Fidaxomicin vs Vancomycin for the Treatment of a First Episode of Clostridium Difficile Infection: A Meta-analysis and Systematic Review.
Clostridium difficile infection (CDI) continues to possess a significant disease burden in the United States (US) as well as all over the world. Given the increase in severity and recurrence rate, the decrease in cure rate, and the fact that the virulent ribotype 027 strain remains one of the most commonly identified strains in the US, the Infectious Diseases Society of America (IDSA) published a clinical practice guideline in February 2018 moving away from metronidazole as the first-line treatment for initial CDI and recommending either oral vancomycin or fidaxomicin. The aim of this study is to evaluate the clinical data available comparing the efficacy of primary treatment of CDI between those two antibiotics. We performed a PubMed, PubMed Central, and ScienceDirect database search without restriction to regions, publication types, or languages. A comprehensive literature search was performed from January 1, 1980 up to March 20, 2018. We used the following keywords in different combinations: Clostridium difficile, Clostridium difficile infection, CDI, C. diff, C. difficile, fidaxomicin, vancomycin, pseudomembranous colitis, and antibiotic-associated colitis. The search was limited to human studies. Data were independently extracted by two reviewers with disagreements resolved by a third author. We pooled an odds ratio (OR) on two primary outcomes: Clinical cure rate and rate of recurrence during the follow-up period. The computer search was also supplemented with manual searches by the authors of the retrieved review articles and primary studies. The search phrase "((Clostridium difficile) AND vancomycin) AND fidaxomicin" had the highest yield results. We identified four observational studies with a total of 2,303 patients with CDI that met our inclusion criteria. Compared with vancomycin, fidaxomicin use was associated with a significantly lower recurrence of CDI with a pooled OR of 0.47 (95% confidence interval (CI), 0.37 - 0.60, I2 = 0). On the other hand, there was no significant association of fidaxomicin use with CDI cure rate compared to vancomycin with a pooled OR of 1.22 (95% CI, 0.93 - 1.60, I2 = 0). In light of the recently updated clinical practice guidelines by the IDSA, our review suggests that fidaxomicin has a more sustained clinical response with a statistically significant lower recurrence rate. Although fidaxomicin appears to be the better drug with statistical significance, its cost-effectiveness continues to be an ongoing controversy. More randomized clinical trials are needed to shed light on this matter to assess if there is any clinical significance in fidaxomicin superiority.


Construction and enhanced cytotoxicity of a [cyanovirin-N]-[Pseudomonas exotoxin] conjugate against human immunodeficiency virus-infected cells.
Cyanovirin-N (CV-N) is a novel 11-kDa anti-HIV(human immunodeficiency virus) protein that binds with high affinity to the viral envelope glycoprotein gp120. In contrast to soluble CD4 and most known neutralizing antibodies that bind gp120, CV-N exerts potent anti-viral activity against primary clinical HIV isolates as well as laboratory-adapted strains of HIV. Here we describe the recombinant production, purification, and characterization of a chimeric toxin molecule, FLAG-CV-N-PE38, that contains CV-N as a gp120-targeting moiety linked to the translocation and cytotoxic domains of Pseudomonas exotoxin A. FLAG-CV-N-PE38 showed enhanced cytotoxicity to HIV-infected, gp120-expressing H9 cells compared to uninfected H9 cells. Competition experiments with free CV-N provided further support that the enhanced FLAG-CV-N-PE38-induced cytotoxicity was due to interactions of the CV-N moiety with cell surface gp120. This study establishes the feasibility of use of CV-N as a gp120-targeting sequence for construction and experimental therapeutic investigations of unique new chimeric toxins designed to selectively destroy HIV-infected host cells.


Fecundity of infertile women with minimal or mild endometriosis and women with unexplained infertility. The Canadian Collaborative Group on Endometriosis.
To assess whether infertile women with minimal or mild endometriosis have lower fecundity than women with unexplained infertility. Prospective cohort study. Twenty-three infertility clinics across Canada. Three hundred thirty-one infertile women aged 20-39 years. Diagnostic laparoscopy for infertility. Infertile women with minimal or mild endometriosis (n = 168) were compared with women with unexplained infertility (n = 263). Both groups were managed expectantly. The women were followed up for 36 weeks after the laparoscopy or, for those who became pregnant, for up to 20 weeks of the pregnancy. Fecundity refers to the probability of becoming pregnant in the first 36 weeks after laparoscopy and carrying the pregnancy for > or = 20 weeks. The fecundity rate is the number of pregnancies per 100 person-months. Fecundity was 18.2% in infertile women with minimal or mild endometriosis and 23.7% in women without endometriosis (log-rank test). The fecundity rate was 2.52 per 100 person-months in women with endometriosis and 3.48 per 100 person-months in women with unexplained infertility. The crude and adjusted fecundity rate ratios were 0.72 and 0.83 (95% confidence interval = 0.53-1.32), respectively. The fecundity of infertile women with minimal or mild endometriosis is not significantly lower than that of women with unexplained infertility.


Dual antiplatelet therapy with clopidogrel and aspirin in symptomatic carotid stenosis evaluated using doppler embolic signal detection: the Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic Carotid Stenosis (CARESS) trial.
Evidence for efficacy of dual antiplatelet therapy in stroke is limited. Symptomatic carotid stenosis patients are at high risk of early recurrent stroke. In this group, asymptomatic microembolic signals (MES), detected by transcranial Doppler ultrasound (TCD), are markers of future stroke and transient ischemic attack (TIA) risk. They offer a surrogate marker to evaluate antiplatelet therapy, but no multicenter study has evaluated the feasibility of this approach. Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic Carotid Stenosis (CARESS) is a randomized, double-blind study in subjects with recently symptomatic > or =50% carotid stenosis. Patients were screened with TCD, and if MES were detected, they were randomized to clopidogrel and aspirin or aspirin monotherapy. Repeated TCD recordings were made on days 2 and 7. MES were detected in 110 of 230 patients by online analysis at baseline, of whom 107 were randomized. Intention-to-treat analysis revealed a significant reduction in the primary end point: 43.8% of dual-therapy patients were MES positive on day 7, as compared with 72.7% of monotherapy patients (relative risk reduction 39.8%; 95% CI, 13.8 to 58.0; P=0.0046). The secondary end point of MES frequency per hour was reduced (compared with baseline) by 61.4% (95% CI, 31.6 to 78.2; P=0.0013) in the dual-therapy group at day 7 and by 61.6% (95% CI, 34.9 to 77.4; P=0.0005) on day 2. There were 4 recurrent strokes and 7 TIAs in the monotherapy group versus no stroke and 4 TIAs in the dual-therapy group that were treatment emergent and ipsilateral to the qualifying carotid stenosis; 2 additional ipsilateral TIAs occurred before treatment started. MES frequency was greater in the 17 patients with recurrent ipsilateral events compared with the 90 without (mean+/-SD: 24.4+/-27.7 versus 8.9+/-11.5 per hour; P=0.0003). In patients with recently symptomatic carotid stenosis, combination therapy with clopidogrel and aspirin is more effective than aspirin alone in reducing asymptomatic embolization. Doppler MES detection is a feasible method to evaluate the efficacy of antiplatelet therapy in multicenter studies.


Fundamental research in molecular biology: its relevance to medicine.
Any research which has shed light on the nature of disease or opened new ways to its prevention or cure is here termed relevant, and the question will be asked whether the research could have been planned with these aims in mind. Examples will be taken from the chemistry and X-ray analysis of proteins and from molecular genetics. Blow and Hartley determined the amino acid sequence and atomic structure of the digestive enzyme chymotrypsin in order to solve the problem of enzymic catalysis. They succeeded but what they found has proved to be of much wider improtance than could have been foreseen at the outset: it gives the key to the mechanism of blood clotting and suggests new methods for its control. X-ray analysis of haemoglobin was started at a time when the structure of proteins was regarded as the central problem of biology, but it did not seem likely then that the results would shed light on the molecular pathology of inherited diseases. Ames made a life-long study of the genetic control of histidine biosynthesis in Salmonella because it represents an example of a widely used biological mechanism, but without expecting it to have any practical applications. Yet his recent exploitation of the system for the rapid and sensitive detection of chemical carcinogens may represent a breakthrough in cancer prevention. This unpredictable relationship of molecular biology to medicine is symptomatic of the subject's youth.


Microfibrillated cellulose and borax as mechanical, O₂-barrier, and surface-modulating agents of pullulan biocomposite coatings on BOPP.
Multifunctional composite coatings on bi-oriented polypropylene (BOPP) films were obtained using borax and microfibrillated cellulose (MFC) added to the main pullulan coating polymer. Spectroscopy analyses suggested that a first type of interaction occurred via hydrogen bonding between the C6OH group of pullulan and the hydroxyl groups of boric acid, while monodiol and didiol complexation represented a second mechanism. The deposition of the coatings yielded an increase in the elastic modulus of the entire plastic substrate (from ∼2GPa of the neat BOPP to ∼3.1GPa of the P/B+/MFC-coated BOPP). The addition of MFC yielded a decrease of both static and kinetic coefficients of friction of approximately 22% and 25%, respectively, as compared to the neat BOPP. All composite coatings dramatically increased the oxygen barrier performance of BOPP, especially under dry conditions. The deposition of the high hydrophilic coatings allowed to obtain highly wettable surfaces (water contact angle of ∼18°).


Epidemiology of cardiorenal syndrome.
The interdependence of cardiac and renal dysfunction has emerged as a focus of intense interest in heart failure management due to the substantial associated morbidity and mortality. Captured in the clinical entity known as cardiorenal syndrome, recent definitions afford discussion of the acute and longitudinal evaluation and management of these patients. This article discusses potential pathophysiologic mechanisms of cardiorenal syndrome, epidemiology, inpatient and long-term care (including investigational therapies and mechanical fluid removal), and end-of-life and palliative care.


