Gender difference in the effect of short-term calorie restriction on body weight and immunological parameters in albino rats.
In the present study, we have assessed the effect of gender on short-term calorie restriction influencing body weight and immunological parameters in albino rats. Adult albino rats (12 females, 12 males) were taken for the study and randomly divided into control and experimental groups of both the genders (n = 6 in each). Following the recording of their basal 24 h food intake and body weight, rats of experimental groups were allowed to undergo food restriction (eat every alternate day) for 21 days, whereas control rats were allowed to eat normally. 7 days before the completion of food restriction, all animals were immunized and different immunological parameters such as: -log2 of anti-SRBC titer (Ab titer), liver weight/body weight ratio (LWBWR), spleen weight/body weight ratio (SWBWR), total globulin (Tg) and albumin/globulin ratio (AGR) were assessed. Following three weeks of intermittent calorie restriction, LWBWR was increased in both male (p < 0.05) and female (p < 0.001) experimental rats compared to their respective controls. Though the increase in SWBWR was not statistically significant in male rats, the increase was significant in female rats (p < 0.05). The SRBC titer and total globulin concentration were increased significantly in both male (p < 0.01) and female (p < 0.001) experimental rats. The decrease AGR was more in female compared to male rats (p < 0.01). The decrease in body weight following calorie restriction was significantly correlated with alteration in their immunological parameters. Short-term intermittent calorie restriction was found to facilitate immunity, especially in female rats, which promises future research on health promoting effects of calorie control.


Applications of nanomaterials in electrochemical enzyme biosensors.
A biosensor is defined as a kind of analytical device incorporating a biological material, a biologically derived material or a biomimic intimately associated with or integrated within a physicochemical transducer or transducing microsystem. Electrochemical biosensors incorporating enzymes with nanomaterials, which combine the recognition and catalytic properties of enzymes with the electronic properties of various nanomaterials, are new materials with synergistic properties originating from the components of the hybrid composites. Therefore, these systems have excellent prospects for interfacing biological recognition events through electronic signal transduction so as to design a new generation of bioelectronic devices with high sensitivity and stability. In this review, we describe approaches that involve nanomaterials in direct electrochemistry of redox proteins, especially our work on biosensor design immobilizing glucose oxidase (GOD), horseradish peroxidase (HRP), cytochrome P450 (CYP2B6), hemoglobin (Hb), glutamate dehydrogenase (GDH) and lactate dehydrogenase (LDH). The topics of the present review are the different functions of nanomaterials based on modification of electrode materials, as well as applications of electrochemical enzyme biosensors.


Bidirectional regulation over the development and expression of loss of control over cocaine intake by the anterior insula.
Increasing evidence suggests that the anterior insular cortex (AIC) plays a major role in cocaine addiction, being implicated in both impaired insight and associated decision-making and also craving and relapse. However, the nature of the involvement of the insula in the development and maintenance of cocaine addiction remains unknown, thereby limiting our understanding of its causal role in addiction. We therefore investigated whether pre- and post-training bilateral lesions of the AIC differentially influenced the development and the expression of the escalation of cocaine self-administration during extended access to the drug. In a series of experiments, Sprague Dawley rats received bilateral excitotoxic lesions of the AIC either prior to, or after 3 weeks of training under 12-h extended self-administration conditions, which are known to promote a robust escalation of intake. We also investigated the influence of AIC lesions on anxiety, as measured in an elevated plus maze and sensitivity to conditioned stimuli (CS)- or drug-induced reinstatement of an extinguished instrumental response. Whereas, post-escalation lesions of the AIC, as anticipated, restored control over cocaine intake and prevented drug-induced reinstatement, pre-training lesions resulted in a facilitation of the development of loss of control with no influence over the acquisition of cocaine self-administration or anxiety. AIC lesions differentially affect the development and maintenance of the loss of control over cocaine intake, suggesting that the nature of the contribution of cocaine-associated interoceptive mechanisms changes over the course of escalation and may represent an important component of addiction.


Association of Helicobacter pylori infection with dyspeptic symptoms in patients undergoing gastroduodenoscopy.
To determine the prevalence of Helicobacter pylori in patients with non-ulcer dyspepsia and ulcer disease as well as in a control population undergoing endoscopic retrograde cholangiopancreatography (ERCP) for suspected pancreatic or biliary disease. Forty-six eligible patients undergoing upper endoscopy at Massachusetts General Hospital were studied over a period of 18 months, as well as 24 patients undergoing ERCP for presumed pancreatic or biliary disease. Two biopsy specimens from the fundus and two from the antrum were taken for microbiologic and histopathologic analysis. Sera were examined by enzyme-linked immunoabsorbent assay. All specimens were processed in a blind fashion. Chi-square test with Yates' correction was used for statistical analysis. H. pylori was found in 31 of 46 (67%) study patients and in six of 24 (25%) control patients (by microbiologic or histologic techniques) (p less than 0.01). H. pylori was found in all patients with peptic ulcer disease and in 60% of patients without ulcers. No association between H. pylori and any specific gastrointestinal symptom was observed. H. pylori was identified in the fundus as often as in the antrum, although in the antrum the organism was more often associated with histologic gastritis. Compared with histology, serologic assays for IgG and IgA antibodies to H. pylori had sensitivities of 100% and 94%, and specificities of 86% and 76%, respectively. Reexamination of selected specimens without knowledge of their identity revealed that the specificity of serology exceeded 94% while the sensitivity of histologic and microbiologic studies may have been closer to 80%. H. pylori was more common in dyspeptic patients than in our control subjects undergoing ERCP. Multiple biopsy sites from fundus and antrum are required to exclude infection. Serologies of IgG and IgA were sensitive and specific for H. pylori, suggesting a possible role for non-endoscopic diagnosis of this infection. The frequent association of H. pylori with active inflammation rather than with quiescent gastritis is consistent with a pathologic role of this organism.


ATP is required for receptor-mediated endocytosis in intact cells.
We have demonstrated a requirement for cellular ATP in the receptor-mediated endocytosis of transferrin. This has been accomplished using a novel assay for endocytosis based on acquisition of resistance to the membrane impermeable reducing agent, glutathione (GSH). Diferric-transferrin was conjugated to biotin via a cleavable disulfide bond and iodinated. Internalization of 125I-biotin-S-S-transferrin (125I-BSST) was quantitated by adsorption to avidin-Sepharose after treatment of cells with GSH. Receptor-mediated endocytosis of 125I-BSST was severely inhibited in ATP-depleted cells. Similar results were obtained when ATP was depleted by incubation of cells either under a N2-atmosphere or in the presence of NaN3 and NaF. The latter treatment, alone, also resulted in a loss of surface transferrin receptors which could not be correlated to reductions in cellular ATP. In contrast to the acquisition of GSH resistance, the apparent internalization of 125I-BSST as assessed by inaccessibility to antitransferrin antibodies reached control levels in ATP-depleted cells. Our biochemical and morphological data suggested that, although ATP is required for receptor-mediated endocytosis, in ATP-depleted cells ligands can become efficiently sequestered into deeply invaginated pits that are inaccessible to large probes such as antibodies, but remain accessible to small molecules such as GSH.


Increased passive ankle stiffness and reduced dorsiflexion range of motion in individuals with diabetes mellitus.
The purpose of our study was to compare ankle range of motion and stiffness in individuals with and without diabetes mellitus using a reliable and valid technique and to document the effect of knee flexion and severity of pathology on ankle range of motion and stiffness. Twenty-five individuals with diabetes mellitus and 64 nondiabetic individuals, similar in age and gender profile, participated in this study. Results revealed that individuals with diabetes mellitus had both significantly lower peak dorsiflexion range of motion (5.1 and 11.5 degrees, p < 0.001) and higher passive ankle stiffness (0.016 and 0.008 Nm/kg/degree, p < 0.01) than non-diabetic individuals. In individuals with diabetes mellitus, a positive relationship between glycemic control and duration of diabetes mellitus and ankle stiffness ((r(2) = 0.48 and 0.24 respectively, p < 0.01 for both) was found. While decreased range of motion and increased stiffness in the diabetes mellitus population seem clinically intuitive, as far as we know this is the first study to confirm the concurrent existence of both these findings in the plantarflexors in individuals with diabetes mellitus. We applied a reliable and valid technique, one that allowed control of confounding factors such as knee flexion position and differences in determination of end range of motion, and documented a mean 41% loss in dorsiflexion excursion. Changes in the muscle, stemming from underlying pathology, are hypothesized to account for a significant part of the lost range of motion. Changes in ankle range of motion and stiffness may have important implications in plantar loading and ulcer formation.


Origins, genetic structure, and systematics of the narrow endemic peatmosses (Sphagnum): S. guwassanense and S. triseriporum (Sphagnaceae).
Sphagnum dominates vast expanses of wetland habitats throughout the northern hemisphere and species delimitation within the genus is important because floristic changes associated with a warming global climate may have measureable impacts on large-scale ecological processes. Most northern hemisphere peatmoss species (Sphagnum) have circumboreal ranges, but the Japanese species generally known as S. calymmatophyllum is endemic to Honshu Island. This prompted a population genetic and phylogenetic analysis to resolve the origin(s), population structure, and phylogenetic relationships of this morphologically variable species. • Sixty plants collected from Mt. Gassan and Mt. Hakkoda were genotyped for 12 microsatellite loci. Two plastid loci and three anonymous nuclear loci were sequenced in a subset of the plants, plus representatives from 10 closely related species. • Gametophytes exhibited fixed or nearly fixed heterozygosity at 9-10 of the 12 microsatellite loci. Two genetic groups were resolved by the microsatellite data, individuals showed no evidence of admixture, and the two groups of plants differ in morphology. They are heterozygous for different sets of alleles. The two taxa share plastid DNA sequences with two species that are common in Alaska. • Two taxa were distinguished: S. guwassanense and S. triseriporum. Both are allopolyploids; they originated independently from different but closely related progenitors. The maternal progenitor was likely either S. orientale or S. inexspectatum. The two allopolyploid taxa are heterozygous for (different) private microsatellite alleles, and one progenitor could be extinct.


