, results have varied considerably between studies and gray matter (GM) integrity has been largely neglected in these investigations. Given impaired working memory processing after mTBI and its possible association with Alzheimer's disease, we investigated hippocampal integrity and parcellated this structure into five subregions: subiculum, cornu ammonis (CA) 1, CA 2/3, CA 4/dentate gyrus, and stratum radiatum/lacunosum-moleculare. We also employed shape analysis of bilateral hippocampi to explore whether morphological changes had occurred due to the traumatic injury and conducted neuropsychological memory tests. The sample comprised 15 subjects with mTBI (18-55 years, nine female) and 13 age- and sex-matched healthy control subjects (19-57 years, nine female). Voxelwise analyses showed significantly increased mean diffusivity in patients, compared with controls, in the right hippocampus and three of its five subregions (family-wise error corrected p < 0.05). Additionally, results from probabilistic tractography indicated impaired CA 1 connectivity after mTBI (Benjamini-Hochberg false discovery rate [FDR] corrected p < 0.05). Shape of bilateral hippocampi did not significantly differ between groups (Benjamini-Hochberg FDR corrected p > 0.05). Subjects with mTBI reported more symptoms and performed worse in a non-standard verbal working memory task. Based on these preliminary findings, we were able to demonstrate altered diffusivity of hippocampal subregions following mTBI, indicating impaired GM microstructural integrity. These differences highlight the potential of diffusion imaging for investigation of subtle yet relevant changes in GM microstructure not detected otherwise following mTBI.


Benefits and risks of adjuvant treatment with zoledronic acid in stage II/III breast cancer. 10 years follow-up of the AZURE randomized clinical trial (BIG 01/04).
Adjuvant bisphosphonates improve disease outcomes in postmenopausal early breast cancer (EBC) but the long-term effects are poorly described. The AZURE trial (ISRCTN79831382) was designed to determine whether adjuvant zoledronic acid (ZOL) improves disease outcomes in EBC. Previous analyses showed no effect on overall outcomes but identified benefits in postmenopausal women. Here we present the long-term risks and benefits of adjuvant ZOL with 10-years follow-up. 3360 patients with stage II/III breast cancer were included in an academic, international, phase III, randomized, open label trial. Patients were followed up on a regular schedule until 10 years. Patients were randomized on a 1:1 basis to standard adjuvant systemic therapy +/- intravenous ZOL 4 mg every 3-4 weeks x6, and then at reduced frequency to complete 5 years treatment. The primary outcome was disease free survival (DFS). Secondary outcomes included invasive DFS (IDFS), overall survival (OS), sites of recurrence, skeletal morbidity and treatment outcomes according to primary tumor amplification of the transcription factor, MAF. Pre-planned subgroup analyses focused on interactions between menopausal status and treatment effects. With a median follow up of 117 months [IQR 70.4-120.4), DFS and IDFS were similar in both arms (HRDFS = 0.94, 95%CI = 0.84-1.06, p = 0.340; HRIDFS = 0.91, 95%CI = 0.82-1.02, p = 0.116). However, outcomes remain improved with ZOL in postmenopausal women (HRDFS = 0.82, 95%CI = 0.67-1.00; HRIDFS = 0.78, 95%CI = 0.64-0.94). In the 79% of tested women with a MAF FISH negative tumor, ZOL improved IDFS (HRIDFS = 0.75, 95%CI = 0.58-0.97) and OS HROS = 0.69, 95%CI = 0.50-0.94), irrespective of menopause. ZOL did not improve disease outcomes in MAF FISH + tumors. Bone metastases as a first DFS recurrence (BDFS) were reduced with ZOL (HRB-DFS = 0.76, 95%CI = 0.63-0.92, p = 0.005). ZOL reduced skeletal morbidity with fewer fractures and skeletal events after disease recurrence. 30 cases of osteonecrosis of the jaw in the ZOL arm (1.8%) have occurred. Disease benefits with adjuvant ZOL in postmenopausal early breast cancer persist at 10 years of follow-up. The biomarker MAF identified a patient subgroup that derived benefit from ZOL irrespective of menopausal status.


The relationship between positive aspects of caring, anxiety and depression in the caregivers of cancer patients: The mediational role of burden.
The aim of this study was to examine how the burden of caregivers of patients with an advanced oncological illness mediates the relationship between positive aspects of care, depression and anxiety. Quantitative study with a cross-sectional design. One hundred informal adult caregivers of patients with advanced oncological illness who attended the pain and palliative care unit or the psychological unit at the Instituto de Cancerologia Clinica las Americas (Medellin, Colombia) completed self-report assessments including positive aspects of care (PAC), burden and anxiety/depression measured using the HADS (Hospitalized Anxiety Depression Scale). The partial least squares Structural Equation Modelling (PLS-SEM) approach was selected to validate the hypotheses of the study. Most of the participants were women (86%), with a mean age of 46.52 years (SD=15.05). Most of the participants reported experiencing both PAC and anxiety. They also scored low for burden. PAC exerted a negative effect on Burden, whereas Burden contributed positively to Anxiety and Depression. The indirect impact of PAC on Anxiety and Depression was significant p < .00. Positive aspects of care in advanced cancer caregivers constitutes a protective factor against caregiver's burden, depression and anxiety. Health staff can promote caregivers' adaptation and wellbeing emphasizing these PAC.