[Safety of immunotherapy and skin tests with allergens in children younger than five years].
It has been demonstrated that specific immunotherapy, in addition to its preventive properties, is an effective and safe therapeutic resource for allergic asthma, allergic rhinitis and allergy to insect's venom; however, its use in patients younger than five years has been limited due to the risk of systemic reactions. To know the frequency and severity of systemic reactions in children younger than five years and to know if a greater risk of systemic reactions in this group of age is real. We included 239 patients from one to five years of age with diagnosis of allergic disease and verified its specific sensitivity with skin tests or RAST and were treated with specific immunotherapy. A detailed registry of the application of specific immunotherapy was kept from every patient, with special attention to any symptom present during the first 30 minutes post application of specific immunotherapy or skin test. From January 1996 to June 2005, 6,689 injections were applied to 239 patients. Only one patient of 36 months of age presented with a delayed systemic reactions characterized by generalized hives, itching, runny nose, water eyes, 90 minutes post injection. The patient was under treatment with Dermatophagoides farinae and pteronissinus (house dust mites) with a dose of 1AU for allergic rhinitis. The systemic reactions were treated easily and without complications with a single dose of intramuscular epinephrine (0.15cc, 1:1000) and oral antihistamine. Patients younger than five years are not in greater risk of systemic reactions from specific immunotherapy or skin tests than the older children or adults and the treatment of those systemic reactions does not imply greater difficulty. Because of its preventive properties, safety and effectiveness in lowering the severity of symptoms of allergic diseases, we concluded that specific immunotherapy should be considered at early age, prescribed and administered only by specialist in pediatric allergy and in optimal conditions of safety.


NTP Toxicology and Carcinogenesis Studies of CS2 (94% o-Chlorobenzalmalononitrile, CAS No. 2698-41-1) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).
CS2 (94% o-chlorobenzalmalononitrile [CS]; 5% Cab-O-Sil(R). colloidal silica; 1% hexamethyldisilizane), an eye and respiratory irritant, is used as an aerosol to control riots. NTP Toxicology and Carcinogenesis studies were conducted by exposing groups of F344/N rats and B6C3F1 mice of each sex for 6 hours per day, 5 days per week for 2 weeks, 13 weeks, or 2 years, to a CS2 aerosol. Genetic toxicology studies with CS2 were conducted in Salmonella typhimurium, mouse lymphoma cells, and Chinese hamster ovary (CHO) cells. Fourteen-Day Studies: At exposure concentrations of 0, 1, 3, 10, 30, or 100 mg/m3 CS2, all rats exposed to 30 or 100 mg/m3 and all mice exposed to 10, 30, or 100 mg/m3 died before the end of the studies. Compound-related clinical signs observed included erythema, blepharospasm, listlessness, nasal discharge, and mouse breathing. Thirteen-Week Studies: At exposure concentrations of 0, 0.4, 0.75, 1.5, 3, or 6 mg/m3, 1/10 male rats exposed to 6 mg/m3 died before the end of the studies. Final mean body weights of rats exposed to 1.5 mg/m3 or more were 17%-44% lower than that of controls for males and 10%-24% lower for females. The absolute and relative thymus weights were reduced for exposed male and female rats, particularly at 6 mg/m3. Compound-related lesions of the nasal passage in rats included focal erosion with regenerative hyperplasia and squamous metaplasia of the respiratory epithelium and suppurative inflammation. Acute inflammation and hyperplasia of the respiratory epithelium were seen in the larynx and trachea of some exposed rats. All mice exposed to 6 mg/m3 and 1/10 males and 1/10 females exposed to 3 mg/m3 died before the end of the studies. Final mean body weights of mice exposed to 3 mg/m3 were 13% lower than that of controls for males and 9% lower for females. Compound-related lesions of the nasal passage in mice included squamous metaplasia of the nasal respiratory epithelium and inflammation. Based on these results, CS2 exposure concentrations for the 2-year studies were 0, 0.075, 0.25, or 0.75 mg/m3 for 6 hours per day, 5 days per week for 105 weeks for groups of 50 rats of each sex. Groups of 50 mice of each sex were exposed to 0, 0.75, or 1.5 mg/m3 on the same schedule. Body Weights and Survival in the Two-Year Studies: Final mean body weights of rats exposed to 0.75 mg/m3 were 7%-11% lower than those of controls. Final mean body weights of mice exposed to CS2 were lower than those of controls (male: 5% and 9%; female: 10% and 17%). No compound-related clinical signs were observed. No significant differences in survival were seen for any group of rats or mice of either sex. Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Compound-related nonneoplastic lesions occurred in the nasal passage of exposed rats and mice. In exposed rats, hyperplasia and squamous metaplasia of the respiratory epithelium and degeneration of the olfactory epithelium with ciliated columnar and/or squamous metaplasia were observed. Focal chronic inflammation and proliferation of the periosteum of the turbinate bones were increased slightly in rats at the top exposure concentration. Suppurative inflammation with hyperplasia and squamous metaplasia of the respiratory epithelium occurred in exposed mice. There were no compound-related increased incidences of neoplasms in rats or mice exposed to CS2. In exposed female mice, there were pronounced decreases in the incidences of adenomas of the pituitary pars distalis (control, 13/47; 0.75 mg/m3, 5/46; 1.5 mg/m3, 1/46) and decreased incidences of malignant lymphomas (21/50; 12/50; 8/50). Genetic Toxicology: The responses in Salmonella gene mutation tests with CS2 were equivocal in one laboratory for strain TA100 in the absence of exogenous metabolic activation (S9) and equivocal in another laboratory for TA97 with S9; in all other strains tested, CS2 was clearly negative with or without S9. CS2 induced trifluorothymidine resistance in mouse L5178Y/TK lymphoma cells in the absence of S9; it was not tested with S9. CS2 induced both sister chromatid exchangeslymphoma cells in the absence of S9; it was not tested with S9. CS2 induced both sister chromatid exchanges and chromosomal aberrations in CHO cells with and without S9. Conclusions: Under the conditions of these inhalation studies, there was no evidence of carcinogenic activity of CS2 for male or female F344/N rats exposed to 0.075, 0.25, or 0.75 mg/m3 in air for up to 2 years. There was no evidence of carcinogenic activity for male or female B6C3F1 mice exposed to 0.75 or 1.5 mg/m3 in air for up to 2 years. Concentration-related decreases in the incidences of pituitary gland adenomas and lymphomas were observed in female mice. Exposure to CS2 caused degeneration and squamous metaplasia of the olfactory epithelium, hyperplasia and metaplasia of the respiratory epithelium, and proliferation of the periosteum of the nasal passage of rats. In mice, exposure to this compound caused suppurative inflammation and hyperplasia and squamous metaplasia of the respiratory epithelium of the nasal passage.


Effect of the flavonoid quercetin on inflammation and lipid peroxidation induced by Helicobacter pylori in gastric mucosa of guinea pig.
Helicobacter pylori infection induces an inflammatory response in the gastric mucosa. Activation of polymorphonuclear leukocytes can produce oxidative damage to gastric tissue through intermediary radicals of oxygen and nitrogen. Vegetable extracts containing polyphenols of the flavonoid family have antibacterial activity, and the flavonoid quercetin possesses anti-H. pylori activity in vitro. The aim of this study was to analyze the effect of oral administration of pure quercetin on inflammation and lipid peroxidation induced by H. pylori in the gastric mucosa of the guinea pig. Sixty days after oral infection with H. pylori guinea pigs received 200 mg/kg of quercetin daily by mouth for 15 days. The infiltration index of inflammatory cells and bacterial density in both the pyloric antrum and corpus were histologically determined by myeloperoxidase histochemistry, hematoxylin-eosin, and modified Giemsa stains. The lipid hydroperoxide content was assessed by the orange xylenol spectrophotometric method. Quercetin significantly reduced the infiltration index of mononuclear cell and bacterial colonization in the pyloric antrum and corpus. In the antrum of infected quercetin-treated animals, a significant diminution of neutrophil leukocyte infiltration was observed compared with the infected nonquercetin-treated animals. In the antrum, the lipid hydroperoxide concentration was significantly decreased in infected animals treated with quercetin, whereas in the corpus no significant differences were observed. Our results indicate that in vivo oral quercetin administration decreases H. pylori infection in the gastric mucosa and reduces both the inflammatory response and lipid peroxidation.


Hypolipidemic effect of polymethylenemethane thiosulfonates: inhibitors of acetoacetyl coenzyme A thiolase.
A new series of bifunctional thiosulfonates of the general formula CH3SO2S-(CH2)n-SSO2CH3(SS1 polymethylene bis methane thiosulfonate) with variable polymethylene chain lengths (n = 6, 8, 10 and 12) were evaluated for their hypolipidemic action on serum cholesterol and triglyceride levels in rats. Their action was based on their specific inhibitory effect on cytoplasmic acetoacetyl-CoA thiolase, one of the key enzymes in cholesterol biosynthesis. These compounds inhibited the enzyme in vitro and in vivo. The inhibition in vitro was in the order of n = 12 greater than n = 10 greater than n = 8 greater than n = 6 greater than, where n is the number of methylene groups inserted between the two thiosulfonate groups. In vivo, the compounds produced variable hypocholesterolemic and/or hypotriglyceridemic effects when injected into groups of newly weaned rats fed standard chow, high fat or high carbohydrate diets. When the enzyme activity was measured in isolated liver homogenates in vitro after injections of the drugs in vivo, 80% of original thiolase activity was lost. This inhibition of enzyme activity did not seem to be rate limiting for their hypolipidemic action in vivo as these effects did not correlate with the inhibition of the isolated enzyme. The lack of correlation between in vitro and in vivo activity might be due to the compounds affecting other enzyme systems and/or due to their differential disposition in vivo.


[Vesicle cycle in the presynaptic nerve terminal].
Presynaptic nerve terminals contain a great number ofsynaptic vesicles filled with neurotransmitter. The transmission of information in synapses is mediated by release of transmitter from vesicles: exocytosis, after their fusion with presynaptic membrane. At the functioning synapses, the continuous recycling of synaptic vesicles occurs (vesicle cycle), which provides multiple reuse of vesicular membrane material during synaptic activity. Vesicle cycle consists of large number of steps, including vesicle fusion--exocytosis, formation of new vesicles--endocytosis, vesicle sorting, filling of vesicles with transmitter, intraterminal vesicle transport driving the vesicles to different vesicle pools and preparing to next exocytic event. At this paper, I presented the latest literature and our data regarding the steps and mechanisms of vesicle cycle at synapses. Special attention was paid to neuromuscular synapse as the most thoroughly investigated and as my favorite preparation.