Update on liver transplantation-newer aspects
Liver transplantation (LT) remains the only therapeutic option offering gold standard treatment for end-stage liver disease (ESLD) and acute liver failure (ALF), as well as for certain early-stage liver tumors. Currently, the greatest challenge facing LT is the simple fact that there are not enough adequate livers for all the potential patients that could benefit from LT. Despite efforts to expand the donor pool to include living and deceased donors, organ shortage is still a major problem in many countries. To solve this problem, the use of marginal liver grafts has become an inevitable choice. Although the definition of marginal grafts or criteria for expanded donor selection has not been clarified yet, they are usually defined as grafts that may potentially cause primary nonfunction, impaired function, or late loss of function. These include steatotic livers, older donors, donors with positive viral serology, split livers, and donation after cardiac death (DCD). Therefore, to get the best outcome from these liver grafts, donor-recipient selection should be vigilant. Alcohol- related liver disease (ALD) is one of the most common indications for LT in Europe and North America. Traditionally, LT for alcoholic liver disease was kept limited for patients who have achieved 6 months of abstinence, in part due to social and ethical concerns regarding the use of a limited resource. However, the majority of patients with severe alcoholic hepatitis who fail medical therapy will not live long enough to meet this requirement. Besides, the initial results of early liver transplantation (ELT) without waiting for 6 months of abstinence period are satisfactory in severe alcoholic hepatitis (SAH). It will be important to take care of these patients from a newer perspective.


Incidence of postoperative seizures with and without levetiracetam pretreatment in dogs undergoing portosystemic shunt attenuation.
In dogs with congenital portosystemic shunts (CPS), postligation seizures can be challenging to treat and often result in mortality. Levetiracetam (LEV) is a novel anticonvulsive drug that is commonly used in humans with seizure disorders who have hepatic comorbidity. To compare the incidence of postoperative seizures in dogs that underwent surgical attenuation of an extrahepatic CPS and preoperatively received either LEV or no anticonvulsant medication. A total of 126 dogs undergoing attenuation of an extrahepatic CPS that preoperatively received either LEV or no anticonvulsant medication. Retrospective case review. Information obtained included signalment, duration of clinical signs, presence of neurologic abnormalities before surgery, preoperative bile acid and ammonia concentrations, diagnostic imaging modality, duration of hospitalization, postoperative complications including seizures, and discharge status. Bayesian Poisson regression was used to estimate the risk of seizures in LEV-treated dogs when compared with untreated dogs. Levetiracetam was administered to 33% (42/126) of dogs. No dog treated with LEV experienced postoperative seizures, whereas 5% (4/84) of dogs not treated with LEV experienced postoperative seizures. The relative risk of seizures was significantly (P < .0002) < 1 for the LEV-treated dogs, indicating LEV protection against development of postoperative seizures. No dog that experienced postoperative seizures survived to discharge from the hospital. Levetiracetam administered at 20 mg/kg p.o. q8h for a minimum of 24 hours before surgery significantly decreased the risk of postoperative seizures and death in dogs undergoing surgical attenuation of extrahepatic CPS with ameroid ring constrictors.


Development of an electronic public health case report using HL7 v2.5 to meet public health needs.
Clinicians are required to report selected conditions to public health authorities within a stipulated amount of time. The current reporting process is mostly paper-based and inefficient and may lead to delays in case investigation. As electronic medical records become more prevalent, electronic case reporting is becoming increasingly feasible. However, there is no existing standard for the electronic transmission of case reports from healthcare to public health entities. We identified the major requirements of electronic case reports and verified that the requirements support the work processes of the local health departments. We propose an extendable standards-based model to electronically transmit case information and associated laboratory information from healthcare to public health entities. The HL7 v2.5 message model is currently being implemented to transmit electronic case reports from Intermountain Healthcare to the Utah Department of Health.


Quantification of Hyphomicrobium populations in activated sludge from an industrial wastewater treatment system as determined by 16S rRNA analysis.
The bacterial community structure of the activated sludge from a 25 million-gal-per-day industrial wastewater treatment plant was investigated using rRNA analysis. 16S ribosomal DNA (rDNA) libraries were created from three sludge samples taken on different dates. Partial rRNA gene sequences were obtained for 46 rDNA clones, and nearly complete 16S rRNA sequences were obtained for 18 clones. Seventeen of these clones were members of the beta subdivision, and their sequences showed high homology to sequences of known bacterial species as well as published 16S rDNA sequences from other activated sludge sources. Sixteen clones belonged to the alpha subdivision, 7 of which showed similarity to Hyphomicrobium species. This cluster was chosen for further studies due to earlier work on Hyphomicrobium sp. strain M3 isolated from this treatment plant. A nearly full-length 16S rDNA sequence was obtained from Hyphomicrobium sp. strain M3. Phylogenetic analysis revealed that Hyphomicrobium sp. strain M3 was 99% similar to Hyphomicrobium denitrificans DSM 1869(T) in Hyphomicrobium cluster II. Three of the cloned sequences from the activated sludge samples also grouped with those of Hyphomicrobium cluster II, with a 96% sequence similarity to that of Hyphomicrobium sp. strain M3. The other four cloned sequences from the activated sludge sample were more closely related to those of the Hyphomicrobium cluster I organisms (95 to 97% similarity). Whole-cell fluorescence hybridization of microorganisms in the activated sludge with genus-specific Hyphomicrobium probe S-G-Hypho-1241-a-A-19 enhanced the visualization of Hyphomicrobium and revealed that Hyphomicrobium appears to be abundant both on the outside of flocs and within the floc structure. Dot blot hybridization of activated sludge samples from 1995 with probes designed for Hyphomicrobium cluster I and Hyphomicrobium cluster II indicated that Hyphomicrobium cluster II-positive 16S rRNA dominated over Hyphomicrobium cluster I-positive 16S rRNA by 3- to 12-fold. Hyphomicrobium 16S rRNA comprised approximately 5% of the 16S rRNA in the activated sludge.


Efficacy and Prognostic Value of Partial Sensory Rhizotomy and Microvascular Decompression for Primary Trigeminal Neuralgia: A Comparative Study.
BACKGROUND This study aimed to compare the efficacy and prognostic value of partial sensory rhizotomy (PSR) and microvascular decompression (MVD) for primary trigeminal neuralgia (PTN). MATERIAL AND METHODS From June 2010 to June 2012, 117 patients with PTN were recruited for the study, of which 52 cases were treated with MVD (the MVD group) and 65 cases were treated with PSR (the PSR group). Visual Analog Scoring (VAS) was performed at 1 and 2 weeks, and at 1, 3, and 6 month after surgery. The overall response rate (ORR) was determined 1 month after surgery. Barrow Neurological Institute score was adopted to value the reoccurrence at 6, 12, 24, and 36 months after surgery. A 3-year follow-up was conducted and the complications were recorded. RESULTS The ORR 2 weeks after surgery in the MVD and PSR groups was 98.08% and 84.62%, respectively. One and 2 weeks after surgery, the VAS was lower in the MVD group than in the PSR group, but there was no significant difference in VAS between the 2 groups at 1, 3, and 6 months after surgery. Three years after surgery, the recurrence rate was significantly lower in the MVD group than in the PSR group. The recurrence-free survival time was longer in the MVD group than in the PSR group. The occurrence rates of herpes and total postoperative complications were significantly higher in the PSR group than in the MVD group. CONCLUSIONS Compared with PSR, MVD is more suitable for PTN treatment, with less disturbance, lower recurrence rate, and better efficacy.


Incorporation of fragment X into fibrin clots renders them more susceptible to lysis by plasmin.
Bleeding, the most serious complication of thrombolytic therapy with tissue-type plasminogen activator (t-PA), is thought to result from lysis of fibrin in hemostatic plugs and from the systemic lytic state caused by unopposed plasmin. One mechanism by which systemic plasmin can impair hemostasis is by partially degrading fibrinogen to fragment X, a product that retains clottability but forms clots with reduced tensile strength that stimulate plasminogen activation by t-PA more than fibrin clots. The purpose of this study was to elucidate potential mechanisms by which fragment X accelerates t-PA-mediated fibrinolysis. In the presence of t-PA, clots containing fragment X were degraded faster than fibrin clots and exhibited higher rates of plasminogen activation. Although treatment with carboxypeptidase B, an enzyme that reduces plasminogen binding to fibrin, prolonged the lysis times of fragment X and fibrin clots, clots containing fragment X still were degraded more rapidly. Furthermore, plasmin or trypsin also degraded clots containing fragment X more rapidly than fibrin clots, suggesting that this effect is largely independent of plasminogen activation. Fragment X-derived degradation products were not preferentially released by plasmin from clots composed of equal concentrations of fibrinogen and fragment X, indicating that fragment X does not constitute a preferential site for proteolysis. These data suggest that structural changes resulting from incorporation of fragment X into clots promote their lysis. Thus, attenuation of thrombolytic therapy-induced fragment X formation may reduce the risk of bleeding.


Q-ball imaging.
Magnetic resonance diffusion tensor imaging (DTI) provides a powerful tool for mapping neural histoarchitecture in vivo. However, DTI can only resolve a single fiber orientation within each imaging voxel due to the constraints of the tensor model. For example, DTI cannot resolve fibers crossing, bending, or twisting within an individual voxel. Intravoxel fiber crossing can be resolved using q-space diffusion imaging, but q-space imaging requires large pulsed field gradients and time-intensive sampling. It is also possible to resolve intravoxel fiber crossing using mixture model decomposition of the high angular resolution diffusion imaging (HARDI) signal, but mixture modeling requires a model of the underlying diffusion process.Recently, it has been shown that the HARDI signal can be reconstructed model-independently using a spherical tomographic inversion called the Funk-Radon transform, also known as the spherical Radon transform. The resulting imaging method, termed q-ball imaging, can resolve multiple intravoxel fiber orientations and does not require any assumptions on the diffusion process such as Gaussianity or multi-Gaussianity. The present paper reviews the theory of q-ball imaging and describes a simple linear matrix formulation for the q-ball reconstruction based on spherical radial basis function interpolation. Open aspects of the q-ball reconstruction algorithm are discussed.