Interaction of PCB congeners and 2,3,7,8-TCDD in the rat liver: an electron microscope study.
Polyhalogenated aromatic compounds such as polychlorinated biphenyls (PCBs) and polychlorinated dibenzo-p-dioxins continue to be environmental contaminants because of their bioaccumulation in the food chain and resistance to biodegradation. This study was undertaken to determine if WHO-IPCS PCB congeners or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) individually or their coadministration in rats produced morphological alterations in the liver. Groups (N = 5) of female Sprague Dawley rats received TCDD (0, 2.5, 25, 250, 1,000 ng/kg bw/day) or PCB (0, 2, 20 micrograms/kg bw/day) either alone, or each dose of PCB coadministered with that of TCDD. The test substances were dissolved in corn oil and given by gavage at 0.2 ml/100 g bw/day for 28 days. At the end of the experiment the rats were killed and liver samples were prepared for transmission electron microscopy. Electron micrographs of the liver from animals of the control groups revealed characteristic normal hepatocyte architecture. An increase in smooth endoplasmic reticulum (SER) profiles and a corresponding decrease in the profiles of rough endoplasmic reticulum (RER) proportional to the increased doses of the compounds was revealed in the micrographs. Coadministration of PCBs and TCDD induced greater SER proliferation and a greater decrease in the number of RER profiles compared to either compound administered individually. The PCBs and TCDD at the doses used apparently interacted to induce hepatic ultrastructural alterations. These changes may represent an attempt by the organism to metabolize and neutralize the effects of xenobiotics.


Effect of First-line S-1 Plus Oxaliplatin With or Without Ramucirumab Followed by Paclitaxel Plus Ramucirumab on Advanced Gastric Cancer in East Asia: The Phase 2 RAINSTORM Randomized Clinical Trial.
Ramucirumab, a human IgG 1 antibody against vascular endothelial growth factor receptor 2, has been shown to improve progression-free survival and overall survival in patients with advanced gastric cancer in the second-line setting. To compare progression-free survival for S-1 and oxaliplatin plus ramucirumab with that for S-1 and oxaliplatin plus placebo in patients with advanced gastric cancer. This phase 2, double-blind randomized clinical trial (RAINSTORM [First-line S-1 Plus Oxaliplatin With or Without Ramucirumab Followed by Paclitaxel Plus Ramucirumab in Patients With Advanced Gastric Cancer]) was conducted from October 12, 2015, to April 11, 2018, at 36 sites in Japan, South Korea, and Taiwan. Participants were chemotherapy-naive patients (n = 189) with metastatic gastric or gastroesophageal adenocarcinoma. Analyses of the full analysis set and safety population were conducted between November 27, 2017, and June 4, 2018. Patients randomized to the ramucirumab plus S-1 and oxaliplatin arm received S-1, 80 to 120 mg/d twice daily, on days 1 to 14 and oxaliplatin, 100 mg/m2, on day 1 with ramucirumab, 8 mg/kg, on days 1 and 8 in part A (21-day cycle). Patients randomized to the placebo plus S-1 and oxaliplatin arm received the same S-1 and oxaliplatin dosage as well as placebo on days 1 and 8 in part A. Eligible patients received second-line paclitaxel, 80 mg/m2, on days 1, 8, and 15 and ramucirumab, 8 mg/kg, on days 1 and 15 in part B (28-day cycle). The primary end point was progression-free survival, analyzed using the stratified log-rank test; the hazard ratio (HR) was estimated using the stratified Cox proportional hazards regression model. Secondary end points included overall survival and adverse events. In total, 189 patients were randomized and received treatment: 96 to the ramucirumab plus S-1 and oxaliplatin arm and 93 to the placebo plus S-1 and oxaliplatin arm. Among the 189 patients, 121 (64.0%) were male, and the median (range) age was 62.0 (26-84) years. Median progression-free survival was not prolonged in the ramucirumab plus S-1 and oxaliplatin arm compared with the placebo plus S-1 and oxaliplatin arm (6.34 [80% CI, 5.65-6.93] vs 6.74 [80% CI, 5.75-7.13] months; HR, 1.07; 80% CI, 0.86-1.33; P = .70). Median overall survival was 14.65 (80% CI, 12.39-15.67) months in the ramucirumab plus S-1 and oxaliplatin arm and 14.26 (80% CI, 13.83-17.31) months in the placebo plus S-1 and oxaliplatin arm (HR, 1.11; 80% CI, 0.89-1.40; P = .55). The most commonly reported grade 3 or higher treatment-emergent adverse events in the ramucirumab plus S-1 and oxaliplatin arm in part A were decreased neutrophil count (14 patients [14.6%]), hypertension (10 patients [10.4%]), and anemia (10 patients [10.4%]). In this randomized clinical trial, the addition of ramucirumab to first-line S-1 and oxaliplatin treatment did not prolong progression-free survival or overall survival compared with S-1 and oxaliplatin alone among East Asian patients with advanced gastric cancer; no new safety signals for ramucirumab were identified. ClinicalTrials.gov identifier: NCT02539225.