Members of the CDY family have different expression patterns: CDY1 transcripts have the best correlation with complete spermatogenesis.
The CDY family of genes is of special interest because some of them are included in chromosome-Y microdeletions detected among infertile men and are apparently involved in the spermiogenetic process. In this study, we employed the reverse transcriptase/polymerase chain reaction technique to test the RNA expression of the various transcripts of these genes in testicular biopsies of 84 azoospermic men who had been classified by comprehensive histology and cytology analyses. We also evaluated the feasibility of detecting CDY expression in biopsies taken by testicular sperm extraction versus acquisition by aspiration. There was a significant association between the type of testicular impairment and the expression of CDY1 and CDY2 transcripts. CDY2 was expressed whenever germ cells were present, but CDY1 major and especially CDY1 minor and short transcripts were identified almost exclusively when mature spermatids/spermatozoa were detected. The expression of CDY1 minor and short transcripts detected in aspirated specimens was less efficient than that in testicular tissue acquired by extraction. It is suggested that CDY2 is apparently required in the early stages of spermatogenesis, whereas CDY1 transcripts are required later on in the process. The findings of this study imply different functional roles for CDY isoforms during spermatogenesis. However, in consideration of the high levels of identity between CDY1 and CDY2 (98% at the protein level), the delayed up-regulation of CDY1 transcripts could be attributable to temporal changes in dosage requirements.


Minimizing Collateral Brain Injury Using a Protective Layer of Fibrin Glue: Technical Note.
Neurosurgical procedures expose the brain surface to a constant risk of collateral injury. We describe a technique where the brain surface is covered with a protective layer of fibrin glue and discuss its advantages. A thin layer of fibrin glue was applied on the brain surface after its exposure in 34 patients who underwent different craniotomies for tumoral and vascular lesions. Data of 35 more patients who underwent standard microsurgical technique were collected as a control group. Cortical and pial injuries were evaluated using an intraoperative visual scale. Eventual abnormal signals at the early postoperative T2-weighted fluid-attenuated inversion recovery (T2FLAIR) magnetic resonance imaging (MRI) sequences were evaluated in oncological patients. Total pial injury was noted in 63% of cases where fibrin glue was not used. In cases where fibrin glue was applied, a significantly lower percentage of 26% (P < 0.01) had pial injuries. Only 9% had injuries in areas covered with fibrin glue (P < 0.0001). Early postoperative T2FLAIR MRI confirmed the differences of altered signal around the surgical field in the two populations. We propose beside an appropriate and careful microsurgical technique the possible use of fibrin glue as alternative, safe, and helpful protection during complex microsurgical dissections. Its intrinsic features allow the neurosurgeon to minimize the cortical manipulation preventing minor collateral brain injury.


Development of the squamate naso-palatal complex: detailed 3D analysis of the vomeronasal organ and nasal cavity in the brown anole Anolis sagrei (Squamata: Iguania).
Despite the diverse morphology of the adult squamate naso-palatal complex - consisting of the nasal cavity, vomeronasal organ (VNO), choanal groove, lacrimal duct and superficial palate - little is known about the embryology of these structures. Moreover, there are no comprehensive studies concerning development of the nasal cavity and VNO in relation to the superficial palate. In this investigation, we used X-ray microtomography and histological sections to describe embryonic development of the naso-palatal complex of iguanian lizard, the brown anole (Anolis sagrei). The purpose of the study was to describe the mechanism of formation of adult morphology in this species, which combines the peculiar anole features with typical iguanian conditions. Considering the uncertain phylogenetic position of the Iguania within Squamata, embryological data and future comparative studies may shed new light on the evolution of this large squamate clade. Development of the naso-palatal complex was divided into three phases: early, middle and late. In the early developmental phase, the vomeronasal pit originates from medial outpocketing of the nasal pit, when the facial prominences are weakly developed. In the middle developmental phase, the following events can be noted: the formation of the frontonasal mass, separation of the vestibulum, appearance of the lacrimal duct, and formation of the choanal groove, which leads to separation of the VNO from the nasal cavity. In late development, the nasal cavity and the VNO attain their adult morphology. The lacrimal duct establishes an extensive connection with the choanal groove, which eventually becomes largely separated from the oral cavity. Unlike in other tetrapods, the primordium of the lacrimal duct in the brown anole develops largely beyond the nasolacrimal groove. In contrast to previous studies on squamates, the maxillary prominence is found to participate in the initial fusion with the frontonasal mass. Moreover, formation of the choanal groove occurs due to the fusion of the vomerine cushion to the subconchal fold, rather than to the choanal fold. The loss or significant reduction of the lateral nasal concha is secondary. Some features of anole adult morphology, such as the closure of the choanal groove, may constitute adaptations to vomeronasal chemoreception.


EGFR Inhibition Potentiates FGFR Inhibitor Therapy and Overcomes Resistance in FGFR2 Fusion-Positive Cholangiocarcinoma.
FGFR inhibitors are approved for the treatment of advanced cholangiocarcinoma harboring FGFR2 fusions. However, the response rate is moderate, and resistance emerges rapidly due to acquired secondary FGFR2 mutations or due to other less-defined mechanisms. Here, we conducted high-throughput combination drug screens, biochemical analysis, and therapeutic studies using patient-derived models of FGFR2 fusion-positive cholangiocarcinoma to gain insight into these clinical profiles and uncover improved treatment strategies. We found that feedback activation of EGFR signaling limits FGFR inhibitor efficacy, restricting cell death induction in sensitive models and causing resistance in insensitive models lacking secondary FGFR2 mutations. Inhibition of wild-type EGFR potentiated responses to FGFR inhibitors in both contexts, durably suppressing MEK/ERK and mTOR signaling, increasing apoptosis, and causing marked tumor regressions in vivo. Our findings reveal EGFR-dependent adaptive signaling as an important mechanism limiting FGFR inhibitor efficacy and driving resistance and support clinical testing of FGFR/EGFR inhibitor therapy for FGFR2 fusion-positive cholangiocarcinoma. We demonstrate that feedback activation of EGFR signaling limits the effectiveness of FGFR inhibitor therapy and drives adaptive resistance in patient-derived models of FGFR2 fusion-positive cholangiocarcinoma. These studies support the potential of combination treatment with FGFR and EGFR inhibitors as an improved treatment for patients with FGFR2-driven cholangiocarcinoma. This article is highlighted in the In This Issue feature, p. 1171.


Lesser-known plants of potential use in agriculture and forestry.
To help feed, clothe, and house an increasing population, to make marginal lands more productive, to meet challenging resource needs, and to reforest the devastated tropics, we need a revitalized worldwide investigation of little-known plant species. Such an effort would expand our agricultural resource base and ease our dangerous dependence on a relative handful of crops. It would build a more stable food supply for drought-stricken Africa and other parts of the Third World, and it would reclothe many of the barren lands where erosion now threatens disaster. Some plants that are now virtually unknown are likely to become mainstays of international agriculture and industry.


Fabrication of a dual-purpose surgical template for correct labiopalatal positioning of dental implants.
An implant-supported prosthesis can potentially provide a functional and esthetic reconstruction, provided that the implants are precisely placed in the predetermined location and angulation. Since the accurate placement of osseointegrated implants in the anterior maxilla with questionable bone support is often a clinical challenge, the use of computed tomography and surgical guides is crucial. This article describes a technique to fabricate a template that served as a guide for radiographic evaluation and was then modified for use in the surgical phase of the treatment.


Use of Leishmania donovani field isolates expressing the luciferase reporter gene in in vitro drug screening.
Currently available primary screens for the selection of candidate antileishmanial compounds are not ideal. These techniques are time-consuming, laborious, and difficult to scale and require macrophages, which limit their use for high-throughput screening. We have developed Leishmania donovani field isolates that constitutively express the firefly luciferase reporter gene (luc) as a part of an episomal vector. An excellent correlation between parasite number and luciferase activity was observed. luc expression was stable, even in the absence of drug selection, for 4 weeks. The transfectants were infective to macrophages, and intracellular amastigotes exhibited luciferase activity. The suitability of these recombinant field isolates for in vitro screening of antileishmanial drugs was established. The luciferase-expressing sodium stibogluconate-resistant cell lines offer a model for the screening of compounds for resistance. The system is in routine use at the Central Drug Research Institute, Lucknow, India, for high-throughput screening of newly synthesized compounds.


Comparison of radiographic quality and adverse reactions in myelography with iopamidol and metrizamide.
A randomized double-blind study was conducted to compare the radiographic quality and adverse reactions in myelography of the two nonionic water-soluble contrast media, iopamidol and metrizamide. A total of 46 myelograms were obtained, 28 with iopamidol and 18 with metrizamide. Untoward reactions consisted of nausea, headaches, back and leg pain, neuropsychiatric findings, and urinary retention. Iopamidol caused no reactions in 20 of the 28 cases, while metrizamide caused no reactions in only three of 18 cases. Film quality evaluation showed 22 of the 28 studies with iopamidol were judged excellent, whereas only 11 of the 18 metrizamide studies were judged excellent. The results of this study suggest that iopamidol produces better quality studies with fewer and milder adverse reactions than metrizamide.


Effectiveness of a Batteryless and Wireless Wearable Sensor System for Identifying Bed and Chair Exits in Healthy Older People.
Aging populations are increasing worldwide and strategies to minimize the impact of falls on older people need to be examined. Falls in hospitals are common and current hospital technological implementations use localized sensors on beds and chairs to alert caregivers of unsupervised patient ambulations; however, such systems have high false alarm rates. We investigate the recognition of bed and chair exits in real-time using a wireless wearable sensor worn by healthy older volunteers. Fourteen healthy older participants joined in supervised trials. They wore a batteryless, lightweight and wireless sensor over their attire and performed a set of broadly scripted activities. We developed a movement monitoring approach for the recognition of bed and chair exits based on a machine learning activity predictor. We investigated the effectiveness of our approach in generating bed and chair exit alerts in two possible clinical deployments (Room 1 and Room 2). The system obtained recall results above 93% (Room 2) and 94% (Room 1) for bed and chair exits, respectively. Precision was >78% and 67%, respectively, while F-score was >84% and 77% for bed and chair exits, respectively. This system has potential for real-time monitoring but further research in the final target population of older people is necessary.


