Pharmacokinetics of 2 novel formulations of modified-release oral testosterone alone and with finasteride in normal men with experimental hypogonadism.
Oral administration of testosterone might be useful for the treatment of testosterone deficiency. However, current "immediate-release" formulations of oral testosterone exhibit suboptimal pharmacokinetics, with supraphysiologic peaks of testosterone and its metabolite, dihydrotestosterone (DHT), immediately after dosing. To dampen these peaks, we have developed 2 novel modified-release formulations of oral testosterone designed to slow absorption from the gut and improve hormone delivery. We studied these testosterone formulations in 16 normal young men enrolled in a 2-arm, open-label clinical trial. Three hundred-mg and 600-mg doses of immediate-release and modified fast-release or slow-release formulations were administered sequentially to 8 normal men rendered hypogonadal by the administration of the gonadotropin-releasing hormone antagonist acyline. Blood for measurement of serum testosterone, DHT, and estradiol was obtained before and 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours after each dose. A second group of 8 men was studied with the coadministration of 1 mg of the 5α-reductase inhibitor finasteride daily throughout the treatment period. Serum testosterone was increased with all formulations of oral testosterone. The modified slow-release formulation significantly delayed the postdose peaks of serum testosterone and reduced peak concentrations of serum DHT compared with the immediate-release formulation. The addition of finasteride further increased serum testosterone and decreased serum DHT. We conclude that the oral modified slow-release testosterone formulation exhibits superior pharmacokinetics compared with immediate-release oral testosterone both alone and in combination with finasteride. This formulation might have efficacy for the treatment of testosterone deficiency.


[Metazoan parasites of the pearl cichlid, Geophagus brasiliensis (Quoy and Gaimard, 1824) (Osteichthyes: Cichlidae) from the Lajes Reservoir, Rio de Janeiro, Brazil].
During May 2002 and January 2003, 65 specimens of pearl cichlid, Geophagus brasiliensis (Quoy & Gaimard, 1824), collected from the Lajes Reservoir, Rio de Janeiro, Brazil (22 degrees 42'-22 degrees 50'S, 43 degrees 53' -44 degrees 05'W), were necropsied to study their infracommunities of metazoan parasites. Fifty three fishes (81.5%) were parasitized by one or more metazoan. Six species of parasites were collected. The hirudinean Glossiphonid not identified was the majority (60%) of the parasite specimens collected and was the dominant species, with highest abundance and prevalence. The parasites of G. brasiliensis showed the typical aggregated pattern of distribution. No species of parasites of the pearl cichlid had correlation between the host's total length and parasite prevalence and abundance. The sex of hosts did not influence prevalence and abundance of any parasite species. The mean of Berger- Parker's index of dominance was 0.77 +/- 0.38. The mean species diversity in the infracommunities of G. brasiliensis was H = 0.154 +/- 0.06, with no correlation with the host's total length. The parasite community of G. brasiliensis from Lajes Reservoir is characterized by the low species richness and diversity.


[Trans and postoperative myocardial infarct in heart surgery].
1. A study was made of 34 cases (33%) of myocardial infarction trans and immediately postoperative which occurred in 11,210 surgical interventions with and without extracorporeal circulation. 2. This presents a statistical relation of the frequency of myocardial infarction in realtion to the heart disease acquired with or without extracorporeal circulation with the mitral, aortic, and double prosthesis of the mitral and aortic valves. A correlation was also made with the ischemic heart disease subjected to revascularization. The same analysis was carried out in the congenital heart disease with or without extracorporeal circulation. 3. In all cases the antecedents, precipitating factors, and the clinical picture were studied and in 12 cases the necropsy was analized. The principal finding was transmural myocardial infarction with electrocardiographic proof and serial enzymes. 4. The group was divided into two sub-groups; Group "A" with acute myocardial infarction transoperative, and Group "B" with acute myocardial infarction in the first eight postoperative days. The electrical and mechanical complications were analized. 5. A correlation was made of the causes of mortality related to the type of congenital or acquired heart disease with or without extracorporeal circulation. 6. The frequency of this entity was studied with the total time of aortic clamping, and the complications such as the low cardiac output syndrome, rupture of the wall, aneurysms, acute pulmonary edema, and with the disturbances of rhythm and conduction. 7. The presence of 33.3% of normal coronaries in these of necropsy was emphasized. 8. The importance of the coronary profile of this group in relation to the consequences of a stress from anesthesia, surgery, extracorporeal circulation, and aortic clamping is mentioned. 9. The diagnostic parameters such as arterial hypotension with or without the low cardiac output syndrome, enzyme levels, and the action of the potassium ion are mentioned. 10. An analysis is made of the possible etiological factors of the precipitation of the myocardial necrosis in the cases with normal coronaries and those in which there was no important obstruction of the coronary macrocirculation. 11. In the subgroup "A" it was found that the frequency of myocardial infarction was less than in the subgroup "B", but there was greater mortality in group "A". The possible causal factors are analized.


[Neuro-Behçet: clinicopathological findings in an autopsy case].
Behçet's disease (BD) was first described by Hulusi Behçet in 1937 as a triad of oral aphthae, genital ulcers and uveitis. It affects most of tissues and organs without exception and has a prevalence of neurologic involvement between 5 and 30%. Histopathological research of autopsy cases is limited, even though the cause of death is confirmed in this study. A 30-years-old man without prior medical history of interest debuting with a BD with progressive neurological manifestations and fatal evolution. The autopsy showed, in gross examination, oral and scrotal ulcers. Moreover, the brain revealed a marked cerebral edema, opaque leptomeninges and hemorrhagic infarction of the left frontal lobule extended to the homolateral ventricular cavity. In the brain stem, multiples hemorrhagic infarctions and hemorrhage in the fourth ventricle. The microscopic examination showed a generalized perivascular lymphocytic and neutrophilic inflammation in small and medium vessels with intense diapedesis bleeding. This phenomenon was predominant in brain stem. The necropsy studies of patients with neuro-Behcet's disease are scarce. We report the clinicopathological findings in a patient with BD and neurological involvement, in which stands out a cerebral vascular affectation predominant in brain stem.


Solubilization and growth of Candida pseudotropicalis in water-in-oil microemulsions.
Some new aspects of microbiology in water-in-oil microemulsions are investigated using Candida pseudotropicalis in a hexadecane solution containing Tween85/Span80 (each 5% wt:wt) as surfactant, and limited amount of water (up to 3%, vol:vol), Microemulsion solutions containing cells up to 10 mg fresh weight per milliliter can be prepared, which display a greater time stability and a much smaller light scattering than aqueous suspensions having the same cell concentration. This is ascribed to a lower aggregation tendency of the cells in the microemulsion environment. It is also shown that C. pseudotropicalis cells are able to grow (up to a factor of approximately 6-7 within a few days) in the microemulsion system containing nutrient medium in the aqueous microphase; but they are also able to grow at the expense of the hexadecane. This is proved with radioactive-labeled hexadecane by measuring the increase of radioactivity in the cells as well as the emission of (14)CO(2). The growth rate of the cells is then compared with the growth rate of cellular proteins during cell reproduction in the microemulsion system. Two regimes are observed: a first one, in which cells growth rate and protein growth rate proceed parallel to each other; and a second one (established after 0.5-1 day) characterized by depletion of proteins in the microemulsion system. The implications of these findings for cell metabolism in microemulsion and for possible biotechnological applications are discussed.


Importance of monitoring in high risk surgical patients.
Increased metabolic requirements by surgical trauma is responsible of the changes in cardiac index and oxygen delivery (DO2), represent compensatory adaptation in circulatory functions stimulated by increased metabolic needs. The amount of this compensation varies with age, gender, severity of illness, operation type, associated medical conditions, shock duration, complications, organ failure, and outcome. Hypotension, low cardiac index, arterial hemoglobin desaturation, low oxygen delivery, and low oxygen consumption served and sometimes are persistent over time; these abnormalities were more notorious in the nonsurvivors than in the survivors. Lethal circulatory dysfunctions may begin during the intraoperative period but become more apparent before and are responsible of organ failure during postoperative stages. An approach that measures adequacy of tissue perfusion is a fundamental objective in anesthesia and critical care medicine. Traditional measures of tissue perfusion have included arterial pressure monitoring, urine output, arterial pH and blood lactate. These measures have major limitations, and changes in these measures may significantly lag behind clinical interventions. After trauma and major surgery despite normalization of these variables, global tissue hypoxia may still persist. Unrecognized or untreated conditions may lead to organ failure and death. In critical or high risk patients, early invasive monitoring is necessary to precisely define the adequacy of the cardiac response and to individually tailor therapy. The care provided in the first hours significantly impacts the progression of organ failure and mortality. Although this period is brief compared with the total length of hospitalization, physiological determinants of outcome may be established before ICU admission. Early postoperative monitoring revealed differences in survivor and nonsurvivor patterns and provided goals for improving outcome.


[Effect of high dosages of fentanyl and piritramide upon haemodynamics, coronary blood flow and myocardial oxygen consumption (author's transl)].
High dosages of narcotic analgesics are frequently utilized as the sole anaesthetic agents for patients requiring open-heart surgery. The purpose of this study was to investigate the effect of high dosages of fentanyl and piritramide upon the cardiovascular system. In anaesthetized dogs (N2O:O2=2:1; 0.5 vol% halothane) 0.03 mg/kg fentanyl (=8) and 1.5 mg/kg piritramide (n=8) respectively were given intravenously as a bolus. After the administration of fentanyl there was a slight decrease in blood pressure (10%). The hypotension was the result of a decrease in cardiac output (thermodilution technique) by 13% due to bradycardia. Total peripheral resistance and myocardial contractility remained unaffected. Similar effects were only found late after injection of piritramide, since there was an initial cardiovascular response to piritramide characterized by a marked fall in blood pressure (29%). The major cause of arterial hypotension was peripheral vasodilatation. Load data and the decrease in max dp/dt however indicated also a slight myocardial depression. The altered haemodynamics led to a decrease in myocardial oxygen consumption with both narcotics, which was nearly paralleled by a reduction in coronary blood flow. The narrowing of arteriovenous oxygen difference of the heart proved coronary dilatatory properties of fentanyl and especially of piritramide. This study indicated that high dosages of fentanyl have advantages in comparison to high dosages of piritramide. The clinical implications of the results are discussed.