Reconciling oil palm expansion and climate change mitigation in Kalimantan, Indonesia.
Our society faces the pressing challenge of increasing agricultural production while minimizing negative consequences on ecosystems and the global climate. Indonesia, which has pledged to reduce greenhouse gas (GHG) emissions from deforestation while doubling production of several major agricultural commodities, exemplifies this challenge. Here we focus on palm oil, the world's most abundant vegetable oil and a commodity that has contributed significantly to Indonesia's economy. Most oil palm expansion in the country has occurred at the expense of forests, resulting in significant GHG emissions. We examine the extent to which land management policies can resolve the apparently conflicting goals of oil palm expansion and GHG mitigation in Kalimantan, a major oil palm growing region of Indonesia. Using a logistic regression model to predict the locations of new oil palm between 2010 and 2020 we evaluate the impacts of six alternative policy scenarios on future emissions. We estimate net emissions of 128.4-211.4 MtCO2 yr(-1) under business as usual expansion of oil palm plantations. The impact of diverting new plantations to low carbon stock land depends on the design of the policy. We estimate that emissions can be reduced by 9-10% by extending the current moratorium on new concessions in primary forests and peat lands, 35% by limiting expansion on all peat and forestlands, 46% by limiting expansion to areas with moderate carbon stocks, and 55-60% by limiting expansion to areas with low carbon stocks. Our results suggest that these policies would reduce oil palm profits only moderately but would vary greatly in terms of cost-effectiveness of emissions reductions. We conclude that a carefully designed and implemented oil palm expansion plan can contribute significantly towards Indonesia's national emissions mitigation goal, while allowing oil palm area to double.


Caffeine use among active duty US Army soldiers.
Eighty-percent of the US adult population regularly consumes caffeine, but limited information is available on the extent and patterns of use. Caffeine use is a public health issue and its risks and benefits are regularly considered in scientific literature and the lay media. Recently, new caffeine-containing products have been introduced and are widely available on Army bases and are added to rations to maintain cognitive performance. This study surveyed caffeine consumption and demographic characteristics in 990 US Army soldiers. Data were weighted by age, sex, rank, and Special Forces status. Total caffeine intake and intake from specific products were estimated. Logistic regression was used to examine relationships between caffeine use and soldier demographic and lifestyle characteristics. Eighty-two percent of soldiers consumed caffeine at least once a week. Mean daily caffeine consumption was 285 mg/day (347 mg/day among regular caffeine consumers). Male soldiers consumed, on average, 303 mg/day and females 163 mg/day (regular consumers: 365 mg/day for male soldiers, 216 mg/day for female soldiers). Coffee was the main source of caffeine intake. Among young males, energy drinks were the largest source of caffeine intake, but their intake was not greater than older males. Regression analysis indicated an association of higher caffeine intake with male sex, white race, and tobacco use (P<0.01). Most soldiers consume caffeine in levels accepted as safe, but some consume greater quantities than recommended, although definitive information on safe upper limits of caffeine intake is not available. Labels of caffeine-containing products should provide caffeine content so individuals can make informed decisions.


Optical properties of Bacillus subtilis spores from 0.2 to 2.5 num.
We have used spectral reflectance and transmittance measurements combined with Kramers-Krönig analyses to obtain the real (n) and imaginary (k) parts of the complex refractive index, N = n + ik, of Bacillus subtilis spores over a wavelength interval from 0.2 to 2.5 mum. Samples were in the form of thin solid films, pressed pellets, and suspensions in water and glycerol. The optical constants of spores suspended in water were found to differ from those of spores suspended in glycerol. In addition, spores previously exposed to water in earlier experiments and subsequently dried exhibited different optical constants from spores that had not been exposed to water.


