Chemical Analysis of Counterfeit Hepatitis C Drug Found in Japan.
In January 2017, counterfeits of the hepatitis C drug 'HARVONI® Combination Tablets' (HARVONI®) were found at a pharmacy chain through unlicensed suppliers in Japan. A total of five lots of counterfeit HARVONI® (samples 1-5) bottles were found, and the ingredients of the bottles were all in tablet form. Among them, two differently shaped tablets were present in two of the bottles (categorized as samples 2A, 2B, 4A, and 4B). We analyzed the total of seven samples by high-resolution LC-MS, GC-MS and NMR. In samples 2A, 3 and 4B, sofosbuvir, the active component of another hepatitis C drug, SOVALDI® Tablets 400 mg (SOVALDI®), was detected. In sample 4A, sofosbuvir and ledipasvir, the active components of HARVONI®, were found. A direct comparison of the four samples and genuine products showed that three samples (2A, 3, 4B) are apparently SOVALDI® and that sample 2A is HARVONI®. In samples 1 and 5, several vitamins but none of the active compounds usually found in HARVONI® (i.e., sofosbuvir and ledipasvir) were detected. Our additional investigation indicates that these two samples are likely to be a commercial vitamin supplement distributed in Japan. Sample 2B, looked entirely different from HARVONI® and contained several herbal constitutents (such as ephedrine and glycyrrhizin) that are used in Japanese Kampo formulations. A further analysis indicated that sample 2B is likely to be a Kampo extract tablet of Shoseiryuto which is distributed in Japan. Considering this case, it is important to be vigilant to prevent a recurrence of distribution of counterfeit drugs.


Alteration of functional loads after tongue volume reduction.
An earlier study revealed that the patterns of biomechanical loads on bones around the tongue altered significantly right after tongue volume reduction surgery. The current study was to examine whether these alterations persist or vanish over time post-surgery. Five sibling pairs of 12-week-old Yucatan minipigs were used. For each pair, one had surgery reducing tongue volume by about 15% (reduction) while the other had same incisions without tissue removal (sham). All animals were raised for 4 weeks after surgery. Three rosette strain gauges were placed on the bone surfaces of pre-maxilla (PM), mandibular incisor (MI), and mandibular molar (MM); two single-element gauges were placed across the pre-maxilla-maxillar suture (PMS) and mandibular symphysis (MSP), and two pressure transducers were placed on the bone surfaces of hard palate (PAL) and mandibular body (MAN). These bone strains and pressures were recorded during natural mastication. Overall amount of all loads increased significantly as compared to those in previous study in all animals. Instead of decreased loads in reduction animals as seen in that study, shear strains at PM, MI, and MM, tensile strains at PMS, and pressure at MAN were significantly higher in reduction than sham animals. Compared to the sham, strain dominance shifted at PM, MI, and MM and orientation of tensile strain altered at MI in reduction animals. A healed volume-reduced tongue may change loading regime significantly by elevating loading and altering strain-dominant pattern and orientation on its surrounding structures, and these changes are more remarkable in mandibular than maxillary sites.


Comprehensive Review of Red Meat Consumption and the Risk of Cancer.
Red and processed meat consumption rates are increasing in the United States. In this review, we present the current evidence that links red meat consumption and cancer development. A literature search was conducted in the PubMed and Google Scholar databases to review red meat consumption and its association with breast cancer and gastrointestinal cancer. Due to the presence of heme iron, which triggers oxidative reactions that eventually result in tumor formation, red meat consumption is strongly associated with the development of breast cancer. Ingestion of red meat increases Helicobacter pylori infections, resulting in enhanced expression of the CagA gene and the secretion of pro-inflammatory cytokines. This is the leading cause of gastric cancer. There is a strong correlation between heterocyclic amines and polycyclic aromatic hydrocarbons in red meat and the development of pancreatic cancer. However, additional research is necessary to confirm this finding. Adult colorectal cancer is caused by the formation of heterocyclic amines and DNA adducts due to the intake of red and processed meats cooked at higher temperatures. The consumption of poultry is associated with a reduced risk of breast and gastrointestinal cancers, but the results are inconsistent. The evidence is strong for the association between red meat and breast cancer and most gastric cancers. The presence of aromatic hydrocarbons, heterocyclic amines, and heme iron in red meat has been found to be behind tumorigenesis. Poultry has been shown to have a low association with cancer, but additional research is needed.