Differential expression profile analysis of cisplatin‑regulated miRNAs in a human gastric cancer cell line.
Cisplatin, one of the most commonly used drugs in combination chemotherapy, is an effective anti‑tumor agent widely used for diverse tumor types. MicroRNAs (miRNAs/miRs) are involved in the occurrence, development, diagnosis and treatment of cancer. Therefore, the aim of the current study was to explore whether cisplatin exerts anticancer effects by causing differential expression of miRNAs in human gastric cancer cells. The human gastric cancer cell line NCI‑N87 was cultured with a certain dose of cisplatin and high‑throughput sequencing combined with reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) was performed to detect cisplatin‑regulated miRNAs. miRNAs upregulated and downregulated following cisplatin exposure were analyzed. High‑throughput sequencing revealed 33 upregulated and 16 downregulated miRNAs. A total of five significantly upregulated and five significantly downregulated miRNAs were identified by RT‑qPCR. The expression levels of hsa‑miR‑1246 and hsa‑miR‑892b were consistent with the results obtained from high‑throughput sequencing. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway clustering of cisplatin‑regulated miRNAs revealed that the miRNAs regulated genes involved in several biological processes and signaling pathways. The results obtained in the current study suggested that cisplatin may exert an important anticancer effect in gastric cancer via complex biological processes and signaling pathways.


Combining prenylation inhibitors causes synergistic cytotoxicity, apoptosis and disruption of RAS-to-MAP kinase signalling in multiple myeloma cells.
The high incidence of activating RAS mutations, coupled with accumulating evidence linking RAS to multiple myeloma (MM) pathogenesis, indicate that novel therapies utilising inhibitors of RAS prenylation and signalling may be successful in the management of this disease. While preclinical studies investigating prenylation inhibitors, such as lovastatin, farnesyltransferase inhibitors (FTI) and geranylgeranyltransferase inhibitors (GGTI), have been promising, recent phase I/II clinical trials with FTI R115777 were disappointing, suggesting resistance to FTI monotherapy. To address this issue, the effects of FTI, GGTI and lovastatin alone and in combination were analysed in MM cell lines and primary cells. FTI treatment blocked H-RAS processing, but was ineffective at inhibiting K- and N-RAS prenylation because of alternative geranylgeranylation of these isoforms. However, combinations of FTI and GGTI or lovastatin were found to synergistically inhibit MM cell proliferation, migration, K- and N-RAS processing, RAS-to-mitogen-activated protein kinase signalling and to induce apoptosis. In contrast to FTI, lovastatin and some GGTI were found to cause intracellular accumulation of Rho proteins. Our results suggest that clinical efficacy of prenylation inhibitors in MM are limited by alternative prenylation of several small G-proteins, such as RhoB, K- and N-RAS. Furthermore, strategies combining FTI with GGTI or statins may provide greater efficacy in MM treatment.


A patient-safety and professional perspective on non-conveyance in ambulance care: a systematic review.
This systematic review aimed to describe non-conveyance in ambulance care from patient-safety and ambulance professional perspectives. The review specifically focussed at describing (1) ambulance non-conveyance rates, (2) characteristics of non-conveyed patients, (3) follow-up care after non-conveyance, (4) existing guidelines or protocols, and (5) influencing factors during the non-conveyance decision making process. We systematically searched MEDLINE, PubMed, CINAHL, EMBASE, and reference lists of included articles, in June 2016. We included all types of peer-reviewed designs on the five topics. Couples of two independent reviewers performed the selection process, the quality assessment, and data extraction. We included 67 studies with low to moderate quality. Non-conveyance rates for general patient populations ranged from 3.7%-93.7%. Non-conveyed patients have a variety of initial complaints, common initial complaints are related to trauma and neurology. Furthermore, vulnerable patients groups as children and elderly are more represented in the non-conveyance population. Within 24 h-48 h after non-conveyance, 2.5%-6.1% of the patients have EMS representations, and 4.6-19.0% present themselves at the ED. Mortality rates vary from 0.2%-3.5% after 24 h, up to 0.3%-6.1% after 72 h. Criteria to guide non-conveyance decisions are vital signs, ingestion of drugs/alcohol, and level of consciousness. A limited amount of non-conveyance guidelines or protocols is available for general and specific patient populations. Factors influencing the non-conveyance decision are related to the professional (competencies, experience, intuition), the patient (health status, refusal, wishes and best interest), the healthcare system (access to general practitioner/other healthcare facilities/patient information), and supportive tools (online medical control, high risk card). Non-conveyance rates for general and specific patient populations vary. Patients in the non-conveyance population present themselves with a variety of initial complaints and conditions, common initial complaints or conditions are related to trauma and neurology. After non-conveyance, a proportion of patients re-enters the emergency healthcare system within 2 days. For ambulance professionals the non-conveyance decision-making process is complex and multifactorial. Competencies needed to perform non-conveyance are marginally described, and there is a limited amount of supportive tools is available for general and specific non-conveyance populations. This may compromise patient-safety.


Comparison of outcomes for patients with and without a serious mental illness presenting to hospital for chronic obstruction pulmonary disease: retrospective observational study using administrative data.
There are few data on the profile of those with serious mental illness (SMI) admitted to hospital for physical health reasons. To compare outcomes for patients with and without an SMI admitted to hospital in England where the primary reason for admission was chronic obstructive pulmonary disease (COPD). This was a retrospective, observational analysis of the English Hospital Episodes Statistics data-set for the period from 1 April 2018 to 31 March 2019, for patients aged 18-74 years with COPD as the dominant reason for admission. Patient with an SMI (psychosis spectrum disorder, bipolar disorder) were identified. Data were available for 54 578 patients, of whom 2096 (3.8%) had an SMI. Patients with an SMI were younger, more likely to be female and more likely to live in deprived areas than those without an SMI. The burden of comorbidity was similar between the two groups. After adjusting for covariates, SMI was associated with significantly greater risk of length of stay than the median (odds ratio 1.24, 95% CI 1.12-1.37, P ≤ 0.001) and with 30-day emergency readmission (odds ratio 1.51, 95% confidence interval 1.34-1.69, P ≤ 0.001) but not with in-hospital mortality. Clinicians should be aware of the potential for poorer outcomes in patients with an SMI even when the SMI is not the primary reason for admission. Collaborative working across mental and physical healthcare provision may facilitate improved outcomes for people with SMI.


HIF-1α restricts NF-κB-dependent gene expression to control innate immunity signals.
Hypoxia and inflammation are intimately linked. It is known that nuclear factor κB (NF-κB) regulates the hypoxia-inducible factor (HIF) system, but little is known about how HIF regulates NF-κB. Here, we show that HIF-1α represses NF-κB-dependent gene expression. HIF-1α depletion results in increased NF-κB transcriptional activity both in mammalian cells and in the model organism Drosophila melanogaster. HIF-1α depletion enhances the NF-κB response, and this required not only the TAK-IKK complex, but also CDK6. Loss of HIF-1α results in an increased angiogenic response in mammalian cancer cells and increased mortality in Drosophila following infection. These results indicate that HIF-1α is required to restrain the NF-κB response, and thus prevents excessive and damaging pro-inflammatory responses.


Location of appendix in pregnancy: does it change?
This study aimed to determine the change in anatomical location of appendix in full-term pregnancy. This was a descriptive cross-sectional study. Liaquat National University Hospital, Karachi, Pakistan, Department of General Surgery, January 01 to July 31, 2010. Full-term pregnant women undergoing caesarean section were enrolled. The anatomical position of the appendix was noted by visual inspection with reference to the transtubercular plane (TTP). SPSS-10 was used for analysis. Seventy-seven full-term pregnant female patients who underwent caesarean section were included in the study. Their mean age was 29 years, the mean height was 5.3 feet, and mean gestational age was 38 weeks. Appendix was found at the normal anatomical location in 63 out of 77 patients (81.8%), while it was located above the TTP in 14 patients (18.2%). Appendix does not migrate up with increasing gestational age in the majority of pregnant women. In most full-term pregnant female patients, appendix is located at the normal anatomical position.


Concurrence of turner's syndrome and anorexia nervosa.
The ninth known case of the concurrence of anorexia nervosa and Turner's syndrome is presented. The question whether the presence of Turner's syndrome represents a greater risk for a patient to develop anorexia nervosa is considered.


Acute ethanol inhibits calcium influxes into esophageal smooth but not striated muscle: a possible mechanism for ethanol-induced inhibition of esophageal contractility.
In both humans and cats, EtOH administered in vivo and acutely decreases contractility of smooth muscle of lower esophageal sphincter (LES) and lower esophagus (LE), but not striated muscle of upper esophagus. To see if these effects are associated with perturbation of Ca++ homeostasis, esophageal muscle slices were incubated in vitro with EtOH and then 45Ca++. At steady-state Ca++ uptake, some slices were exposed to 1 microM carbachol (CCH). Although 100 mM EtOH had no effect on Ca++ uptake into resting or stimulated striated muscle of upper esophagus, it significantly inhibited Ca++ uptake into smooth muscle of LES and LE. For unstimulated LE and resting LES, 100 mM EtOH significantly inhibited both initial uptake and steady-state levels, whereas lower doses had no significant effect. EtOH at 100 mM also affected changes in Ca++ content induced by CCH stimulation. CCH increased total exchangeable tissue Ca++ content in LE, whereas it decreased Ca++ content in LES. EtOH at 100 mM blunted these CCH-induced effects in both LES and LE. In contrast to resting muscle, inhibition of CCH-stimulated LE muscle was not limited to 100 mM EtOH, because substantial and significant inhibition was also seen at EtOH doses of 25 and 50 mM, doses which are relevant even in social drinking. Thus, EtOH inhibition of Ca++ influx into esophageal muscle is selective for smooth muscle, can occur at pharmacologically relevant EtOH doses and could be the underlying mechanism for EtOH's inhibition of contractility of esophageal smooth muscle.