Via freedom to coercion: the emergence of costly punishment.
In human societies, cooperative behavior in joint enterprises is often enforced through institutions that impose sanctions on defectors. Many experiments on so-called public goods games have shown that in the absence of such institutions, individuals are willing to punish defectors, even at a cost to themselves. Theoretical models confirm that social norms prescribing the punishment of uncooperative behavior are stable-once established, they prevent dissident minorities from spreading. But how can such costly punishing behavior gain a foothold in the population? A surprisingly simple model shows that if individuals have the option to stand aside and abstain from the joint endeavor, this paves the way for the emergence and establishment of cooperative behavior based on the punishment of defectors. Paradoxically, the freedom to withdraw from the common enterprise leads to enforcement of social norms. Joint enterprises that are compulsory rather than voluntary are less likely to lead to cooperation.


Phylogeography of a morphologically diverse Neotropical montane species, the Common Bush-Tanager (Chlorospingus ophthalmicus).
The Common Bush-Tanager (Chlorospingus ophthalmicus) is distributed in Neotropical cloud-forests from Mexico to Argentina and contains 25 subspecies divided into eight subspecies groups based on biogeography, eye coloration, presence of a postocular spot and chest band. All of Central America is occupied by a single subspecies group; whereas the Andes are believed to be occupied by seven additional subspecies groups. We used five mitochondrial genes to investigate the phylogeography and possible species limits of the ophthalmicus complex. A total of 14 monophyletic lineages were uncovered within the ophthalmicus complex, including three clades currently classified as separate species (C. semifuscus, inornatus and tacarcunae). Divergence estimates for these clades date between 0.8 and 5.2 million years ago (Ma). Contrary to expectations based on morphological diversity, phylogeographic structure was greatest in Mexico and Central America and weakest in the Andes. Morphological and genetic divergences were not significantly correlated and most morphologically defined subspecies groups were not supported. Our evidence suggests the ophthalmicus complex originated in Mexico ca. 6.0 Ma (million years ago) and spread south into the Andes ca. 4.7 Ma before the completion of the Isthmus of Panama. Three genetically divergent lineages of ophthalmicus that formed in the Andes possess a complex checkerboard distribution, with a single lineage represented by disjunct populations from Venezuela and the southern Andes, while intervening populations in Ecuador and Central Peru form two genetically and morphologically divergent lineages.


Codivergence and multiple host species use by fig wasp populations of the Ficus pollination mutualism.
The interaction between insects and plants takes myriad forms in the generation of spectacular diversity. In this association a species host range is fundamental and often measured using an estimate of phylogenetic concordance between species. Pollinating fig wasps display extreme host species specificity, but the intraspecific variation in empirical accounts of host affiliation has previously been underestimated. In this investigation, lineage delimitation and codiversification tests are used to generate and discuss hypotheses elucidating on pollinating fig wasp associations with Ficus. Statistical parsimony and AMOVA revealed deep divergences at the COI locus within several pollinating fig wasp species that persist on the same host Ficus species. Changes in branching patterns estimated using the generalized mixed Yule coalescent test indicated lineage duplication on the same Ficus species. Conversely, Elisabethiella and Alfonsiella fig wasp species are able to reproduce on multiple, but closely related host fig species. Tree reconciliation tests indicate significant codiversification as well as significant incongruence between fig wasp and Ficus phylogenies. The findings demonstrate more relaxed pollinating fig wasp host specificity than previously appreciated. Evolutionarily conservative host associations have been tempered by horizontal transfer and lineage duplication among closely related Ficus species. Independent and asynchronistic diversification of pollinating fig wasps is best explained by a combination of both sympatric and allopatric models of speciation. Pollinator host preference constraints permit reproduction on closely related Ficus species, but uncertainty of the frequency and duration of these associations requires better resolution.


Role of Pre-Operative Blood Transfusion and Subcutaneous Fat Thickness as Risk Factors for Surgical Site Infection after Posterior Thoracic Spine Stabilization.
Surgical site infections (SSIs) increase morbidity and mortality rates and generate additional cost for the healthcare system. Pre-operative blood transfusion and the subcutaneous fat thickness (SFT) have been described as risk factors for SSI in other surgical areas. The purpose of this study was to assess the impact of pre-operative blood transfusion and the SFT on the occurrence of SSI in posterior thoracic spine surgery. In total, 244 patients (median age 55 y; 97 female) who underwent posterior thoracic spine fusions from 2008 to 2012 were reviewed retrospectively. Patient-specific characteristics, pre-operative hemoglobin concentration/hematocrit values, the amount of blood transfused, and the occurrence of a post-operative SSI were documented. The SFT was measured on pre-operative computed tomography scans. Surgical site infection was observed in 26 patients (11%). The SFT was 13 mm in patients without SSI and 14 mm in those with infection (p=0.195). The odds ratio for patients with pre-operative blood transfusion to present with SSI was 3.1 (confidence interval [CI] 1.4-7.2) and 2.7 (CI 1.1-6.4) when adjusted for age. There was no difference between the groups with regard to pre-operative hemoglobin concentration (p=0.519) or hematocrit (p=0.908). The SFT did not differ in the two groups. Allogeneic red blood cell transfusion within 48 h prior to surgery was an independent risk factor for SSI after posterior fusion for the fixation of thoracic spine instabilities. Pre-operative blood transfusion tripled the risk, whereas SFT had no influence on the occurrence of SSI.