Biochemical characterization and inhibitory effects of dinophysistoxin-1, okadaic acid and microcystine 1-r on protein phosphatase 2a purified from the mussel Mytilus chilensis.
Protein phosphatases are involved in many cellular processes. One of the most abundant and best studied members of this class is protein phosphatase type-2A (PP2A). In this study, PP2A was purified from the mussel Mytilus chilensis. Using both SDS-PAGE and size exclusion gel filtration under denaturant conditions, it was confirmed that the PP2A fraction was essentially pure. The isolated enzyme is a heterodimer and the molecular estimated masses of the subunits are 62 and 28 kDa. The isolated PP2A fraction has a notably high p-NPP phosphatase activity, which is inhibited by NaCl. The hydrolytic p-NPP phosphatase activity is independent of the MgCl2 concentration. The time courses of the inhibition of the PP2A activity of p-NPP hydrolysis by increasing concentrations of three phycotoxins that are specific inhibitors of PP2A are shown. Inhibitions caused by Okadaic acid, dinophysistoxin-1 (DTX1, 35-methylokadiac acid) and Microcystine L-R are dose-dependent with inhibition constants (Ki) of 1.68, 0.40 and 0.27 nM respectively. Microcystine L-R, the most potent phycotoxin inhibitor of PP2A isolated from Mytilus chilensis with an IC50 = 0.25 ng/ml, showed the highest specific inhibition effect an the p-NPP hydrolisis. The calculated IC50 for DTX1 and OA was 0.75 ng/ml and 1.8 ng/ml respectively.


Molecular evolution of inversions in Drosophila pseudoobscura: the amylase gene region.
The amylase region of the third chromosome of Drosophila pseudoobscura has been cloned and localized to cytological band 73A. It is contained within a series of highly polymorphic inversions and serves as a convenient tool for a molecular evolutionary analysis of the inverted gene arrangements. Amylase in D. pseudoobscura is a family of three genes, and some chromosomes have deletions for one or two of them. Two overlapping clones covering 26 kilobases were isolated and used as probes to survey DNA restriction map polymorphism among 28 lines, representing five of the major inversion types found in natural populations, as well as single chromosomes from the closely related species Drosophila persimilis and Drosophila miranda. Restriction-site differences are considerably greater among the various gene arrangements than among chromosomes with the same gene arrangement. Clustering the restriction map haplotypes yielded a dendrogram concordant with the phylogeny generated independently from cytogenetic considerations. The inversion polymorphism is estimated to be about 2 million years old.


[Laparoscopic treatment of splenic cysts].
Splenic cysts are uncommon. The symptoms are usually vague, but complications such as haemorrhage, rupture and infection may occur. The majority of splenic cysts are seen in children and young adults. Surgical treatment is recommended and splenic preservation is advantageous. We present two patients with splenic cysts successfully treated with laparoscopic resection of the cyst wall.


Metabolic pathway monitoring of phenalinolactone biosynthesis from Streptomyces sp. Tü6071 by liquid chromatography/mass spectrometry coupling.
A rapid and precise analytical method for the investigation of natural products is required for pathway monitoring of the biosynthesis of secondary metabolites. Phenalinolactones, used in antibiotic research, are produced by Streptomyces sp. Tü6071. For the analysis of those compounds, prior to mass spectrometric analysis, an efficient separation technique is required. For the identification of phenalinolactones from liquid cultures of Streptomyces sp. Tü6071, a new method comprising the combination of solid-phase extraction (SPE) prior to liquid chromatography/electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS) was established. MS/MS product ion scans were applied for phenalinolactone detection and structure elucidation, performed in negative mode and optimized for sensitivity and specificity. For the discovery of new intermediates, a MS/MS precursor ion scan was applied. Analysis of the extracts revealed that the Oasis® MAX cartridge, containing a quaternary amine functionality, is the most efficient SPE material for purification of phenalinolactones, since it allowed sufficient enrichment and detection of intermediates from the biosynthetic pathway by LC/ESI-MS/MS. Using the precursor ion scan technique, two new secondary metabolites, PL IM1 with m/z 672.6 and PL IM2 with m/z 433.3, have been detected. The structures of the new intermediates are postulated and arranged into the biosynthetic pathway of phenalinolactones. A precise analytical method was established for the identification of phenalinolactones by combining purification from Streptomyces using SPE prior to LC/ESI-MS/MS. By optimising LC/ESI-MS/MS settings, this method has been successfully applied for pathway monitoring of secondary metabolites. Application of a precursor ion scan allowed for the identification of unknown intermediates in biosynthetic pathways.


[Paediatric neurology and habilitation in Norway].
Based on results from a national survey we discuss the status and prospects of Norwegian child neurology and habilitation. A questionnaire on neurology and habilitation was sent to all 22 Norwegian departments of paediatrics. All departments responded. The organisation of services varied considerably. Only one department registered children admitted for neurological disorders specifically. Habilitation was mainly based on out-patient services. The number of out-patient neurology consultations in relation to regional population varied with a factor of 5.3 from the department with lowest to the one with highest number of cases. Corresponding factors were 5.9 for number of habilitation consultations per year, 3.6 for paediatricians in child neurology and habilitation, and 5.6 for allied health professionals working in habilitation units. In Norway there were 61 physicians working in child neurology and habilitation. Several departments were active in work on methodology. Research was mainly carried out in university departments. Child neurology and habilitation services are available in all Norwegian counties. There is need for more systematic registration of clinical activities, for research, including the effect of treatment and interventions, more work on methodology, more posts for graduate medical education in the field, better organisation of services for in-patients, and closer cooperation between paediatric, habilitation and community care services.


Binding Analysis Using Accelerated Molecular Dynamics Simulations and Future Perspectives.
Biomolecular recognition such as binding of small molecules, nucleic acids, peptides and proteins to their target receptors plays key roles in cellular function and has been targeted for therapeutic drug design. Molecular dynamics (MD) is a computational approach to analyze these binding processes at an atomistic level, which provides valuable understandings of the mechanisms of biomolecular recognition. However, the rather slow biomolecular binding events often present challenges for conventional MD (cMD), due to limited simulation timescales (typically over hundreds of nanoseconds to tens of microseconds). In this regard, enhanced sampling methods, particularly accelerated MD (aMD), have proven useful to bridge the gap and enable all-atom simulations of biomolecular binding events. Here, we will review the recent method developments of Gaussian aMD (GaMD), ligand GaMD (LiGaMD) and peptide GaMD (Pep-GaMD), which have greatly expanded our capabilities to simulate biomolecular binding processes. Spontaneous binding of various biomolecules to their receptors has been successfully simulated by GaMD. Microsecond LiGaMD and Pep-GaMD simulations have captured repetitive binding and dissociation of small-molecule ligands and highly flexible peptides, and thus enabled ligand/peptide binding thermodynamics and kinetics calculations. We will also present relevant application studies in simulations of important drug targets and future perspectives for rational computer-aided drug design.


Parenteral clindamycin phosphate: pharmacology with normal and abnormal liver function and effect on nasal staphylococci.
Parenteral clindamycin was evaluated in 41 patients with a variety of infections. The four major findings were as follows. (i) Five hours after the intravenous administration of 600 mg of clindamycin, the mean serum concentration in patients with "moderate to severe" hepatic dysfunction was 24.3 mug/ml, and in those with normal liver function it was 8.3 mug/ml (P < 0.02). This suggests that the dose of clindamycin might be modified in patients with liver disease. (ii) There was a positive association between the 5-h serum clindamycin level and the degree of elevation of the serum glutamic oxaloacetic transaminase. (iii) No significant side effects were observed. Of 24 patients with preexisting hepatic dysfunction, 5 showed deterioration and 5 showed improvement of liver function during therapy. (iv) Whereas all pre-treatment isolates of Staphylococcus epidermidis from the anterior nares were susceptible to clindamycin, 6 of 9 post-treatment isolates were resistant, most probably due to selection of resistant organisms.


The yddV-dos operon controls biofilm formation through the regulation of genes encoding curli fibers' subunits in aerobically growing Escherichia coli.
In bacteria, intracellular amounts of the signal molecule cyclic di-GMP (c-di-GMP) are determined by biosynthetic enzymes, or diguanylate cyclases (DGCs), and degradative enzymes, or c-di-GMP phosphodiesterases (c-PDEs). In Escherichia coli, the production of curli fibers, an important adhesion factor, responds to c-di-GMP. The yddV-dos operon, which encodes a DGC and a c-PDE acting as a protein complex, is highly expressed at a low growth temperature and in the stationary phase, i.e. conditions that also stimulate curli production. We show that perturbations in the balance between YddV and Dos, obtained either through inactivation of the yddV gene or through overproduction of either YddV or Dos, strongly affect curli production. Both YddV and Dos proteins regulate the transcription of the csgBAC operon, which encodes curli structural subunits, while not affecting the expression of the regulatory operon csgDEFG. Consistent with the role of both YddV and Dos proteins as oxygen sensors, their effects on csgBAC gene expression were dramatically reduced in cells grown under anoxic conditions. Our results show that the yddV-dos operon plays an important role in the expression of curli-encoding genes in aerobically growing E. coli, and suggest that YddV and Dos, through their opposite activities, might finely tune curli production in response to oxygen availability.


[Smoking cessation in patients with cardiopulmonary diseases].
To determine the smoking cessation rates of outpatients with cardiopulmonary disease and the differences between non-cardiopulmonary diseases. Two hundred and two active smokers with comorbid diseases were prospectively evaluated between September 2004 and January 2008 in this observational study. All of the patients answered Fagerstrom test for nicotine dependence with a regular questionnaire of general characteristics. Behavioral counseling therapies were administered to all of the subjects. Nicotine replacement therapy, bupropion or combination therapies were the pharmacological therapies after running the baseline spirometry and carbon monoxide oximetry tests. Subjects were classified as patients with cardiopulmonary disease (124) and non-cardiopulmonary diseases (78), based on medical history. Student t and Chi-square tests were used for statistical analyses. The age of smoking was similar but total amount of smoked tobacco was higher (p<0.05) in the cardiopulmonary diseases group. In this group, the main smoking cessation reason was the existing disease (51%) (p<0.05). There was no other significant difference between two groups including treatment protocols. The smoking cessation rates were less (40%) with high relapses (12%) in cardiopulmonary diseases group (p<0.01 and p=0.01 respectively). In the subgroup analysis, treatment procedures were equivalent (p>0.05). Results of this analysis confirm that, tobacco dependence is still a severe but necessary condition for the patients with cardiopulmonary diseases. Additionally neither of the treatment protocols was superior to the others.