Predictors of deterioration of lung function in cystic fibrosis.
The severity of lung disease in cystic fibrosis (CF) may be related to the type of mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, and to environmental and immunological factors. Since pulmonary disease is the main determinant of morbidity and mortality in CF, it is important to identify factors that can explain and predict this variation. The aim of this longitudinal study of the whole Swedish CF population over age 7 years was to correlate genetic and clinical data with the rate of decline in pulmonary function. The statistical analysis was performed using the mixed model regression method, supplemented with calculation of relative risks for severe lung disease in age cohorts.The severity of pulmonary disease was to some extent predicted by CFTR genotype. Furthermore, the present investigation is the first long-term study showing a significantly more rapid deterioration of lung function in patients with concomitant diabetes mellitus. Besides diabetes mellitus, pancreatic insufficiency and chronic Pseudomonas colonization were found to be negative predictors of pulmonary function. In contrast to several other reports, we found no significant differences in lung function between genders. Patients with pancreatic sufficiency have no or only a slight decline of lung function with age once treatment is started, but an early diagnosis in this group is desirable.


Electrophysiological effects of capsaicin on guinea pig papillary muscles.
The cardiac electrophysiological effects of capsaicin (CAP) were examined in guinea pig papillary muscles using intracellular microelectrode technique. The results obtained are as follows: (1) the duration of action potential (APD) in normal papillary muscles was decreased by CAP (30, 60, 120 micromol/L) in a concentration-dependent manner; (2) in partially depolarized papillary muscles, 60 micromol/L CAP not only reduced APD, but also decreased the amplitude of action potential, overshoot and maximal velocity of phase 0 depolarization; (3) pretreatment with L-type Ca(2+) channel agonist Bay K8644 (0.5 micromol/L) could completely block the effects of CAP (60 micromol/L); (4) pretreatment with ruthenium red (20 micromol/L), a vanilloid receptor (VR) blocker, did not affect the actions of capsaicin on papillary muscles. All these results suggest that the effects of CAP on papillary muscles are likely due to a decrease in calcium influx which is not mediated by VR.


Dietary protein, aging and nutritional geometry.
Nearly a century of research has shown that nutritional interventions can delay aging and age- related diseases in many animal models and possibly humans. The most robust and widely studied intervention is caloric restriction, while protein restriction and restriction of various amino acids (methionine, tryptophan) have also been shown to delay aging. However, there is still debate over whether the major impact on aging is secondary to caloric intake, protein intake or specific amino acids. Nutritional geometry provides new perspectives on the relationship between nutrition and aging by focusing on calories, macronutrients and their interactions across a landscape of diets, and taking into account compensatory feeding in ad libitum-fed experiments. Nutritional geometry is a state-space modelling approach that explores how animals respond to and balance changes in nutrient availability. Such studies in insects and mice have shown that low protein, high carbohydrate diets are associated with longest lifespan in ad libitum fed animals suggesting that the interaction between macronutrients may be as important as their total intake.


Sexual function in women in rural Tamil Nadu: disease, dysfunction, distress and norms.
We examined the nature, prevalence and explanatory models of sexual concerns and dysfunction among women in rural Tamil Nadu. Married women between 18 and 65 years of age, from randomly selected villages in Kaniyambadi block, Vellore district, Tamil Nadu, were chosen by stratified sampling technique. Sexual functioning was assessed using the Female Sexual Function Index (FSFI). The modified Short Explanatory Model Interview (SEMI) was used to assess beliefs about sexual concerns and the General Health Questionnaire-12 (GHQ-12) was used to screen for common mental disorders. Sociodemographic variables and other risk factors were also assessed. Most of the women (277; 98.2%) contacted agreed to participate in the study. The prevalence of sexual dysfunction, based on the cut-off score on the FSFI, was 64.3%. However, only a minority of women considered it a problem (4.7%), expressed dissatisfaction (5.8%) or sought medical help (2.5%). The most common explanatory models offered for sexual problems included an unhappy marriage,stress and physical problems. Factors associated with lower FSFI included older age, illiteracy, as well as medical illness and sexual and marital factors such as menopause, poor quality of marital relationship, history of physical abuse and lack of privacy. The diagnosis of female sexual dysfunction needs to be nuanced and based on the broader personal and social context. Our findings argue that there is a need to use models that employ personal, local and contextual standards in assessing complex behaviours such as sexual function.


Are cause of subfertility and in vitro fertilization treatment risk factors for an earlier start of menopause?
To study whether women diagnosed with unexplained subfertility reach the menopause transition and natural menopause earlier than women with tubal subfertility, in an in vitro fertilization (IVF)-treated population, and to examine the influence of the number of IVF cycles on the occurrence of an early menopause transition and natural menopause. This retrospective cohort study included 12 IVF clinics in the Netherlands. A nationwide retrospective cohort study was conducted among women whose first IVF cycle was stimulated with gonadotrophins in the Netherlands between 1983 and 1995 (n = 7,842). Most of the women were in their late 30s at the end of the follow-up period (range 24-55 y). The main outcome measures were the relative risk (RR) of having reached natural menopause and the risks (RR) of having entered the menopause transition or natural menopause according to the cause of subfertility and the number of IVF cycles. Women with unexplained subfertility did not have an increased risk of entering the menopause transition or natural menopause (adjusted RR = 0.5; 95% CI, 0.2-1.5; and RR = 0.8; 95% CI, 0.6-1.1). After a 5-year follow-up period, we found no increased risk for entering the menopause transition or natural menopause among women who had undergone six or more IVF cycles when compared with women who had undergone only one IVF cycle (adjusted RR = 0.4; 95% CI, 0.1-1.7; and RR = 0.9; 95% CI, 0.6-1.6). Underlying causes of unexplained subfertility do not predispose women to an early start of menopause. Although the number of IVF cycles was not associated with early menopause, longer follow-up is needed.


Standardized guinea pig model for Q fever vaccine reactogenicity.
Historically, vaccination with Coxiella burnetii whole cell vaccines has induced hypersensitivity reactions in humans and animals that have had prior exposure to the pathogen as a result of infection or vaccination. Intradermal skin testing is routinely used to evaluate exposure in humans, and guinea pig hypersensitivity models have been developed to characterize the potential for reactogenicity in vaccine candidates. Here we describe a refinement of the guinea pig model using an alternate vaccine for positive controls. An initial comparative study used viable C. burnetii to compare the routes of sensitizing exposure of guinea pigs (intranasal vs intraperitoneal), evaluation of two time points for antigen challenge (21 and 42 days) and an assessment of two routes (intradermal and subcutaneous) of challenge using the ruminant vaccine Coxevac as the antigenic control. Animals sensitized by intraperitoneal exposure exhibited slightly larger gross reactions than did those sensitized by intranasal exposure, and reactions were more pronounced when skin challenge was performed at 42 days compared to 21 days post-sensitization. The intradermal route proved to be the optimal route of reactogenicity challenge. Histopathological changes at injection sites were similar to those previously reported and a scoring system was developed to compare reactions between groups receiving vaccine by intradermal versus subcutaneous routes. Based on the comparative study, a standardized protocol for assessment of vaccine reactogenicity in intranasally-sensitized animals was tested in a larger confirmatory study. Results suggest that screens utilizing a group size of n = 3 would achieve 90% power for detecting exposure-related reactogenic responses of the magnitude induced by Coxevac using either of two outcome measures.


Biophotonic patterns of optical interactions between fish eggs and embryos.
The optical (non-substantial) interactions between various biological samples have been evident in a number of cases mainly by the effects on their functional activity and developmental patterns. However, the mechanisms of these interactions have remained obscure. Effect of optical interaction has been observed on the intensity and Fourier patterns of biophoton emission of fish embryos. We demonstrate that: (1) the short-term optical interactions are accompanied by a gradual decrease of a total emission intensity of the interacting batches; (2) this effect is spread laterally to that part of a batch which does not have any direct optical contacts with its partner; and (3) the long-term optical contacts lead to a mutual exchange of spectral characteristics of interacting batches in which the total spectral density values are reversed (often with an overshoot). The reversal rate depends upon the developmental distance between the optical partners and the initial differences of their spectral characteristics. The results are discussed in terms of a sub-radiance and Le Chatelier principle.


Selenium and vitamin E improve the in vitro maturation, fertilization and culture to blastocyst of porcine oocytes.
Selenium (Se) and vitamin E (Vit-E), as integral parts of antioxidant systems, play important roles for sperm and embryos in vitro. In this study, the effects of Se and Vit-E on the maturation, in vitro fertilization and culture to blastocysts of porcine oocytes and accumulation of ammonia in the culture medium during different development stages were investigated. The maturation was performed in modified tissue culture medium (mTCM)-199 supplemented with 10% (v/v) porcine follicular fluid, the fertilization medium was modified Tyrode's albumin lactate pyruvate (mTALP), and the embryo culture medium was modified North Carolina State University (mNCSU)-23. Se in the form of sodium selenite (SS) and seleon-L-methionine (SeMet) and Vit-E at different concentrations were also used. The incorporation and oxidation of (14)C(U)-glucose were assessed with a liquid scintillation counter. In this study, SeMet and SeMet+Vit-E increased oocyte maturation, fertilization and incorporation and oxidation of (14)C(U)-glucose significantly (P<0.05) compared with the control and other treatments. In addition, embryo development, specifically in terms of the numbers of morulae and blastocysts, significantly increased (P<0.05) with SeMet and SeMet+Vit-E. In contrast, the accumulation of ammonia was reduced with SeMet and SeMet+Vit-E compared with other treatments. These findings indicate that SeMet and SeMet+Vit-E may play important roles in reducing the accumulation of ammonia and subsequently in increasing the rate of maturation of porcine oocytes and fertilization, as well as development of the blastocyst and utilization of glucose in in vitro maturation, fertilization and culture to blastocysts of porcine oocytes.


Glycogen turnover forms lactate during exercise.
The power needs of muscle are supplied by rapid anaerobic glycogenolytic ATP generation. Lactate is built up by the mismatch between steady state energy needs and short-term power demands and the increased concentration drives the lactate shuttle. In this model, contributions to fatigue should be looked for in the flux of glucose through glycogen rather than in the concentrations of fuel.