From Visual Perception to Aesthetic Appeal: Brain Responses to Aesthetically Appealing Natural Landscape Movies.
During aesthetically appealing visual experiences, visual content provides a basis for computation of affectively tinged representations of aesthetic value. How this happens in the brain is largely unexplored. Using engaging video clips of natural landscapes, we tested whether cortical regions that respond to perceptual aspects of an environment (e.g., spatial layout, object content and motion) were directly modulated by rated aesthetic appeal. Twenty-four participants watched a series of videos of natural landscapes while being scanned using functional magnetic resonance imaging (fMRI) and reported both continuous ratings of enjoyment (during the videos) and overall aesthetic judgments (after each video). Although landscape videos engaged a greater expanse of high-level visual cortex compared to that observed for images of landscapes, independently localized category-selective visual regions (e.g., scene-selective parahippocampal place area and motion-selective hMT+) were not significantly modulated by aesthetic appeal. Rather, a whole-brain analysis revealed modulations by aesthetic appeal in ventral (collateral sulcus) and lateral (middle occipital sulcus, posterior middle temporal gyrus) clusters that were adjacent to scene and motion selective regions. These findings suggest that aesthetic appeal per se is not represented in well-characterized feature- and category-selective regions of visual cortex. Rather, we propose that the observed activations reflect a local transformation from a feature-based visual representation to a representation of "elemental affect," computed through information-processing mechanisms that detect deviations from an observer's expectations. Furthermore, we found modulation by aesthetic appeal in subcortical reward structures but not in regions of the default-mode network (DMN) nor orbitofrontal cortex, and only weak evidence for associated changes in functional connectivity. In contrast to other visual aesthetic domains, aesthetically appealing interactions with natural landscapes may rely more heavily on comparisons between ongoing stimulation and well-formed representations of the natural world, and less on top-down processes for resolving ambiguities or assessing self-relevance.


The impact of the COVID-19 pandemic on vaccine coverage in Kilifi, Kenya: A retrospective cohort study.
The COVID-19 pandemic caused unprecedented disruption in health service delivery, globally. This study sought to provide evidence on the impact of the pandemic on vaccine coverage in Kilifi County, Kenya. We conducted a vaccine coverage survey between April and June 2021 within the Kilifi Health and Demographic Surveillance System (KHDSS). Simple random sampling was used to identify 1500 children aged 6 weeks-59 months. Participants were grouped into three retrospective cohorts based on when they became age-eligible for vaccination: before the pandemic, during the first year, or during the second year of the pandemic. Survival analysis with Cox regression was used to evaluate the association between the time-period at which participants became age-eligible for vaccination and the rate of vaccination within a month of age-eligibility for the third dose of pentavalent vaccine (Pentavalent-3) and within three months of age-eligibility for the first dose of Measles vaccine (MCV-1). A total of 1,341 participants were included in the survey. Compared to the pre-COVID-19 baseline period, the rate of vaccination within a month of age-eligibility for Pentavalent-3 was not significantly different in the first year of the pandemic (adjusted hazard ratio [aHR] 1.03, 95 % confidence interval [CI] 0.90-1.18) and was significantly higher during the second year of the pandemic (aHR 1.33, 95 % CI 1.07-1.65). The rate of vaccination with MCV-1 within three months of age-eligibility was not significantly different among those age-eligible for vaccination during the first year of the pandemic (aHR 1.04, 95 % CI 0.88-1.21) and was 35 % higher during the second year of the pandemic (95 % CI 1.11-1.64), compared to those age-eligible pre-COVID-19. After adjusting for known determinants of vaccination, the COVID-19 pandemic did not adversely affect the rate of vaccination within the KHDSS.


The reliability of toe systolic pressure and the toe brachial index in patients with diabetes.
The Ankle Brachial Index is a useful clinical test for establishing blood supply to the foot. However, there are limitations to this method when conducted on people with diabetes. As an alternative to the Ankle Brachial Index, measuring Toe Systolic Pressures and the Toe Brachial Index have been recommended to assess the arterial blood supply to the foot. This study aimed to determine the intra and inter-rater reliability of the measurement of Toe Systolic Pressure and the Toe Brachial Index in patients with diabetes using a manual measurement system. This was a repeated measures, reliability study. Three raters measured Toe Systolic Pressure and the Toe Brachial Index in thirty participants with diabetes. Measurement sessions occurred on two occasions, one week apart, using a manual photoplethysmography unit (Hadeco Smartdop 45) and a standardised measurement protocol. The mean intra-class correlation for intra-rater reliability for toe systolic pressures was 0.87 (95% LOA: -25.97 to 26.06 mmHg) and the mean intra-class correlation for Toe Brachial Indices was 0.75 (95% LOA: -0.22 to 0.28). The intra-class correlation for inter-rater reliability was 0.88 for toe systolic pressures (95% LOA: -22.91 to 29.17.mmHg) and 0.77 for Toe Brachial Indices (95% LOA: -0.21 to 0.22). Despite the reasonable intra-class correlation results, the range of error (95% LOA) was broad. This raises questions regarding the reliability of using a manual sphygmomanometer and PPG for the Toe Systolic Pressure and Toe Brachial Indice.


The Impact of Model-Misspecification on Model Based Personalised Dosing.
Model Based Personalised Dosing (MBPD) requires a population pharmacokinetic (PK) or pharmacodynamic model to determine the optimal dose of medication for an individual. Often several models are published, and the decision of which model is implemented in MBPD may have a large impact on its clinical utility. As quoted by Box, "all models are wrong, the practical question is how wrong can they be and still be useful". Voriconzole, a triazole antifungal and the example used in this manuscript, currently has nine population PK models published. To assess the impact of model-misspecification on MBPD, five structurally mis-specified models for voriconazole were developed. Intensive plasma concentrations were simulated for 100 virtual subjects. The dose adjustments required to reach a target exposure were determined by using the empirical Bayes estimates of the PK parameters under each of the mis-specified models. The predicted plasma concentrations and the probability of clinical outcomes, upon following the dose recommendations, were determined. Models that did not contain non-linear clearance performed poorly, with a median dose recommendation 155-310 mg higher than appropriate doses, when only one plasma concentration was available. Removal of body weight and CYP2C9 genotype as covariates had no clinically significant impact on outcomes. In summary, the removal of important structural components, such as non-linear clearance in the case of voriconazole, had a large impact on the clinical utility of MBPD. The removal of patient covariates, even highly influential covariates such as CYP2C9 genotype for voriconazole, had no clinical impact.


A case of pituitary stalk interruption syndrome with intermittent seizures as the first presentation.
Pituitary stalk interruption syndrome (PSIS) is a congenital disease with isolated growth hormone deficiency (GHD) or multiple anterior pituitary hormone deficiencies (MPHD). The typical clinical manifestations of PSIS are growth retardation, hypoglycemia or delayed pubertal development. However, few reports showed cases of PSIS were diagnosed with acute epileptic seizures accompanied by hyponatremia. Here, we report an 18-year-old female presenting with episodes of intermittent seizures for 13 years. The electrolyte examination on many occasions has shown hyponatremia, even as low as 99.9 mmol/L. However, the cause of hyponatremia has not been further discussed. The patient had short stature and no pubertal development. The laboratory tests revealed growth hormone deficiency, secondary adrenal insufficiency, hypothyroidism and hypogonadotropic hypogonadism. MRI showed an ectopic hyperintense signal of the posterior pituitary and no visible anterior pituitary gland or stalk. The hormone replacement therapy helped to raise the sodium concentration to a normal level and in the termination of seizures.


A tumor-selective somatostatin analog (TT-232) with strong in vitro and in vivo antitumor activity.
We report a series of new in vitro and in vivo data proving the selective antitumor activity of our somatostatin structural derivative, TT-232. In vitro, it inhibited the proliferation of 20 different human tumor cell lines in the range of 50-95% and induced a very strong apoptosis. In vivo TT-232 was effective on transplanted animal tumors (Colon 26, B16 melanoma, and S180 sarcoma) and on human tumor xenografts. Treatment of MDA-MB-231 human breast cancer xenografted in mice with low submaximal doses of TT-232 [0.25 and 0.5 mg/kg of body weight (b.w.)] caused an average 80% decrease in the tumor volume resulting in 30% tumor-free animals surviving for longer than 200 days. Treatment of prostate tumor (PC-3) xenografted animals with 20 mg/kg of b.w. of TT-232 for 3 weeks resulted in 60% decrease in tumor volume and 100% survival even after 60 days, while 80% of nontreated animals perished. We have demonstrated that TT-232 did not bind to the membrane preparation of rat pituitary and cortex and had no antisecretory activity. TT-232 was not toxic at a dose of 120 mg/kg of b.w. in mice. Long-term incubation (24 h) of tumor cells with TT-232 caused significant inhibition of tyrosine kinases in good correlation with the apoptosis-inducing effect. The level of p53 or KU86 did not change following TT-232 treatment, suggesting a p53-independent apoptotic effect. Preincubation of human breast cancer cells (MDA-MB-453) with TT-232 for 2 h decreased the growth factor receptor autophosphorylation. All of these data suggest that TT-232 is a promising and selective antitumor agent.


The Rare Disease Bank of Japan: establishment, current status and future challenges.
Research on rare diseases cannot be performed without appropriate samples from patients with such diseases. Due to the limited number of such patients, securing biosamples of sufficient quality for extensive research is a challenge and represents an important barrier to the advancement of research on rare diseases. To tackle this problem, the Rare Disease Bank (RDB) was established in 2009 at the National Institute of Biomedical Innovation (NIBIO; currently, the National Institutes of Biomedical Innovation, Health and Nutrition in Japan). Since then, the RDB has focused on three objectives: (1) emphasizing the importance of collecting biosamples from patients with rare diseases, together with appropriate clinical information, from various medical facilities nationwide; (2) maintaining strict high-quality sample management standards; and (3) sharing biosamples with research scientists across Japan for the advancement of research on rare diseases. As of August 2017, the bank has collected 4147 biosamples from patients with rare diseases, including DNA, serum, plasma, and cell samples from various university hospitals and other medical institutions across the country, and provided various research institutions with 13,686 biosample aliquots from 2850 cases. In addition, the management committee has successfully established a bank system that provides high-quality biosamples together with the results of human leukocyte antigen analysis. It is anticipated that the RDB, through the collection and sharing of biosamples with the medical research community, will enhance the understanding, prevention, and treatment of rare diseases in Japan and the world at large.