Xanthenone-based hydrazones as potent α-glucosidase inhibitors: Synthesis, solid state self-assembly and in silico studies.
Xanthenone based hydrazone derivatives (5a-n) have been synthesized as potential α-glucosidase inhibitors. All synthesized compounds (5a-n) are characterized by their FTIR, 1H NMR, 13C NMR and HRMS, and in case of 5g also by X-ray crystallographic technique. The compounds unveiled a varying degree of α-glucosidase inhibitory activity when compared with standard acarbose (IC50 = 375.38 ± 0.12 µM). Amongst the series, compound 5l (IC50 = 62.25 ± 0.11 µM) bearing a trifluoromethyl phenyl group is found to be the most active compound. Molecular modelling is performed to establish the binding pattern of the more active compound 5l, which revealed the significance of substitution pattern. The pharmacological properties of molecules are also calculated by MedChem Designer which determines the ADME (absorption, distribution, metabolism, excretion) properties of molecules. The solid state self-assembly of compound 5g is discussed to show the conformation and role of iminoamide moiety in the molecular packing.


Response of arterial blood pressure to static exercise in relation to muscle mass, force development, and electromyographic activity.
In young men, the arterial blood pressure response during static exercise at 40% of maximal voluntary contraction (MVC) and the response after the contraction with a cuff inflated both were increased when a greater mass of skeletal muscle was involved. Also in men with a previously injured leg, the arterial systolic pressure and the smoothed, rectified electromyographic activity (EMG) were greater during static contraction of the large, strong leg than during static contraction of the small, weak leg at the same percent MVC. However, the arterial systolic pressure and the EMG were almost the same during contraction of either leg when the same force was developed. Finally, in young men, either the force developed was held constant at 20% MVC or the level of the initial EMG at 20% MVC was held constant for 5 minutes. During the force-constant experiments, the EMG doubled and correlated with the 40% increase in mean arterial pressure (r = 0.89). In the EMG-constant experiments, force declined to about 12% MVC with an increase of only 20% in mean arterial pressure. These studies of the response of arterial blood pressure to static muscular contractions can best be explained by both central and peripheral control mechanisms. The central control mechanism "central command" is probably related to the central activity for recruitment of motor units and the peripheral control mechanism is probably mediated by muscle afferents which are excited by metabolic changes in the contracting skeletal muscle.


A long-term siRNA strategy regulates fibronectin overexpression and improves vascular lesions in retinas of diabetic rats.
A sustained gene modulatory strategy is necessary for regulating abnormal gene expression in diabetic retinopathy, a long-term complication. We investigated the efficacy of a small interference RNA (siRNA) strategy in mediating the long-term downregulatory effect of fibronectin (FN) overexpression in vivo. Streptozotocin-induced diabetic rats were intravitreally injected with 3 µM of FN-siRNA at six week intervals over a period of 4.5 months. Retinal FN protein expression, vascular basement membrane (BM) thickness, and retinal vascular cell loss were assessed by western blot, electron microscopy, and retinal trypsin digest, respectively. Retinal FN expression and BM thickness were significantly increased in diabetic rat retinas compared to those in non-diabetic control rats (188±14.2% of control versus 100±7.4% of control, p<0.002; 72.5±5.0 nm versus 51.5±4.8 nm, p<0.001, respectively). FN-siRNA treatment reduced FN overexpression and BM thickening (145±19.9% of control and 56.4±2.8 nm, respectively) and significantly reduced the number of acellular capillaries (35%) and pericyte loss (55%) compared to those of untreated diabetic eyes. These findings suggest that BM thickening is an important target for preventing vascular cell loss in a diabetic retina, and that the siRNA approach could be useful for long-term gene modulation in diabetic retinopathy.


Phytoagents for cancer management: regulation of nucleic acid oxidation, ROS, and related mechanisms.
Accumulation of oxidized nucleic acids causes genomic instability leading to senescence, apoptosis, and tumorigenesis. Phytoagents are known to reduce the risk of cancer development; whether such effects are through regulating the extent of nucleic acid oxidation remains unclear. Here, we outlined the role of reactive oxygen species in nucleic acid oxidation as a driving force in cancer progression. The consequential relationship between genome instability and cancer progression highlights the importance of modulation of cellular redox level in cancer management. Current epidemiological and experimental evidence demonstrate the effects and modes of action of phytoagents in nucleic acid oxidation and provide rationales for the use of phytoagents as chemopreventive or therapeutic agents. Vitamins and various phytoagents antagonize carcinogen-triggered oxidative stress by scavenging free radicals and/or activating endogenous defence systems such as Nrf2-regulated antioxidant genes or pathways. Moreover, metal ion chelation by phytoagents helps to attenuate oxidative DNA damage caused by transition metal ions. Besides, the prooxidant effects of some phytoagents pose selective cytotoxicity on cancer cells and shed light on a new strategy of cancer therapy. The "double-edged sword" role of phytoagents as redox regulators in nucleic acid oxidation and their possible roles in cancer prevention or therapy are discussed in this review.


The effect of isometric contraction on the regulation of force tremor in the contralateral limb.
This study examined how regulating force tremor in a single limb is altered when the opposite limb is actively engaged in a force generating task. Index finger abduction force and first dorsal interosseous (FDI) activity were assessed in thirteen healthy subjects, at target forces from 5% to 60% MVC for the non-dominant limb (unilateral task), and again when the dominant limb simultaneously generated a submaximal abduction force (bilateral task). When the non-dominant limb generated force at 20% MVC, tremor was greater during the bilateral task compared with the unilateral task; a finding reflected in the amplitude of peak power of force. Bilateral responses were also examined during a prolonged 60% MVC unilateral contraction. Force tremor and muscle activity amplitude increased while the frequency of activity decreased for the contracting limb. Additionally, force tremor significantly decreased towards the end of the prolonged contraction in the contralateral limb. Overall, it appears that the process of performing isometric contractions invokes tremor-related changes in the opposite limb at selective force targets, and performing prolonged unilateral contractions invokes tremor-related changes in the opposite limb when it is at rest.


Repetitive busulfan administration after hematopoietic stem cell gene therapy associated with a dominant HDAC7 clone in a nonhuman primate.
The risk of genotoxicity of retroviral vector-delivered gene therapy targeting hematopoietic stem cells (HSCs) has been highlighted by the development of clonal dominance and malignancies in human and animal gene therapy trials. Large-animal models have proven invaluable to test the safety of retroviral vectors, but the detection of clonal dominance may require years of follow-up. We hypothesized that hematopoietic stress may accelerate the proliferation and therefore the detection of abnormal clones in these models. We administered four monthly busulfan (Bu) infusions to induce hematopoietic stress in a healthy rhesus macaque previously transplanted with CD34+ cells transduced with retroviral vectors carrying a simple marker gene. Busulfan administration resulted in significant cytopenias with each cycle, and prolonged pancytopenia after the final cycle with eventual recovery. Before busulfan treatment there was highly polyclonal marking in all lineages. After Bu administration clonal diversity was markedly decreased in all lineages. Unexpectedly, we found no evidence of selection of the MDS1/EVI1 clones present before Bu administration, but a clone with a vector integration in intron 1 of the histone deacetylase-7 (HDAC7) gene became dominant in granulocytes over time after Bu administration. The overall marking level in the animal was increased significantly after Bu treatment and coincident with expansion of the HDAC7 clone, suggesting an in vivo advantage for this clone under stress. HDAC7 expression was upregulated in marrow progenitors containing the vector. Almost 5 years after Bu administration, the animal developed progressive cytopenias, and at autopsy the marrow showed complete lack of neutrophil or platelet maturation, with a new population of approximately 20% undifferentiated blasts. These data suggest that chemotherapeutic stress may accelerate vector-related clonal dominance, even in the absence of drug resistance genes expressed by the vector. This model may both accelerate the detection of abnormal clones to facilitate analysis of genotoxicity for human gene therapy, and help assess the safety of administering myelotoxic chemotherapeutic agents in patients previously engrafted with vector-containing cells.


A large and giant bifurcation aneurysm model in canines: proof of feasibility.
To our knowledge, no reproducible animal model of a giant bifurcation type aneurysm has been described. It was our aim to develop a 1-stage and reproducible model of a venous pouch giant aneurysm in canines. Nine canines were involved. Bilateral CCAs were exposed. The left CCA was divided and its distal segment was swung to the right side. Using the right CCA and the distal segment of the left CCA, either a bifurcation or a terminal arterial structure was constructed. Bilateral external jugular veins were also exposed. A 30-mm vein segment was harvested from each side. Each vein graft was split and unfolded to make 2 venous sheets. These sheets were then joined top-to-bottom so as to form a single cylinder in such a way that original adventitial side of the venous sheets was on the exterior surface. In 2 instances, pieces of polytetrafluoroethylene were employed along with the venous sheets. The combined vein graft was then incorporated into the arterial anastomosis. Lastly, the top of the venous pouch was closed. No medications for anticoagulant or antiplatelet were used throughout the study period. Follow-up imaging studies were performed. It took 2.5 hours on average for 2 operators to create an aneurysm. Eight of the 9 aneurysms were patent at follow-up. The cause of the spontaneous thrombosis was unclear despite autopsy. All the aneurysms had a maximum diameter >20 mm. We demonstrated and illustrated a 1-stage and reproducible procedure to create a model of a venous pouch bifurcation giant aneurysm in canines.


Correlates of sexually transmitted disease infection among adults living with HIV.
This study examined the prevalence of sexually transmitted diseases (STDs) as well as the relationships between STDs and coping strategies used to deal with the stress of living with HIV among adults. The sample comprised 179 men and women, 58% were Caucasian, 54% were male, more than half (61%) were diagnosed with AIDS, 43% were heterosexual, and 39% reported an STD post-HIV diagnosis. Logistic regression analysis indicated that individuals reporting longer time elapsed since HIV diagnosis and greater use of emotion-focused coping were more likely to report STDs. There was an interaction effect between time and coping such that the less time that elapsed since HIV diagnosis and the more an individual used emotion-focused coping, the more likely they were to report an STD. Tailoring interventions to address specific stressors associated with length of time living with HIV, may be a particularly effective prevention strategy.


