Dipeptidyl Peptidase 4 Inhibition for Prophylaxis of Acute Graft-versus-Host Disease.
Dipeptidyl peptidase 4 (DPP-4; also known as CD26), a transmembrane receptor expressed on T cells, has a costimulatory function in activating T cells. In a mouse model, down-regulation of CD26 prevented graft-versus-host disease (GVHD) but preserved graft-versus-tumor effects. Whether inhibition of DPP-4 with sitagliptin may prevent acute GVHD after allogeneic stem-cell transplantation is not known. We conducted a two-stage, phase 2 clinical trial to test whether sitagliptin plus tacrolimus and sirolimus would reduce the incidence of grade II to IV acute GVHD from 30% to no more than 15% by day 100. Patients received myeloablative conditioning followed by mobilized peripheral-blood stem-cell transplants. Sitagliptin was given orally at a dose of 600 mg every 12 hours starting the day before transplantation until day 14 after transplantation. A total of 36 patients who could be evaluated, with a median age of 46 years (range, 20 to 59), received transplants from matched related or unrelated donors. Acute GVHD occurred in 2 of 36 patients by day 100; the incidence of grade II to IV GVHD was 5% (95% confidence interval [CI], 1 to 16), and the incidence of grade III or IV GVHD was 3% (95% CI, 0 to 12). Nonrelapse mortality was zero at 1 year. The 1-year cumulative incidences of relapse and chronic GVHD were 26% (95% CI, 13 to 41) and 37% (95% CI, 22 to 53), respectively. GVHD-free, relapse-free survival was 46% (95% CI, 29 to 62) at 1 year. Toxic effects were similar to those seen in patients undergoing allogeneic stem-cell transplantation. In this nonrandomized trial, sitagliptin in combination with tacrolimus and sirolimus resulted in a low incidence of grade II to IV acute GVHD by day 100 after myeloablative allogeneic hematopoietic stem-cell transplantation. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT02683525.).


The Efficacy of Buprenorphine in Major Depression, Treatment-Resistant Depression and Suicidal Behavior: A Systematic Review.
Although several pharmacological options to treat depression are currently available, approximately one third of patients who receive antidepressant medications do not respond adequately or achieve a complete remission. Thus, novel strategies are needed to successfully address those who did not respond, or partially respond, to available antidepressant pharmacotherapy. Research findings revealed that the opioid system is significantly involved in the regulation of mood and incentives salience and may be an appropriate target for novel therapeutic agents. The present study aimed to systematically review the current literature about the use of buprenorphine (BUP) for major depression, treatment-resistant depression (TRD), non-suicidal self-injury (NSSI) behavior, and suicidal behavior. We investigated Pubmed and Scopus databases using the following keywords: "buprenorphine AND depression", "buprenorphine AND treatment resistant depression", "buprenorphine AND suicid*", "buprenorphine AND refractory depression". Several evidence demonstrate that, at low doses, BUP is an efficacious, well-tolerated, and safe option in reducing depressive symptoms, serious suicidal ideation, and NSSI, even in patients with TRD. However, more studies are needed to evaluate the long-term effects, and relative efficacy of specific combinations (e.g., BUP + samidorphan (BUP/SAM), BUP + naloxone (BUP/NAL), BUP + naltrexone) over BUP monotherapy or adjunctive BUP treatment with standard antidepressants, as well as to obtain more uniform guidance about the optimal BUP dosing interval.


The effect of thoracic epidural nerve block with dezocine and ropivacaine on arterial oxygen saturation and IDO gene expression during pulmonary ventilation in lung resection surgery.
During lung resection surgery, the blood supply to the lungs increases the intrapulmonary shunt and reduces arterial oxygenation in patients. Ventilation anesthesia of a lung may affect oxygenation. The present study aimed to compare intravenous anesthesia with and without thoracic epidural block (dezocine and ropivacaine) on oxygen saturation during lung ventilation in patients undergoing lung resection surgery. For this purpose, this study was performed as a double-blind, randomized clinical trial. Sixty patients who were candidates for lung resection were divided into two intervention groups (thoracic epidural block with dezocine and ropivacaine and intravenous anesthesia) and a control group (placebo thoracic epidural block and intravenous anesthesia). Hemodynamic variables, Aldert score, and possible complications were compared between the two groups before surgery and after recovery. Also, the expression level of the IDO gene was evaluated using the real-time PCR technique. SPSS, t-test, Mann-Whitney U, Chi-square, and Fisher performed data analysis and comparison. The results showed that the changes in hemodynamic variables and PaO2, SaO2, and ETCO2 were not statistically significant between the two groups. Aldrete's score at entry and exit of recovery was similar between the two groups. During the recovery period, the percentage of pain or chills in the group under complete intravenous anesthesia was significantly higher. There was no significant difference between the two groups regarding the frequency of nausea and hypotension. Also, the results of IDO gene expression showed that general anesthesia with the thoracic epidural block (dezocine and ropivacaine), which is involved in inducing immunological tolerance and suppressing immune responses, has no significant effect. The stress of performing surgery before surgery can play a role in suppressing the patient's immunity, and anesthesia of the thoracic epidural block (dezocine and ropivacaine) has no significant effect on IDO expression. In general, thoracic epidural block with complete intravenous anesthesia has no significant effect on oxygen saturation in ventilated lungs compared with intravenous anesthesia alone. Nevertheless, this combination significantly reduces postoperative pain and chills.


Important early advances in squamous cell carcinoma of the head and neck.
Therapeutic advances in squamous cell carcinomas of the head and neck (SCCHN) are attained by improvement in locoregional and/or distant disease control, as well as by reduction in treatment-related morbidity-especially long-term complications affecting normal organ functions and quality of life. New technological innovations in surgical management, such as transoral robotic surgery (TORS), and in radiotherapy (RT), such as proton and carbon ion therapy, bring promises of equal or superior efficacy outcomes coupled with the potential to minimize normal tissue toxicity. Scientific insights in the systemic treatment of SCCHN, such as novel approaches to overcome epidermal growth factor receptor (EGFR) resistance, may enable more effective molecular targeting in SCCHN beyond the current armamentarium of available agents. An overarching theme of these early multidisciplinary advances is to enable the delivery of precision-based therapeutic regimens from both the technical and scientific perspectives. Rigorous clinical trial evaluations are necessary to help define their roles in practice.


Noninvasive temporary cardiac stimulation.
A new noninvasive temporary cardiac pacemaker-monitor has been developed to stimulate effective ventricular contraction in ventricular asystole or symptomatic bradycardia. It is quickly and easily applied, safe, and well tolerated even in conscious patients. It produced electrical cardiac responses in 105 of 134 patients; almost all of the remaining 29 patients were severely hypoxic. Stimulation was clinically useful in 82 patients: 20 of 43 were resuscitated from emergency arrest and 23 of 26 from expected arrest; 38 of 40 were successfully treated in readiness for an expected arrest that did not materialize; and one of nine patients with tachycardia was tested noninvasively for likelihood of recurrent ventricular tachycardia.


Crk associates with ERM proteins and promotes cell motility toward hyaluronic acid.
Cell migration is a well organized process regulated by the extracellular matrix-mediated cytoskeletal reorganization. The signaling adaptor protein Crk has been shown to regulate cell motility, but its precise role is still under investigation. Herein, we report that Crk associates with ERM family proteins (including ezrin, radixin, and moesin), activates RhoA, and promotes cell motility toward hyaluronic acid. The binding of Crk with ERMs was demonstrated both by transient and stable protein expression systems in 293T cells and 3Y1 cells, and it was shown that v-Crk translocated the phosphorylated form of ERMs to microvilli in 3Y1 cells by immunofluorescence and immunoelectron microscopy. This v-Crk-dependent formation of microvilli was suppressed by inhibitors of Rho-associated kinase, and the activity of RhoA was elevated by coexpression of c-Crk-II and ERMs in 3Y1 cells. In concert with the activation of RhoA by Crk, Crk was found to associate with Rho-GDI, which has been shown to bind to ERMs. Furthermore, upon hyaluronic acid treatment, coexpression of c-Crk-II and ERMs enhanced cell motility, whereas the sole expression of c-Crk-II or either of the ERMs decreased the motility of 3Y1 cells. These results suggest that Crk may be involved in regulation of cell motility by a hyaluronic acid-dependent mechanism through an association with ERMs.


Cannabis & ENT: State certification-An expanding yet unregulated system.
1) Ascertain the status of cannabis legalization by state, 2) Explore the process required to obtain cannabis credentials for both the patient and the physician, 3) Determine the level of interest of otolaryngologists in the medicinal cannabis, and 4) Explore possible research directions into efficacy and potential complications. Descriptive study. Internet searches were conducted to identify each state's Medical Cannabis Program website. The qualifying conditions, list of approved-practitioners, process required for both practitioners and patients for approval were noted. Lists of approved practitioners were analyzed to determine the prevalence of board-certified otolaryngologists. Of the 33 states that authorize medicinal cannabis, eight provide lists of approved-practitioners, six of which provide specialty information. A total of 24 Otolaryngologists can be found of the 5944 physicians on these six lists. All otolaryngologists were located in highly-populated metropolitan areas with a mean number of 29.9 years in practice. Significant variations exist between each state including legal definitions and qualifying conditions. Lack of consistent regulation across the country drives uncertainty regarding the adoption of medicinal cannabis. Very few otolaryngologists in the country are registered to certify patients for medical cannabis. While the medicinal use of cannabis may currently have limited applications within otolaryngology, many areas that have yet to be explored.


Fatty liver and elevated transaminases with heterozygous apolipoprotein B deficiency.
Asymptomatic fatty liver and elevated transaminases is a common occurrence with varied etiology. Apolipoprotein (apo) B deficiency is an uncommon cause of fatty liver and elevated transaminases. The typical lipid profile low cholesterol low LDL (low density lipoprotein) suggests diagnosis of apo B deficiency and an invasive procedure like liver biopsy can be avoided in such patients.