Molecular characterization of Anaplasma platys strains from dogs in Sicily, Italy.
The genetic diversity of Anaplasma platys (Rickettsiales: Anaplasmataceae) strains is currently poorly defined. The present study was designed to characterize A. patys strains in dogs from Palermo, Sicily, Italy, using a combination of PCR and sequence analysis of the 16S rDNA, heat shock operon groESL and citrate synthase (gltA) genes. Blood was collected from 344 dogs (111 pet dogs, 122 pound dogs and 111 hunting dogs) during 2003-2005 in the Province of Palermo, Sicily, Italy. The prevalence of A. platys in dogs in Sicily, as demonstrated by PCR and sequence analysis of the 16S rDNA, groESL and gltA genes, was 4%. None of the samples were positive for A. marginale, A. centrale, A. ovis and A. phagocytophilum DNA. Three different gltA genotypes of A. platys were identified in dogs from Sicily. Two of the gltA sequences of Sicilian A. platys strains were different from sequences reported previously. However, one of the gltA, 16S rDNA and groESL sequences were identical to the sequence of A. platys strains from other regions of the world characterized previously. At least three different strains of A. platys were identified in dogs from Sicily by PCR and sequence analyses of the 16S rDNA, groESL and gltA genes. The results reported herein suggested that genetic diversity of A. platys strains may be similar to A. ovis, but lower than the diversity reported for A. marginale and A. phagocytophilum. This lower genetic diversity may have resulted from restricted movement of infected hosts compared to A. marginale-infected cattle and/or the limited host range of A. ovis and A. platys as compared with A. phagocytophilum. These results expand our knowledge about A. platys and encourage further research for analysis of the genetic variation of A. platys strains worldwide.


Constrictive pericarditis--a curable diastolic heart failure.
Constrictive pericarditis can result from a stiff pericardium that prevents satisfactory diastolic filling. The distinction between constrictive pericarditis and other causes of heart failure, such as restrictive cardiomyopathy, is important because pericardiectomy can cure constrictive pericarditis. Diagnosis of constrictive pericarditis is based on characteristic haemodynamic and anatomical features determined using echocardiography, cardiac catheterization, cardiac MRI, and CT. The Mayo Clinic echocardiography and cardiac catheterization haemodynamic diagnostic criteria for constrictive pericarditis are based on the unique features of ventricular interdependence and dissociation of intrathoracic and intracardiac pressures seen when the pericardium is constricted. A complete pericardiectomy can restore satisfactory diastolic filling by removing the constrictive pericardium in patients with constrictive pericarditis. However, if inflammation of the pericardium is the predominant constrictive mechanism, anti-inflammatory therapy might alleviate this transient condition without a need for surgery. Early diagnosis of constrictive pericarditis is, therefore, of paramount clinical importance. An improved understanding of how constrictive pericarditis develops after an initiating event is critical to prevent this diastolic heart failure. In this Review, we discuss the aetiology, pathophysiology, and diagnosis of constrictive pericarditis, with a specific emphasis on how to differentiate this disease from conditions with similar clinical presentations.


Human language cortex: localization of memory, syntax, and sequential motor-phoneme identification systems.
Subdivisions of the human peri-Sylvian language cortex were derived from stimulation mapping during craniotomies under local anesthesia. Naming, reading, short-term verbal memory, single and sequential orofacial movements, and phoneme identification were tested. Sequential orofacial movements and phoneme identification were altered from the same brain sites and thus identified a common system for language production and understanding. This system surrounded a final motor pathway for speech and was surrounded by a separate short-term verbal-memory system. Between the sequential motor-phoneme identification and memory systems were sites where only naming or reading were altered, including sites related exclusively by syntax.


A novel reverse-genetic approach (SIMF) identifies Mutator insertions in new Myb genes.
We have developed a new strategy designated SIMF (Systematic Insertional Mutagenesis of Families), to identify DNA insertions in many members of a gene family simultaneously. This method requires only a short amino acid sequence conserved in all members of the family to make a degenerate oligonucleotide, and a sequence from the end of the DNA insertion. The SIMF strategy was successfully applied to the large maize R2R3 Myb family of regulatory genes, and Mutator insertions in several novel Myb genes were identified. Application of this technique to identify insertions in other large gene families could significantly decrease the effort involved in screening at the same time for insertions in all members of groups of genes that share a limited sequence identity.


Implementing diagnostic stewardship to improve diagnosis of urinary tract infections across three medical centers: A qualitative assessment.
Urine-culture diagnostic stewardship aims to decrease misdiagnosis of urinary tract infections (UTIs); however, these interventions are not widely adopted. We examined UTI diagnosis and management practices to identify barriers to and facilitators of diagnostic stewardship implementation. Using a qualitative descriptive design, we conducted semistructured interviews at 3 Veterans' Affairs medical centers. Interviews were conducted between November 2021 and May 2022 via Zoom videoconferencing using an interview guide and visual prototypes of proposed interventions. Interviewees were asked about current practices and thoughts on proposed interventions for urine-culture ordering, processing, and reporting. We used a rapid analysis matrix approach to summarize key interview findings and compare practices and perceptions across sites. We interviewed 31 stakeholders and end users. All sites had an antimicrobial stewardship program but limited initiatives targeting appropriate diagnosis and management of UTIs. The majority of those interviewed identified the importance of diagnostic stewardship. Perceptions of specific interventions ranged widely by site. For urine-culture ordering, all 3 sites agreed that documentation of symptomology would improve culturing practices but did not want it to interrupt workflow. Representatives at 2 sites expressed interest in conditional urine-culture processing and 1 was opposed. All sites had similar mechanisms to report culture results but varied in perceptions of the proposed interventions. Feedback from end users was used to develop a general diagnostic stewardship implementation checklist. Interviewees thought diagnostic stewardship was important. Qualitative assessment involving key stakeholders in the UTI diagnostic process improved understanding of site-specific beliefs and practices to better implement interventions for urine-culture ordering, processing, and reporting.


The physiological effects of hypobaric hypoxia versus normobaric hypoxia: a systematic review of crossover trials.
Much hypoxia research has been carried out at high altitude in a hypobaric hypoxia (HH) environment. Many research teams seek to replicate high-altitude conditions at lower altitudes in either hypobaric hypoxic conditions or normobaric hypoxic (NH) laboratories. Implicit in this approach is the assumption that the only relevant condition that differs between these settings is the partial pressure of oxygen (PO2), which is commonly presumed to be the principal physiological stimulus to adaptation at high altitude. This systematic review is the first to present an overview of the current available literature regarding crossover studies relating to the different effects of HH and NH on human physiology. After applying our inclusion and exclusion criteria, 13 studies were deemed eligible for inclusion. Several studies reported a number of variables (e.g. minute ventilation and NO levels) that were different between the two conditions, lending support to the notion that true physiological difference is indeed present. However, the presence of confounding factors such as time spent in hypoxia, temperature, and humidity, and the limited statistical power due to small sample sizes, limit the conclusions that can be drawn from these findings. Standardisation of the study methods and reporting may aid interpretation of future studies and thereby improve the quality of data in this area. This is important to improve the quality of data that is used for improving the understanding of hypoxia tolerance, both at altitude and in the clinical setting.


Dietary Intakes of Recipients of Faecal Microbiota Transplantation: An Observational Pilot Study.
This study reports on the dietary intake of recipients of faecal microbiota transplantation (FMT), comparing this with dietary guidelines, and investigates the relationship between dietary intake and clinical outcomes. Males and females aged ≥ 16 years with irritable bowel syndrome or inflammatory bowel disease undergoing FMT were invited to complete validated symptom and quality of life (QOL) questionnaires and three-day weighed food diaries. Descriptive statistics were calculated for symptom scores, QOL scores, nutrients, and food group servings, and compared to Australian population norms, nutrient reference values, and dietary guidelines. The relationship between dietary intake, symptoms, and QOL was assessed. Participants (n = 18) reported baseline symptoms of urgency, abdominal pain, nausea, and bloating and reduced QOL. Of the participants who completed food diaries, 8/14 met the recommended 30 g of fibre when including supplements. Participants met the recommendations for micronutrients and food groups except calcium, fruit, and dairy/dairy alternatives. There was a non-significant trend towards lower symptom severity scores in participants who met the fibre target. The high degree of variability in participant fibre intakes highlights diet as a key variable that has not been previously controlled for in FMT intervention studies. Future studies examining FMT should include dietary analysis of habitual intake of the recipients and donors.


Ways of relating to death: views of older people resident in nursing homes.
Few studies shed light on what older people themselves consider a good or dignified death. This study is part of a larger project where interviews were used to follow 12 nursing home residents over time. The aim of the present study was to reach a deeper understanding of seven older people's thoughts, feelings and attitudes towards death. The participants were interviewed on four occasions across 18-24 months, and the interviews were analysed using a hermeneutic method. The findings revealed three main themes: 1. Zest for life, 2. Indifferent attitude, 3. Longing for death. The themes mirror the complexity of what ageing and nearing the end of life can mean. A strong desire among the participants was to be more involved in their own personal care and in everyday life at the nursing home. Person-oriented care based on the philosophy of palliative care, and including conversation as a natural component, might promote the older person's possibilities to obtain a good death.


Parental reported benefits and shortcomings of cochlear implantation: Pilot study findings from Southeast Asia.
The aim of the study was to understand the reported benefits and shortcomings by parents of children with cochlear implants and who contribute towards the cost of the implant. Thirty parents of children with cochlear implants from a hearing impaired school in Southeast Asia completed open-ended questionnaires and the data were analysed using content analysis. A wide range of benefits and shortcomings were reported. However, it is notable that the single most reported shortcoming was related to cost. The results suggest that, even though, in general, the reports about benefits and shortcomings were similar to previous results from western countries, the emphasis given to various aspects of shortcomings was different. In particular, it appears that parentally reported outcomes could be related to many factors including the hearing healthcare system with the costs involved for the implanted individuals and their families. These findings help us understand the parental perspectives of the success of cochlear implantation and will be useful during parental counselling sessions.