Oral vitamin B12 for patients suspected of subtle cobalamin deficiency: a multicentre pragmatic randomised controlled trial.
Evidence regarding the effectiveness of oral vitamin B12 in patients with serum vitamin B12 levels between 125-200 pM/l is lacking. We compared the effectiveness of one-month oral vitamin B12 supplementation in patients with a subtle vitamin B12 deficiency to that of a placebo. This multicentre (13 general practices, two nursing homes, and one primary care center in western Switzerland), parallel, randomised, controlled, closed-label, observer-blind trial included 50 patients with serum vitamin B12 levels between 125-200 pM/l who were randomized to receive either oral vitamin B12 (1000 μg daily, N = 26) or placebo (N = 24) for four weeks. The institution's pharmacist used simple randomisation to generate a table and allocate treatments. The primary outcome was the change in serum methylmalonic acid (MMA) levels after one month of treatment. Secondary outcomes were changes in total homocysteine and serum vitamin B12 levels. Blood samples were centralised for analysis and adherence to treatment was verified by an electronic device (MEMS; Aardex Europe, Switzerland). ISRCTN 22063938. Baseline characteristics and adherence to treatment were similar in both groups. After one month, one patient in the placebo group was lost to follow-up. Data were evaluated by intention-to-treat analysis. One month of vitamin B12 treatment (N = 26) lowered serum MMA levels by 0.13 μmol/l (95%CI 0.06-0.19) more than the change observed in the placebo group (N = 23). The number of patients needed to treat to detect a metabolic response in MMA after one month was 2.6 (95% CI 1.7-6.4). A significant change was observed for the B12 serum level, but not for the homocysteine level, hematocrit, or mean corpuscular volume. After three months without active treatment (at four months), significant differences in MMA levels were no longer detected. Oral vitamin B12 treatment normalised the metabolic markers of vitamin B12 deficiency. However, a one-month daily treatment with 1000 μg oral vitamin B12 was not sufficient to normalise the deficiency markers for four months, and treatment had no effect on haematological signs of B12 deficiency.


Single-Nucleotide Polymorphism-Based Genetic Risk Score and Patient Age at Prostate Cancer Diagnosis.
Few studies have evaluated the association between a single-nucleotide polymorphism-based genetic risk score (GRS) and patient age at prostate cancer (PCa) diagnosis. To test the association between a GRS and patient age at PCa diagnosis and to compare the performance of a GRS with that of family history (FH) in PCa risk stratification. A cohort study of 3225 white men was conducted as a secondary analysis of the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) chemoprevention trial, a 4-year, randomized, double-blind, placebo-controlled multicenter study conducted from March 2003 to April 2009 to evaluate the safety and efficacy of dutasteride in reducing PCa events. Participants were confirmed to be cancer free by prostate biopsy (6-12 cores) within 6 months prior to the study and underwent 10 core biopsies every 2 years per protocol. The dates for performing data analysis were from July 2016 to October 2019. A well-established, population-standardized GRS was calculated for each participant based on 110 known PCa risk-associated single-nucleotide polymorphisms, which is a relative risk compared with the general population. Men were classified into 3 GRS risk groups based on predetermined cutoff values: low (<0.50), average (0.50-1.49), and high (≥1.50). Prostate cancer diagnosis-free survival among men of different risk groups. Among 3225 men (median age, 63 years [interquartile range, 58-67 years]) in the study, 683 (21%) were classified as low risk, 1937 (60%) as average risk, and 605 (19%) as high risk based on GRS alone. In comparison, 2789 (86%) were classified as low or average risk and 436 (14%) as high risk based on FH alone. Men in higher GRS risk groups had a PCa diagnosis-free survival rate that was worse than that of those in the lower GRS risk group (χ2 = 53.3; P < .001 for trend) and in participants with a negative FH of PCa (χ2 = 45.5; P < .001 for trend). Combining GRS and FH further stratified overall genetic risk, indicating that 957 men (30%) were at high genetic risk (either high GRS or positive FH), 1667 men (52%) were at average genetic risk (average GRS and negative FH), and 601 men (19%) were at low genetic risk (low GRS and negative FH). The median PCa diagnosis-free survival was 74 years (95% CI, 73-75 years) for men at high genetic risk, 77 years (95% CI, 75 to >80 years) for men at average genetic risk, and more than 80 years (95% CI, >80 to >80 years) for men at low genetic risk. In contrast, the median PCa diagnosis-free survival was 73 years (95% CI, 71-76 years) for men with a positive FH and 77 years (95% CI, 76-79 years) for men with a negative FH. This study suggests that a GRS is significantly associated with patient age at PCa diagnosis. Combining FH and GRS may better stratify inherited risk than FH alone for developing personalized PCa screening strategies.


Regulation of recombination between gtfB/gtfC genes in Streptococcus mutans by recombinase A.
Streptococcus mutans produces 3 types of glucosyltransferases (GTFs), whose cooperative action is essential for cellular adhesion. The recombinase A (RecA) protein is required for homologous recombination. In our previous study, we isolated several strains with a smooth colony morphology and low GTF activity, characteristics speculated to be derived from the GTF fusions. The purpose of the present study was to investigate the mechanism of those fusions. S. mutans strain MT8148 was grown in the presence of recombinant RecA (rRecA) protein, after which smooth colonies were isolated. The biological functions and sequences of the gtfB and gtfC genes of this as well as other clinical strains were determined. The sucrose-dependent adherence rates of those strains were reduced as compared to that of MT8148. Determination of the sequences of the gtfB and gtfC genes showed that an approximately 3500 bp region was deleted from the area between them. Furthermore, expression of the recA gene was elevated in those strains as compared to MT8148. These results suggest that RecA has an important role in fusions of gtfB and gtfC genes, leading to alteration of colony morphology and reduction in sucrose-dependent adhesion.


Prevention of type 2 diabetes: insulin resistance and beta-cell function.
Type 2 diabetes is increasing worldwide in epidemic proportions. Its associated morbidity and mortality is imposing a major burden on the health care system. Based on a better understanding of the pathophysiology of glucose intolerance, clinical trials on the prevention of diabetes have been performed. It has now been demonstrated that diet and exercise, metformin, acarbose, and troglitazone can prevent or at least delay the development of diabetes in subjects with impaired glucose tolerance (IGT). It is now generally accepted that insulin resistance and beta-cell dysfunction are major factors involved in the development of diabetes. The relative contribution of insulin resistance versus beta-cell dysfunction on the pathogenesis of diabetes has aroused much debate. These two processes should be studied in relation to one another: their relationship is best described as hyperbolic in nature. When this relationship is taken into consideration, it becomes evident that subjects at risk of developing type 2 diabetes have beta-cell dysfunction before they develop glucose intolerance. Insulin resistance may be mostly explained by the presence of obesity and accelerate the progression to diabetes in subjects with the propensity to beta-cell failure. By the time hyperglycemia occurs, impairment in both insulin sensitivity and insulin secretion are present. There are still few data on insulin sensitivity and insulin secretion from the trials on the prevention of diabetes. The few data that we do have suggest that most interventions mostly have an effect on insulin resistance. By reducing insulin resistance, they protect and preserve the beta-cell function. No intervention has yet shown any direct effect on beta-cell function.


[Is preoperative bone scintigraphy in early stage of breast cancer T1N0 indicated and meaningful?].
In the Czech Republic bone scintigraphy has still been performed routinely as a part of preoperative staging examinations of early breast carcinomas, which had been in 42% diagnosed in the national breast cancer screening program. The incidence of synchronnous distant metastases was analysed for a subgroup of T1N0 breast carcinomas using the database of the Czech National Cancer Registry. Out of 21,675 women with T1N0 breast carcinomas diagnosed in the decade of 2001-2010 the potential occurence of various distant metastases (M1) was estimated in 147 cases (0,68%). Since only approximately 40% of all distant metastases were skeletal (M1 OSS), the pro-bability of bone metastases in T1N0 breast cancer does not exceed 0,3-0,4%. Distant metastases were present in 0,5% in a subgroup of well and moderately differentiated carcinomas and up to 1,2% in poorly differentiated and anaplastic tumors, however, only a minor part (0,2% and 0,5%, respectively) involved bones. We conclude that preoperative bone scintigraphy is overused and undue in more than 99% of Czech women with early breast cancer T1N0. Skeletal scintigraphy as a staging procedure for small breast carcinoma T1N0 may perhaps be recommended only postoperatively and very selectively with regards to individual risk factors and symptomatology.


Long-Lasting Input-Specific Experience-Dependent Changes of Hippocampus Synaptic Function Measured in the Anesthetized Rat.
How experience causes long-lasting changes in the brain is a central question in neuroscience. The common view is that synaptic function is altered by experience to change brain circuit functions that underlie conditioned behavior. We examined hippocampus synaptic circuit function in vivo, in three groups of animals, to assess the impact of experience on hippocampus function in rats. The "conditioned" group acquired a shock-conditioned place response during a cognitively-challenging, hippocampus synaptic plasticity-dependent task. The no-shock group had similar exposure to the environmental conditions but no conditioning. The home-cage group was experimentally naive. After the one-week retention test, under anesthesia, we stimulated the perforant path inputs to CA1, which terminate in stratum lacunosum moleculare (slm), and to the dentate gyrus (DG), which terminate in the molecular layer. We find synaptic compartment specific changes that differ amongst the groups. The evoked field EPSP (fEPSP) and pre-spike field response are enhanced only at the DG input layer and only in conditioned animals. The DG responses, measured by the population spiking activity and post-spike responses, are enhanced in both the conditioned and no-shock groups compared to home-cage animals. These changes are pathway specific because no differences are observed in slm of CA1. These findings demonstrate long-term, experience-dependent, pathway-specific alterations to synaptic circuit function of the hippocampus.


Three-Class Differential Diagnosis among Alzheimer Disease, Frontotemporal Dementia, and Controls.
Biomarkers derived from brain magnetic resonance (MR) imaging have promise in being able to assist in the clinical diagnosis of brain pathologies. These have been used in many studies in which the goal has been to distinguish between pathologies such as Alzheimer's disease and healthy aging. However, other dementias, in particular, frontotemporal dementia, also present overlapping pathological brain morphometry patterns. Hence, a classifier that can discriminate morphometric features from a brain MRI from the three classes of normal aging, Alzheimer's disease (AD), and frontotemporal dementia (FTD) would offer considerable utility in aiding in correct group identification. Compared to the conventional use of multiple pair-wise binary classifiers that learn to discriminate between two classes at each stage, we propose a single three-way classification system that can discriminate between three classes at the same time. We present a novel classifier that is able to perform a three-class discrimination test for discriminating among AD, FTD, and normal controls (NC) using volumes, shape invariants, and local displacements (three features) of hippocampi and lateral ventricles (two structures times two hemispheres individually) obtained from brain MR images. In order to quantify its utility in correct discrimination, we optimize the three-class classifier on a training set and evaluate its performance using a separate test set. This is a novel, first-of-its-kind comparative study of multiple individual biomarkers in a three-class setting. Our results demonstrate that local atrophy features in lateral ventricles offer the potential to be a biomarker in discriminating among AD, FTD, and NC in a three-class setting for individual patient classification.