Identification of the major outer membrane proteins of Aeromonas salmonicida.
Aeromonas salmonicida subsp. salmonicida is a Gram-negative bacterium that is the etiological agent of furunculosis, a serious infectious disease of salmonids. Aeromonas spp. are ubiquitous waterborne bacteria responsible for a wide spectrum of diseases among aquatic organisms and humans. Bacterial outer membrane proteins (OMPs) play a significant role in virulence as they comprise the outermost surface in contact with host cells and immune defense factors. To identify the major OMPs of A. salmonicida a proteomic analysis was undertaken using a carbonate OMP-enrichment protocol. The enriched OMP-extracts were separated by 2-dimensional electrophoresis (2-DE) and the spots identified using liquid chromatography/mass spectrometry/mass spectrometry (LC/MS/MS) via an electrospray ionization source. In total, 76 unique proteins were identified from the 125 spots observed on the 2-D gel. The surface layer (S-layer) VapA protein dominated the A. salmonicida OMP 2-D profile, accounting for 60% of the protein on the 2-D gels. Among the other outer membrane proteins identified were at least 10 porins and various receptors involved in nutrient acquisition. Also identified in the carbonate insoluble fraction were phosphoglycerate kinase, enolase and others that lacked classical export sorting signals. The putative association of these proteins with the cell surface might provide new insights concerning the biological and pathogenic roles of these molecules in A. salmonicida infection. This work represents the first systematic attempt to characterize the cell surface of A. salmonicida.


Advances in Micelle-based Drug Delivery: Cross-linked Systems.
There are several barriers that drug molecules encounter in body beginning from kidney filtration and reticulo-endothelial system (RES) clearance to cellular trafficking. Multifunctional nanocarriers have a great potential for the delivery of drugs by enhancing therapeutic activity of existing methodologies. A variety of nanocarriers are constructed by different material types, which have unique physicochemical properties for drug delivery applications. Micelles formed by amphiphilic polymers are one of the most important drug/nanocarrier formulation products, in which the core part is suitable for encapsulation of hydrophobic agent whereas the outer shell can be utilized for targeting the drug to the disease area. Micelles as self-assembled nanostructures may encounter difficulties in biodistribution of encapsulated drugs because they have a tendency to be dissociated in dilution or high ionic strength. Therefore, therapeutic efficiency is decreased and it requires high amount of drug to be administered to achieve more efficient result. To overcome this problem, covalently stabilized structures produced by cross-linking in core or shell part, which can prevent the micelle dissociation and regulate drug release, have been proposed. These systems can be designed as responsive systems in which cross-links are degradable or hydrolysable under specific conditions such as low pH or reductive environment. These are enhancing characteristics in drug delivery because their cleavage allows the release of bioactive agent encapsulated in the carrier at a certain site or time. This review describes the chemical methodologies for the preparation of cross-linked micelles, and reports an update of latest studies in literature.


[A Case of Minimal Thyroid Carcinoma Diagnosed by a Solitary Pulmonary Metastasis].
We report a case of minimal thyroid carcinoma diagnosed by a solitary pulmonary metastasis. A 70's man visited a medical practitioner because of chest discomfort, and there was an abnormality on the chest X-ray. Chest computed tomography(CT) showed a nodule in the right middle lobe of the lung. Positron emission tomography with 18-fluorodeoxyglucose(FDG)-PET revealed increased FDG uptake in that tumor, but did not reveal any other lesion. The tumor was clinically suspected to be a carcinoid tumor, primary lung cancer, metastatic lung cancer, or a benign tumor. Right middle lobe lobectomy was performed, and the tumor was diagnosed as a metastasis from a thyroid papillary carcinoma by pathological diagnosis during surgery. After surgery, we found a tumor in the left lobe of the thyroid by CT and US. Because the patient did not desire 131I therapy, he underwent a left hemithyroidectomy and neck dissection. There was a papillary carcinoma 1.0 cm in the thyroid gland and there were 3 cervical lymph node metastases. There has been no recurrence for 11 years after surgery.