Patterns of beverage purchases amongst British households: A latent class analysis.
Beverages, especially sugar-sweetened beverages (SSBs), have been increasingly subject to policies aimed at reducing their consumption as part of measures to tackle obesity. However, precision targeting of policies is difficult as information on what types of consumers they might affect, and to what degree, is missing. We fill this gap by creating a typology of beverage consumers in Great Britain (GB) based on observed beverage purchasing behaviour to determine what distinct types of beverage consumers exist, and what their socio-demographic (household) characteristics, dietary behaviours, and weight status are. We used cross-sectional latent class analysis to characterise patterns of beverage purchases. We used data from the 2016 GB Kantar Fast-Moving Consumer Goods (FMCG) panel, a large representative household purchase panel of food and beverages brought home, and restricted our analyses to consumers who purchase beverages regularly (i.e., >52 l per household member annually) (n = 8,675). Six categories of beverages were used to classify households into latent classes: SSBs; diet beverages; fruit juices and milk-based beverages; beer and cider; wine; and bottled water. Multinomial logistic regression and linear regression were used to relate class membership to household characteristics, self-reported weight status, and other dietary behaviours, derived from GB Kantar FMCG. Seven latent classes were identified, characterised primarily by higher purchases of 1 or 2 categories of beverages: 'SSB' (18% of the sample; median SSB volume = 49.4 l/household member/year; median diet beverage volume = 38.0 l), 'Diet' (16%; median diet beverage volume = 94.4 l), 'Fruit & Milk' (6%; median fruit juice/milk-based beverage volume = 30.0 l), 'Beer & Cider' (7%; median beer and cider volume = 36.3 l; median diet beverage volume = 55.6 l), 'Wine' (18%; median wine volume = 25.5 l; median diet beverage volume = 34.3 l), 'Water' (4%; median water volume = 46.9 l), and 'Diverse' (30%; diversity of purchases, including median SSB volume = 22.4 l). Income was positively associated with being classified in the Diverse class, whereas low social grade was more likely for households in the classes SSB, Diet, and Beer & Cider. Obesity (BMI > 30 kg/m2) was more prevalent in the class Diet (41.2%, 95% CI 37.7%-44.7%) despite households obtaining little energy from beverages in that class (17.9 kcal/household member/day, 95% CI 16.2-19.7). Overweight/obesity (BMI > 25 kg/m2) was above average in the class SSB (66.8%, 95% CI 63.7%-69.9%). When looking at all groceries, households from the class SSB had higher total energy purchases (1,943.6 kcal/household member/day, 95% CI 1,901.7-1,985.6), a smaller proportion of energy from fruits and vegetables (6.0%, 95% CI 5.8%-6.3%), and a greater proportion of energy from less healthy food and beverages (54.6%, 95% CI 54.0%-55.1%) than other classes. A greater proportion of energy from sweet snacks was observed for households in the classes SSB (18.5%, 95% CI 18.1%-19.0%) and Diet (18.8%, 95% CI 18.3%-19.3%). The main limitation of our analyses, in common with other studies, is that our data do not include information on food and beverage purchases that are consumed outside the home. Amongst households that regularly purchase beverages, those that mainly purchased high volumes of SSBs or diet beverages were at greater risk of obesity and tended to purchase less healthy foods, including a high proportion of energy from sweet snacks. These households might additionally benefit from policies targeting unhealthy foods, such as sweet snacks, as a way of reducing excess energy intake.


Platinum(ii) complexes with rutaecarpine and tryptanthrin derivatives induce apoptosis by inhibiting telomerase activity and disrupting mitochondrial function.
Four new platinum(ii) complexes, [Pt(Rut)(DMSO)Cl2] (Rut-Pt), [Pt(Try)(DMSO)Cl2] (Try-Pt), [Pt(ITry)(DMSO)Cl2] (ITry-Pt) and [Pt(BrTry)(DMSO)Cl2] (BrTry-Pt), with rutaecarpine (Rut), tryptanthrin (Try), 8-iodine-tryptanthrin (ITry) and 8-bromo-tryptanthrin (BrTry) as ligands were synthesized and fully characterized. In these complexes, the platinum(ii) adopts a four-coordinated square planar geometry. The inhibitory activity evaluated by the MTT assay showed that BrTry-Pt (IC50 = of 0.21 ± 0.25 μM) could inhibit the growth of T-24 tumor cells (human bladder cancer cell line) more so than the other three complexes. In addition, all of these Pt complexes exhibited low toxicity against non-cancerous HL-7702 cells. BrTry-Pt induced cell cycle arrest in the S phase, leading to the down-regulation of cyclin A and CDK2 proteins. BrTry-Pt acts as a telomerase inhibitor targeting the c-myc promoter. In addition, BrTry-Pt also caused mitochondrial dysfunction. Importantly, the in vitro anticancer activity of BrTry-Pt was higher than those of Rut-Pt, Try-Pt and ITry-Pt, and it was more selective for T-24 cells than for non-cancerous HL-7702 cells.


DNMT3A mutations promote anthracycline resistance in acute myeloid leukemia via impaired nucleosome remodeling.
Although the majority of patients with acute myeloid leukemia (AML) initially respond to chemotherapy, many of them subsequently relapse, and the mechanistic basis for AML persistence following chemotherapy has not been determined. Recurrent somatic mutations in DNA methyltransferase 3A (DNMT3A), most frequently at arginine 882 (DNMT3AR882), have been observed in AML and in individuals with clonal hematopoiesis in the absence of leukemic transformation. Patients with DNMT3AR882 AML have an inferior outcome when treated with standard-dose daunorubicin-based induction chemotherapy, suggesting that DNMT3AR882 cells persist and drive relapse. We found that Dnmt3a mutations induced hematopoietic stem cell expansion, cooperated with mutations in the FMS-like tyrosine kinase 3 gene (Flt3ITD) and the nucleophosmin gene (Npm1c) to induce AML in vivo, and promoted resistance to anthracycline chemotherapy. In patients with AML, the presence of DNMT3AR882 mutations predicts minimal residual disease, underscoring their role in AML chemoresistance. DNMT3AR882 cells showed impaired nucleosome eviction and chromatin remodeling in response to anthracycline treatment, which resulted from attenuated recruitment of histone chaperone SPT-16 following anthracycline exposure. This defect led to an inability to sense and repair DNA torsional stress, which resulted in increased mutagenesis. Our findings identify a crucial role for DNMT3AR882 mutations in driving AML chemoresistance and highlight the importance of chromatin remodeling in response to cytotoxic chemotherapy.


Inhibitors of protein synthesis and RNA synthesis prevent neuronal death caused by nerve growth factor deprivation.
We have developed an experimental paradigm to study the mechanism by which nerve growth factor (NGF) allows the survival of sympathetic neurons. Dissociated sympathetic neurons from embryonic day-21 rats were grown in vitro for 7 d in the presence of NGF. Neurons were then deprived of trophic support by adding anti-NGF antiserum, causing them to die between 24 and 48 h later. Ultrastructural changes included disruption of neurites, followed by cell body changes characterized by an accumulation of lipid droplets, changes in the nuclear membrane, and dilation of the rough endoplasmic reticulum. No primary alterations of mitochondria or lysosomes were observed. The death of NGF-deprived neurons was characterized biochemically by assessing [35S]methionine incorporation into TCA precipitable protein and by measuring the release of the cytosolic enzyme adenylate kinase into the culture medium. Methionine incorporation began to decrease approximately 18 h post-deprivation and was maximally depressed by 36 h. Adenylate kinase began to appear in the culture medium approximately 30 h after deprivation, reaching a maximum by 54 h. The death of NGF-deprived neurons was entirely prevented by inhibiting protein or RNA synthesis. Cycloheximide, puromycin, anisomycin, actinomycin-D, and dichlorobenzimidazole riboside all prevented neuronal death subsequent to NGF deprivation as assessed by the above morphologic and biochemical criteria. The fact that sympathetic neurons must synthesize protein and RNA to die when deprived of NGF indicates that NGF, and presumably other neurotrophic factors, maintains neuronal survival by suppressing an endogenous, active death program.


EMPHASISCHECKER: A Tool for Guiding Chart and Caption Emphasis.
Recent work has shown that when both the chart and caption emphasize the same aspects of the data, readers tend to remember the doubly-emphasized features as takeaways; when there is a mismatch, readers rely on the chart to form takeaways and can miss information in the caption text. Through a survey of 280 chart-caption pairs in real-world sources (e.g., news media, poll reports, government reports, academic articles, and Tableau Public), we find that captions often do not emphasize the same information in practice, which could limit how effectively readers take away the authors' intended messages. Motivated by the survey findings, we present EMPHASISCHECKER, an interactive tool that highlights visually prominent chart features as well as the features emphasized by the caption text along with any mismatches in the emphasis. The tool implements a time-series prominent feature detector based on the Ramer-Douglas-Peucker algorithm and a text reference extractor that identifies time references and data descriptions in the caption and matches them with chart data. This information enables authors to compare features emphasized by these two modalities, quickly see mismatches, and make necessary revisions. A user study confirms that our tool is both useful and easy to use when authoring charts and captions.


Impact of improved cookstoves on indoor air pollution and adverse health effects among Honduran women.
Elevated indoor air pollution levels due to the burning of biomass in developing countries are well established. Few studies have quantitatively assessed air pollution levels of improved cookstoves and examined these measures in relation to health effects. We conducted a cross-sectional survey among 79 Honduran women cooking with traditional or improved cookstoves. Carbon monoxide and fine particulate matter (PM(2.5)) levels were assessed via indoor and personal monitoring. Pulmonary function and respiratory symptoms were ascertained. Finger-stick blood spot samples were collected to measure C-reactive protein (CRP) concentrations. The use of improved stoves was associated with 63% lower levels of personal PM(2.5), 73% lower levels of indoor PM(2.5), and 87% lower levels of indoor carbon monoxide as compared to traditional stoves. Women using traditional stoves reported symptoms more frequently than those using improved stoves. There was no evidence of associations between cookstove type or air quality measures with lung function or CRP.


The rough colony morphotype of Mycobacterium avium exhibits high virulence in human macrophages and mice.
Introduction. The incidence of Mycobacterium avium complex (MAC) pulmonary disease (MAC PD), a refractory chronic respiratory tract infection, is increasing worldwide. MAC has three predominant colony morphotypes: smooth opaque (SmO), smooth transparent (SmT) and rough (Rg).Aim. To determine whether colony morphotypes can predict the prognosis of MAC PD, we evaluated the virulence of SmO, SmT and Rg in mice and in human macrophages.Methodology. We compared the characteristics of mice and human macrophages infected with the SmO, SmT, or Rg morphotypes of M. avium subsp. hominissuis 104. C57BL/6 mice and human macrophages derived from peripheral mononuclear cells were used in these experiments.Results. In comparison to SmO- or SmT-infected mice, Rg-infected mice revealed severe pathologically confirmed pneumonia, increased lung weight and increased lung bacterial burden. Rg-infected macrophages revealed significant cytotoxicity, increased bacterial burden, secretion of proinflammatory cytokines (TNF-α and IL-6) and chemokines (CCL5 and CCL3), and formation of cell clusters. Rg formed larger bacterial aggregates than SmO and SmT. Cytotoxicity, bacterial burden and secretion of IL-6, CCL5 and CCL3 were induced strongly by Rg infection, and were decreased by disaggregation of the bacteria.Conclusion. M. avium Rg, which is associated with bacterial aggregation, has the highest virulence among the predominant colony morphotypes.