Inclusion of the dose from kilovoltage cone beam CT in the radiation therapy treatment plans.
Cone beam CT is increasingly being used for daily patient positioning verification during radiation therapy treatments. The daily use of CBCT could lead to accumulated patient doses higher than the older technique of weekly portal imaging. There have been several studies focusing on measurement or calculation of the patient dose from CBCT recently. This study investigates the feasibility of configuring a kV x-ray source in a commercial treatment planning system to calculate the dose to patient resulting from an IGRT procedure. The method proposed in this article can be used to calculate dose from CBCT imaging procedure and include that in the patient treatment plans. The kilovoltage beam generated by the CBCT imager has been modeled using the planning system. The modeled profiles agree with the measured ones to within 5%. The modeled beam was used to calculate dose to phantom in the pelvic region and the calculations were compared to TLD measurements. The agreement between calculated and measured doses ranges from 0% to 19% in soft tissue with larger variations observed near and within the bone. The modeling of the beam produces reasonable results and the dose calculation comparisons indicate the potential for computing kilovoltage CBCT doses using a treatment planning system. Further improvements in the dose calculation algorithm are necessary, especially for dose calculations in and near the bone.


Characteristics of asthma care provided by hospitals in a large metropolitan area: results from the Chicago Asthma Surveillance Initiative.
Little is known of the approaches of United States hospitals to the management of persons with asthma. The purpose of this study is to characterize the extent to which hospitals within a large community have implemented various types of asthma-specific health-care delivery processes. A cross-sectional, self-administered survey was mailed to a "key informant" in asthma care at each of the hospitals in the Chicago area. The survey instrument covered the following content areas: asthma-related inpatient services, asthma-related outpatient services, selected asthma-related quality improvement activities, and asthma-related community outreach. The survey was administered between August 1996 and January 1997. Data were collected from respondents at 59 of the 89 eligible hospitals, yielding a response rate of 66.3%. Of the responding hospitals, 42.4% indicated they had clinical practice guidelines for inpatient asthma management, and 37.3% reported using critical pathways. Four selected aspects of bedside care were also explored. All of the responding hospitals reported routine provision of nebulization therapy at the bedside, and nearly all routinely obtained peak flow measurements (96.6%). In the area of patient instruction, 93.2% provided bedside evaluation of proper inhaler technique, and 86.4% routinely provided instruction on the use of peak flowmeters. Only 54.0% of the hospitals reported routinely administering some type of asthma education program prior to discharge. The hospitals with clinical practice guidelines in place were also more likely to have critical pathways (p < 0.01); to have asthma-specific ICU policies/guidelines/critical pathways (p < 0.01); to provide bedside instruction on the use of peak flowmeters (p < 0.01); to provide an asthma education (p < 0.01) prior to discharge; and to conduct utilization review. Very few hospitals indicated that they had community outreach programs for asthma care. The results of this survey suggest that among Chicago-area hospitals appropriate bedside care for persons with asthma is provided, but there are large variations in other types of asthma services and programs. The hospitals that have adopted asthma clinical practice guidelines are more likely to have other asthma-specific quality improvement activities than hospitals without guidelines. This relationship between use of guidelines and quality of services needs further exploration, as it may prove to be an important marker for hospitals with staff that are interested in improving asthma care.


CYP2A6, CYP1A1, and CYP2D6 polymorphisms in lung cancer patients from central south China.
Lung cancer is a common cause of cancer-related death. The link between risk of lung cancer susceptibility and genetic polymorphisms in metabolic enzymes is well documented. In this study, the relationships between lung cancer susceptibility and polymorphisms in the phase I metabolic enzyme genes CYP1A1, CYP2D6, and CYP2A6 were investigated. Genomic DNA was isolated from the peripheral blood of 201 healthy controls and 168 lung carcinoma patients from the Han ethnic group of Hunan Province in Central South China. Polymorphisms of the investigated genes were analyzed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and two-step allelic-specific PCR assays. No significant differences were found between the frequencies in cases and controls for the genotypes wild-type (WW), heterozygous mutant, or homozygous mutant; for CYP1A1 or CYP2D6; or for the genotypes WW, heterozygous deletion, or null genotype for CYP2A6. The three-locus model (CYP2A6/CYP1A1/CYP2D6) had a maximum test sample accuracy that was significant (P < 0.001) with a cross-validation consistency of 10. These results indicated that the three-order interaction of CYP2A6, CYP1A1, and CYP2D6 polymorphisms might increase genetic susceptibility to lung cancer. We report the involvement of a three-order interaction between CYP1A1, CYP2A6, and CYP2D6 polymorphisms in lung cancer risk in people in Central South China, although no relationship between lung cancer risk and individual gene polymorphisms was found.


[Long-term results and complications of halo fixation and extension].
Halo fixation has proved eminently suitable for introducing corrective forces into various regions of the vertebral column. The local complications necessitating changes of screws are directly related to the tightness of the screws. By carefully checking the tightness of the screws with a torque screwdriver complications due to the screws can largely be avoided. The magnitude of the force introduced and the duration of halo fixation are of secondary importance under these conditions. No penetrations of the screws or persistent infections were found; thanks to the spacers, severe injuries due to the halo tearing out as a result of a fall can be avoided. The considerably higher rate of complications and the severe complications with the halo cast fixation are caused by the rigid connection between the halo and thoracic plaster or respectively the plastic jacket, and the specific features of observation of the course in particular conditions e.g., Bechterew's disease.


Examination of Epstein-Barr virus and C-type proviral sequences in American and African lymphomas and derivative cell lines.
While Epstein-Barr viral (EBV) DNA is nearly always detectable in African Burkitt's lymphoma (BL), the relatively low frequency of BL in EBV-positive African children and the infrequent finding of EBV in American BL suggest that other cofactors may contribute to the malignant transformation. Among these possible cofactors are type C oncornaviruses. To evaluate this possibility, we screened the cellular DNA from 16 lymphomas (2 African, 14 American) and the DNA from 20 lymphoma-derived cell lines (4 African, 16 American) with a radiolabeled viral DNA probe from EBV and two oncornaviral probes (murine amphotropic 1504A virus and simian sarcoma virus). The radiolabeled EBV DNA probe hybridized with 18 of 36 tumor or cell line DNA's. Only 2 of 11 American BL tumors contained detectable EBV sequences. However, the cell lines derived from three EBV-negative tumors converted in vitro to EBV positivity, suggesting that some of the tumor cells could be infected with EBV. In contrast, none of the tumors or the cell lines derived therefrom hybridized with either the 1504A or the simian sarcoma virus probes, decreasing the likelihood that type C viruses are cofactors with EBV.


Atomic-Scale Images of the Growth Surface of Ca1-xSrxCuO2 Thin Films.
The surface microstructure of c-axis (Ca,Sr)CuO(2) thin films, grown by laser molecular beam epitaxy on SrTiO(3)(001) substrates, was studied by ultrahigh-vacuum scanning tunneling microscopy (STM). Images were obtained for codeposited Ca1-xSrxCuO(2) thin films, which show a layered-type growth mode. The surfaces consist of atomically flat terraces separated by steps that are one unit cell high. A pronounced dependence of the growth mechanism on the Sr/Ca ratio of the films was observed. Atomic resolution STM images of the CuO(2) sheets in the ab plane show a square lattice with an in-plane spacing of 4 angstroms; the lattice contains different concentrations of point defects, depending on the polarity of the sample-tip bias.


A model for the regulation of delta-aminolaevulinate synthetase induction in rat liver.
A reciprocal relationship exists between the cytochrome P-450 content and delta-aminolaevulinate synthetase activity in adult rats. In young rats the basal delta-aminolaevulinate synthetase activity is higher and the cytochrome P-450 content is lower compared with the adult rat liver. Administration of allylisopropylacetamide neither induces the enzyme nor causes degradation of cytochrome P-450 in the young rat liver, unlike adult rat liver. Allylisopropylacetamide fails to induce delta-aminolaevulinate synthetase in adrenalectomized-ovariectomized animals or intact animals pretreated with successive doses of the drug, in the absence of cortisol. The cortisol-mediated induction of the enzyme is sensitive to actinomycin D. Allylisopropylacetamide administration degrades microsomal haem but not nuclear haem. Haem does not counteract the decrease in cytochrome P-450 content caused by allylisopropylacetamide administration, but there is evidence for the formation of drug-resistant protein-bound haem in liver microsomal material under these conditions. Phenobarbital induces delta-aminolaevulinate synthetase under conditions when there is no breakdown of cytochrome P-450. On the basis of these results and those already published, a model is proposed for the regulation of delta-aminolaevulinate synthetase induction in rat liver.


Drawbacks and Unexpected Advantages of the Response to Modeling Posttraumatic Stress Disorder in Old Wistar Rats.
In modeling post-traumatic stress disorder (PTSD), old Wistar rats exhibit the same general signs of a PTSD-like condition as young rats do. The ratio of testosterone to corticosterone levels was assessed as a new index and proved to provide a guideline for dividing the rat population into low- and high-anxiety groups when modeling PTSD. Several features were observed in behavior, psycho-emotional manifestations, hormone levels, and myocardial state in old rats. A sharp rise in circulating testosterone was for the first time shown to occur in old, but not young, rats in stress, contributing to a more rapid decision as to where to move in the labyrinth space. Priority data were obtained on dysfunctional accumulation of mitochondria in the myocardium in intact and stressed old rats. The information obtained may be useful in developing drugs against harmful consequences of PTSD and senile changes in the myocardium.