Does association of opioid use with pain and function differ by fibromyalgia or widespread pain status?
Many consider chronic opioid therapy (COT) to be ineffective for fibromyalgia, but empirical evidence is limited. Among patients identified as initiating COT, we examined whether fibromyalgia was associated with different relationships of opioid use to pain and activity interference outcomes 12 months later. We obtained electronic data on diagnoses and opioid prescriptions. We obtained patient self-report data, including pain and activity interference measures, at baseline, 4 months, and 12 months. Among 1218 patients, 429 (35%) met our definition of fibromyalgia. Patients with and without fibromyalgia who had intermittent/lower-dose or regular/higher-dose opioid use at 12 months had similar 12-month pain intensity scores. However, among patients with minimal/no opioid use at 12 months, 12-month pain intensity was greater for those with fibromyalgia (adjusted mean = 5.15 [95% confidence interval, 4.80-5.51]; 0-10 scale) than for those without (4.44 [4.15-4.72]). Similar patterns were observed for 12-month activity interference. Among patients who discontinued opioids by 12 months, those with fibromyalgia were more likely to report bothersome side effects and less likely to report pain improvement as important reasons for discontinuation (P < 0.05). In sum, at 12 months, among patients who had discontinued opioids or used them minimally, those with fibromyalgia had worse outcomes and were less likely to have discontinued because of pain improvement. Among patients continuing COT, pain and activity interference outcomes were worse than those of patients with minimal/no opioid use and did not differ for those with fibromyalgia vs those with diverse other chronic pain conditions.


Spontaneous lateral sphenoid cephaloceles: anatomic factors contributing to pathogenesis and proposed classification.
Spontaneous lateral sphenoid cephaloceles arise from bony defects in the lateral sphenoid, in the absence of predisposing factors such as trauma, surgery, mass, or congenital skull base malformation. We reviewed CT and MR imaging findings and clinical data of 26 patients with spontaneous lateral sphenoid cephaloceles to better understand anatomic contributions to pathogenesis, varying clinical and imaging manifestations, and descriptive terminology. Two types of spontaneous lateral sphenoid cephaloceles were identified. In 15 of 26 patients, a type 1 spontaneous lateral sphenoid cephalocele was noted, herniating into a pneumatized lateral recess of the sphenoid sinus, and typically presenting with CSF leak and/or headache. In 11 of 26 patients, a type 2 spontaneous lateral sphenoid cephalocele was noted, isolated to the greater sphenoid wing without extension into the sphenoid sinus, presenting with seizures, headaches, meningitis, cranial neuropathy, or detected incidentally. All patients had sphenoid arachnoid pits, and 61% of patients had an empty or partially empty sella, suggesting that altered CSF dynamics may play a role in their genesis.


Meningeal and brainstem infiltration by a malignant mesothelioma.
Malignant mesothelioma is an uncommon neoplasia which primarily involves the pleura or peritoneum. Central nervous system involvement is rare. A rare presentation of metastatic pleural mesothelioma, which had infiltrated the meninges and brainstem, is described. The patient presented with diplopia following a 2-week history of malaise, myalgia, mild headache and diarrhoea. Clinical examination found global areflexia, cerebellar ataxia and bilateral sixth nerve palsies. Differential diagnoses included the Miller-Fisher variant of Guillain-Barre syndrome, malignant meningitis and infectious meningitis. The patient was treated with immunoglobulins, plasmaphoresis and corticosteroids; however, he deteriorated and died 31 days after admission. Retrospective examination of the MRI of the brain found diffuse low attenuation changes within the pons and cerebral peduncles. Postmortem examination favoured a diagnosis of an early sarcomatoid malignant mesothelioma of pleural origin with leptomeningeal metastatic deposits.


Febuxostat: a selective xanthine-oxidase/xanthine-dehydrogenase inhibitor for the management of hyperuricemia in adults with gout.
Febuxostat, a nonpurine selective inhibitor of both the oxidized and reduced forms of xanthine oxidase, was approved in February 2009 by the US Food and Drug Administration for the management of hyperuricemia in adults with gout. The purpose of this review was to summarize available information about the clinical use of febuxostat, including its chemistry, pharmacology, pharmacokinetics, pharmacodynamics, clinical efficacy, and safety profile. A search of the medical literature using PubMed (1949-August 2009) and the Iowa Drug Information Service (1966-August 2009) was performed to identify all published articles about febuxostat. Key search terms included febuxostat, hyperuricemia, gout, TMX-67, and TEI-6720. Articles were limited to those published in English. Reference lists of the primary set of articles identified were reviewed for pertinent articles and scientific meeting abstracts not identified in the original search. A total of 88 published articles (including 14 human studies) were identified in the original search. Review of the references of these 88 articles yielded 7 additional trials published in abstract form. Clinical trial data from this review were obtained from these 21 studies. Dose-dependent reductions from baseline in serum urate occur with febuxostat. Clinical trials found that 40 mg/d of febuxostat was noninferior to conventionally dosed allopurinol (300 mg/d) in the percentage of subjects achieving the primary end point of serum urate <6.0 mg/dL (45% for febuxostat vs 42% for allopurinol), whereas 80 mg/d of febuxostat was reported to be superior (67% vs 42%; P < 0.001). Febuxostat 40 and 80 mg/d appeared to be well tolerated in the populations studied, with adverse events mostly limited to liver enzyme elevations (6.6% and 4.6%, respectively), nausea (1.1% and 1.3%), arthralgias (1.1% and 0.7%), and rash (0.5% and 1.6%). Febuxostat does not require dosage adjustment in patients with mild to moderate renal impairment (creatinine clearance, 30-89 mL/min). Because of the risk of acute gout flares occurring when febuxostat treatment is initiated, concomitant therapy with colchicine or an NSAID for >or=8 weeks is recommended. Febuxostat is the first agent marketed in the United States to treat hyperuricemia of gout since allopurinol was approved in 1964. In English-language published clinical trials, it was found to be noninferior to allopurinol and generally well tolerated.


Efficacy of testing for illegal medication in horses.
The efficacy of testing for illegal drugs in race horses was surveyed by evaluating 27 questionnaires received from 28 racing jurisdictions polled. Large variations in the number of samples tested and drugs detected were reported. Some jurisdictions reported only illegal medications, whereas others also reported permitted medications. To facilitate comparison, stimulants, depressants, local anesthetics, narcotic analgesics, and tranquilizers were classified as hard drugs. Other drugs, which are legal in some jurisdictions, were classified as soft. To evaluate the efficacy of testing, positive test results were compared for hard drugs only. Positive test results varied from zero in some jurisdictions for some years to 14.8/1,000 samples tested for one small jurisdiction in one year. The mean rates over the years 1975 to 1983 varied from 0.2 to 6.5/1,000, with a modal positive test result of about 1/1,000. Beside the fact that prerace blood testing is less effective than is postrace urine testing, no cause for these variations in the positive test results could be identified. The positive test results also were compared for jurisdictions with differing medication rules for phenylbutazone (PBZ). Jurisdictions that did not allow PBZ had a mean positive test result for hard drugs of about 1.3 +/- 0.9/1,000 samples tested. Jurisdictions that allowed more liberal use of PBZ had a mean positive test result for hard drugs of about 1.3 +/- 1.0/1,000 samples tested. Seemingly, the presence of PBZ in equine forensic samples did not reduce the ability of forensic laboratories to detect the use of hard or illegal drugs.


[Tumors of the central nervous system].
Central nervous system (CNS) tumors constitute a heterogeneous group of neoplasms that share a considerable morbidity and mortality rate. Recent advances in the underlying oncogenic mechanisms of these tumors have led to new classification systems, which, in turn, allow for a better diagnostic approach and therapeutic planning. Most of these neoplasms occur sporadically and several risk factors have been found to be associated with their development, such as exposure to ionizing radiation or electromagnetic fields and the concomitant presence of conditions like diabetes, hypertension and Parkinson's disease. A relatively minor proportion of primary CNS tumors occur in the context of hereditary syndromes. The purpose of this review is to analyze the etiopathogenesis, clinical presentation, diagnosis and therapy of CNS tumors with particular emphasis in the putative risk factors mentioned above.


Poverty and program participation among immigrant children.
Researchers have long known that poverty in childhood is linked with a range of negative adult socioeconomic outcomes, from lower educational achievement and behavioral problems to lower earnings in the labor market. But few researchers have explored whether exposure to a disadvantaged background affects immigrant children and native children differently. George Borjas uses Current Population Survey (CPS) data on two specific indicators of poverty-the poverty rate and the rate of participation in public assistance programs-to begin answering that question. He finds that immigrant children have significantly higher rates both of poverty and of program participation than do native children. Nearly half of immigrant children are being raised in households that receive some type of public assistance, compared with roughly one-third of native children. Although the shares of immigrant and native children living in poverty are lower, the rate for immigrant children is nonetheless about 15 percentage points higher than that for native children-about the same as the gap in public assistance. Poverty and program participation rates among different groups of immigrant children also vary widely, depending in part on place of birth (foreign- or U.S.-born), parents (immigrant or native), and national origin. According to the CPS data, these native-immigrant differences persist into young adulthood. In particular, the program participation and poverty status of immigrant children is strongly correlated with their program participation and poverty status when they become young adults. But it is not possible, says Borjas, to tell whether the link results from a set of permanent factors associated with specific individuals or groups that tends to lead to "good" or "bad" outcomes systematically over time or from exposure during childhood to adverse socioeconomic outcomes, such as poverty or welfare dependency. Future research must explore the causal impact of childhood poverty on immigrant adult outcomes and why it might differ between immigrant and native families. Developing successful policies to address problems caused by the intergenerational breeding of poverty and program participation in the immigrant population depends on understanding this causal mechanism.


[Causes of maternal death in Pará State, Brazil].
To identify the major causes of maternal death in the State of Pará, Brazil. A descriptive, observational and retrospective study was conducted using data from the Mortality Information System (SIM) of the State Department of Public Health of Pará. SIM information was obtained using the TabWin 3.2 software and recorded in a research protocol developed by the investigators. The sample included 383 maternal deaths of 10-49-year-old women, which occurred from 2006 to 2010. Data were analyzed using non-parametric tests (χ2 and G-tests). The BioStat(r) 5.0 software was used for statistical analysis and Microsoft(r) Excel 2007 for the preparation of database and tables. The Maternal Mortality Ratio was 51.9 and did not decrease significantly during the period. Most deaths occurred during the postpartum period (up to 42 days) (51.7%), and some diagnostic confirmation was used. Direct obstetric causes were dominant (90.6%), mainly hypertension (34.6%), with emphasis on eclampsia (70%), and hemorrhage (22.2%). All of these maternal deaths were avoidable (100%). Maternal death in Pará is characterized by occurring during the puerperium (up to 42 days), due mainly to direct obstetric causes, such as hypertension, with emphasis on eclampsia, and hemorrhage. This evidences the need for complete attention with good quality for pregnant women, from prenatal care to puerperium, in the state of Pará.