Dynamic Interaction of Enterovirus 71 and Dendritic Cells in Infected Neonatal Rhesus Macaques.
Enterovirus 71 (EV71) is one of the main pathogens responsible for hand, foot, and mouth disease (HFMD). Infection with EV71 can lead to severe clinical disease via extensive infections of either the respiratory or alimentary tracts in children. Based on the previous pathological study of EV71 infections in neonatal rhesus macaques, our work using this animal model and an EV71 chimera that expresses enhanced green fluorescent protein (EGFP-EV71) primarily explored where EV71 localizes and proliferates, and the subsequent initiation of the pathological process. The chimeric EGFP-EV71 we constructed was similar to the wild-type EV71 (WT-EV71) virus in its biological characteristics. Similar clinical manifestations and histo-pathologic features were equally displayed in neonatal rhesus macaques infected with either WT-EV71 or EGFP-EV71 via the respiratory route. Fluorescent signal tracing in tissues from the animals infected with EGFP-EV71 showed that EV71 proliferated primarily in the respiratory tract epithelium and the associated lymphoid tissues. Immunofluorescence and flow cytometry analyses revealed that EV71 was able to enter a pre-conventional dendritic cell (DC) population at the infection sites. The viremia identified in the macaques infected by WT-EV71 or EGFP-EV71 was present even in the artificial presence of a specific antibody against the virus. Our results suggest that EV71 primarily proliferates in the respiratory tract epithelium followed by subsequent entry into a pre-cDC population of DCs. These cells are then hijacked by the virus and they can potentially transmit the virus from local sites to other organs through the blood circulation during the infection process. Our results suggest that the EV71 infection process in this DC population does not interfere with the induction of an independent immune response against the EV71 infection in the neonatal macaques.


The assessment of antenatal emotional attachment: development of a questionnaire instrument.
The nature of the relationship which female and male expectant parents develop during pregnancy with their unborn baby has both theoretical and clinical significance. It potentially provides a framework for improved understanding of many aspects of psychosomatic obstetrics, including reactions to foetal loss. Existing instruments designed to assess this relationship inadequately differentiate between attitude to the foetus per se versus attitude to the pregnancy state or motherhood role. The present paper presents a theoretical model of the subjective experiences of human attachment. This is utilized to develop a questionnaire to assess the antenatal attachment construct. Item analysis results in a 19-item maternal and 16-item paternal questionnaire with high levels of internal consistency. Each takes approximately five minutes to complete. Finally, the factor structures of the resultant questionnaires are explored.


Understanding the influence of trenbolone acetate and polyamines on proliferation of bovine satellite cells.
Approximately 90% of beef cattle on feed in the United States receive at least one anabolic implant, which results in increased growth, efficiency, and economic return to producers. However, the complete molecular mechanism through which anabolic implants function to improve skeletal muscle growth remains unknown. This study had 2 objectives: (1) determine the effect of polyamines and their precursors on proliferation rate in bovine satellite cells (BSC); and (2) understand whether trenbolone acetate (TBA), a testosterone analog, has an impact on the polyamine biosynthetic pathway. To address these, BSC were isolated from 3 finished steers and cultured. Once cultures reached 75% confluency, they were treated in 1% fetal bovine serum (FBS) and/or 10 nM TBA, 10 mM methionine (Met), 8 mM ornithine (Orn), 2 mM putrescine (Put), 1.5 mM spermidine (Spd), or 0.5 mM spermine (Spe). Initially, a range of physiologically relevant concentrations of Met, Orn, Put, Spd, and Spe were tested to determine experimental doses to implement the aforementioned experiments. One, 12, or 24 h after treatment, mRNA was isolated from cultures and abundance of paired box transcription factor 7 (Pax7), Sprouty 1 (Spry), mitogen-activated protein kinase-1 (Mapk), ornithine decarboxylase (Odc), and S adenosylmethionine (Amd1) were determined, and normalized to 18S. No treatment × time interactions were observed (P ≥ 0.05). Treatment with TBA, Met, Orn, Put, Spd, or Spe increased (P ≤ 0.05) BSC proliferation when compared with control cultures. Treatment of cultures with Orn or Met increased (P ≤ 0.01) expression of Odc 1 h after treatment when compared with control cultures. Abundance of Amd1 was increased (P < 0.01) 1 h after treatment in cultures treated with Spd or Spe when compared with 1% FBS controls. Cultures treated with TBA had increased (P < 0.01) abundance of Spry mRNA 12 h after treatment, as well as increased mRNA abundance of Mapk (P < 0.01) 12 h and 24 h after treatment when compared with 1% FBS control cultures. Treatment with Met increased (P < 0.01) mRNA abundance of Pax7 1 h after treatment as compared with 1% FBS controls. These results indicate that treatments of BSC cultures with polyamines and their precursors increase BSC proliferation rate, as well as abundance of mRNA involved in cell proliferation. In addition, treatment of BSC cultures with TBA, polyamines, or polyamine precursors impacts expression of genes related to the polyamine biosynthetic pathway and proliferation.


Racial Capitalism Within Public Health-How Occupational Settings Drive COVID-19 Disparities.
Epidemiology of the US coronavirus disease 2019 (COVID-19) outbreak focuses on individuals' biology and behaviors, despite centrality of occupational environments in the viral spread. This demonstrates collusion between epidemiology and racial capitalism because it obscures structural influences, absolving industries of responsibility for worker safety. In an empirical example, we analyzed economic implications of race-based metrics widely used in occupational epidemiology. In the United States, White adults have better average lung function and worse hearing than Black adults. Impaired lung function and impaired hearing are both criteria for workers' compensation claims, which are ultimately paid by industry. Compensation for respiratory injury is determined using a race-specific algorithm. For hearing, there is no race adjustment. Selective use of race-specific algorithms for workers' compensation reduces industries' liability for worker health, illustrating racial capitalism operating within public health. Widespread and unexamined belief in inherent physiological inferiority of Black Americans perpetuates systems that limit industry payouts for workplace injuries. We see a parallel in the epidemiology of COVID-19 disparities. We tell stories of industries implicated in the outbreak and review how they exemplify racial capitalism. We call on public health professionals to critically evaluate who is served and neglected by data analysis and to center structural determinants of health in etiological evaluation.


Superior mesenteric artery syndrome coexists with Nutcracker syndrome in a female: a case report.
Superior mesenteric artery (SMA) syndrome, also known as Wilkie's syndrome or Benign duodenal stasis, is a rare benign disease. It could threaten the life if the manifestation is severe and the treatment is inappropriate. In the patients with SMA syndrome, the third portion (transverse part) of the duodenum is compressed externally between the SMA and abdominal aorta (AA) leading to duodenal stasis and gastrointestinal obstruction. SMA syndrome may rarely combine with Nutcracker syndrome when left renal vein (LRV) was compressed between SMA and AA. A 32-year-old female patient presented with complaints of gradually severe bloating, epigastric pain, left flank ache, nausea and occasional vomiting of 1 month's duration. The epigastric and left flank ache was aggravated when the patient was supine and relieved in a prone or left lateral decubitus. The abdominal bloating was associated with early satiety. The vomiting always started 40 min after meal. The patient gave a history of urine stone with drotaverine hydrochloride tablets treatment for two weeks before the gastrointestinal symptoms arising. The patient had no significant surgical history, but had a rapid weight loss of approximately 10 kg with a body mass index (BMI) from 21 kg/m2 to less than 18 kg/m2 over the last two months. An abdominal examination revealed upper abdominal tenderness and distention. The urine routine examination showed no significant abnormality. The findings of initial blood tests and other laboratory investigations were unremarkable. This case reports a female patient with SMA syndrome with Nutcracker syndrome predisposed by Antispasmodics. We highlight the importance of the combination therapy of long-term nutritional supporting and prokinetic agents. Rehabilitating practice after discharge is beneficial to reduce recurrence.


Staphylococcal peptidoglycan interpeptide bridge biosynthesis: a novel antistaphylococcal target?
In staphylococci, crosslinking of the peptide moiety of peptidoglycan is mediated via an additional spacer, the interpeptide bridge, consisting of five glycine residues. The femAB operon, coding for two approximately 50-kDa proteins is known to be involved in pentaglycine bridge formation. Using chemical mutagenesis of the beta-lactam-resistant strain BB270 and genetic, biochemical, and biophysical characterization of mutants selected for loss of beta-lactam resistance and reduced lysostaphin sensitivity it is shown that peptide bridge formation proceeds via three intermediate bridge lengths (cell wall peptides with no, one, three, and five glycine units). To proceed from one intermediate to the next, three genes appear necessary: femX, femA, and femB. The drastic loss of beta-lactam resistance after inactivation of FemA or partial impairment of FemX even beyond the level of the sensitive wild-type strains renders these proteins attractive antistaphylococcal targets.


Developing a Workflow Composite Score to Measure Clinical Information Logistics. A Top-down Approach.
Availability and usage of individual IT applications have been studied intensively in the past years. Recently, IT support of clinical processes is attaining increasing attention. The underlying construct that describes the IT support of clinical workflows is clinical information logistics. This construct needs to be better understood, operationalised and measured. It is therefore the aim of this study to propose and develop a workflow composite score (WCS) for measuring clinical information logistics and to examine its quality based on reliability and validity analyses. We largely followed the procedural model of MacKenzie and colleagues (2011) for defining and conceptualising the construct domain, for developing the measurement instrument, assessing the content validity, pretesting the instrument, specifying the model, capturing the data and computing the WCS and testing the reliability and validity. Clinical information logistics was decomposed into the descriptors data and information, function, integration and distribution, which embraced the framework validated by an analysis of the international literature. This framework was refined selecting representative clinical processes. We chose ward rounds, pre- and post-surgery processes and discharge as sample processes that served as concrete instances for the measurements. They are sufficiently complex, represent core clinical processes and involve different professions, departments and settings. The score was computed on the basis of data from 183 hospitals of different size, ownership, location and teaching status. Testing the reliability and validity yielded encouraging results: the reliability was high with r(split-half) = 0.89, the WCS discriminated between groups; the WCS correlated significantly and moderately with two EHR models and the WCS received good evaluation results by a sample of chief information officers (n = 67). These findings suggest the further utilisation of the WCS. As the WCS does not assume ideal workflows as a gold standard but measures IT support of clinical workflows according to validated descriptors a high portability of the WCS to other hospitals in other countries is very likely. The WCS will contribute to a better understanding of the construct clinical information logistics.


Maintaining Safety in the Prison Environment: A Multilevel Analysis of Inmate Victimisation in Assaults.
Theoretical models of victimisation emphasise the importance of context. However, few studies have assessed the influence of prison environmental variables on inmate harm in physical assaults. This study used a multilevel model approach to examine individual- and facility-level factors associated with the incidence of assaults among inmates housed at correctional centres in New South Wales, Australia. Results supported proposals that institutional routines and conditions may have an influence on risk. Inmates, who spent less time in employment, were placed in special housing arrangements such as protection, or were located in sites with higher security designations or longer routine hours out of cells were more likely to be harmed in assaults. In addition, more than 40% of variance in assaults was associated with differences across correctional centre sites. We draw on routine activities theory to explain relationships between different prison contexts, provision of guardianship, and exposure to motivated offenders in assault outcomes.