Rumen Virus Populations: Technological Advances Enhancing Current Understanding.
The rumen contains a multi-kingdom, commensal microbiome, including protozoa, bacteria, archaea, fungi and viruses, which enables ruminant herbivores to ferment and utilize plant feedstuffs that would be otherwise indigestible. Within the rumen, virus populations are diverse and highly abundant, often out-numbering the microbial populations that they both predate on and co-exist with. To date the research effort devoted to understanding rumen-associated viral populations has been considerably less than that given to the other microbial populations, yet their contribution to maintaining microbial population balance, intra-ruminal microbial lysis, fiber breakdown, nutrient cycling and genetic transfer may be highly significant. This review follows the technological advances which have contributed to our current understanding of rumen viruses and drawing on knowledge from other environmental and animal-associated microbiomes, describes the known and potential roles and impacts viruses have on rumen function and speculates on the future directions of rumen viral research.


The longitudinal relationship between social support and victimization among latino teens.
This study examines the relationship between social support and victimization of Latino youth over time, utilizing the stress prevention and support deterioration models. To address the research questions we utilized data from Waves 1 and 2 (n = 574) of the Dating Violence among Latino Adolescents (DAVILA) study, a national bilingual phone survey of self-identified Latino youth and their caregiver. Cross-lagged panel modeling was used to assess the fit of the two theoretical models to observed patterns of covariance among the victimization and social support variables specified. Results show that victimization at Wave 1 was positively and strongly related to victimization at Wave 2 and social support at Wave 1 was positively and moderately associated with social support at Wave 2. As hypothesized, higher levels of victimization at Wave 1 were significantly related to decreases in social support at Wave 2 (β = -.15). Wave 1 social support was not significantly related to victimization at Wave 2. We did not find support for the stress prevention model but did find support for the support deterioration model. Teens who were victimized tended to have lower levels of subsequent social support, highlighting the need to equip peers, family, and significant others to adequately respond to victimization disclosures.


Identification of fat-cell enhancer regions in Drosophila melanogaster.
The insect fat body is a dynamic tissue involved in maintaining homeostasis. It functions not only in energy storage and intermediary metabolism but also in detoxification, communication and the immune response. Some of these functions are confined to distinct groups of fat body cells. In Drosophila melanogaster, discrete precursor-cell clusters populate the fat body [Hoshizaki, D.K., Blackburn, T., Price, C., Ghosh, M., Miles, K., Ragucci, M. and Sweis, R. (1994) Embryonic fat-cell lineage in Drosophila melanogaster. Development 120: 2489-2499; Hoshizaki, D.K., Lunz, R., Ghosh, M. and Johnson, W. (1995) Identification of fat-cell enhancer activity in Drosophila melanogaster using P-element enhancer traps. Genome 38: 497-506; Riechmann, V., Rehorn, K.P., Reuter, R. and Leptin, M. (1998) The genetic control of the distinction between fat body and gonadal mesoderm in Drosophila. Development 125: 713-723]. Whether these clusters populate defined morphological regions or whether they represent the precursors to functionally similar groups of fat-body cells has not been formally demonstrated. We have identified a 2.1 kb enhancer region from serpent (srp), a GATA transcription factor gene that is sufficient to induce fat-cell formation. This enhancer region drives expression in specific groups of precursor-cell clusters, which we show give rise to defined regions of the mature embryonic fat body. We present evidence that srp expression in different precursor fat cells is controlled by independent cis-acting regulatory regions, and we have tested the role of trans-acting factors in the specification of some of these cells. We suggest that the different positional cues regulating srp expression, and therefore general fat-cell specification, might also be involved in the functional specialization of fat cells. This may be a common mechanism in insects to explain the origin of biochemically distinct regions of the larval/adult fat body.


Willingness to pay for a Rift valley fever (RVF) vaccine among Kenyan cattle producers.
A double bounded contingent valuation (CV) model was used to assess the Willingness to Pay (WTP) for vaccination of cattle against RVF in a sample of 276 livestock producers in Murang'a, Laikipia and Kwale Counties. While the level of awareness about the disease was rather low, nearly all respondents expressed willingness to have their animals vaccinated against the disease. Average WTP was highest in Murang'a (mean = US$1.44) where farmers practice dairy farming using exotic breeds of cattle compared to Laikipia (mean = US$1.24), where both exotic dairy and local breeds of cattle together with their crosses are kept, and Kwale (mean = US$1.01) where local breeds are predominantly kept. These average levels of WTP were 17%-67% higher than the estimated cost incurred by government (US$0.86 per head of cattle) in the most recent vaccination campaign conducted during RVF outbreak. Surprisingly, WTP tended to be lower among producers with many heads of cattle probably because the large herds would translate to bigger total costs. The study recommended support for sensitization campaigns about RVF and its control measures. While the high average levels of WTP implies potential for commercialization of vaccination against RVF, there may be need for price differentiation by region to ensure that sufficiently high numbers of producers vaccinate their animals to prevent outbreaks.