Oltipraz chemoprevention trial in Qidong, People's Republic of China: modulation of serum aflatoxin albumin adduct biomarkers.
In 1995, 234 adults from Qidong, People's Republic of China, were enrolled and followed in a Phase IIa 4-methyl-5-(N-2-pyrazinyl)-1,2-dithiole-3-thione (oltipraz) chemoprevention trial. Residents of this area are at high risk for development of hepatocellular carcinoma, in part due to consumption of aflatoxin-contaminated foods. The intervention was a randomized, placebo-controlled, double-blind study. Elements of the study design and clinical outcomes have been recently published (Jacobson et al, Cancer Epidemiol. Biomark. Prev., 6: 257-265, 1997). The primary objective was to conduct a preliminary assessment of the ability of oltipraz to modulate levels of a validated biomarker of aflatoxin exposure and of the risk of hepatocellular carcinoma by determining levels of aflatoxin-albumin adducts in sera. Healthy eligible individuals were randomized into three arms to receive p.o. 125 mg of oltipraz daily, 500 mg of oltipraz weekly, or placebo for 8 weeks. There were no consistent changes in biomarker levels in the placebo arm over the 16-week observation period, nor was any apparent effect observed in the arm receiving 125 mg of oltipraz each day. However, individuals receiving 500 mg of oltipraz once a week for 8 weeks showed a triphasic response to oltipraz. No effect was observed during the 1st month of the intervention, whereas a significant (P = 0.001) diminution in adduct levels was observed during the 2nd month of active intervention and during the lst month of follow-up. A partial rebound in adduct levels toward baseline values was observed during the 2nd month postintervention. Linear regression models up to week 13 confirmed a significant (P = 0.008) weekly decline of biomarker levels in the group receiving 500 mg of oltipraz once a week. However, despite these effects relative to baseline values within the 500-mg weekly arm, there were no statistically significant differences in biomarker trajectories between treatment arms. The genotype for glutathione S-transferase M1, an oltipraz-inducible isoform involved in the detoxification of aflatoxin B1, did not appear to affect either baseline levels or rates of decline in the biomarker. A follow-up Phase IIb trial with a longer intervention period will be necessary to determine the full extent to which aflatoxin biomarker burden can be reduced and whether diminution of biomarkers can be sustained over the long term.


Immune modulation treatments-where is the evidence?
While advances in assisted reproductive techniques have been substantial, failure of the apparently viable embryo to implant remains a source of distress and frustration to patients and specialists alike. The unique maternal immunological response to the embryo and the notion that defects in early placentation underlie the great complications of pregnancy have focused attention on the therapeutic potential of peri-implantation immunomodulation. On the face of it, the rationale for this approach is very attractive. However, as will be argued in this review, the clinical evidence base supporting the use of immunosuppressive treatments is weak and difficult to apply in practice and fails the needs of both doctors and their patients. This evidence gap is filled by justifications that are based largely on meeting patient expectations and commercial imperatives. However, this does not mean that immunomodulation treatments should be written off as ineffective. The literature in this field, while suffering the same challenges of heterogeneity, small studies, and publication bias as other areas of medicine, does hint at the way forward. Recurrent implantation failure and pregnancy loss are not diagnoses but clinical presentations that require appropriate phenotyping and etiological investigation. We are increasingly gaining the tools to make an "endometrial diagnosis," and these will allow us to design clinical studies of interventions that treat the underlying cause rather than the symptoms of implantation failure. The current evidence base does not support the clinical use of immunomodulation therapies in patients undergoing IVF. However, more discerning phenotyping may identify groups who could benefit.


Fusion of the Cas9 endonuclease and the VirD2 relaxase facilitates homology-directed repair for precise genome engineering in rice.
Precise genome editing by systems such as clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) requires high-efficiency homology-directed repair (HDR). Different technologies have been developed to improve HDR but with limited success. Here, we generated a fusion between the Cas9 endonuclease and the Agrobacterium VirD2 relaxase (Cas9-VirD2). This chimeric protein combines the functions of Cas9, which produces targeted and specific DNA double-strand breaks (DSBs), and the VirD2 relaxase, which brings the repair template in close proximity to the DSBs, to facilitate HDR. We successfully employed our Cas9-VirD2 system for precise ACETOLACTATE SYNTHASE (OsALS) allele modification to generate herbicide-resistant rice (Oryza sativa) plants, CAROTENOID CLEAVAGE DIOXYGENASE-7 (OsCCD7) to engineer plant architecture, and generate in-frame fusions with the HA epitope at HISTONE DEACETYLASE (OsHDT) locus. The Cas9-VirD2 system expands our ability to improve agriculturally important traits in crops and opens new possibilities for precision genome engineering across diverse eukaryotic species.


High-resolution genetic mapping of allelic variants associated with cell wall chemistry in Populus.
QTL cloning for the discovery of genes underlying polygenic traits has historically been cumbersome in long-lived perennial plants like Populus. Linkage disequilibrium-based association mapping has been proposed as a cloning tool, and recent advances in high-throughput genotyping and whole-genome resequencing enable marker saturation to levels sufficient for association mapping with no a priori candidate gene selection. Here, multiyear and multienvironment evaluation of cell wall phenotypes was conducted in an interspecific P. trichocarpa x P. deltoides pseudo-backcross mapping pedigree and two partially overlapping populations of unrelated P. trichocarpa genotypes using pyrolysis molecular beam mass spectrometry, saccharification, and/ or traditional wet chemistry. QTL mapping was conducted using a high-density genetic map with 3,568 SNP markers. As a fine-mapping approach, chromosome-wide association mapping targeting a QTL hot-spot on linkage group XIV was performed in the two P. trichocarpa populations. Both populations were genotyped using the 34 K Populus Infinium SNP array and whole-genome resequencing of one of the populations facilitated marker-saturation of candidate intervals for gene identification. Five QTLs ranging in size from 0.6 to 1.8 Mb were mapped on linkage group XIV for lignin content, syringyl to guaiacyl (S/G) ratio, 5- and 6-carbon sugars using the mapping pedigree. Six candidate loci exhibiting significant associations with phenotypes were identified within QTL intervals. These associations were reproducible across multiple environments, two independent genotyping platforms, and different plant growth stages. cDNA sequencing for allelic variants of three of the six loci identified polymorphisms leading to variable length poly glutamine (PolyQ) stretch in a transcription factor annotated as an ANGUSTIFOLIA C-terminus Binding Protein (CtBP) and premature stop codons in a KANADI transcription factor as well as a protein kinase. Results from protoplast transient expression assays suggested that each of the polymorphisms conferred allelic differences in the activation of cellulose, hemicelluloses, and lignin pathway marker genes. This study illustrates the utility of complementary QTL and association mapping as tools for gene discovery with no a priori candidate gene selection. This proof of concept in a perennial organism opens up opportunities for discovery of novel genetic determinants of economically important but complex traits in plants.


Leaching behaviour of pharmaceuticals in soil-testing-systems: a part of an environmental risk assessment for groundwater protection.
The leaching behaviour of six selected pharmaceuticals was tested in different soils. Leaching experiments are a part of environmental risk assessment to estimate the distribution and fate of these pharmaceuticals in the environment. Based on the results of this assessment their mobility in soil and their potential to contaminate groundwater was evaluated. When assessing the leaching behaviour of these compounds, the influence of the properties (e.g. grain size distribution, pH, Corg) of different soils has to be taken into account. The test results indicated that the leaching potential found could be rated as low for diazepam, ibuprofen, ivermectin and carbamazepine. Therefore, contamination of the groundwater with these substances seems to be unlikely if the groundwater level is covered with sufficient layers of the soils investigated. Clofibric acid and iopromide were very mobile under the experimental conditions and thus, groundwater contamination would be possible if the soil is exposed to these pharmaceuticals, i.e. wastewater irrigation. These results are more or less in agreement with groundwater monitoring data found in the literature for ibuprofen and diazepam which were in general not present in groundwater, while clofibric acid and iopromide were frequently detected. However, a discrepancy was found for carbamazepine, since it occurs very often in groundwater. This discrepancy might be explained by the fact that the leaching tests were performed with soil, whereas in reality the groundwater contamination occurs mainly over river sediments and sub soil from receiving waters.


Transcriptome Display During Testicular Differentiation of Channel Catfish (Ictalurus punctatus) as Revealed by RNA-Seq Analysis.
Channel catfish (Ictalurus punctatus) has been recognized as a dominant freshwater aquaculture species in the United States. It is also a suitable model for studying the mechanisms of sex determination and differentiation because of its sexual plasticity and exhibition of both genetic and environmental sex determination. The testicular differentiation in male channel catfish normally starts between 90 and 102 days postfertilization (dpf), while the ovarian differentiation starts early from 19 dpf. As such, efforts to better understand the postponed testicular development at the molecular level are needed. Toward that end, we conducted transcriptomic comparison of gene expression of male and female gonads at 90, 100, and 110 dpf using high-throughput RNA-Seq. Transcriptomic profiles of male gonads on 90 and 100 dpf exhibited high similarities except for a small number of significantly up-regulated genes that were involved in development of germ cell-supporting somatic cells, while drastic changes were observed during 100-110 dpf, with a group of highly up-regulated genes that were involved in germ cells development, including nanog and pou5f1 Transcriptomic comparison between testes and ovaries identified male-preferential genes, such as gsdf, cxcl12, as well as other cytokines mediated the development of the gonad into a testis. Co-expression analysis revealed highly correlated genes and potential pathways underlying germ cell differentiation and spermatogonia stem cell development. The candidate genes and pathways identified in this study set the foundation for further studies on sex determination and differentiation in catfish as well as other teleosts.