Anterior pituitary dopamine receptors. Demonstration of interconvertible high and low affinity states of the D-2 dopamine receptor.
The interactions of dopaminergic agonists and antagonists with binding sites in bovine anterior pituitary membranes have been investigated with radioligand-binding techniques and computer-modeling procedures. 3H-labeled agonist binding is stereospecific, reversible, saturable, and of high affinity. The rank order of catecholamines, phenothiazines, and related drugs in competing for 3H-agonist binding is indicative of interactions with a D-2 dopamine receptor. Both agonist/3H-agonist and antagonist/3H-agonist competition curves are monophasic and noncooperative (nH = 1) with computer analysis indicating a single class of binding sites. Specific 3H-agonist binding can be completely inhibited by guanine nucleotides. GppNHp us the most potent nucleotide followed by GTP and GDP which are equipotent. The equilibrium binding capacity for 3H-labeled antagonists is twice that for 3H-agonists. Unlabeled antagonists inhibit 3H-antagonist binding competitively and exhibit antagonist/3H-antagonist competition curves which model best to a state of homogeneous affinity. In contrast, unlabeled agonists inhibit 3H-antagonist binding in a heterogeneous fashion displaying multiphasic (nH less than 1) competition curves which can be resolved into high and low affinity binding sites. In the presence of saturating concentrations of guanine nucleotides, however, the agonist/3H-antagonist curves model best to a single affinity state which is identical with the low affinity state seen in control curves. The binding data can be explained by postulating two states of the D-2 dopamine receptor, inducible by agonists but not antagonists and modulated by guanine nucleotides.


Growth of purified lacrimal acinar cells in Matrigel raft cultures.
The objective of this study was to develop a tissue culture system which closely mimics the in situ lacrimal gland for improved study of lacrimal acinar cell physiology. Highly purified preparations of lacrimal acinar cells from adult female New Zealand White rabbits were isolated and grown in suspension culture in the form of Matrigel 'rafts', i.e., aggregates of acinar cells enclosed within a Matrigel coating. The rafts were seeded onto Matrigel-coated culture plates and their growth was followed for up to 28 days. Immunohistochemistry was used to demonstrate the cellular sites of prolactin (PRL), epidermal growth factor (EGF), basic fibroblast growth factor (FGF-2), secretory component (SC) and major histocompatibility complex class-II molecules (MHC-II) within the acinar cells. By 3 days the cultures contained numerous, well-formed acini enclosed within the Matrigel. The acinar epithelial cells demonstrated histotypic polarity, with large, pale-staining, secretory granules aggregated adjacent to the lumen, and exocytotic release of secretory material into the lumen. From 5-10 days the pale-staining secretory granules decreased in number, while the lumenal contents of the acini increased in staining density. Throughout the culturing period as the pale-staining, secretory granules decreased in number, smaller more densely stained, secretory granules increased in number. The number of cells and size of acinar clusters increased steadily throughout the culturing period, and acini frequently achieved dimensions in excess of 0.5 mm. Increases in the size of acinar clusters were often accompanied by an increase in the size of the lumen. Frequently the lumen and its contents bulged asymmetrically towards one edge of the acinus. Immunhistochemistry demonstrated PRL and EGF within the lumens and within the apical cytoplasm of the acinar cells. Acini were strongly immunopositive for SC throughout the 28 day culture period, whereas immunopositivity for MHC-II molecules was strong initially, but diminished dramatically by 21 days. Immunostaining for FGF-2 was most intense on days 1 and 3, with staining throughout the cytoplasm, but became progressively more localized to the periphery of the acini as the culture period lengthened. In cultures of 1-28 days duration, Western blots of cell lysates demonstrated a major band (approximately 40 kDa) for PRL in 3-28 day preparations; a major band (approximately 80 kDa) for SC in 3 day and 7 day preparations that decreased in intensity in 14-28 day preparations; and a major band (approximately 23 kDa) for MHC-II protein in 1-21 day preparations that decreased in intensity in 28 day preparations. Lysosomes increased in number with time in culture, becoming a dominant cytoplasmic feature in 21 and 28 day cultures. Carbachol stimulation of 4 day rafts resulted in increased release of beta-hexosaminidase and SC from the rafts. The authors conclude that Matrigel rafts containing purified lacrimal gland acinar cells offer a highly advantageous system for study of lacrimal acinar cell function and one that correlates well with the in situ gland.


Dissociation of H-2 recognition by antibody and cytotoxic T cells of a cloned murine leukemia cell line.
The differential expression of H-2 specificities recognized by antibody and by cytotoxic T lymphocytes (CTL) has been studied using a clone (FY7) of the C57BL/6 leukemia cell line FBL-3 (H-2b/H-2b). Unlike C57BL/10 spleen cells, EL-4 lymphoma cells and Y57-2C leukemia cells (all H-2b/H-2b), FY7 failed to induce the primary in vitro generation of anti-H-2b CTL by (B10.A x A)F1 (H-2a/H-2a) or B10.D2 x BALB/c)F1 (H-2d/H-2d) responder spleen cells. In addition, FY7 was not lysed by, and did not competitively inhibit anti-H-2b CTL. Quantitative absorption tests with H-2Kb and H-2Db antisera revealed that FY7 expressed these antigens in quantitatively similar amounts to EL-4. The H-2Kb product of FY7 appeared to be identical with that of C57BL/10 spleen cells both in apparent molecular weight and isoelectric point. Yet FY7 failed to inhibit anti-H-2Kb CTL competitively in a cold target inhibition assay. Possible mechanisms are discussed for the lack of T-lymphocyte recognition of the H-2Kb-gene product expressed by FY7.


Biomedical approaches to improve bone healing in distraction osteogenesis: a current update and review.
Induction of new bone formation through distraction osteogenesis (DO) has widespread clinical applications in the treatment of bone defects, limb deformities, and fracture nonunion. However, a lengthy period of external fixation is usually needed to allow the new bone to consolidate, and complications such as refracture at the distraction gap are often seen. To date, little has been reported on the use of biomaterials as carrier materials for sustained release of growth factors in bone regeneration. One area of focus is the delivery of osteogenic factors in an attempt to modulate the formation of bone. These applications allow the efficient delivery of osteogenic growth factors directly into the defect site, resulting in localized drug delivery and reducing possible toxic systemic effects. However, studies on these biomaterials have only just begun; there are still many unanswered questions and unexplored frontiers that can greatly influence the role of nanostructured materials as improved bone implants. This review article seeks to demonstrate the potential of biomaterials to improve biological applications pertinent to osteodistraction.


Emergence of novel Seneca Valley virus strains in China, 2017.
Since early 2017, several outbreaks of Seneca Valley virus (SVV) infection have re-emerged in China. We report the identification of novel SVV KS15-01-like strains showing a notable distinction with previous Chinese SVV strains. The determined SVV strains are currently causing new outbreaks in two provinces in China where no SVV infection has been reported previously, implying the increased epidemic regions and potential threat to local pig breeds of SVV in China.


Detection of broadleaf weeds growing in turfgrass with convolutional neural networks.
Weed infestations reduce turfgrass aesthetics and uniformity. Postemergence (POST) herbicides are applied uniformly on turfgrass, hence areas without weeds are also sprayed. Deep learning, particularly the architecture of convolutional neural network (CNN), is a state-of-art approach to recognition of images and objects. In this paper, we report deep learning CNN (DL-CNN) models that are remarkably accurate at detection of broadleaf weeds in turfgrasses. VGGNet was the best model for detection of various broadleaf weeds growing in dormant bermudagrass [Cynodon dactylon (L.)] and DetectNet was the best model for detection of cutleaf evening-primrose (Oenothera laciniata Hill) in bahiagrass (Paspalum notatum Flugge) when the learning rate policy was exponential decay. These models achieved high F1 scores (>0.99) and overall accuracy (>0.99), with recall values of 1.00 in the testing datasets. The results of the present research demonstrate the potential for detection of broadleaf weed using DL-CNN models for detection of broadleaf weeds in turfgrass systems. Further research is required to evaluate weed control in field conditions using these models for in situ video input in conjunction with a smart sprayer. © 2019 Society of Chemical Industry.


C3G knock-down enhances migration and invasion by increasing Rap1-mediated p38α activation, while it impairs tumor growth through p38α-independent mechanisms.
C3G, a Guanine nucleotide Exchange Factor (GEF) for Rap1 and R-Ras, has been shown to play important roles in development and cancer. Previous studies determined that C3G regulates cell death through down-regulation of p38α MAPK activity. Here, we found that C3G knock-down in MEFs and HCT116 cells promotes migration and invasion through Rap1-mediated p38α hyper-activation. These effects of C3G were inhibited by Rap1 knock-down or inactivation. The enhanced migration observed in C3G depleted HCT116 cells was associated with reduction in E-cadherin expression, internalization of ZO-1, actin cytoskeleton reorganization and decreased adhesion. We also found that matrix metalloproteases MMP2 and MMP9 are involved in the pro-invasive effect of C3G down-regulation. Additionally, our studies revealed that both C3G and p38α collaborate to promote growth of HCT116 cells in vitro and in vivo, possibly by enhancing cell survival. In fact, knocking-down C3G or p38α individually or together promoted cell death in vitro, although only the double C3G-p38α silencing was able to increase cell death within tumors. Notably, we found that the pro-tumorigenic function of C3G does not depend on p38α or Rap1 activation. Altogether, our studies uncover novel mechanisms by which C3G controls key aspects of tumorigenesis.