Hybrid Nanoplatforms Comprising Organic Nanocompartments Encapsulating Inorganic Nanoparticles for Enhanced Drug Delivery and Bioimaging Applications.
Organic and inorganic nanoparticles (NPs) have attracted significant attention due to their unique physico-chemical properties, which have paved the way for their application in numerous fields including diagnostics and therapy. Recently, hybrid nanomaterials consisting of organic nanocompartments (e.g., liposomes, micelles, poly (lactic-co-glycolic acid) NPs, dendrimers, or chitosan NPs) encapsulating inorganic NPs (quantum dots, or NPs made of gold, silver, silica, or magnetic materials) have been researched for usage in vivo as drug-delivery or theranostic agents. These classes of hybrid multi-particulate systems can enable or facilitate the use of inorganic NPs in biomedical applications. Notably, integration of inorganic NPs within organic nanocompartments results in improved NP stability, enhanced bioavailability, and reduced systemic toxicity. Moreover, these hybrid nanomaterials allow synergistic interactions between organic and inorganic NPs, leading to further improvements in therapeutic efficacy. Furthermore, these platforms can also serve as multifunctional agents capable of advanced bioimaging and targeted delivery of therapeutic agents, with great potential for clinical applications. By considering these advancements in the field of nanomedicine, this review aims to provide an overview of recent developments in the use of hybrid nanoparticulate systems that consist of organic nanocompartments encapsulating inorganic NPs for applications in drug delivery, bioimaging, and theranostics.


Optical coherence tomography: clinical applications in medical practice.
Optical Coherence Tomography (OCT) is a success story of scientific and technological co-operation between a physicist and a clinician. The concept of cross-sectional imaging revolutionalized the applicability of OCT in the medical profession. OCT is a non-contact, topographic, biomicroscopic device that provides high resolution, cross-sectional digital images of live biological tissues in vivo and in real time. OCT is based on the property of tissues to reflect and backscatter light involving low-coherence interferometry. The spatial resolution of as little as 3 microns or even less has allowed us to study tissues almost at a cellular level. Overall, OCT is an invaluable adjunct in the diagnosis and follow up of many diseases of both anterior and posterior segments of the eye, primarily or secondary to systemic diseases. The digitalization and advanced software has made it possible to store and retrieve huge patient data for patient services, clinical applications and academic research. OCT has revolutionized the sensitivity and specificity of diagnosis, follow up and response to treatment in almost all fields of clinical practice involving primary ocular pathologies and secondary ocular manifestations in systemic diseases like diabetes mellitus, hypertension, vascular and neurological diseases, thus benefitting non-ophthalmologists as well. Systemically, OCT is proving to be a helpful tool in substantiating early diagnosis in diseases like multiple sclerosis and drug induced retinopathies by detecting early changes in morphology of the retinal nerve fiber layer.


Role of Facial Index and Odontometric Parameters in the Establishment of Stature and Gender of Individuals.
Dental anthropology is an important aspect of bioarchaeology and forensic anthropology. In forensic anthropological studies, identifying an unknown individual from a mangled and decomposing body is a challenging task. Cranial remains are the only critical clues available for personal identification. Age, sex, and stature are significant parameters in establishing the identity of an unrecognized individual. Stature is the natural height of the individual in an upright position. Stature can be estimated from various parts of the body such as long bones, short bones, and skull. Few studies conducted in specific population have established a correlation for predicting stature from cephalometric and odontometric parameters. Thus, the present study was conducted to determine stature and gender based on cephalometric and odontometric parameters in the population of Tamil Nadu. The aim of this study was to investigate the possibility of predicting the stature and gender of an individual based on odontometric measurements, facial height, and bizygomatic width. A total of seventy individuals in the age group of 18-24 years were selected for the study. The facial height, bizygomatic width and length ,mesiodistal and labiolingual diameter of clinical crown of maxillary central,lateral and canine teeth of both the right and left quadrants were measured. The values were analyzed statistically. Through this analysis, regression equations for estimation of stature from odontometric and facial index were derived. Pearson correlation test was carried out to establish a correlation between the stature and the measured parameters. Regression analysis was carried out to establish stature from the odontometric and facial index of the individual. The regression equations were used to get estimated stature in the same sample of volunteers from which regression equations were obtained. Tabulated results showed a probable correlation between various parameters. In our study, a positive correlation between cephalometric measurements, gender, crown length of permanent left central incisor, and combined mesiodistal diameter of permanent maxillary anteriors with stature was found. This can be used as a supplementary method for estimating the stature of unknown human bodies.