Emission pattern of semi-volatile organic compounds from recycled styrenic polymers using headspace solid-phase microextraction gas chromatography-mass spectrometry.
The emission of low molecular weight compounds from recycled high-impact polystyrene (HIPS) has been investigated using headspace solid-phase microextraction (HS-SPME) and gas chromatography-mass spectrometry (GC-MS). Four released target analytes (styrene, benzaldehyde, acetophenone, and 2-phenylpropanal) were selected for the optimisation of the HS-SPME sampling procedure, by analysing operating parameters such as type of SPME fibre (polarity and operating mechanism), particle size, extraction temperature and time. 26 different compounds were identified to be released at different temperatures from recycled HIPS, including residues of polymerisation, oxidated derivates of styrene, and additives. The type of SPME fibre employed in the sampling procedure affected the detection of emitted components. An adsorptive fibre such as carbowax/polydimethylsiloxane (CAR/PDMS fibre) offered good selectivity for both non-polar and polar volatile compounds at lower temperatures; higher temperatures result in interferences from less-volatile released compounds. An absorptive fibre as polydimethylsiloxane (PDMS) fibre is suitable for the detection of less-volatile non-polar molecules at higher temperatures. The nature and relative amount of the emitted compounds increased with higher exposure temperature and smaller polymeric particle size. HS-SPME proves to be a suitable technique for screening the emission of semi-volatile organic compounds (SVOCs) from polymeric materials; reliable quantification of the content of target analytes in recycled HIPS is however difficult due to the complex mass-transfer processes involved, matrix effects, and the difficulties in equilibrating the analytical system.


Association of Childhood Infection With IQ and Adult Nonaffective Psychosis in Swedish Men: A Population-Based Longitudinal Cohort and Co-relative Study.
Associations between childhood infection, IQ, and adult nonaffective psychosis (NAP) are well established. However, examination of sensitive periods for exposure, effect of familial confounding, and whether IQ provides a link between childhood infection and adult NAP may elucidate pathogenesis of psychosis further. To test the association of childhood infection with IQ and adult NAP, to find whether shared familial confounding explains the infection-NAP and IQ-NAP associations, and to examine whether IQ mediates and/or moderates the childhood infection-NAP association. Population-based longitudinal cohort study using linkage of Swedish national registers. The risk set included all Swedish men born between 1973 and 1992 and conscripted into the military until the end of 2010 (n = 771 698). We included 647 515 participants in the analysis. Hospitalization with any infection from birth to age 13 years. Hospitalization with an International Classification of Diseases diagnosis of NAP until the end of 2011. At conscription around age 18 years, IQ was assessed for all participants. At the end of follow-up, the mean (SD) age of participants was 30.73 (5.3) years. Exposure to infections, particularly in early childhood, was associated with lower IQ (adjusted mean difference for infection at birth to age 1 year: -1.61; 95% CI, -1.74 to -1.47) and with increased risk of adult NAP (adjusted hazard ratio for infection at birth to age 1 year: 1.19; 95% CI, 1.06 to 1.33). There was a linear association between lower premorbid IQ and adult NAP, which persisted after excluding prodromal cases (adjusted hazard ratio per 1-point increase in IQ: 0.976; 95% CI, 0.974 to 0.978). The infection-NAP and IQ-NAP associations were similar in the general population and in full-sibling pairs discordant for exposure. The association between infection and NAP was both moderated (multiplicative, β = .006; SE = 0.002; P = .02 and additive, β = .008; SE = 0.002; P = .001) and mediated (β = .028; SE = 0.002; P < .001) by IQ. Childhood infection had a greater association with NAP risk in the lower, compared with higher, IQ range. Early childhood is a sensitive period for the effects of infection on IQ and NAP. The associations of adult NAP with early-childhood infection and adolescent IQ are not fully explained by shared familial factors and may be causal. Lower premorbid IQ in individuals with psychosis arises from unique environmental factors, such as early-childhood infection. Early-childhood infections may increase the risk of NAP by affecting neurodevelopment and by exaggerating the association of cognitive vulnerability with psychosis.


Monitoring of cocoa volatiles produced during roasting by selected ion flow tube-mass spectrometry (SIFT-MS).
Selected ion flow tube-mass spectrometry (SIFT-MS) was used to measure the real-time concentrations of cocoa volatiles in the headspace during roasting. Alkalized and unalkalized Don Homero and Arriba cocoa beans were roasted at 120, 150, and 170 °C in a rotary roaster. The concentrations of total alcohols, acids, aldehydes, esters, ketones, and alkylpyrazines increased, peaked, and decreased within the timeframe used for typical roasting. The concentrations of alkylpyrazines and Strecker aldehydes increased as the roasting temperature increased from 120 to 170 °C. For most of the volatile compounds, there was no significant difference between Arriba and Don Homero beans, but Arriba beans showed higher concentrations of 2-heptanone, acetone, ethyl acetate, methylbutanal, phenylacetaldehyde, and trimethylpyrazine. For unalkalized Don Homero beans (pH 5.7), the time to peak concentration decreased from 13.5 to 7.4 min for pyrazines, and from 12.7 to 7.4 min for aldehydes as the roasting temperature increased from 120 to 170 °C. Also, at 150 °C roasting, the time to peak concentration was shortened from 9 to 5.1 min for pyrazines, and from 9.1 to 5 min for aldehydes as the pH increased from 5.7 to 8.7. SIFT-MS allows for real-time monitoring of the key volatile compounds contributing to chocolate flavor, with minimal sample preparation, thus can be used to facilitate adjusting the roasting conditions, such as temperature and time, to optimize chocolate flavor during roasting. Real-time monitoring during roasting can also be used to evaluate the flavor quality of different types of beans by comparing the concentrations of key flavor compounds.


Different Responses to a High-Fat Diet in IL-6 Conditional Knockout Mice Driven by Constitutive GFAP-Cre and Synapsin 1-Cre Expression.
Interleukin-6 (IL-6) is a major cytokine controlling body weight and metabolism, at least in part through actions in the central nervous system (CNS) from local sources. We herewith report results obtained in conditional IL-6 KO mice for brain cells (Il6ΔGfap and Il6ΔSyn). The reporter RiboTag mouse line demonstrated specific astrocytic expression of GFAP-dependent Cre in the hypothalamus but not in other brain areas, whereas that of synapsin 1-dependent Cre was specific for neurons. Feeding a high-fat diet (HFD) or a control diet showed that Il6ΔGfap and Il6ΔSyn mice were more prone and resistant, respectively, to HFD-induced obesity. Energy intake was not altered in HFD experiments, but it was reduced in Il6ΔSyn male mice following a 24-h fast. HFD increased circulating insulin, leptin, and cholesterol levels, decreased triglycerides, and caused impaired responses to the insulin and glucose tolerance tests. In Il6ΔGfap mice, the only significant difference observed was an increase in insulin levels of females, whereas in Il6ΔSyn mice the effects of HFD were decreased. Hypothalamic Agrp expression was significantly decreased by HFD, further decreased in Il6ΔGfap, and increased in Il6ΔSyn female mice. Hypothalamic Il-6 mRNA levels were not decreased in Il6ΔSyn mice and even increased in Il6ΔGfapmale mice. Microarray analysis of hypothalamic RNA showed that female Il6ΔGfap mice had increased interferon-related pathways and affected processes in behavior, modulation of chemical synaptic transmission, learning, and memory. The present results demonstrate that brain production of IL-6 regulates body weight in the context of caloric excess and that the cellular source is critical.


Chemicals sorbed to environmental microplastics are toxic to early life stages of aquatic organisms.
Microplastics are ubiquitous in aquatic ecosystems, but little information is currently available on the dangers and risks to living organisms. In order to assess the ecotoxicity of environmental microplastics (MPs), samples were collected from the beaches of two islands in the Guadeloupe archipelago, Petit-Bourg (PB) located on the main island of Guadeloupe and Marie-Galante (MG) on the second island of the archipelago. These samples have a similar polymer composition with mainly polyethylene (PE) and polypropylene (PP). However, these two samples are very dissimilar with regard to their contamination profile and their toxicity. MPs from MG contain more lead, cadmium and organochlorine compounds while those from PB have higher levels of copper, zinc and hydrocarbons. The leachates of these two samples of MPs induced sublethal effects on the growth of sea urchins and on the pulsation frequency of jellyfish ephyrae but not on the development of zebrafish embryos. The toxic effects are much more marked for samples from the PB site than those from the MG site. This work demonstrates that MPs can contain high levels of potentially bioavailable toxic substances that may represent a significant ecotoxicological risk, particularly for the early life stages of aquatic animals.


[Medical geography and the French expeditions to Brazil: a description of the naval station in Brazil and the Prata (1868-1870)].
During the XIX century, medicine went through several etiological postulate changes. Medical geography, the discipline closely tied to the interests of the European colonialist enterprise, was in charge of mapping the diseases occurring all over the world. The physicians in European navies were in charge of this important mission. The greatest enemy of European troops and residents, in the colonies and in the hot climate regions were known to be the so-called tropical diseases. In this article, we analyze the official travel account by Bourel-Roncière, a French physician responsible for healthcare on the ship La Circé, from 1868 to 1870. Special attention is given to his personal point of view concerning the diseases and respective treatments, which he studied in collaboration with Brazilian physicians.


Polyclonal HIV envelope-specific breast milk antibodies limit founder SHIV acquisition and cell-associated virus loads in infant rhesus monkeys.
Breast milk HIV-1 transmission is currently the predominant contributor to pediatric HIV infections. Yet, only ~10% of breastfeeding infants born to untreated HIV-infected mothers become infected. This study assessed the protective capacity of natural HIV envelope-specific antibodies isolated from the milk of HIV-infected women in an infant rhesus monkey (RM), tier 2 SHIV oral challenge model. To mimic placental and milk maternal antibody transfer, infant RMs were i.v. infused and orally treated at the time of challenge with a single weakly neutralizing milk monoclonal antibody (mAb), a tri-mAb cocktail with weakly neutralizing and ADCC functionalities, or an anti-influenza control mAb. Of these groups, the fewest tri-mAb-treated infants had SHIV detectable in plasma or tissues (2/6, 5/6, and 7/8 animals infected in tri-mAb, single-mAb, and control-mAb groups, respectively). Tri-mAb-treated infants demonstrated significantly fewer plasma transmitted/founder variants and reduced peripheral CD4+ T cell proviral loads at 8 weeks post-challenge compared to control mAb-treated infants. Abortive infection was observed as detectable CD4+ T cell provirus in non-viremic control mAb- and single mAb-, but not in tri-mAb-treated animals. These results suggest that polyfunctional milk antibodies contribute to the natural inefficiency of HIV-1 transmission through breastfeeding and infant vaccinations eliciting non-neutralizing antibody responses could reduce postnatal HIV transmission.