PaCIR: A tool to enhance pharmacist patient care intervention reporting.
To develop a pharmacist patient care services intervention reporting checklist to be used in conjunction with existing primary reporting tools. The tool should enhance consistent reporting of pharmacist patient care interventions. Tool use in pharmacist-patient care intervention reporting may increase: (1) likelihood for inclusion in higher order analyses and (2) successful replication. Adhering to principles of the Equator Network, a modified Delphi approach was used. An expert group identified guidance need, conducted a thorough literature search confirming need, developed a comprehensive list of potential elements, refined the list via multiple rounds, finalized language and structure, and published the checklist. Multiple rounds of iterative input were completed face to face, in conference calls, and during public comment periods. The finalized list of elements was organized into a logical flow with the use of clear and concise language and then transformed into an intuitive checklist. The core task force identified 9 critical components over a 4-year period Collectively, the input represented more than 200 stakeholders. Stakeholders overwhelmingly supported the inclusion (89%; n = 29) and clarity (91%; n = 26) of each element. The final 9 elements were organized into a checklist to enhance pharmacist patient care intervention reporting (PaCIR). Accompanying each element is a specific explanation justifying its inclusion. An appendix containing published and created examples of how authors may satisfactorily meet each element is provided. Use of the PaCIR checklist will enhance the quality of reporting of pharmacist patient care intervention studies. This enhanced quality can support replication of the studies and increase the likelihood these studies will be considered for inclusion in systematic reviews and meta-analyses. Researchers are urged to consider use of reporting guides such as PaCIR during the project design phase.


Cross-cultural perceptions of facial resemblance between kin.
Humans use facial comparisons to identify their relatives and adjust their behavior accordingly. However, the mechanisms underlying the assessment of facial similarities are poorly known. Here, we investigate the role of exposure to particular faces for the detection of facial similarities by asking judges to detect parent-child pairs using faces from different origins. In a first phase, French and Senegalese judges assessed facial resemblance in French and Senegalese families. In a second phase, Senegalese judges who had immigrated to France, as well as French and Senegalese stationary judges, were asked to rate a second set of Senegalese and French families. The judges showed no differences in their ability to detect parent-child pairs in French and Senegalese families in both the first and second phases. For judges who changed their country of residence, the answer time and duration of stay in the new country were not associated with correct assignment rates. Our results suggest that exposure has a limited role in the ability to process facial resemblance in others, which contrasts with facial recognition processing. We also discuss whether processing facial similarities is a by-product of the facial recognition system or an evolved ability to assess kinship relationships.


Risk of all-cause mortality and vascular events in women versus men with type 1 diabetes: a systematic review and meta-analysis.
Studies have suggested sex differences in the mortality rate associated with type 1 diabetes. We did a meta-analysis to provide reliable estimates of any sex differences in the effect of type 1 diabetes on risk of all-cause mortality and cause-specific outcomes. We systematically searched PubMed for studies published between Jan 1, 1966, and Nov 26, 2014. Selected studies reported sex-specific estimates of the standardised mortality ratio (SMR) or hazard ratios associated with type 1 diabetes, either for all-cause mortality or cause-specific outcomes. We used random effects meta-analyses with inverse variance weighting to obtain sex-specific SMRs and their pooled ratio (women to men) for all-cause mortality, for mortality from cardiovascular disease, renal disease, cancer, the combined outcome of accident and suicide, and from incident coronary heart disease and stroke associated with type 1 diabetes. Data from 26 studies including 214 114 individuals and 15 273 events were included. The pooled women-to-men ratio of the SMR for all-cause mortality was 1·37 (95% CI 1·21-1·56), for incident stroke 1·37 (1·03-1·81), for fatal renal disease 1·44 (1·02-2·05), and for fatal cardiovascular diseases 1·86 (1·62-2·15). For incident coronary heart disease the sex difference was more extreme; the pooled women-to-men ratio of the SMR was 2·54 (95% CI 1·80-3·60). No evidence suggested a sex difference for mortality associated with type 1 diabetes from cancer, or accident and suicide. Women with type 1 diabetes have a roughly 40% greater excess risk of all-cause mortality, and twice the excess risk of fatal and nonfatal vascular events, compared with men with type 1 diabetes. None.


Ascent of dinosaurs linked to an iridium anomaly at the Triassic-Jurassic boundary.
Analysis of tetrapod footprints and skeletal material from more than 70 localities in eastern North America shows that large theropod dinosaurs appeared less than 10,000 years after the Triassic-Jurassic boundary and less than 30,000 years after the last Triassic taxa, synchronous with a terrestrial mass extinction. This extraordinary turnover is associated with an iridium anomaly (up to 285 parts per trillion, with an average maximum of 141 parts per trillion) and a fern spore spike, suggesting that a bolide impact was the cause. Eastern North American dinosaurian diversity reached a stable maximum less than 100,000 years after the boundary, marking the establishment of dinosaur-dominated communities that prevailed for the next 135 million years.


Windowed Radon Transform and Tensor Rank-1 Decomposition for Adaptive Beamforming in Ultrafast Ultrasound.
Ultrafast ultrasound has recently emerged as an alternative to traditional focused ultrasound. By virtue of the low number of insonifications it requires, ultrafast ultrasound enables the imaging of the human body at potentially very high frame rates. However, unaccounted for speed-of-sound variations in the insonified medium often result in phase aberrations in the reconstructed images. The diagnosis capability of ultrafast ultrasound is thus ultimately impeded. Therefore, there is a strong need for adaptive beamforming methods that are resilient to speed-of-sound aberrations. Several of such techniques have been proposed recently but they often lack parallelizability or the ability to directly correct both transmit and receive phase aberrations. In this article, we introduce an adaptive beamforming method designed to address these shortcomings. To do so, we compute the windowed Radon transform of several complex radio-frequency images reconstructed using delay-and-sum. Then, we apply to the obtained local sinograms weighted tensor rank-1 decompositions and their results are eventually used to reconstruct a corrected image. We demonstrate using simulated and in-vitro data that our method is able to successfully recover aberration-free images and that it outperforms both coherent compounding and the recently introduced SVD beamformer. Finally, we validate the proposed beamforming technique on in-vivo data, resulting in a significant improvement of image quality compared to the two reference methods.


Sibling recurrence risk in Dupuytren's disease.
Dupuytren's disease is a complex condition, with both genetic and environmental factors contributing to its aetiology. We aimed to quantify the extent to which genetic factors predispose to the disease, through the calculation of sibling recurrence risk (ls), and to calculate the proportion of heritability accounted for by currently known genetic loci. From 174 siblings of patients with surgically confirmed disease, 100 were randomly selected. Controls were recruited from patients attending an ophthalmology outpatient clinic for eye conditions unrelated to diabetes. There were no statistically significant differences in baseline characteristics between the case and control groups. In siblings, 47% had Dupuytren's disease, compared with 10% of controls, giving a ls of 4.5. Currently known loci that predispose to Dupuytren's disease account for 12.1% of the total heritability of the disease. Dupuytren's disease was significantly more common in siblings than in controls. These results accurately quantify the magnitude of the genetic predisposition to Dupuytren's disease.


Mycobacterium tuberculosis Infection Manipulates the Glycosylation Machinery and the N-Glycoproteome of Human Macrophages and Their Microparticles.
Tuberculosis (TB) remains a prevalent and lethal infectious disease. The glycobiology associated with Mycobacterium tuberculosis infection of frontline alveolar macrophages is still unresolved. Herein, we investigated the regulation of protein N-glycosylation in human macrophages and their secreted microparticles (MPs) used for intercellular communication upon M. tb infection. LC-MS/MS-based proteomics and glycomics were performed to monitor the regulation of glycosylation enzymes and receptors and the N-glycome in in vitro-differentiated macrophages and in isolated MPs upon M. tb infection. Infection promoted a dramatic regulation of the macrophage proteome. Most notably, significant infection-dependent down-regulation (4-26 fold) of 11 lysosomal exoglycosidases, e.g., β-galactosidase, β-hexosaminidases and α-/β-mannosidases, was observed. Relative weak infection-driven transcriptional regulation of these exoglycosidases and a stronger augmentation of the extracellular hexosaminidase activity demonstrated that the lysosome-centric changes may originate predominantly from infection-induced secretion of the lysosomal content. The macrophages showed heterogeneous N-glycan profiles and displayed significant up-regulation of complex-type glycosylation and concomitant down-regulation of paucimannosylation upon infection. Complementary intact N-glycopeptide analysis supported a subcellular-specific manipulation of the glycosylation machinery and altered glycosylation patterns of lysosomal N-glycoproteins within infected macrophages. Interestingly, the corresponding macrophage-derived MPs displayed unique N-glycome and proteome signatures supporting a preferential packaging from plasma membranes. The MPs were devoid of infection-dependent N-glycosylation signatures, but interestingly displayed increased levels of the glyco-initiating oligosaccharyltransferase complex and associated α-glucosidases that correlated with increased formation, N-glycan precursor levels and N-glycan density of infected MPs. In conclusion, this system-wide study provides new insight into the host- and pathogen-driven N-glycoproteome manipulation of macrophages in TB.


Adaptive phenotypic response to climate enabled by epigenetics in a K-strategy species, the fish Leucoraja ocellata (Rajidae).
The relative importance of genetic versus epigenetic changes in adaptive evolution is a hotly debated topic, with studies showing that some species appear to be able to adapt rapidly without significant genetic change. Epigenetic mechanisms may be particularly important for the evolutionary potential of species with long maturation times and low reproductive potential ('K-strategists'), particularly when faced with rapidly changing environmental conditions. Here we study the transcriptome of two populations of the winter skate (Leucoraja ocellata), a typical 'K-strategist', in Atlantic Canada; an endemic population in the southern Gulf of St Lawrence and a large population on the Scotian Shelf. The endemic population has been able to adapt to a 10°C higher water temperature over short evolutionary time (7000 years), dramatically reducing its body size (by 45%) significantly below the minimum maturation size of Scotian Shelf and other populations of winter skate, as well as exhibiting other adaptations in life history and physiology. We demonstrate that the adaptive response to selection has an epigenetic basis, cataloguing 3653 changes in gene expression that may have enabled this species to rapidly respond to the novel environment. We argue that the epigenetic augmentation of species evolutionary potential (its regulation though gene expression) can enable K-strategists to survive and adapt to different environments, and this mechanism may be particularly important for the persistence of sharks, skates and rays in the light of future climate change.