The Dutch-Flemish PROMIS Physical Function item bank exhibited strong psychometric properties in patients with chronic pain.
The objective of this study was to assess the psychometric properties of the Dutch-Flemish Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function item bank in Dutch patients with chronic pain. A bank of 121 items was administered to 1,247 Dutch patients with chronic pain. Unidimensionality was assessed by fitting a one-factor confirmatory factor analysis and evaluating resulting fit statistics. Items were calibrated with the graded response model and its fit was evaluated. Cross-cultural validity was assessed by testing items for differential item functioning (DIF) based on language (Dutch vs. English). Construct validity was evaluated by calculation correlations between scores on the Dutch-Flemish PROMIS Physical Function measure and scores on generic and disease-specific measures. Results supported the Dutch-Flemish PROMIS Physical Function item bank's unidimensionality (Comparative Fit Index = 0.976, Tucker Lewis Index = 0.976) and model fit. Item thresholds targeted a wide range of physical function construct (threshold-parameters range: -4.2 to 5.6). Cross-cultural validity was good as four items only showed DIF for language and their impact on item scores was minimal. Physical Function scores were strongly associated with scores on all other measures (all correlations ≤ -0.60 as expected). The Dutch-Flemish PROMIS Physical Function item bank exhibited good psychometric properties. Development of a computer adaptive test based on the large bank is warranted.


Identification of tetranectin-targeting monoclonal antibodies to treat potentially lethal sepsis.
For the clinical management of sepsis, antibody-based strategies have only been attempted to antagonize proinflammatory cytokines but not yet been tried to target harmless proteins that may interact with these pathogenic mediators. Here, we report an antibody strategy to intervene in the harmful interaction between tetranectin (TN) and a late-acting sepsis mediator, high-mobility group box 1 (HMGB1), in preclinical settings. We found that TN could bind HMGB1 to reciprocally enhance their endocytosis, thereby inducing macrophage pyroptosis and consequent release of lactate dehydrogenase and apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain. The genetic depletion of TN expression or supplementation of exogenous TN protein at subphysiological doses distinctly affected the outcomes of potentially lethal sepsis, revealing a previously underappreciated beneficial role of TN in sepsis. Furthermore, the administration of domain-specific polyclonal and monoclonal antibodies effectively inhibited TN/HMGB1 interaction and endocytosis and attenuated the sepsis-induced TN depletion and tissue injury, thereby rescuing animals from lethal sepsis. Our findings point to a possibility of developing antibody strategies to prevent harmful interactions between harmless proteins and pathogenic mediators of human diseases.


Separated flow demonstrated by digitized cineangiography compared with LDV.
In order to demonstrate separated flow in vivo, a method for the computerized analysis of cineangiographies has been developed, tested in vitro, and compared with LDV. A pulsatile flow was created in a glass model bifurcation, and velocity profiles were obtained with LDV at several phase angles. The flow was cinefilmed during contrast injection and the images were digitized. The computer then transformed the image sequence into parametric images representing arrival times of the contrast. The separation regions demonstrated with LDV were identified as areas with delayed contrast arrival. A preliminary analysis of a cineangiography in vivo is also included.


The use of epidemiologic methods in family practice.
Epidemiologic methods of research can be readily used in family practice. Since the 19th century, family physicians have used epidemiologic methods in making important contributions to the understanding of disease. Using these methods requires an organized practice including patient registers, encounter data, and detailed records. Descriptive studies can define certain characteristics that are related to disease. Case-control and cohort studies can provide evidence for the association of risk factors and disease. A stepwise outline for carrying out a study is presented.


Exosomal Components and Modulators in Colorectal Cancer: Novel Diagnosis and Prognosis Biomarkers.
The relatively high incidence and mortality rates for colorectal carcinoma (CRC) make it a formidable malignant tumor. Comprehensive strategies have been applied to predict patient survival and diagnosis. Various clinical regimens have also been developed to improve the therapeutic outcome. Extracellular vesicles (EVs) are recently proposed cellular structures that can be produced by natural or artificial methods and have been extensively studied. In addition to their innate functions, EVs can be manipulated to be drug carriers and exert many biological functions. The composition of EVs, their intravesicular components, and the surrounding tumor microenvironment are closely related to the development of colorectal cancer. Determining the expression profiles of exocytosis samples and using them as indicators for selecting effective combination therapy is an indispensable direction for EV study and should be regarded as a novel prediction platform in addition to cancer stage, prognosis, and other clinical assessments. In this review, we summarize the function, regulation, and application of EVs in the colon cancer research field. We provide an update on and discuss potential values for clinical applications of EVs. Moreover, we illustrate the specific markers, mediators, and genetic alterations of EVs in colorectal carcinogenesis. Furthermore, we outline the vital markers present in the EVs and discuss their plausible uses in colon cancer patient therapy in combination with the currently used clinical strategies. The development and application of these EVs will significantly improve the accuracy of diagnosis, lead to more precise prognoses, and may lead to the improved treatment of colorectal cancer.


Control of specific carbon dioxide production in a fed-batch culture producing recombinant protein using a soft sensor.
The feeding of a fed-batch cultivation producing recombinant protein was controlled by a soft sensor set-up. It was assumed that the control approach could be based on the cell's production of carbon dioxide and that this parameter indicates the metabolic state occurring at induced protein expression. The soft sensor used the on-line signals from a carbon dioxide analyser and a near-infrared (NIR) probe for biomass to estimate the specific production rate qCO2. Control experiments were carried out with various qCO2 set-points where we observe that the feeding of nutrients to the culture could easily be controlled and resulted in a decreased variability compared to uncontrolled cultivations. We therefore suggest that this control approach could serve as an alternative to other commonly applied methods such as controlling the cell's overflow metabolism of acetate or the cell's specific growth rate. However, further studies of the internal metabolic fluxes of CO2 during protein expression would be recommended for a more precise characterization of the relationship between qCO2 and protein expression in order to fully interpret the control behaviour.


The nucleotide sequence of the 5S RNA of chicken embryo fibroblasts.
The nucleotide sequence of uniformly 32P-labelled chicken 5S RNA has been determined by analysing the end-products of T1 and pancreatic ribonuclease digestion. These oligonucleotides can be aligned by homology with the human sequence to give a sequence differing in only seven positions from that of Man. The sequence deduced here differs in two position from that previously published for chicken 5S RNA.


Influence of contouring and hardness of foot orthoses on ratings of perceived comfort.
Comfort is a vital component of orthosis therapy. The purpose of this study was to examine what features of orthoses (design or hardness) influence the perception of comfort by using previously established footwear comfort measures: 100-mm visual analog scale (VAS) and ranking scale. Twenty subjects were consecutively allocated to two experiments consisting of five sessions of repeated measures. Comfort measures were taken from four prefabricated orthosis in each session using the VAS (experiment 1) and ranking scale (experiment 2). Subjects in experiment 1 were also asked to rate each orthosis relative to their shoe using a criterion scale. Measures were taken in both walking and jogging. A soft-flat orthosis was found to be significantly more comfortable than all contoured orthoses, including one of the same hardness using both the VAS and ranking scale. Using the VAS, differences between the soft-flat and contoured orthoses were also found to be clinically meaningful for dimensions of overall comfort and arch cushioning (>10.2 mm). Perceived comfort of orthoses significantly differed between walking and jogging on the VAS but was not clinically meaningful. Comparisons between the VAS and criterion scale detected a VAS difference of 11.34 mm between orthoses judged as comfortable as my shoe and slightly more comfortable than my shoe. There was a VAS difference of 17.49 mm between orthoses judged as comfortable as my shoe and slightly less comfortable than my shoe. Healthy subjects prioritize contouring over hardness when judging the comfort of orthoses. Clinically meaningful changes were required to change or enhance the comfort of orthoses standardized in material type and fabrication.


Structural and kinetic analysis of Schistosoma mansoni Adenylosuccinate Lyase (SmADSL).
Schistosoma mansoni is the parasite responsible for schistosomiasis, a disease that affects about 218 million people worldwide. Currently, both direct treatment and disease control initiatives rely on chemotherapy using a single drug, praziquantel. Concerns over the possibility of resistance developing to praziquantel, have stimulated efforts to develop new drugs for the treatment of schistosomiasis. Schistosomes do not have the de novo purine biosynthetic pathway, and instead depend entirely on the purine salvage pathway to supply its need for purines. The purine salvage pathway has been reported as a potential target for developing new drugs against schistosomiasis. Adenylosuccinate lyase (SmADSL) is an enzyme in this pathway, which cleaves adenylosuccinate (ADS) into adenosine 5'-monophosphate (AMP) and fumarate. SmADSL kinetic characterization was performed by isothermal titration calorimetry (ITC) using both ADS and SAICAR as substrates. Structures of SmADSL in Apo form and in complex with AMP were elucidated by x-ray crystallography revealing a highly conserved tetrameric structure required for their function since the active sites are formed from residues of three different subunits. The active sites are also highly conserved between species and it is difficult to identify a potent species-specific inhibitor for the development of new therapeutic agents. In contrast, several mutagenesis studies have demonstrated the importance of dimeric interface residues in the stability of the quaternary structure of the enzyme. The lower conservation of these residues between SmADSL and human ADSL could be used to lead the development of anti-schistosomiasis drugs based on disruption of subunit interfaces. These structures and kinetics data add another layer of information to Schistosoma mansoni purine salvage pathway.


[Stereotaxic cingulotomy in the complex treatment of a schizophrenic patient with obsessive-compulsive disorder, resistant to treatment].
The authors describe a case of continuous conservative treatment of a patient suffering from severe obsessions. At the definite stage of the disease, the patient underwent psychosurgical operation--bilateral anterior stereotaxic cingulotomy . The surgical intervention was necessitated by dramatic and steady deterioration of the patient's condition, loss of work fitness, suggesting official registration of disability; appearance of suicidal intentions. After the operation the patient started his work again in accordance with his specialty; the question about disability registration did not arise any more.


Pacemaker-related endocarditis. Report of 7 cases and review of the literature.
We report on 7 patients with pacemaker endocarditis diagnosed during the workup of long-standing fever. Persistent positive blood cultures and echocardiography led to the diagnosis in 6 patients whereas autopsy was diagnostic in another. Causative microorganisms were Staphylococcus epidermidis (3), Staphylococcus lugdunensis (1), Pseudomonas aeruginosa (1), Streptococcus bovis (1), and Streptococcus mitis-Streptococcus sanguis (1). Pulmonary embolism was present in nearly 50% of the cases, a figure clearly higher than previously reported. In all but 1 case the initial medical approach was not successful, and thus the pacing system was finally removed. None of the cases relapsed after the removal. We have reviewed the literature regarding pacemaker endocarditis, particularly with respect to treatment.