Seasonality of reproductive events and early mortality in a colony of hamadryas baboons (Papio hamadryas hamadryas) over a 30-year period: Capital breeding and life history patterns in a food-provisioned population seasonally thermally stressed.
In environments where energy demands and resource availability vary seasonally, individuals are expected to time the optimal allocation of resources to support survival and reproduction. Although female baboons are regarded as all year round, capital breeders, we wondered how they would respond in an ecological scenario where food were not limiting, foraging effort were negligible, and they were thermally stressed during the cold winter. This study analyzes a 30-year database of conceptions, births, resumptions of postlactational ovarian activity, menarches, and prenatal and early postnatal reproductive failures recorded in a food-provisioned colony of hamadryas baboons located in a temperate zone (40°25'N) to search for seasonal patterns in their life-history patterns and explore its fitness consequences. The results show that the study females exhibited moderate seasonality and behaved like capital breeders; ovarian activity peaked during the period of benign weather conditions (spring and early summer) and births and lactation peaked during the period when they were thermally stressed and faced a negative energy balance (winter). Mistimed conceptions were more likely to fail than timed conceptions were, although this association could be artefactual due to the difficulty to accurately detect prenatal losses. Insolation and, to a lesser extent, temperature were positively associated with conceptions, resumptions of postlactational ovarian activity and onsets of menarche, and negatively associated with births. These findings highlight the extent of plasticity (width of peaks) and resiliency (retention of a capital breeding tactic even under highly seasonally thermally stressful cold conditions) in how primates can adjust their life history patterns and solve tradeoffs in a scenario of strong seasonal variation. Am. J. Primatol. 78:1149-1164, 2016. © 2016 Wiley Periodicals, Inc.


Sensitivity and Specificity of Swedish Interactive Threshold Algorithm and Standard Full Threshold Perimetry in Primary Open-angle Glaucoma.
Perimetry is one of the mainstays in glaucoma diagnosis and treatment. Various strategies offer different accuracies in glaucoma testing. Our aim was to determine and compare the diagnostic sensitivity and specificity of Swedish Interactive Threshold Algorithm (SITA) Fast and Standard Full Threshold (SFT) strategies of the Humphrey Field Analyzer (HFA) in identifying patients with visual field defect in glaucoma disease. This prospective observational case series study was conducted in a university-based eye hospital. A total of 37 eyes of 20 patients with glaucoma were evaluated using the central 30-2 program and both the SITA Fast and SFT strategies. Both strategies were performed for each strategy in each session and for four times in a 2-week period. Data were analyzed using the Student's t-test, analysis of variance, and chi-square test. The SITA Fast and SFT strategies had similar sensitivity of 93.3%. The specificity of SITA Fast and SFT strategies was 57.4% and 71.4% respectively. The mean duration of SFT tests was 14.6 minutes, and that of SITA Fast tests was 5.45 minutes (a statistically significant 62.5% reduction). In gray scale plots, visual field defect was less deep in SITA Fast than in SFT; however, more points had significant defect (p < 0.5% and p < 1%) in pattern deviation plots in SITA Fast than in SFT; these differences were not clinically significant. In conclusion, the SITA Fast strategy showed higher sensitivity for detection of glaucoma compared to the SFT strategy, yet with reduced specificity; however, the shorter test duration makes it a more acceptable choice in many clinical situations, especially for children, elderly, and those with musculoskeletal diseases.


Essential Oil of Mentha aquatica var. Kenting Water Mint Suppresses Two-Stage Skin Carcinogenesis Accelerated by BRAF Inhibitor Vemurafenib.
The v-raf murine sarcoma viral homolog B1 (BRAF) inhibitor drug vemurafenib (PLX4032) is used to treat melanoma; however, epidemiological evidence reveals that it could cause cutaneous keratoacanthomas and squamous cell carcinoma in cancer patients with the most prevalent HRASQ61L mutation. In a two-stage skin carcinogenesis mouse model, the skin papillomas induced by 7,12-dimethylbenz[a]anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA) (DT) resemble the lesions in BRAF inhibitor-treated patients. In this study, we investigated the bioactivity of Mentha aquatica var. Kenting Water Mint essential oil (KWM-EO) against PDV cells, mouse keratinocytes bearing HRASQ61L mutation, and its effect on inhibiting papilloma formation in a two-stage skin carcinogenesis mouse model with or without PLX4032 co-treatment. Our results revealed that KWM-EO effectively attenuated cell viability, colony formation, and the invasive and migratory abilities of PDV cells. Induction of G2/M cell-cycle arrest and apoptosis in PDV cells was also observed. KWM-EO treatment significantly decreased the formation of cutaneous papilloma further induced by PLX4032 in DT mice (DTP). Immunohistochemistry analyses showed overexpression of keratin14 and COX-2 in DT and DTP skin were profoundly suppressed by KWM-EO treatment. This study demonstrates that KWM-EO has chemopreventive effects against PLX4032-induced cutaneous side-effects in a DMBA/TPA-induced two-stage carcinogenesis model and will be worth further exploration for possible application in melanoma patients.


Establishment of critical hygiene indices for meat cooling processes evaluated by a temperature function integration method.
A temperature function integration technique that involves the calculation of the potential growth of Escherichia coli to obtain a process hygiene index (PHI) is the New Zealand industry standard method for assessing the potential for growth of enteric bacteria during meat cooling processes. The existing criteria to determine the acceptability of a cooling process with PHI values take no account of the differences between meat products and thus limit processing flexibility. A methodology was developed to set criteria for processing acceptability, based on the frequency distribution of the indicator organism E. coli number on meat carcasses immediately after slaughter (in log2 CFU per square centimeter) and a requirement that the E. coli numbers at the end of the cooling process be less than or equal to some maximum acceptable level. This methodology was used, along with accepted guidelines for maximum acceptable levels of E. coli in the meat and measured initial E. coli numbers for the whole New Zealand meat industry, to develop a set of PHI criteria that would be satisfied by a good-practice meat processing operation. A Monte Carlo modeling approach was used to illustrate the implications of these criteria if they had been applied to cooling processes for beef and lamb previously evaluated by the authors. If the proposed criteria were adopted, the maximum allowable PHI for beef cooling could be higher than that for lamb cooling because of the lower initial E. coli numbers found on beef than on lamb carcasses.


Pain buddy: A novel use of m-health in the management of children's cancer pain.
Over 12,000 children are diagnosed with cancer every year in the United States. In addition to symptoms associated with their disease, children undergoing chemotherapy frequently experience significant pain, which is unfortunately often undertreated. The field of m-Health offers an innovative avenue for pain assessment and intervention in the home setting. The current study describes the development and initial evaluation of a tablet-based program, Pain Buddy, aimed to enhance pain management and foster improved quality of life in children ages 8-18 years undergoing cancer treatment. An animated avatar-based tablet application was developed using state-of-the-art software. Key aspects of Pain Buddy include daily pain and symptom diaries completed by children, remote monitoring of symptoms by uploading patient's data through internet to a cloud server, cognitive and behavioral skills training, interactive three-dimensional avatars that guide children through the program, and an incentive system to motivate engagement. Twelve children between the ages of 8 and 18 participated in a pilot study of Pain Buddy. Children were highly satisfied with the program. Pain and appetite disturbances were most frequently endorsed. Symptom trigger alerts to outside providers were largely related to clinically significant pain. Children infrequently used analgesics, and reported using some non-pharmacological pain management strategies. Pain Buddy appears to be a promising tool to improve pain and symptom management in children undergoing cancer treatment. Results from the current study will inform future improvements to Pain Buddy, in preparation for a randomized controlled trial to assess the efficacy of this innovative treatment.


Use of silver-hydrogel urinary catheters on the incidence of catheter-associated urinary tract infections in hospitalized patients.
Urinary tract infections (UTIs) account for 40% of all nosocomial infections, and about 80% of these are associated with the use of urinary catheters. They not only contribute to excess morbidity and mortality, but they also significantly add to the cost of hospitalization. Clinical trials with silver-coated urinary catheters have shown conflicting results. However, recent trials with silver-hydrogel urinary catheters have shown a reduction in nosocomial UTIs, and these catheters appear to offer cost savings. The University of Massachusetts Medical Center is a teaching, tertiary hospital with 18% of its beds in intensive care units. The silver-hydrogel urinary catheters were introduced in October 1997. The rate of catheter-associated UTIs with silver-hydrogel urinary catheter use was compared with a historical baseline UTI rate that was established for January 1996 and January 1997 with the standard, noncoated catheters. The cost of a nosocomial catheter-associated UTI was estimated by calculating the hospital charges resulting from all urinary catheter-associated UTIs in 1 month. A cost-analysis of silver-hydrogel urinary catheter use was performed. The rate of catheter-associated UTIs for noncoated catheters was 4.9/1000 patient-days compared with 2.7/1000 patient-days for the silver-hydrogel catheters, a reduction of 45% (P =.1). The average cost (calculated with hospital charges) of a catheter-associated UTI at our institution was estimated to be $1214.42 US dollars, with a median of $613.72 US dollars. The estimated cost-saving ranged from $12,563.52 US dollars to $142,314.72 US dollars. The use of silver-hydrogel urinary catheters resulted in a nonsignificant reduction in catheter-associated UTIs and a modest cost-saving.


Validation of the HIV Risk Assessment of Sexual Partnerships (H-RASP): Comparison to a 2-Month Prospective Diary Study.
The HIV Risk Assessment of Sexual Partnerships (H-RASP) was developed in order to create a retrospective measure of sexual risk-taking that can account for the differing contexts of sexual partnership(s) within a specified period of time. In order to validate the H-RASP relative to other methods of measuring sexual risk-taking, measurements from the H-RASP were compared to data from a prospective diary study of 95 young men who have sex with men over the same two-month period. We found that the H-RASP was not significantly different at measuring participants' total number of sexual partners and total number of anal sex partners in comparison with the diaries. The two measures were significantly different in measurement of total number of condomless anal sex (CAS) partners and number of CAS acts within partnerships, such that participants on average estimated more CAS partners and acts in the H-RASP. The two measures shared 40.8% of variance on measurement of CAS partners and 44.6% of variance on CAS acts within partnerships. These results suggest that even though the H-RASP is not a perfect replication of prospective diary data, it captures a moderate proportion of the same variance, and, in the case of CAS acts within partnerships, a proportion of the variance that likely would not be measured by retrospective measures that do not ask about behaviors specific to partnerships.