Xanthotropis, a new genus in the Neotropical millipede subfamily Aphelidesminae (Diplopoda, Polydesmida, Aphelidesmidae).
The monotypic taxon Xanthotropis n. gen. is established to accommodate Haematotropis media Golovatch, Hoffman Spelda, 2004, known only from the vicinity of Manaus, Brazil, as it is incompatible with both its originally assigned genus and Aphelidesmus Brölemann, 1898, a suggested alternative. Xanthotropis is defined primarily by minute teeth on paranota 2-4, a sublinear posterior margin of the telson, and an elongated, distally expanded/laminate acropodite. The Aphelidesmidae Brölemann, 1916, range from northeastern Mexico and Tobago to northern Brazil and southwestern Peru; a questionable more-northerly record, from Monterey, Mexico, requires verification with fresh material. One of two families of the polydesmidan superfamily Platyrhacoidea (Leptodesmidea), Aphelidesmidae comprises two subfamilies, the nominate and Amplininae Hoffman, 1954. The latter has been addressed by several authors, and we here review Aphelidesminae by providing full synonymies, a literature review, and a key to its four genera: Aphelidesmus Brölemann, 1898; Haematotropis and Ochrotropis, both by Jeekel, 2000; and Xanthotropis n. gen.


A numerical study of fixed frequency reflectometry measurements of plasma filaments with radial and poloidal velocity components.
A 2D finite-differences time-domain full-wave code is used to simulate the measurements of plasma filaments with fixed frequency O-mode reflectometry. The plasma is modeled by a linear slab plasma plus a Gaussian perturbation propagating in a direction that can vary from poloidal to radial. The plasma background density gradient is chosen in agreement with the steep edge transport barrier of H-modes in the ASDEX Upgrade (AUG) tokamak. Illustrative results are presented and different types of reflectometry responses are observed depending on filament sizes and propagation directions. The reflectometry signatures obtained here with numerical simulations support previous experimental findings on filament measurements.


Diaphragm dysfunction: a comprehensive review from diagnosis to management.
Although the diaphragm represents a critical component of the respiratory pump, the clinical presentations of diaphragm dysfunction are often non-specific and can be mistaken for other more common causes of dyspnoea. While acute bilateral diaphragm dysfunction typically presents dramatically, progressive diaphragm dysfunction associated with neuromuscular disorders and unilateral hemidiaphragm dysfunction may be identified incidentally or by recognising subtle associated symptoms. Diaphragm dysfunction should be considered in individuals with unexplained dyspnoea, restrictive respiratory function tests or abnormal diaphragm position on plain chest imaging. A higher index of suspicion should occur for individuals with profound orthopnoea, those who have undergone procedures in proximity to the phrenic nerve(s) or those with co-morbid conditions that are associated with diaphragm dysfunction, particularly neuromuscular disorders. A systematic approach to the evaluation of diaphragm function using non-invasive diagnostic techniques such as respiratory function testing and diaphragm imaging can often confirm a diagnosis. Neurophysiological assessment may confirm diaphragm dysfunction and assist in identifying an underlying cause. Identifying those with or at risk of respiratory failure can allow institution of respiratory support, while specific cases may also benefit from surgical plication or phrenic nerve pacing techniques.


3D femoral neck anteversion measurements based on the posterior femoral plane in ORTHODOC system.
This study provides a robust measuring method of the femoral neck anteversion angle for use in a total hip replacement pre-planning program. The femora of 24 patients (69.3 +/- 6.3 years old) were CT-scanned and converted into three-dimensionally volume-rendered models in ORTHODOC (ISS Inc., CA, USA) which is the pre-planning software for ROBODOC surgery. The Mod.ISS method (the modified ISS method), designed by authors, measures the anteversion angle of the proximal-most femoral neck confluence on the plane perpendicular to the femoral mechanical axis. 3D FNC method proposed by the authors of the present study involves measurement of the anteversion angle of three-dimensional femoral neck center on a plane perpendicular to the posterior femoral plane and parallel to the posterior condylar axis. Here, we found that interobserver reproducibility was 1.8 degrees (SD = 1.3) for the Mod.ISS method and 2.4 (SD = 1.9) for the proposed 3D FNC method. The anteversion angle of the local femoral neck axis was measured as theta = 25.3(L/D) + [corrected] 5.4 in L/D = 0.1-0.6, where L/D is distance (L) from the proximal-most neck confluence along the femoral mechanical axis, normalized with respect to the diameter of the femoral head (D). At L/D = 0.5, the anteversion angle of the femoral neck axis was coincident with the average femoral neck anteversion determined by the 3D FNC method. We conclude that the 3D FNC method is a gold standard for measuring the femoral neck anteversion applicable during both pre-operative and post-operative stages, because its femoral neck center can be determined in three-dimensional space during both stages.