Cationic lipids delay the transfer of plasmid DNA to lysosomes.
Plasmid 35S DNA, naked or associated with different cationic lipid preparations was injected to rats. Subcellular distribution of radioactivity in the liver one hour after injection, was established by centrifugation methods. Results show that at that time, 35S DNA has reached lysosomes. On the contrary, when 35S DNA was complexed with lipids, radioactivity remains located in organelles whose distribution after differential and isopycnic centrifugation, is clearly distinct from that of arylsulfatase, lysosome marker enzyme. Injection of Triton WR 1339, a specific density perturbant of lysosomes, four days before 35S DNA injection causes a density decrease of radioactivity bearing structures, apparent one hour after naked 35S DNA injection but visible only after more than five hours, when 35S DNA associated with a cationic lipid is injected. These observations show that cationic lipids delay the transfer to lysosomes, of plasmid DNA taken up by the liver.


A Comparison of Different Schemes of Neoadjuvant Chemotherapy Followed by Concurrent Chemotherapy and Radiotherapy for Locally Advanced Cervical Cancer: A Retrospective Study.
To examine the clinical significance of unoperated cervical cancer patients treated with different neoadjuvant chemotherapy (NACT) schemes followed by concurrent chemotherapy and radiotherapy (CCRT). This retrospective analysis included women with locally advanced cervical cancer treated with NACT-CCRT between September 2011 and September 2014. Neoadjuvant chemotherapy included paclitaxel plus cisplatin (TP group; 62 patients) or paclitaxel plus loplatin (TL group; 58 patients), which were administered three weekly, and cisplatin or loplatin, which were administered weekly for synchronous chemotherapy. External beam radiation therapy (50.4-56.35 Gy/28 f, 180-215 cGy/f, 5 f/w) was followed by intracavitary brachytherapy (5 Gy per fraction, mostly 5 fractions, Ir192 based). One hundred twenty women were included in the analysis. The complete/partial response rate was 99.2% after treatment. The one-year, three-year, and five-year survival rates were 99.2%, 82.5%, and 70.8%, respectively. In the TP and TL groups, the three-year and five-year survival rates were 85.5% vs 77.6% and 75.8% vs 65.5%, respectively, with no significant difference. The 5-year overall survival (OS) rates between patients with stage IIB and stage IIIB disease were not significantly different (69.2% vs 64.7%). In the TP group, grade 3 or 4 digestive reactions were more frequent than those in the TL group. Leukopenia, neutropenia, and thrombocytopenia were more common in the TL group. No significant difference was found in anemia, radiation enteritis, radiation proctitis, or radiation cystitis between the groups. Lobaplatin may be used as an alternative drug for patients with severe digestive system reactions or contraindications to cisplatin, but hematological toxicity must be considered, particularly in dose-intensive schemes. Neoadjuvant chemotherapy followed by concurrent chemotherapy and radiotherapy (NACT-CCRT) warrants further prospective study in cervical cancer patients with a wide range of tumor invasion (eg, mass size ≥5 cm or stage IIIB).


The Prevalence and Impact of Model Violations in Phylogenetic Analysis.
In phylogenetic inference, we commonly use models of substitution which assume that sequence evolution is stationary, reversible, and homogeneous (SRH). Although the use of such models is often criticized, the extent of SRH violations and their effects on phylogenetic inference of tree topologies and edge lengths are not well understood. Here, we introduce and apply the maximal matched-pairs tests of homogeneity to assess the scale and impact of SRH model violations on 3,572 partitions from 35 published phylogenetic data sets. We show that roughly one-quarter of all the partitions we analyzed (23.5%) reject the SRH assumptions, and that for 25% of data sets, tree topologies inferred from all partitions differ significantly from topologies inferred using the subset of partitions that do not reject the SRH assumptions. This proportion increases when comparing trees inferred using the subset of partitions that rejects the SRH assumptions, to those inferred from partitions that do not reject the SRH assumptions. These results suggest that the extent and effects of model violation in phylogenetics may be substantial. They highlight the importance of testing for model violations and possibly excluding partitions that violate models prior to tree reconstruction. Our results also suggest that further effort in developing models that do not require SRH assumptions could lead to large improvements in the accuracy of phylogenomic inference. The scripts necessary to perform the analysis are available in https://github.com/roblanf/SRHtests, and the new tests we describe are available as a new option in IQ-TREE (http://www.iqtree.org).


Contraception needs and pregnancy termination in sub-Saharan Africa: a multilevel analysis of demographic and health survey data.
Women in sub-Saharan Africa (SSA) have a higher risk of unintended pregnancies that are more likely to be terminated, most of which are unsafe with associated complications. Unmet need for contraception is highest in SSA and exceeds the global average. This study investigates the association between unmet/met need for contraception and pregnancy termination SSA. We used pooled data from Demographic and Health Surveys conducted from January 2010 to December 2018 in 32 countries in SSA. Our study involved 265,505 women with diverse contraception needs and with complete data on all variables of interest. Multilevel logistic regression at 95% CI was used to investigate the association between individual and community level factors and pregnancy termination. We found an overall pregnancy termination rate of 16.27% ranging from 9.13% in Namibia to 38.68% in Gabon. Intriguingly, women with a met need for contraception were more likely to terminate a pregnancy [aOR = 1.11; 95% CI 1.07-1.96] than women with unmet needs. Women with secondary education were more likely to terminate a pregnancy as compared to those without education [aOR = 1.23; 95% CI 1.19-1.27]. With regards to age, we observed that every additional age increases the likelihood of terminating a pregnancy. At the contextual level, the women with female household heads were less likely to terminate a pregnancy [aOR = 0.95; 95% CI 0.92-0.97]. The least socio-economically disadvantaged women were less likely to terminate a pregnancy compared to the moderately and most socio-economically disadvantaged women. Our study contributes towards the discussion on unmet/met need for contraception and pregnancy termination across SSA. Women with met need for contraception have higher odds of terminating a pregnancy. The underlying cause of this we argued could be poor adherence to the protocols of contraceptives or the reluctance of women to utilise contraceptives after experiencing a failure. Governments of SSA and non-governmental organisations need to take pragmatic steps to increase met needs for contraception and also utilise mass media to encourage women to adhere to the prescription of contraceptives in order to reduce the incidence of unplanned pregnancies and unsafe abortions.


Identification and molecular cloning of insecticidal toxins from the venom of the brown spider Loxosceles intermedia.
The venom of Loxosceles intermedia was investigated for the presence of insecticidal toxins active against Spodoptera frugiperda (Lepdoptera: Noctuidade), an insect that has caused great reductions in corn production in Brazil. A combination of gel filtration (Sephadex G-100) and ion-exchange chromatography (Carboxymethyl Cellulose, CM 52) resulted in four major fractions that were submitted to biological assay. Fraction 4 was further purified by a reverse phase HPLC (C18 Column) resulting in peptides active against Spodoptera frugiperda. Three new potential insecticidal toxins named LiTx x 1, LiTx x 2 and LiTx x 3 were identified. The partial amino terminal sequences of these peptides were obtained and used to clone the corresponding cDNAs with the help of degenerate oligonucleotides. The amino acid sequence deduced from the cDNA of LiTx x 1, LiTx x 2 and LiTx x 3 revealed mature proteins of approximately 7.4, 7.9 and 5.6 kDa.


Control of thermoregulatory sweating is altered by hydration level and exercise intensity.
The purpose of this study was to examine the thermoregulatory sweating control parameters of threshold temperature and sensitivity to determine whether 1) these variables were altered by hypohydration level and exercise intensity and 2) these alterations, if present, were additive and independent. Nine heat-acclimated men completed a matrix of nine trials: three exercise intensities of 25, 45, and 65% maximal O2 uptake and three hydration levels, i.e., euhydration and hypohydration (Hy) at 3 and 5% of body weight. During each trial, subjects attempted 50 min of treadmill exercise in a warm room (30 degrees C dry bulb, 50% relative humidity) while esophageal temperature and upper arm sweating rate were continuously measured. Hypohydration was achieved by exercise and fluid restriction the day preceding the trials. The following new findings were made: 1) threshold temperature increased in graded manner with hypohydration level (approximately 0.06 degree C/% Hy); 2) sensitivity decreased in a graded manner with hypohydration level (approximately 0.06 units/%Hy); 3) threshold temperature was not altered by exercise intensity; and 4) sensitivity increased from low- to moderate- and high-intensity exercise. We conclude that both hypohydration level and exercise intensity produce independent effects on control of thermoregulatory sweating.


A rapid and highly specific technique to detect hepatitis C RNA in frozen sections of liver.
To develop a polymerase chain reaction (PCR) based technique that would permit the rapid and highly specific detection of hepatitis C virus (HCV) RNA extracted from frozen liver tissue. Samples of liver tissue from 18 patients undergoing orthotopic liver transplantation were studied. Nine patients were HCV positive. Total RNA was extracted from between one and 10 sections, 10 microns thick, from each tissue sample. HCV RNA was amplified by (1) conventional, multistep reverse transcription PCR (RT-PCR) and by (2) combined, single step RT-PCR using coupled oligonucleotide primers based on the sequence of the 5' untranslated region of the viral genome. Positive results were confirmed by dot blot analysis using a digoxigenin labelled oligoprobe (Alx 89). HCV RNA was detected in the nine HCV positive patients by both conventional and combined RT-PCR. HCV RNA was not detected in the HCV negative patients. As little as 500 ng total RNA was needed as the template to yield detectable amounts of amplified cDNA. The digoxigenin labelled oligoprobe hybridised with HCV RNA positive specimens only. The combined, single step RT-PCR is a rapid and sensitive technique for detecting HCV RNA in frozen liver tissue.