Naringin abrogates osteoclastogenesis and bone resorption via the inhibition of RANKL-induced NF-κB and ERK activation.
Osteolytic bone diseases including osteoporosis are commonly accompanied with enhanced osteoclast formation and bone resorption. Naringin, a natural occurring flavonoid has been found to protect against retinoic acid-induced osteoporosis and improve bone quality in rats. Here, we showed that naringin perturbs osteoclast formation and bone resorption by inhibiting RANK-mediated NF-κB and ERK signaling. Naringin suppressed gene expression of key osteoclast marker genes. Naringin was found to inhibit RANKL-induced activation of NF-κB by suppressing RANKL-mediated IκB-α degradation. In addition, naringin inhibited RANKL-induced phosphorylation of ERK. This study identifies naringin as an inhibitor for osteoclast formation and bone resorption, and provides evidence that natural compounds such as naringin might be beneficial as an alternative medicine for the prevention and treatment of osteolysis.


Postnatal development of rat pups after maternal exposure to diethanolamine.
Diethanolamine (DEA), a widely used surfactant, was administered to pregnant mice at the oral LD10 resulting in failure of pups to grow and thrive through postnatal day (PND) 3 [National Toxicology Program, 1987; York et al., Teratology 37:503-504, 1988]. The toxicity profile for DEA differs among rodent species. This study investigated DEA-induced postnatal toxicity in a second species. Timed-mated Sprague-Dawley rats were dosed (0, 50, 125, 200, 250, or 300 mg DEA/kg/day, p.o.) on gestational days (GD) 6-19. Dams and pups were monitored for body weight, feed/water intake, clinical signs, litter size, and sex ratio. At necropsy (PND 21), maternal liver and kidney weights and number of uterine implantation sites were recorded. The high-dose group was terminated early due to excessive toxicity. The estimated maternal LD10 was 218 mg/kg/day. Maternal effects included decreased body weight and relative feed intake (>or=200 mg/kg/day), transiently reduced relative water intake (125 and 250 mg/kg/day), and increased absolute kidney weight (>or=125 mg/kg/day). Postimplantation loss (PND 0) and pup mortality (PND 0-4) were increased (>or=200 and >or=125 mg/kg/day, respectively). Pup body weight was reduced (>or=200 mg/kg/day) as late as PND 21. This study demonstrates reduced postnatal growth and survival in a second species after gestational exposure to DEA, persistence of toxic effects through the end of lactation, possibly due to long elimination half-life, and maternal and developmental toxicity no-observed-adverse-effect level (NOAELs) (50 mg/kg/day) and lowest-observed-adverse-effect level (LOAELs) (125 mg/kg/day) for oral DEA exposure during embryo/fetal development in the rat.


High-sensitivity C-reactive protein (hs-CRP) levels and its relationship with components of polycystic ovary syndrome in Indian adolescent women with polycystic ovary syndrome (PCOS).
C-reactive protein (CRP) is a risk marker for type 2 diabetes mellitus and cardiovascular diseases. In polycystic ovary syndrome (PCOS), limited data are available on high-sensitivity C-reactive protein (hs-CRP) levels and its relationship with components of PCOS especially in Indian women. The objective was to determine serum hs-CRP concentration in adolescent women with and without PCOS and to assess possible correlations of serum hs-CRP levels with components of PCOS in Indian women. One hundred and sixty women with PCOS and sixty non-PCOS women having normal menstrual cycles were included. Clinical assessment included anthropometry, Ferriman-Gallwey (FG) score and blood pressure (BP) measurement. Laboratory evaluation included estimation of T4, TSH, LH, FSH, total testosterone, prolactin, cortisol, 17OHP, hs-CRP, lipid profile, and insulin, and glucose after 2-h oral glucose tolerance test. Homeostasis Model Assessment Insulin resistance index (HOMA-IR) and Quantitative Insulin Sensitivity Check Index (QUICKI) and glucose intolerance was calculated. FG score, LH, FSH, total Testosterone, HOMA-IR and QUICKI were significantly different among women with or without PCOS (p < 0.01). Although hs-CRP levels showed a higher trend in women having PCOS, there was no significant difference between the groups (p > 0.05). A significant and positive correlation was found between hs-CRP and body mass index (BMI) (r = 0.308, p < 0.01) among PCOS group. The results in Indian adolescent women suggest that hs-CRP levels may not per se be associated with PCOS, rather can be related to fat mass in this subset of subjects.


Estimating predictive stimulus features from psychophysical data: The decision image technique applied to human faces.
One major challenge in the sensory sciences is to identify the stimulus features on which sensory systems base their computations, and which are predictive of a behavioral decision: they are a prerequisite for computational models of perception. We describe a technique (decision images) for extracting predictive stimulus features using logistic regression. A decision image not only defines a region of interest within a stimulus but is a quantitative template which defines a direction in stimulus space. Decision images thus enable the development of predictive models, as well as the generation of optimized stimuli for subsequent psychophysical investigations. Here we describe our method and apply it to data from a human face classification experiment. We show that decision images are able to predict human responses not only in terms of overall percent correct but also in terms of the probabilities with which individual faces are (mis-) classified by individual observers. We show that the most predictive dimension for gender categorization is neither aligned with the axis defined by the two class-means, nor with the first principal component of all faces-two hypotheses frequently entertained in the literature. Our method can be applied to a wide range of binary classification tasks in vision or other psychophysical contexts.


Phase I study of the adoptive immunotherapy of human cancer with lectin activated autologous mononuclear cells.
In previous in vitro studies, the authors showed that phytohemagglutinin (PHA) stimulated peripheral blood lymphocytes (PBL) from cancer patients to generate cells that were lytic for fresh autologous tumor but not for lymphocytes or lymphoblasts. Thus, after IRB approval, a phase I clinical protocol was instituted in cancer patients who had failed all other therapy to determine the toxicity and effects, in vivo, of the infusion of large numbers of such PHA activated autologous PBL. Ten patients were treated on the protocol, six with sarcoma, one with melanoma, and three with colorectal cancer. Up to a total of 1.7 X 10(11) PBL were obtained from 7 to 15 successive leukaphereses, the cells from each leukapheresis being incubated in vitro in medium containing PHA and human AB serum for 2 days and then reinfused following the next leukapheresis 2 days later. Toxicity encountered included fever and chills in 10/10 patients, headaches in 5/10, nausea and vomiting in 3/10, and requirement for erythrocyte transfusion in 8/10. No evidence for autoimmune disease, abnormal serum chemical or coagulation studies, or pulmonary emboli was found. 111Indium trafficing studies showed distribution of infused cells mainly to the spleen and liver, with some accumulation in the lungs and tumor especially after repeated infusions. In 9/10 patients, activated PBL were detected in the peripheral circulation by the sixth leukapheresis. Evidence for this was found by assaying the incorporation of tritiated thymidine (3H-Tdr) into, and lysis of fresh tumor cells by, unstimulated PBL from successive leukaphereses. No tumor regression was seen in these patients with bulk disease. These studies demonstrated that large numbers of PHA-activated PBL can be safely obtained and infused into humans, achieving an increase in the number of circulating activated cells with evidence of migration of cells to tumor, lungs, liver and spleen. Further studies of the use of activated lymphocyte infusion in conjunction with chemotherapy in humans are in progress.


Cost Effectiveness of Insulin Degludec Plus Liraglutide (IDegLira) in a Fixed Combination for Uncontrolled Type 2 Diabetes Mellitus in Sweden.
Patients with uncontrolled type 2 diabetes mellitus (T2DM) are a priority group for intensified therapy without weight gain and with low risk of hypoglycaemia. This study evaluates the cost effectiveness of insulin degludec plus liraglutide (IDegLira, Xultophy®) compared with six potential intensification treatment options for patients with T2DM that is uncontrolled with basal insulin. The Swedish Institute for Health Economics (IHE) Cohort Model of Type 2 Diabetes was used with Swedish input data, a 40-year time frame and a societal perspective. The comparators for treatment intensification included insulin glargine, neutral protamine Hagedorn (NPH) insulin, insulin aspart plus either glargine or NPH, and liraglutide plus either glargine or NPH. Clinical data for all comparators (except NPH insulin) were based on an indirect treatment comparison of several studies. Prices were obtained from the 2014 Swedish Dental and Pharmaceutical Benefits Agency (Tandvårds- och läkemedelsförmånsverket [TLV]) database, and utility values were obtained from published studies. Sensitivity analyses were undertaken. Overall incremental cost-effectiveness ratios (ICER) were Swedish krona (SEK) 70,000 or lower per quality-adjusted life-year (QALY). IDegLira compared with intensified basal insulin showed an ICER of SEK 28,000 per QALY versus insulin glargine, SEK70,000 per QALY versus NPH insulin and SEK 60,000 per QALY versus NPH insulin plus liraglutide. IDegLira was dominant over insulin glargine plus liraglutide and insulin aspart plus insulin glargine or NPH insulin. Results were driven by the difference in glycated haemoglobin (HbA1c) reduction between treatments, as confirmed by sensitivity analyses. IDegLira is estimated to be a cost-effective treatment in Sweden compared with commonly used intensification treatments for patients with T2DM uncontrolled with basal insulin.


Pediatric vaccination and vaccine-preventable disease acquisition: associations with care by complementary and alternative medicine providers.
This study investigated provider-based complementary/alternative medicine use and its association with receipt of recommended vaccinations by children aged 1-2 years and with acquisition of vaccine-preventable disease by children aged 1-17 years. Results were based on logistic regression analysis of insurance claims for pediatric enrollees covered by two insurance companies in Washington State during 2000-2003. Primary exposures were use of chiropractic, naturopathy, acupuncture, or massage practitioner services by pediatric enrollees or members of their immediate families. Outcomes included receipt by children aged 1-2 years of four vaccine combinations (or their component vaccines) covering seven diseases, and acquisition of vaccine-preventable diseases by enrollees aged 1-17 years. Children were significantly less likely to receive each of the four recommended vaccinations if they saw a naturopathic physician. Children who saw chiropractors were significantly less likely to receive each of three of the recommended vaccinations. Children aged 1-17 years were significantly more likely to be diagnosed with a vaccine-preventable disease if they received naturopathic care. Use of provider-based complementary/alternative medicine by other family members was not independently associated with early childhood vaccination status or disease acquisition. Pediatric use of complementary/alternative medicine in Washington State was significantly associated with reduced adherence to recommended pediatric vaccination schedules and with acquisition of vaccine-preventable disease. Interventions enlisting the participation of complementary/alternative medicine providers in immunization awareness and promotional activities could improve adherence rates and assist in efforts to improve public health.