Correction of tuberous breast deformity: A retrospective study comparing lipofilling versus breast implant augmentation.
Breast implants and, more recently, autologous fat grafting are the two most common treatments used to correct tuberous breast deformity (TBD). The post-surgical quality of life between the two techniques is not well demonstrated. This study aimed to compare satisfaction and health-related quality of life in patients affected by TBD between these two techniques. All TBD patients operated between January 2008 and May 2015 were retrospectively identified, and only those treated with implants or lipofilling were included. Satisfaction was evaluated at least 6 months after surgery with the postoperative Breast-Q® augmentation module. From January 2008 to May 2015, 62 patients were recruited in our study, and 37 patients were evaluated using a Breast-Q questionnaire after at least 6 months of follow-up. Breast implant-augmented patients were significantly more satisfied concerning the "satisfaction with breasts" module (p = 0.002) and the "satisfaction with outcome" module (p = 0.00008). A question-by-question analysis revealed several interesting and significant differences, showing higher scores in most of the questions in the breast implant group. Patients in the lipofilling group, interestingly, had a mean of 1.6 interventions compared to the mean 1.36 interventions in the implant group (p = 0.23). This reflects the need to perform more surgical sessions in the lipofilling group to achieve a satisfactory result. Our study demonstrated that tuberous breast correction with implants can achieve better satisfaction along with good outcomes than lipofilling usually does.


Evaluation of the efficacy of an internet-based pain education and exercise program for chronic musculoskeletal pain in comparison with online self-management booklet: a protocol of a randomised controlled trial with assessor-blinded, 12-month follow-up, and economic evaluation.
Chronic musculoskeletal pain is one of the main causes of years lived with disability and generates the highest cost of health care among chronic pain conditions. Internet-based treatments have been shown to be an alternative for the treatment of musculoskeletal conditions, in addition to reducing barriers such as travel, high demands on the public health system, lack of time, lack of insurance coverage for private care, and high costs for long-term treatment. The aim of this clinical trial is to develop and test the effectiveness and cost-effectiveness of, an internet-based self-management program based on pain education and exercise for people with chronic musculoskeletal pain. This is a prospectively registered, assessor-blinded, two-arm randomised controlled trial with economic evaluation comparing the Internet-based pain education and exercise intervention with a control group that will receive an online booklet. One hundred and sixty patients will be recruited from Sao Paulo, Brazil. Follow-ups will be conducted in post-treatment, 6 and 12 months after randomisation. The conduct of the study, as well as the evaluations and follow-ups will be carried out entirely remotely, through online platforms and telephone calls. The primary outcome will be pain intensity at post-treatment (8 weeks) measured using the 11-item Pain Numerical Rating Scale. Secondary outcomes will be biopsychosocial factors presents in the chronic musculoskeletal pain condition. Costs due to chronic musculoskeletal pain will be also measured, and cost-effectiveness analysis from a societal perspective will performed. Our hypothesis is that internet-based pain education and exercise will be better than an online booklet in reducing pain and improving biopsychosocial outcomes in patients with chronic musculoskeletal pain. In addition, we believe that there will be good acceptance of patients for the internet-based intervention and that internet-based intervention will be more cost effective than the online booklet. The study was prospectively registered at ClinicalTrials.gov ( NCT04274439 , registered 18 February 2020).


Cholesterol 25-hydroxylase suppresses avian reovirus replication by its enzymatic product 25-hydroxycholesterol.
Avian reovirus (ARV) causing viral arthritis/tenosynovitis and viral enteritis in domestic fowl has significantly threatened on the poultry industry worldwide. ARV is a non-enveloped fusogenic virus that belongs to the Reoviridae family. Previous research revealed that cellular cholesterol in lipid rafts is essential for ARV replication. It has been reported that cholesterol 25-hydroxylase (CH25H) and its product 25-hydroxycholesterol (25HC) have antiviral activities against enveloped viruses. However, few studies characterized the association of non-enveloped viruses with CH25H and the role of CH25H in the regulation of ARV replication. In this study, the expression of chicken CH25H (chCH25H) was found to be upregulated in ARV-infected cells at the early stage of infection. The results of overexpression and knockdown assays revealed that chCH25H has a significant antiviral effect against ARV infection. Furthermore, a 25HC treatment significantly inhibited ARV replication in a dose-dependent manner at both the entry and post-entry stages, and a chCH25H mutant lacking hydroxylase activity failed to inhibit ARV infection. These results indicate that CH25H, depending on its enzyme activity, exerts the antiviral effect against ARV via the synthesis of 25HC. In addition, we revealed that 25HC produced by CH25H inhibits viral entry by delaying the kinetics of ARV uncoating, and CH25H blocks cell-cell membrane fusion induced by the p10 protein of ARV. Altogether, our findings showed that CH25H, as a natural host restriction factor, possessed antiviral activity against ARV targeting viral entry and syncytium formation, through an enzyme activity-dependent way. This study may provide new insights into the development of broad-spectrum antiviral therapies.


Drp-1-Dependent Mitochondrial Fragmentation Contributes to Cobalt Chloride-Induced Toxicity in Caenorhabditis elegans.
Excess cobalt may lead to metallosis, characterized by sensorineural hearing loss, visual, and cognitive impairment, and peripheral neuropathy. In the present study, we sought to address the molecular mechanisms of cobalt-induced neurotoxicity, using Caenorhabditis elegans as an experimental model. Exposure to cobalt chloride for 2 h significantly decreased the survival rate and lifespan in nematodes. Cobalt chloride exposure led to increased oxidative stress and upregulation of glutathione S-transferase 4. Consistently, its upstream regulator skn-1, a mammalian homolog of the nuclear factor erythroid 2-related factor 2, was activated. Among the mRNAs examined by quantitative real-time polymerase chain reactions, apoptotic activator egl-1, proapoptotic gene ced-9, autophagic (bec-1 and lgg-1), and mitochondrial fission regulator drp-1 were significantly upregulated upon cobalt exposure, concomitant with mitochondrial fragmentation, as determined by confocal microscopy. Moreover, drp-1 inhibition suppressed the cobalt chloride-induced reactive oxygen species generation, growth defects, and reduced mitochondrial fragmentation. Our novel findings suggest that the acute toxicity of cobalt is mediated by mitochondrial fragmentation and drp-1 upregulation.


Insulin resistance and compensatory insulin secretion in middle-aged persons with hypertriglyceridemia.
Insulin secretion and insulin sensitivity were measured in hypertriglyceridemic patients using the frequently sampled intravenous glucose tolerance test. Three groups of men who were matched for age and body mass index were studied: eight healthy control subjects (C), seven patients with mild hypertriglyceridemia and normal glucose tolerance (TG), and seven with well-controlled type 2 diabetes with hypertriglyceridemia (TG-DM). The first-phase insulin response was increased by 116% in the TG group and decreased by 59% in the TG-DM group. The second phase of insulin secretion was increased in both TG groups (TG by 310% and TG-DM by 250%). The mean insulin sensitivity index (SI) was reduced by 50% in the TG group and by 60% in the TG-DM group. Glucose effectiveness (SG) was reduced by 30% in the TG-DM group compared with the control subjects.


Verminous encephalitis in a horse produced by nematodes in the family protostrongylidae.
Parasitic granulomatous eosinophilic inflammation was observed in the central nervous system (CNS) of a 6-month-old Arabian colt from New York state. Inflammation was associated with eggs, larvae, and adult nematodes in the cerebellum. Nematodes had histological characteristics of the superfamily Metastrongyloidea. The presence of dorsal-spined larvae in the CNS was further indicative of infection with a nematode in the family Protostrongylidae. Infections were most compatible with Parelaphostrongylus tenuis but specific diagnosis was not possible. This is the first definitive report of a protostrongylid nematode infection in a horse.


Interactive magnetic resonance imaging-guided biopsy in the head and neck: initial patient experience.
Because of its excellent soft tissue resolution, magnetic resonance imaging (MRI) can optimize image guidance for interventional and surgical procedures. Notably, needle biopsy of head and neck lesions has been used for years, deeper lesions often requiring some form of image guidance. The closed space of diagnostic MRI scanners proves cumbersome for intervention. The authors report on the first head and neck image-guided biopsies performed in a new, investigational "open configuration" intraoperative MRI scanner. Vertical space between the scanner's upright coils gives access to the patient while imaging; image acquisition is as fast as 2 sec/image. Biopsies were performed on seven patients (parotid, parapharyngeal space, second cervical vertebra); five specimens were diagnostic. Both general anesthesia and intravenous sedation were used. The procedures were without complications. Imaging provided definition of anatomy to direct needle placement. Access to the patient allowed for both percutaneous and transoral approaches. The environment of the open magnet is well suited for biopsy of the head and neck, and near real-time intraoperative MRI has promise for guiding more complex head and neck procedures. Further study should optimize the quality of the images and the interactibility of localization and targeting and fully utilize MRI's three-dimensional imaging capabilities.


Toward a biochemical understanding of human intervertebral disc degeneration and herniation. Contributions of nitric oxide, interleukins, prostaglandin E2, and matrix metalloproteinases.
Normal and herniated human intervertebral disc specimens were cultured to study the effects of interleukin-1 beta on the production of nitric oxide, interleukin-6, prostaglandin E2, and matrix metalloproteinases. The effects of endogenously produced nitric oxide on the synthesis of other mediators also were studied. To test the hypothesis that the cells of the intervertebral disc are metabolically active and are capable of responding to biochemical stimuli such as interleukin-1 beta in a manner that could engender degenerative changes. As part of this study, the authors also investigated some of the possible autocrine regulatory mechanisms that may operate during the biochemical responses of disc cells. The authors previously showed, for the first time, that herniated cervical and lumbar disc specimens spontaneously produce increased amounts of nitric oxide, interleukin-6, prostaglandin E2, and certain matrix metalloproteinases. These results suggest that these biochemical agents are in some manner involved with degenerative processes in the intervertebral disc. This novel hypothesis merits further evaluation; the current communication reports the results of experiments designed to do so. Fourteen normal, nondegenerated discs (control group) were obtained from seven patients undergoing anterior spinal surgery for trauma or lumbar scoliosis. Thirty-six herniated discs (18 lumbar and 18 cervical) were obtained from 30 patients undergoing surgery for persistent radiculopathy. The specimens were placed into tissue culture and incubated for 72 hours in the presence or absence of interleukin-1 beta and NG-monomethyl-L-arginine, and inhibitor of nitric oxide synthases, and the media were subsequently collected for biochemical analysis. Biochemical assays for matrix metalloproteinases, nitric oxide, interleukin-6, and prostaglandin E2 were performed. Normal, control disc specimens significantly increased their production of matrix metalloproteinases, nitric oxide, interleukin-6, and prostaglandin E2 in response to interleukin-1 beta. Herniated lumbar and cervical discs, which were spontaneously releasing increased levels of these biochemical agents, further increased their production of nitric oxide, interleukin-6, and prostaglandin E2 in response to interleukin-1 beta. Blocking the biosynthesis of nitric oxide in interleukin-1 beta-stimulated disc cells provoked a large increase in the production of interleukin-6. Cells of the intervertebral discs are biologically responsive and increase their production of matrix metalloproteinases, nitric oxide, interleukin-6, and prostaglandin E2 when stimulated by interleukin-1 beta. The effect is more dramatic in normal, nondegenerated discs where spontaneous synthesis of these mediators is low. Nevertheless, cells of the herniated degenerated discs where spontaneous production was high were still capable of further increasing their synthesis of several of these biochemical agents in response to interleukin-1 beta. Endogenously produced nitric oxide appears to have a strong inhibitory effect on the production of interleukin-6, which suggests that autocrine mechanisms play an important role in the regulation of disc cell metabolism.