Prevalence and risk factors for multimorbidity in older US patients with late-stage melanoma.
Presence of multimorbidity can affect prognosis, treatment, and outcomes of individuals with cancer. However, the prevalence and factors associated with multimorbidity among older late-stage melanoma is not well studied. We estimated the prevalence of any type of pre-existing multimorbidity (autoimmune disorder (AD), physical health conditions (PHC), and mental health conditions (MHC)) among older adults with late-stage melanoma in the United States. We further examined the association of patient-level factors to multimorbidity in late-stage melanoma. We derived data on older fee-for-service Medicare beneficiaries (age ≥ 66 years) diagnosed with late-stage melanoma between 2011 and 2015 (N = 4,519) from the linked Surveillance, Epidemiology, and End Results cancer registry and Medicare claims. We defined multimorbidity as the prevalence of two or more chronic conditions prior to the diagnosis of melanoma. We used unadjusted and adjusted logistic regressions to examine the association of patient-level factors to multimorbidity. An overwhelming majority (85%) of older patients with late-stage melanoma had multimorbidity. Pre-existing PHC multimorbidity (84%) was the most prevalent, followed by AD (12%), and MHC (6%). Age and region were associated with any and PHC multimorbidity. Sex, marital status, and region were factors associated with pre-existing AD while sex, marital status, and dual eligibility were associated with MHC multimorbidity. Pre-existing multimorbidity was highly prevalent among older individuals with late-stage melanoma; prevalence rates and factors associated with multimorbidity varied by type of chronic conditions. This highlights the need for developing systematic approaches to optimizing care of older patients with late-stage melanoma and multimorbidity.


Supramolecular photocyclodimerization of 2-hydroxyanthracene with a chiral hydrogen-bonding template, cyclodextrin and serum albumin.
2-Hydroxyanthracene (HA) in its neutral form smoothly photocyclodimerized to four stereoisomeric [4 + 4]-cyclodimers, which were isolated and characterized for the first time, whereas the anionic form of HA turned out to be photochemically inert. Enantiodifferentiating photocyclodimerization of HA in the presence of a chiral hydrogen-bonding template (TKS159), γ-cyclodextrin (γ-CDx) and bovine serum albumin (BSA) was examined to afford chiral syn-head-to-tail and anti-head-to-head cyclodimers in modest enantiomeric excesses with TKS159 and γ-CDx, but practically no photocyclodimerization proceeded in the presence of BSA probably due to the ionization of HA in the binding sites.


A computational strategy to select optimized protein targets for drug development toward the control of cancer diseases.
In this report, we describe a strategy for the optimized selection of protein targets suitable for drug development against neoplastic diseases taking the particular case of breast cancer as an example. We combined human interactome and transcriptome data from malignant and control cell lines because highly connected proteins that are up-regulated in malignant cell lines are expected to be suitable protein targets for chemotherapy with a lower rate of undesirable side effects. We normalized transcriptome data and applied a statistic treatment to objectively extract the sub-networks of down- and up-regulated genes whose proteins effectively interact. We chose the most connected ones that act as protein hubs, most being in the signaling network. We show that the protein targets effectively identified by the combination of protein connectivity and differential expression are known as suitable targets for the successful chemotherapy of breast cancer. Interestingly, we found additional proteins, not generally targeted by drug treatments, which might justify the extension of existing formulation by addition of inhibitors designed against these proteins with the consequence of improving therapeutic outcomes. The molecular alterations observed in breast cancer cell lines represent either driver events and/or driver pathways that are necessary for breast cancer development or progression. However, it is clear that signaling mechanisms of the luminal A, B and triple negative subtypes are different. Furthermore, the up- and down-regulated networks predicted subtype-specific drug targets and possible compensation circuits between up- and down-regulated genes. We believe these results may have significant clinical implications in the personalized treatment of cancer patients allowing an objective approach to the recycling of the arsenal of available drugs to the specific case of each breast cancer given their distinct qualitative and quantitative molecular traits.


The sword of Damocles: an illustrative example of the life-saving effect of the collateral circulation.
There is an ongoing debate on the effective importance of the collateral network, especially in the current era, where most patients with significant coronary artery disease are revascularized, be it percutaneously or surgically; thus, people may question a significant benefit of the coronary collateral circulation. However, the presented 61-year-old male patient demonstrates an unambiguous situation of a life-saving effect of the collateral circulation. The patient presented without any angina symptoms and with only mild shortness of breath on moderate to severe exertion. A subsequent angiography revealed a complete chronic occlusion of the main coronary artery. The entire left coronary system was provided by well-developed right to left collaterals. Additionally, the patient had an 80-90% stenosis of his mid-right coronary artery (RCA). The entire blood supply to the heart had to pass this lesion to provide the RCA area and also the left anterior descending and left circumflex areas via collaterals. This extreme example illustrates the potentially lifesaving effect of the coronary collateral circulation. Obviously, the entire myocardium can in some cases be perfused entirely via one critically stenosed vessel.


HIV Infection is associated with compositional and functional shifts in the rectal mucosal microbiota.
Regardless of infection route, the intestine is the primary site for HIV-1 infection establishment and results in significant mucosal CD4+ T lymphocyte depletion, induces an inflammatory state that propagates viral dissemination, facilitates microbial translocation, and fosters establishment of one of the largest HIV reservoirs. Here we test the prediction that HIV infection modifies the composition and function of the mucosal commensal microbiota. Rectal mucosal microbiota were collected from human subjects using a sponge-based sampling methodology. Samples were collected from 20 HIV-positive men not receiving combination anti-retroviral therapy (cART), 20 HIV-positive men on cART and 20 healthy, HIV-negative men. Microbial composition of samples was analyzed using barcoded 16S Illumina deep sequencing (85,900 reads per sample after processing). Microbial metagenomic information for the samples was imputed using the bioinformatic tools PICRUST and HUMAnN. Microbial composition and imputed function in HIV-positive individuals not receiving cART was significantly different from HIV-negative individuals. Genera including Roseburia, Coprococcus, Ruminococcus, Eubacterium, Alistipes and Lachnospira were depleted in HIV-infected subjects not receiving cART, while Fusobacteria, Anaerococcus, Peptostreptococcus and Porphyromonas were significantly enriched. HIV-positive subjects receiving cART exhibited similar depletion and enrichment for these genera, but were of intermediate magnitude and did not achieve statistical significance. Imputed metagenomic functions, including amino acid metabolism, vitamin biosynthesis, and siderophore biosynthesis differed significantly between healthy controls and HIV-infected subjects not receiving cART. HIV infection was associated with rectal mucosal changes in microbiota composition and imputed function that cART failed to completely reverse. HIV infection was associated with depletion of some commensal species and enrichment of a few opportunistic pathogens. Many imputed metagenomic functions differed between samples from HIV-negative and HIV-positive subjects not receiving cART, possibly reflecting mucosal metabolic changes associated with HIV infection. Such functional pathways may represent novel interventional targets for HIV therapy if normalizing the microbial composition or functional activity of the microbiota proves therapeutically useful.


Paving the road to hell: why change programs ultimately fail.
A successful change program must have clearly delineated and honestly defined goals. Change requires conviction, money, and effort and the willingness to invest all three. Change programs fail when any of these requirements are lacking. Many health care executives have the conviction, but are unwilling to spend the money or expend the effort. Some lack conviction, despite having money; the effort is merely spinning wheels with no forward motion. Often all three are lacking, despite an outward appearance to the contrary--the result of management delusions. Employees are quick to see through misleading and insincere schemes. It is much easier to foster trust from the outset than to rebuild it after it has been violated.


Delta opioid receptor immunoreactive boutons appose bulbospinal CI neurons in the rat.
Bulbospinal sympathoexcitatory neurons in the rostral ventrolateral medulla are inhibited by activation of delta opioid receptors. However, it is not known whether this opioidergic effect is pre- or post- synaptic. Here, using retrograde tracing and immunocytochemistry in adult rats, we provide evidence that the delta opioid receptor is located on boutons that are presynaptic to both catecholaminergic and non-catecholaminergic neurons that project to the spinal cord. We suggest that the sympathoinhibitory action of delta opioid receptor activation in the rostral ventrolateral medulla is mediated presynaptically, resulting in a reduction of excitatory neurotransmitter release from boutons that oppose sympathoexcitatory bulbospinal neurons.


Complications with non-endoscopic percutaneous gastrostomy in 31 cats and 10 dogs: a retrospective study.
Percutaneous gastrostomy tubes were placed non-endoscopically in 31 cats and 10 dogs using either a rigid insertion tube (n = 13) or an Eld gastrostomy tube applicator (n = 28). Tubes were placed successfully in 38 of the 41 animals and the consequent feeding was of therapeutic benefit to 31 of the animals. Six of 41 died or were euthanased for reasons unrelated to gastrostomy. In four cases (10 per cent), gastrostomy failed with respect to correct tube placement or tube feeding. Overall complications occurred in 18 of 41 animals. Severe procedural complications occurred in two cats; a cardiorespiratory arrest during pharyngeal manipulation and erroneous tube placement through the distal oesophagus. Moderate late complications included peristomal food leakage (n = 2), peristomal abscess (n = 2) and pyloric outflow obstruction by a migrated tube (n = 1). Complications associated with the feeding procedure, nausea and vomiting (n = 3), led to aspiration pneumonia in one case.


Functional implications of radial diaphyseal curvature.
A recent study (Galtés et al.: Am J Phys Anthropol 135 (2008) 293-300) demonstrated that during pronation, pronator teres exerts a favorable force for radial lateral bending. On the basis of this finding, we hypothesized that the pattern of muscular loading exerted on the radius by this muscle might play a role as a mechanical stimulus involved in radial bowing. The current work relates the hypertrophy of the forearm muscles to the degree of lateral curvature of the radial diaphysis. The analysis is based on an original osteometrical index to estimate radial curvature, and it applies a visual reference method to grade the osteological appearance of 10 entheses of 104 radii from archaeological and contemporary samples. Using these morphological data as an indirect method to measure the association between muscular hypertrophy and bone curvature, this study reveals that the pattern of muscular loading exerted on the apex of the radial shaft by the pronator teres muscle may play an important role as a mechanical stimulus involved in diaphyseal bowing.


Knowledge of and adherence to fruit and vegetable recommendations and intakes: results of the 2003 health information national trends survey.
Attention to cancer-relevant communication (e.g., fruit/vegetable intake recommendations) through various media has been shown to be a pivotal step in reduction of the cancer burden, thus underscoring the importance of examining associations between exposure to health media and knowledge of and adherence to fruit/vegetable intake recommendations. The purpose of the present study was to assess factors associated with fruit/vegetable intake knowledge and behavior. The authors analyzed data collected from the 2003 Health Information National Trends Survey to evaluate the effect of fruit/vegetable intake knowledge on behavior, and the relationship of this effect with biobehavioral, sociodemographic, and communication characteristics. Participants who were knowledgeable of fruit/vegetable intake recommendations and consumed at least 5 fruit/vegetable servings per day were classified as informed compliers. Associations were observed for being an informed complier and paying "a lot" of attention to health media on the radio, in the newspaper, and in magazines and "a little" or "some" attention to health media in magazines or on the Internet. The recent explosion of available cancer-related information through various media underscores the importance of examining associations between exposure to health media and knowledge of and adherence to fruit/vegetable intake recommendations.