The genetic control of immunity to Plasmodium infection.
Malaria remains a major worldwide public health problem with ~207 million cases and ~627,000 deaths per year, mainly affecting children under five years of age in Africa. Recent efforts at elaborating a genetic architecture of malaria have focused on severe malaria, leading to the identification of two new genes and confirmation of previously known variants in HBB, ABO and G6PD, by exploring the whole human genome in genome-wide association (GWA) studies. Molecular pathways controlling phenotypes representing effectiveness of host immunity, notably parasitemia and IgG levels, are of particular interest given the current lack of an efficacious vaccine and the need for new treatment options. We propose a global causal framework of malaria phenotypes implicating progression from the initial infection with Plasmodium spp. to the development of the infection through liver and blood-stage multiplication cycles (parasitemia as a quantitative trait), to clinical malaria attack, and finally to severe malaria. Genetic polymorphism may control any of these stages, such that preceding stages act as mediators of subsequent stages. A biomarker of humoral immunity, IgG levels, can also be integrated into the framework, potentially mediating the impact of polymorphism by limiting parasitemia levels. Current knowledge of the genetic basis of parasitemia levels and IgG levels is reviewed through key examples including the hemoglobinopathies, showing that the protective effect of HBB variants on malaria clinical phenotypes may partially be mediated through parasitemia and cytophilic IgG levels. Another example is the IgG receptor FcγRIIa, encoded by FCGR2A, such that H131 homozygotes displayed higher IgG2 levels and were protective against high parasitemia and onset of malaria symptoms as shown in a causal diagram. We thus underline the value of parasitemia and IgG levels as phenotypes in the understanding of the human genetic architecture of malaria, and the need for applying GWA approaches to these phenotypes.


Exceptional response to oral metronomic chemotherapy in a rare case of sinonasal mucosal melanoma.
Sinonasal mucosal melanoma is a rare malignancy with limited treatment options and a poor prognosis. They are usually diagnosed at an advanced stage owing to their late and nonspecific clinical presentation. Here we present a case of relapsed refractory unresectable malignant melanoma involving the right nasal cavity managed with Oral Metronomic Chemotherapy (OMCT). A 75-year-old male patient was diagnosed with unresectable malignant melanoma involving the right nasal cavity and showed radiological progression after initial management with four cycles of Dacarbazine. He was then shifted to OMCT (Cyclophosphamide, Celecoxib and Tamoxifen), as immunotherapy could not be given due to financial constraints, on which he showed approximately 40% reduction in tumour size after 6 months. This result can have important clinical implications in resource constrained settings, where the use of immunotherapy is limited by great financial burden.


Host genetics, steatosis and insulin resistance among African Americans and Caucasian Americans with hepatitis C virus genotype-1 infection.
Hepatic steatosis is the accumulation of fat in liver cells. Insulin resistance (IR) occurs when normal amounts of insulin do not stimulate insulin activity in cells. Both conditions have been described in hepatitis C virus (HCV) infection and are thought to be biologically related. This study examined the association of genetic variants with steatosis and IR among 167 African Americans and 184 Caucasian Americans with HCV genotype-1. Steatosis was defined as at least 5% of fat in cells on liver biopsy. IR was quantified as a score greater than 2 from the Homeostasis Model Assessment, version 2.2 (HOMA2-IR). Associations were investigated by estimating odds ratios separately by race. Statistically significant associations (p < 0.05) were observed for variants in interleukin-10 (IL10), leptin receptor (LEPR), interleukin-6 (IL6) and transforming growth factor beta-1 (TGF-beta1) for both outcomes. Some significant interactions were observed between IL10,LEPR and TGF-beta1 polymorphisms and HOMA2-IR scores when examining steatosis. The interaction of HOMA2-IR and IL10 was consistent in both races whereas for LEPR and TGF-beta1 the interactions were statistically significant in only one of the racial groups.These results could imply that some IL10,LEPR and TGF-beta1 polymorphisms may modify an association between steatosis and IR.


A review of pesticide exposure and cancer incidence in the agricultural health study cohort.
We reviewed epidemiologic evidence related to occupational pesticide exposures and cancer incidence in the Agricultural Health Study (AHS) cohort. Studies were identified from the AHS publication list available on a Medline/PubMed database search in March 2009. Findings related to lifetime-days and/or intensity-weighted lifetime-days of pesticide use are the primary focus of this review, because these measures allow for the evaluation of potential exposure-response relationships. Most of the 32 pesticides examined were not strongly associated with cancer incidence in pesticide applicators. Increased rate ratios and positive exposure-response patterns were reported for 12 pesticides currently registered in Canada and/or the United States. Exposure misclassification is also a concern in the AHS and may limit the analysis of exposure-response patterns. Epidemiologic evidence outside the AHS remains limited with respect to most of the observed associations, but animal toxicity data support the biological plausibility of relationships observed six pesticides. Continued follow-up is needed to clarify associations reported to date. In particular, further evaluation of registered pesticides is warranted.