UV monitoring of microwave-heated reactions--a feasibility study.
UV/Visible spectroscopy has been used to monitor the progress of the formation of benzimidazole from the reaction between 1,2-diaminobenzene and formic acid. The reaction was performed at three concentration levels, each becoming more dilute so that at the most dilute level direct UV monitoring from the reaction sample was possible. At each level the reaction was conducted by conventional and by microwave heating. The success of the microwave reaction at the most dilute levels encourages the construction of a microwave reactor/UV/Vis spectrometer hybrid instrument for the monitoring of this and other reactions.


Abnormal immunostaining for dystrophin in isoproterenol-induced acute myocardial injury in rats: evidence for change in dystrophin in the absence of genetic defect.
Abnormalities in the gene for Duchenne muscular dystrophy produce skeletal and myocardial changes, by impairing dystrophin production in patients with Duchenne and Becker muscular dystrophy. However, it is not known whether myocardial dystrophin may be altered in patients with other heart diseases. To investigate whether changes in myocardial dystrophin may be induced by acute myocardial injury, the immunostaining patterns of myocardial dystrophin were examined, together with those of myocardial actin, in rats with isoproterenol-induced myocardial damage. Hearts were excised at 6, 12, 24 and 48 h, and 1 and 4 weeks after the subcutaneous administration of 100 mg/kg of isoproterenol. Frozen serial sections were prepared for haematoxylin and eosin staining, and for immunostaining for dystrophin and actin. The immunostaining patterns of actin were used as an indicator of cell injury. The myocardial cells observed were classified into four types, according to staining pattern: normal for both actin and dystrophin (Type 1): normal for actin, but abnormal for dystrophin (Type 2); abnormal for actin, but normal for dystrophin (Type 3); and abnormal for both actin and dsytrophin (Type 4). The percentage of myocardial cells with abnormal staining (Types 2, 3 and 4) at 6, 12, 24 and 48 h after isoproterenol injection was 22.4, 12.6, 16.0 and 2.4%, respectively; most cells were Types 3 and 4. One week after injection or later, no Type 3 or 4 cells were detected, while the percentages of Type 2 cells were 2.7% for 1 week and 2.2% for 4 weeks, significantly higher than the corresponding value in the control group. In conclusion, changes in myocardial dystrophin may occur in isoproterenol-induced myocardial injury in rats.


Provision of pain management by a pharmacist with prescribing authority.
The clinical and financial outcomes of a pain clinic managed by a pharmacist with prescribing authority are described. Pharmacist clinicians in a for-profit, integrated health system recently received permission to bill for their services in certain ambulatory clinics. A pharmacist clinician, who had an individual Drug Enforcement Administration number and whose services are billable under New Mexico law, was chosen to assume the medication management responsibilities in a clinic where 90% of the patient population is treated for chronic non-cancer-related pain. No additional personnel were needed, and no additional space was required, eliminating overhead for the space and utilities needed for operating a new clinic. With the ability to bill for the pharmacist clinician's services, a new model for justification of clinical pharmacy services was developed for the ambulatory care clinics. The revenue generated was tracked by a medical billing system, and clinical outcomes were tracked using the clinic's database for patients' individual visual analogue scale (VAS) pain scores. Between June 2004 and June 2005, an average of 18 patients were seen by the pharmacist clinician each day. The clinic generated 107,550 dollars of actual revenue and saved the health plan over 450,000 dollars. There was a consistent decrease in mean VAS pain scores with continued visits. Patients with chronic non-cancer-related pain were managed effectively by a pharmacist with prescribing authority and refill authorization in a pain management clinic. The favorable clinical outcomes, revenue generated, and cost savings achieved justified the pharmacist clinician's services in this health system.


An acute and subacute neurotoxicity assessment of trichlorfon.
The toxicity of trichlorfon (O,O-dimethyl-2,2,2,-trichloro-1-hydroxyethylphosphonate, Dipterex, Dylox), reported to elicit delayed neurotoxicity in man and chickens, was studied by administering single subcutaneous doses of 100 or 300 mg/kg to adult White Leghorn hens. At 24 h posttreatment, the birds were observed for visible signs of neurotoxicity, were euthanized, and samples of blood plasma, brain, and spinal cord (cervical and thoracic regions) were obtained for quantification of cholinesterase and neurotoxic esterase (NTE) activities. In subacute studies, hens were dosed with trichlorfon (100 mg/kg) every 72 h for a total of six doses. Seventy-two hours after the final dose the hens were euthanized, the brains, spinal cords, and distal sciatic nerves were removed for enzymatic and (or) histological examination. Parallel acute and subacute studies were conducted using diisopropyl phosphorofluoridate (DFP), a known neurotoxic agent, at subcutaneous dosages of 1.0 mg/kg. In the acute studies, both DFP and trichlorfon markedly inhibited tissue cholinesterase activities but only DFP elicited a significant inhibition of NTE. In the subacute studies, DFP produced a characteristic central-peripheral distal axonopathy in the 18-day period of study which was confirmed by clinical and morphological evidence and by marked inhibition of neuronal NTE. Trichlorfon caused little or no obvious neurotoxicity, an observation that was supported by minimal morphological changes and impairment of walking ability and no inhibition of brain or spinal cord NTE.


Fiber tracking from DTI using linear state space models: detectability of the pyramidal tract.
Diffusion tensor imaging (DTI) is an emerging and promising tool to provide information about the course of white matter fiber tracts in the human brain. Based on specific acquisition schemes, diffusion tensor data resemble local fiber orientations allowing for a reconstruction of the fiber bundles. Current techniques to calculate fascicles range from simple heuristic tracking solutions to Bayesian and differential equations approaches. Most methods are based only on local diffusion information, often resulting in bending or kinking fiber paths in voxels with reduced diffusion properties. In this article we present a new tracking approach based on linear state space models encompassing an inherent smoothness criterion to avoid too wiggly tracked fiber bundles. The new technique will be described formally and tested on simulated and real data. The performance tests are focused on the pyramidal tract, where we employed a test-retest study and a group comparison in healthy subjects. Anatomical course was confirmed in a patient with selective degeneration of the pyramidal tract. The potential of the presented technique for improved neurosurgical planning is demonstrated by visualization of a tumor-induced displacement of the motor pathways. The paper closes with a thorough discussion of perspectives and limitations of the new tracking approach.


Differential expression of cytochrome P450 enzymes from the CYP2C subfamily in the human brain.
Cytochrome P450 enzymes from the CYP2C subfamily play a prominent role in the metabolic clearance of many drugs. CYP2C enzymes have also been implicated in the metabolism of arachidonic acid to vasoactive epoxyeicosatrienoic acids. CYP2C8, CYP2C9, and CYP2C19 are expressed in the adult liver at significant levels; however, the expression of CYP2C enzymes in extrahepatic tissues such as the brain is less well characterized. Form-specific antibodies to CYP2C9 and CYP2C19 were prepared by affinity purification of antibodies raised to unique peptides. CYP2C9 and CYP2C19 were located in microsomal fractions of all five human brain regions examined, namely the frontal cortex, hippocampus, basal ganglia, amygdala, and cerebellum. Both CYP2C9 and CYP2C19 were detected predominantly within the neuronal soma but with expression extending down axons and dendrites in certain regions. Finally, a comparison of cortex samples from alcoholics and age-matched controls suggested that CYP2C9 expression was increased in alcoholics.


An altered fibronectin matrix induces anoikis of human squamous cell carcinoma cells by suppressing integrin alpha v levels and phosphorylation of FAK and ERK.
Fibronectin regulates many cellular processes, including migration, proliferation, differentiation, and survival. Previously, we showed that squamous cell carcinoma (SCC) cell aggregates escape suspension-induced, p53-mediated anoikis by engaging in fibronectin-mediated survival signals through focal adhesion kinase (FAK). Here we report that an altered matrix, consisting of a mutated, nonfunctional high-affinity heparin-binding domain and the V region of fibronectin (V+H-), induced anoikis in human SCC cells; this response was blocked by inhibitors of caspase-8 and caspase-3. Anoikis was mediated by downregulation of integrin alpha v in a panel of SCC cells and was shown to be proteasome-dependent. Overexpression of integrin alpha v or FAK inhibited the increase in caspase-3 activation and apoptosis, whereas suppression of alpha v or FAK triggered a further significant increase in apoptosis, indicating that the apoptosis was mediated by suppression of integrin alpha v levels and dephosphorylation of FAK. Treatment with V+H- decreased the phosphorylation of extracellular signal-regulated kinase (ERK) 1 and 2, and direct activation of ERK by constitutively active MEK1, an ERK kinase, increased ERK1 and ERK2 phosphorylation and inhibited the increase in apoptosis induced by V+H-. ERK acted downstream from alpha v and FAK signals, since alpha v and FAK overexpression inhibited both the decrease in ERK phosphorylation and the increase in anoikis triggered by V+H-. These findings provide evidence that mutations in the high-affinity heparin-binding domain in association with the V region of fibronectin, or altered fibronectin matrices, induce anoikis in human SCC cells by modulating integrin alpha v-mediated phosphorylation of FAK and ERK.


Complete genome sequence of Vibrio parahaemolyticus strain PH1273, isolated from aquacultured shrimp in the Philippines.
We announce the complete genome sequence of Vibrio parahaemolyticus strain PH1273. This strain was collected from a Penaeus vannamei pond in the Philippines in 2015. Genome analysis revealed that it lacks the gene pirAB responsible for causing acute hepatopancreatic necrosis disease but encode multiple secretion systems and the associated effectors.