[Noninvasive mask ventilation of the lungs in the treatment of acute respiratory insufficiency in heart surgery patients in the postoperative period].
Noninvasive ventilation of the lungs using a mask (NIVLM) was used in 54 patients with hypercapnic (n = 14) and hypoxemic (n = 40) respiratory failure. Respironics (USA) nasal and facial masks were applied. Ventilation regimens were selected individually. Trigger monitored ventilation, intermittent forced ventilation of the lungs, and assisted ventilation with positive expiratory pressure, biphasic positive pressure in the airways, and constant positive pressure in the respiratory contour were used. The efficacy of NIVLM in patients with hypercapnic respiratory failure was 100%. The pCO2 and ETCO2 normalized in all patients both during and after discontinuation of NIVLM. Despite a relatively long period of ventilation (229 +/- 72 min), the patients did not complain of discomfort during the procedure; no complications or individual intolerance of nasal or facial masks were observed. In patients with hypoxemic respiratory failure NIVLM resulted in a decrease of dyspnea, increase of respiratory volume, etc. The detected changes did not disappear after NIVLM was discontinued. Individual tolerance of nasal and facial masks was somewhat worse in this group: patients complained of stuffiness, lack of air, difficult respiration. Six patients (18.2%) developed episodes of psychomotor excitation which required sedative and analgesic therapy. In general, the efficacy of NIVLM was 91%, but resolution of respiratory failure without repeated intubation of the trachea was attained in only 33 patients (87%) with the hypoxemic condition. The mean duration of NIVLM in this group was 464 +/- 47 min. Hence, NIVLM is an effective method for respiratory support in patients with both hypoxemic and hypercapnic respiratory failure, which helps decrease the duration of forced ventilation of the lungs or do without repeated intubation of the trachea.


The genomic echoes of the last Green Sahara on the Fulani and Sahelian people.
The population history of the Sahara/Sahelian belt is understudied, despite previous work highlighting complex dynamics.1,2,3,4,5,6,7 The Sahelian Fulani, i.e., the largest nomadic pastoral population in the world,8 represent an interesting case because they show a non-negligible proportion of an Eurasian genetic component, usually explained by recent admixture with northern Africans.1,2,5,6,7,9,10,11,12 Nevertheless, their origins are largely unknown, although several hypotheses have been proposed, including a possible link to ancient peoples settled in the Sahara during its last humid phase (Green Sahara, 12,000-5,000 years before present [BP]).13,14,15 To shed light about the Fulani ancient genetic roots, we produced 23 high-coverage (30×) whole genomes from Fulani individuals from 8 Sahelian countries, plus 17 samples from other African groups and 3 from Europeans as controls, for a total of 43 new whole genomes. These data have been compared with 814 published modern whole genomes2,16,17,18 and with relevant published ancient sequences (> 1,800 samples).19 These analyses showed some evidence that the non-sub-Saharan genetic ancestry component of the Fulani might have also been shaped by older events,1,5,6 possibly tracing the Fulani origins to unsampled ancient Green Saharan population(s). The joint analysis of modern and ancient samples allowed us to shed light on the genetic ancestry composition of such ancient Saharans, suggesting a similarity with Late Neolithic Moroccans and possibly pointing to a link with the spread of cattle herding. We also identified two different Fulani clusters whose admixture pattern may be informative about the historical Fulani movements and their later involvement in the western African empires.


Fluorescent characterisation of differentiated myotubes using flow cytometry.
Flow cytometry is routinely used in the assessment of skeletal muscle progenitor cell (myoblast) populations. However, a full gating strategy, inclusive of difficult to interpret forward and side scatter data, which documents cytometric analysis of differentiated myoblasts (myotubes) has not been reported. Beyond changes in size and shape, there are substantial metabolic and protein changes in myotubes allowing for their potential identification within heterogenous cell suspensions. To establish the utility of flow cytometry for determination of myoblasts and myotubes, C2C12 murine cell populations were assessed for cell morphology and metabolic reprogramming. Laser scatter, both forward (FSC; size) and side (SSC; granularity), measured cell morphology, while mitochondrial mass, reactive oxygen species (ROS) generation and DNA content were quantified using the fluorescent probes, MitoTracker green, CM-H2 DCFDA and Vybrant DyeCycle, respectively. Immunophenotyping for myosin heavy chain (MyHC) was utilised to confirm myotube differentiation. Cellular viability was determined using Annexin V/propidium iodide dual labelling. Fluorescent microscopy was employed to visualise fluorescence and morphology. Myotube and myoblast populations were resolvable through non-intuitive interpretation of laser scatter-based morphology assessment and mitochondrial mass and activity assessment. Myotubes appeared to have similar sizes to the myoblasts based on laser scatter but exhibited greater mitochondrial mass (159%, P<0.0001), ROS production (303%, P<0.0001), DNA content (18%, P<0.001) and expression of MyHC (147%, P<0.001) compared to myoblasts. Myotube sub-populations contained a larger viable cluster of cells which were unable to be fractionated from myoblast populations and a smaller population cluster which likely contains apoptotic bodies. Imaging of differentiated myoblasts that had transited through the flow cytometer revealed the presence of intact, 'rolled-up' myotubes, which would alter laser scatter properties and potential transit through the laser beam. Our results indicate that myotubes can be analysed successfully using flow cytometry. Increased mitochondrial mass, ROS and DNA content are key features that correlate with MyHC expression but due to myotubes 'rolling up' during flow cytometric analysis, laser scatter determination of size is not positively correlated; a phenomenon observed with some size determination particles and related to surface properties of said particles. We also note a greater heterogeneity of myotubes compared to myoblasts as evidenced by the 2 distinct sub-populations. We suggest that acoustic focussing may prove effective in identifying myotube sub populations compared to traditional hydrodynamic focussing. This article is protected by copyright. All rights reserved.


Perceived appropriateness of alcohol screening and brief advice programmes in Colombia, Mexico and Peru and barriers to their implementation in primary health care - a cross-sectional survey.
Providing alcohol screening and brief advice (SBA) in primary health care (PHC) can be an effective measure to reduce alcohol consumption. To aid successful implementation in an upper middle-income country context, this study investigates the perceived appropriateness of the programme and the perceived barriers to its implementation in PHC settings in three Latin American countries: Colombia, Mexico and Peru, as part of larger implementation study (SCALA). An online survey based on the Tailored Implementation for Chronic Diseases (TICD) implementation framework was disseminated in the three countries to key stakeholders with experience in the topic and/or setting (both health professionals and other roles, for example regional health administrators and national experts). In total, 55 respondents participated (66% response rate). For responses to both appropriateness and barriers questions, frequencies were computed, and country comparisons were made using Chi square and Kruskal-Wallis non-parametric tests. Alcohol SBA was seen as an appropriate programme to reduce heavy alcohol use in PHC and a range of providers were considered suitable for its delivery, such as general practitioners, nurses, psychologists and social workers. Contextual factors such as patients' normalised perception of their heavy drinking, lack of on-going support for providers, difficulty of accessing referral services and lenient alcohol control laws were the highest rated barriers. Country differences were found for two barriers: Peruvian respondents rated SBA guidelines as less clear than Mexican (Mann-Whitney U = -18.10, P = 0.001), and more strongly indicated lack of available screening instruments than Colombian (Mann-Whitney U = -12.82, P = 0.035) and Mexican respondents (Mann-Whitney U = -13.56, P = 0.018). The study shows the need to address contextual factors for successful implementation of SBA in practice. General congruence between the countries suggests that similar approaches can be used to encourage widespread implementation of SBA in all three studied countries, with minor tailoring based on the few country-specific barriers.


Efavirenz-based simplification after successful early lopinavir-boosted-ritonavir-based therapy in HIV-infected children in Burkina Faso and Côte d'Ivoire: the MONOD ANRS 12206 non-inferiority randomised trial.
The 2016 World Health Organization guidelines recommend all children <3 years start antiretroviral therapy (ART) on protease inhibitor-based regimens. But lopinavir/ritonavir (LPV/r) syrup has many challenges in low-income countries, including limited availability, requires refrigeration, interactions with anti-tuberculous drugs, twice-daily dosing, poor palatability in young children, and higher cost than non-nucleoside reverse transcriptase inhibitor (NNRTI) drugs. Successfully initiating LPV/r-based ART in HIV-infected children aged <2 years raises operational challenges that could be simplified by switching to a protease inhibitor-sparing therapy based on efavirenz (EFV), although, to date, EFV is not recommended in children <3 years. The MONOD ANRS 12026 study is a phase 3 non-inferiority open-label randomised clinical trial conducted in Abidjan, Côte d'Ivoire, and Ouagadougou, Burkina Faso (ClinicalTrial.gov registry: NCT01127204). HIV-1-infected children who were tuberculosis-free and treated before the age of 2 years with 12-15 months of suppressive twice-daily LPV/r-based ART (HIV-1 RNA viral load (VL) <500 copies/mL, confirmed) were randomised to two arms: once-daily combination of abacavir (ABC) + lamivudine (3TC) + EFV (referred to as EFV) versus continuation of the twice-daily combination zidovudine (ZDV) or ABC + 3TC + LPV/r (referred to as LPV). The primary endpoint was the difference in the proportion of children with virological suppression by 12 months post-randomisation between arms (14% non-inferiority bound, Chi-squared test). Between May 2011 and January 2013, 156 children (median age 13.7 months) were initiated on ART. After 12-15 months on ART, 106 (68%) were randomised to one of the two treatment arms (54 LPV, 52 EFV); 97 (91%) were aged <3 years. At 12 months post-randomisation, 46 children (85.2%) from LPV versus 43 (82.7%) from EFV showed virological suppression (defined as a VL <500 copies/mL; difference, 2.5%; 95% confidence interval (CI), -11.5 to 16.5), whereas seven (13%) in LPV and seven (13.5%) in EFV were classed as having virological failure (secondary outcome, defined as a VL ≥1000 copies/mL; difference, 0.5%; 95% CI, -13.4 to 12.4). No significant differences in adverse events were observed, with two adverse events in LPV (3.7%) versus four (7.7%) in EFV (p = 0.43). On genotyping, 13 out of 14 children with virological failure (six out of seven EFV, seven out of seven LPV) had a drug-resistance mutation: nine (five out of six EFV, four out of seven LPV) had one or more major NNRTI-resistance mutations whereas none had an LPV/r-resistance mutation. At the VL threshold of 500 copies/mL, we could not conclusively demonstrate the non-inferiority of EFV on viral suppression compared to LPV because of low statistical power. However, non-inferiority was confirmed for a VL threshold of <1000 copies/mL. Resistance analyses highlighted a high frequency of NNRTI-resistance mutations. A switch to an EFV-based regimen as a simplification strategy around the age of 3 years needs to be closely monitored. ClinicalTrial.gov registry n° NCT01127204 , 19 May 2010.


Tuberculin reactivity in schoolchildren, Kassala State, Sudan.
Tuberculin skin test (TST) is widely used for the assessment of Bacillus Calmette-Guérin (BCG) vaccine efficacy and screening of latent TB infection (LTBI). Poor or no data are available on the reactivity of tuberculin in Kassala State. The aim of the present study was to assess the response to the BCG vaccine and to estimate the prevalence of LTBI and the annual rate annual risk of tuberculous infection (ARTI) among vaccinated school children using TST. School-based cross-sectional study was conducted in three localities of Kassala State during 2016-2018. A cluster random sampling method was used for the enrolment. Five tuberculin units of 0.1 mL were injected intradermally in the left forearm of 2568 school children aged 5-15 years. The test was performed after the assessment of child health, nutrition status, and BCG scar status. Tuberculin reaction size was interpreted after 48-72 h. The collected data were analyzed using SPSS (v 20). The classical method was used to estimate ARTI. Overall, there was no reaction in 81.5% of children. Only 0.66% of children had induration 10 mm-28 mm, indicating the prevalence of latent TB with an annual risk of 0.1%. Tuberculin reactivity was statistically significant affected by child age, gender, geographical location, and nutrition status (P < 0.05), whereas BCG scar status had no effect (P > 0.05). The study documented a high proportion of tuberculin nonreactivity irrespective of BCG vaccination status and provides data on the prevalence of latent infection among studied groups. Further studies are needed to address the reasons of low and nonreactivity of tuberculin, and evaluation of the BCG vaccine is recommended.


Opiate receptor gradients in monkey cerebral cortex: correspondence with sensory processing hierarchies.
In order to obtain information on the possible functions of endogenous opiates in the primate cerebral cortex, we assessed the distribution of mu-like opiate receptors (which selectively bind 3H-labeled naloxone) and delta-like opiate receptors (which selectively bind 3H-labeled D-Ala2, D-Leu5-enkephalin) throughout the cerebral cortex of the rhesus monkey. Stereospecific [3H]naloxone binding sites increased in a gradient along hierarchically organized cortical systems that sequentially process modality-specific sensory information of a progressively more complex nature. Specific [3H]enkephalin binding sites, in contrast, were relatively evenly distributed throughout the cerebral cortex. These results, in combination with electrophysiological studies of monkeys and humans, suggest that mu-like opiate receptors may play a role in the affective filtering of sensory stimuli at the cortical level, that is, in emotion-induced selective attention.


Effects of cell density and biomacromolecule addition on the flow behavior of concentrated mesenchymal cell suspensions.
With the rapidly growing interest in the use of mesenchymal stromal cells (MSCs) for cell therapy and regenerative medicine applications, either alone as an injected suspension, or dispersed within injectable hydrogel delivery systems, greater understanding of the structure-function-property characteristics of suspensions of adhesion-dependent mesenchymal cells is required. In this paper, we present the results of an experimental study into the flow behavior of concentrated suspensions of living cells of mesenchymal origin (fibroblasts) over a wide range of cell concentrations, with and without the addition of hyaluronic acid (HA), a commonly utilized biomolecule in injectable hydrogel formulations. We characterize the change in the shear viscosity as a function of shear stress and shear rate for cell volume fractions varying from 20 to 60%. We show that high volume fraction suspensions of living mesenchymal cells, known to be capable of homotypic interactions, exhibit highly complex but reproducible rheological footprints, including yield stress, shear thinning and shear-induced fracture behaviors. We show that with the addition of HA, we can significantly modify and tailor the rheology of these cell suspensions at all volume fractions. Using FACS and confocal imaging, we show that the observed effect of HA addition is due to a significantly modulation in the formation of cellular aggregates in these suspensions, and thus the resultant volume spanning network. Considering the aggregates as fractal structures, we show that by taking into account the changes in volume fractions with shear, we are able to plot a master curve for the range of conditions investigated and extract from it the average adhesion force between individual cells, across a population of millions of cells. The outcomes of this study not only provide new insight into the complexity of the flow behaviors of concentrated, adhesive mesenchymal cell suspensions, and their sensitivity to associative biomacromolecule addition, but also a novel, rapid method by which to measure the average adhesion force between individual cells, and the impacts of biomacromolecules on this important parameter.


COVID-19 with Different Severities: A Multicenter Study of Clinical Features.
Rationale: The coronavirus disease (COVID-19) pandemic is now a global health concern.Objectives: We compared the clinical characteristics, laboratory examinations, computed tomography images, and treatments of patients with COVID-19 from three different cities in China.Methods: A total of 476 patients were recruited from January 1, 2020, to February 15, 2020, at three hospitals in Wuhan, Shanghai, and Anhui. The patients were divided into four groups according to age and into three groups (moderate, severe, and critical) according to the fifth edition of the Guidelines on the Diagnosis and Treatment of COVID-19 issued by the National Health Commission of China.Measurements and Main Results: The incidence of comorbidities was higher in the severe (46.3%) and critical (67.1%) groups than in the moderate group (37.8%). More patients were taking angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers in the moderate group than in the severe and critical groups. More patients had multiple lung lobe involvement and pleural effusion in the critical group than in the moderate group. More patients received antiviral agents within the first 4 days in the moderate group than in the severe group, and more patients received antibiotics and corticosteroids in the critical and severe groups. Patients >75 years old had a significantly lower survival rate than younger patients.Conclusions: Multiple organ dysfunction and impaired immune function were the typical characteristics of patients with severe or critical illness. There was a significant difference in the use of angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers among patients with different severities of disease. Involvement of multiple lung lobes and pleural effusion were associated with the severity of COVID-19. Advanced age (≥75 yr) was a risk factor for mortality.


Racial discrimination, racial identity, and impostor phenomenon: A profile approach.
This study examined the association between racial discrimination and the impostor phenomenon (IP) and the moderating influence of racial identity on this relationship. One hundred fifty-seven African American college students (68% female; mean age = 18.63) completed measures of racial discrimination, racial identity, and IP during 2 waves of data collection. Utilizing latent profile analyses, 4 patterns of racial identity were identified: Undifferentiated, Multiculturalist, Race-Focused, and Humanist. Racial discrimination predicted higher subsequent levels of IP. Racial identity did not moderate the impact of racial discrimination; however, students in the Multiculturalist and Humanist groups reported the lowest and highest levels of IP at Wave 2, respectively. IP is influenced by racial discrimination experiences as well as by the significance and meaning that individuals ascribe to being African American. (PsycINFO Database Record


[Comprative evaluation of the immediate results of gastrectomy with different types of esophago-intestinal anastomosis].
Using the experience with 207 gastrectomies the author presents an analysis of a dependence of incompetency of enteroesophageal anastomosis sutures on the operative approach, extent of surgery, method of enteroesophagostomy, number of suture rows. The author's data evidence that incompetency of anastomosis sutures in gastrectomy is the principal cause of mortality in the postoperative period. The mortality due to suture incompetency while using a thoracoabdominal access is considerably higher than in transabdominal approach. The Sapozhnikov-Judin technic yields the least per cent of anastomotic suture incompetency (2%), whereas the Gilyarovich method--the highest (18.7%). The use of three-row sutures in formation of the anastomosis decreases twice the percent of suture incompetency. Extension of gastrectomy to a combined one does not increase the percentage of suture incompetency. Constant improvement of the Sapozhnikov-Judin method might permit to reduce to a minimum the anastomosis suture incompetency in gastrectomy.


Bone Mineral Densitometry Reporting: Pearls and Pitfalls.
Dual-energy X-ray absorptiometry (DXA) is the method of choice for assessing bone mineral density (BMD). Unfortunately, the performance and interpretation of DXA can be challenging and errors are common. In fact, it has been reported that up to 90% of BMD reports contain at least 1 error. Errors can be the result of technique or interpretative in nature or both and can result in inappropriate diagnosis and management. In this article, we review the various types of pitfalls frequently encountered by physicians interpreting DXA studies. Being aware of these pitfalls will help readers recognize and avoid them when encountered in clinical practice.


Cognitive change in donepezil treated patients with vascular or mixed dementia.
vascular dementia (VaD) and mixed Alzheimer's disease (AD/VaD) are common. How best to monitor treatment is not clear. Our objective was to compare responsiveness and construct validity of change scores, following donepezil treatment, of the standardized Mini-Mental State Examination (sMMSE) and other measures potentially usable in primary care. A six-month, outcome measurement study. The Disability Assessment for Dementia (DAD), CLOX-1 and 2, Phonetic Fluency, a short Neuropsychiatric Inventory, (the NPI-Q), Clinical Global Impression (CGI) and the SymptomGuide™ (SG) were measured. Construct validity was tested by correlating change scores, and responsiveness by calculating standardized response means (SRMs). Of 148 treated patients, 116 completed. The mean sMMSE increased by 0.7 (95% Confidence Interval (CI) = -0.005, 1.41; p=0.06; SRM= 0.15). There was no statistically significant difference in the DAD. The NPI-Q (-1.4; 95% CI = -2.08, -0.72; p<0.01; SRM=0.24), CLOX-1 (0.9; 95% CI = 0.19, 1.61; p<0.01; SRM=0.21), CLOX-2 (0.9; 95% CI = 0.17, 1.63; p=0.03; SRM=0.26), Phonetic Fluency (0.9; 95% CI = 0.19, 1.61; p=0.02; SRM=0.21) and SG (0.35; 95% CI = 0.20,0.51; p<0.01; SRM=0.28) each detected significant improvement. The CGI suggested improvement in 74 completers (64%) - mostly "minimal" (44/116, 38%) - while 21/116 (18%) were worse. Change scores at 24 weeks were at best modestly correlated with each other (range -0.22 to 0.30). Different measures showed different responsiveness, in a setting in which the mean treatment effect seems to have been small, but clinically detectable. Patient-centered and executive function measures might be useful in vascular and mixed dementia.


Dynamic formation of nanodiamond precursors from the decomposition of carbon suboxide (C3O2) under extreme conditions-A ReaxFF study.
We use molecular dynamics simulations with the ReaxFF-lg potential to model the high pressure pyrolysis of carbon suboxide (C3O2) in mixture with argon as a pressure bath. We show that the reactive simulations catch the experimental behavior of the low-pressure detonation of C3O2 (around 10 bars in shock tube experiments) and allow extrapolations to the high-pressure range of solid-state explosive detonation (up to 60 GPa). While at low pressure carbonaceous nanostructures are formed through the aggregation of species such as carbon dimers C2, it appears that the high pressure deeply modifies the process, with the aggregation of growing CxOy heterostructures, in which the oxygen amount is driven by the pressure and the temperature. Pressures in the order of 60 GPa lead to high oxygen ratios, which prevent carbon atoms to get four carbon neighbors (the first condition to get a diamond structure). But a pressure lowering leads to a substantial carbon enrichment through CO2/CO release and facilitates the formation of pure sp3-carbon phases where diamond precursors can form. These results give new insights on the conditions leading to nanodiamonds during the detonation of carbon-rich high explosives.


Temperament influences endotoxin-induced changes in rectal temperature, sickness behavior, and plasma epinephrine concentrations in bulls.
This study was designed to determine the influence of temperament on endotoxin-induced changes in body temperature, sickness behavior, and stress hormone concentrations in cattle. Brahman bulls were selected based on temperament score measured 28 d prior to weaning. In dwelling recording devices were used to monitor rectal temperature, and jugular catheters were used to collect blood samples to determine cortisol and epinephrine concentrations before and after LPS administration (0.5 μg/kg body weight). Temperamental bulls had the lowest peak rectal temperature and sickness behavior scores relative to the Calm and Intermediate bulls. Prior to the administration of LPS, Temperamental bulls had greater cortisol and epinephrine concentrations than Calm or Intermediate bulls. Cortisol concentrations increased following LPS administration but were not affected by temperament. Epinephrine concentrations peaked 1 h after LPS administration in Calm bulls. Temperamental bulls did not exhibit an epinephrine response to LPS challenge. These data demonstrate that the temperament of calves can modulate the physiological, behavioral, and endocrine responses of pre-pubertal Brahman bulls to endotoxin challenge. Specifically, temperament differentially affected the rectal temperature, sickness behavior and epinephrine, but not cortisol, responses to LPS challenge.


[Analyzing MMPI examination in patients with neurosis by the criteria of Chinese T score].
In the present paper, the results are summarized of MMPI measurements in 210 cases of neurosis. They, by the criteria of Chinese T score, show an increase in the scales 1, 2, 3 and 7 and have an identical rate of 87.5%. Hence, it is reasonable for the scales above to be designated as the coding model of neurosis. In every type of neurosis the scales 1, 2, 3 and 7 have a tendency to increase, but there is a slight difference in their highest point and kurtosis. In depression neurosis, neurasthenia and anxiety neurosis the scale 2 (D) increases dominantly; in hysteria, the scale 3 (HY); in hypochondria, the scale 1 (HS); in phobic and compulsion neurosis, the scale 7. Therefore, MMPI measurements can be useful for clinical classification of neurosis.


3D Object Proposals Using Stereo Imagery for Accurate Object Class Detection.
The goal of this paper is to perform 3D object detection in the context of autonomous driving. Our method aims at generating a set of high-quality 3D object proposals by exploiting stereo imagery. We formulate the problem as minimizing an energy function that encodes object size priors, placement of objects on the ground plane as well as several depth informed features that reason about free space, point cloud densities and distance to the ground. We then exploit a CNN on top of these proposals to perform object detection. In particular, we employ a convolutional neural net (CNN) that exploits context and depth information to jointly regress to 3D bounding box coordinates and object pose. Our experiments show significant performance gains over existing RGB and RGB-D object proposal methods on the challenging KITTI benchmark. When combined with the CNN, our approach outperforms all existing results in object detection and orientation estimation tasks for all three KITTI object classes. Furthermore, we experiment also with the setting where LIDAR information is available, and show that using both LIDAR and stereo leads to the best result.


Pharmacological Evidence That Dictyostelium Differentiation-Inducing Factor 1 Promotes Glucose Uptake Partly via an Increase in Intracellular cAMP Content in Mouse 3T3-L1 Cells.
Differentiation-inducing factor 1 (DIF-1) isolated from the cellular slime mold Dictyostelium discoideum can inhibit mammalian calmodulin-dependent cAMP/cGMP phosphodiesterase (PDE1) in vitro. DIF-1 also promotes glucose uptake, at least in part, via a mitochondria- and AMPK-dependent pathway in mouse 3T3-L1 fibroblast cells, but the mechanism underlying this effect has not been fully elucidated. In this study, we investigated the effects of DIF-1 on intracellular cAMP and cGMP levels, as well as the effects that DIF-1 and several compounds that increase cAMP and cGMP levels have on glucose uptake in confluent 3T3-L1 cells. DIF-1 at 20 μM (a concentration that promotes glucose uptake) increased the level of intracellular cAMP by about 20% but did not affect the level of intracellular cGMP. Neither the PDE1 inhibitor 8-methoxymethyl-3-isobutyl-1-methylxanthine at 10-200 μM nor the broad-range PDE inhibitor 3-isobutyl-1-methylxanthine at 40-400 μM had any marked effects on glucose uptake. The membrane-permeable cAMP analog 8-bromo-cAMP at 200-1000 μM significantly promoted glucose uptake (by 20-25%), whereas the membrane-permeable cGMP analog 8-bromo-cGMP at 3-100 μM did not affect glucose uptake. The adenylate cyclase activator forskolin at 1-10 μM promoted glucose uptake by 20-30%. Thus, DIF-1 may promote glucose uptake by 3T3-L1 cells, at least in part, via an increase in intracellular cAMP level.


Practice Patterns for Older Adult Patients With Advanced Cancer: Physician Office Versus Hospital Outpatient Setting.
A shift in outpatient oncology care from the physician's office to hospital outpatient settings has generated interest in the effect of practice setting on outcomes. Our objective was to examine whether medical oncologists' prescribing of drugs and services for older adult patients with advanced cancer is used more in physicians' offices compared with hospital outpatient departments. This was a retrospective comparative study. SEER-Medicare data (2004 to 2011) were used to identify Medicare beneficiaries diagnosed with advanced breast, colon, esophagus, non-small-cell lung, pancreatic, or stomach cancer. Between physicians' offices and hospital outpatient departments, we compared use of selected likely low-value supportive drugs, low-value therapeutic drugs, chemotherapy-related hospitalizations, and hospice. We used hierarchical modeling to assess differences between settings to account for correlation within physicians. Compared with patients treated in a hospital outpatient department, those treated in a physician's office setting were more likely to receive erythropoiesis-stimulating agents (odds ratio, 1.72; 95% CI, 1.53 to 1.94) and granulocyte colony-stimulating factors (odds ratio, 1.28; 95% CI, 1.18 to 1.38). For combination chemotherapy and nanoparticle albumin-bound-paclitaxel in patients with breast cancer, there was a trend toward higher use in physicians' offices, although this was not statistically significant. Chemotherapy-related hospitalizations and hospice did not vary by setting. We found somewhat higher use of several drugs for patients with advanced cancer in physicians' office settings compared with hospital outpatient departments. Findings support research to dissect the mechanisms through which setting might influence physicians' behavior.


Constitutive and inflammatory mediator-regulated fractalkine expression in human ocular tissues and cultured cells.
Fractalkine (FKN) is a dual-adhesion molecule-chemokine that plays a role in inflammation but has not been explored in the eye. In the current study, constitutive expression of FKN was identified in human iris and retina, and its regulation by various cytokines in endothelial cells (ECs) and stromal cells from human iris, retina, and choroid was investigated. Human iris and retina explants were evaluated for FKN mRNA and protein expression using RT-PCR and immunohistochemistry, respectively. Cultured ocular ECs and stromal cells were stimulated with various inflammatory mediators (endotoxin; TNFalpha; interferon-gamma; interleukin (IL)-1alpha, -4, -10, -13, -17, and -18; and/or CD40 ligand, or combinations thereof), with FKN mRNA being subsequently evaluated by cDNA array and/or RT-PCR and FKN protein by enzyme-linked immunoculture assay (ELICA) and/or by Western blot analysis. Iris and retina explants constitutively expressed FKN protein in microvascular ECs and also in several stromal cell types. Iris and retina both express FKN mRNA. TNFalpha upregulated FKN in iris explants. All ocular microvascular ECs and stromal cultures expressed low FKN mRNA and/or protein levels, which were variably upregulated by endotoxin, TNFalpha, interferon-gamma, IL-1alpha, and/or CD40 ligand, but not by IL-18. In ECs, the Th2 cytokines IL-4 and -13, but not IL-10, reduced TNFalpha-induced FKN protein. IL-17, usually considered proinflammatory, reduced TNFalpha-induced FKN protein in ocular ECs. FKN is expressed in various ocular tissues and cells. Inflammatory mediator modulation of ocular FKN expression suggests that this adhesive chemokine may play important roles in regulating leukocyte efflux in inflammatory eye diseases, such as anterior uveitis and retinochoroiditis.


Exotoxin A from various Pseudomonas aeruginosa cultures: in vitro activity measured by enzyme-linked immunosorbent assay (ELISA).
An enzyme-linked immunosorbent assay (ELISA) for the detection of Pseudomonas aeruginosa exotoxin A (toxin A) was developed. The level of toxin A produced by fresh P. aeruginosa isolates was compared to the level of toxin A produced by twelve-months-old subcultures derived from the same strains. Results obtained with the ELISA showed that toxin A was produced in similar amounts both by the fresh isolates and the subcultures. The production of toxin A seems to represent a stable property of the assayed P. aeruginosa strains. This is in contrast to other exoproducts from the same strains, such as extracellular proteinases. Some proteinases were produced at very different levels when freshly isolated P. aeruginosa cultures were compared with their twelve-months-old counterparts, confirming earlier reports in this respect.