Warfarin 2.0--a computer program for warfarin management. Design and clinical use.
Warfarin 2.0 is a computer program that helps physicians optimize treatment of outpatients with warfarin. The main reason for its development was to achieve a good anticoagulation level, avoiding both undertreatment--which causes thromboembolic complications--and overtreatment--which causes hemorrhagic complications. The program was also designed to help educate the anticoagulated patient, standardize warfarin management and audit results of what had been done. The philosophy of continuous quality improvement was applied. Warfarin 2.0 is in clinical operation in the University Hospital, Montevideo, Uruguay, and it has also been used since the end of 1993 in the Favaloro Foundation, Dept. of Hematology, Buenos Aires, Argentina. The results from the first 15 months of use in Montevideo showed an increase in the number of patients being followed (from 91 to 132) and the average number of visits per patient (from one visit every 10.6 weeks to one every 6.5 weeks): The frequency of visits has been in the internationally accepted ranges since the program was implemented. Better anticoagulation levels were achieved after an adjusting period. Unfortunately, the number of undertreated patients is still large, and a thorough analysis of the data is going to be undertaken to continue improving warfarin management.


The kinetics-based enzyme-linked immunosorbent assay for coronavirus antibodies in cats: calibration to the indirect immunofluorescence assay and computerized standardization of results through normalization to control values.
The computer-assisted, kinetics-based enzyme-linked immunosorbent assay for coronavirus antibodies in cats was calibrated to the conventional indirect immunofluorescence assay by linear regression analysis and computerized interpolation (generation of "immunofluorescence assay-equivalent" titers). Procedures were developed for normalization and standardization of kinetics-based enzyme-linked immunosorbent assay results through incorporation of five different control sera of predetermined ("expected") titer in daily runs. When used with such sera and with computer assistance, the kinetics-based enzyme-linked immunosorbent assay minimized both within-run and between-run variability while allowing also for efficient data reduction and statistical analysis and reporting of results.


The hidden epidemic of schistosomiasis in recent African immigrants and asylum seekers to Italy.
The prevalence of schistosomiasis among recent refugees from sub-Saharan Africa in Italy is unknown. This is a retrospective review of African immigrants screened at Centre for Tropical Diseases of Negrar from March 2014 to February 2016. Of the 373 immigrants tested, 34% were positive at least at one schistosomiasis test. The proportion of positive ELISA serology was 103/373 (27.6%). At microscopy, infected subjects were 65/373 (17.4%), (51% Schistosoma haematobium, 38% Schistosoma mansoni, 11% both). CCA antigen for S. mansoni was positive in 47/373 individuals (12.6%). We found a particularly high positivity rate in subjects from Mali (72.1%) and Ivory Coast (48%). This "hidden epidemic" of schistosomiasis cannot be longer neglected, considering the risk of severe complications, and the effective and inexpensive treatment available.


Free Sorting and Association Task: A Variant of the Free Sorting Method Applied to Study the Impact of Dried Sourdough as an Ingredienton the Related Bread Odor.
This paper presents a new variant of the free sorting method developed to analyze the relationship between dried sourdough (DSD) and corresponding DSD-bread (bread) odors. The comparison of DSD and bread sensory characteristics is complicated due to their specific features (for example, acidity for DSD and a characteristic "baked bread" aroma for breads). To analyze them at the same time, this study introduces a new variant of the free sorting method, which adds an association task between DSD and bread after those of free sorting and verbalization. This separation makes it possible to change the product between tasks. It was applied to study the impact of 6 European commercial DSDs on their related DSD-bread. According to our results, this methodology enabled an association between different kinds of products and thus underlined the relationship between them. Moreover, as this methodology contains a verbalization task, it provides product descriptions. Compared with the standard free sorting method, free sorting with an association task gives the distance (i) between DSDs, (ii) between breads, and (iii) between DSDs and breads. The separation of product assessment through sorting and association avoids the separation of products according to their category (DSD or bread).


Ultrasonically induced hyperthermia for adjunctive treatment of intraocular malignant melanoma.
This report describes results of a prospective pilot trial to evaluate the safety and efficacy of hyperthermia as an adjunct to enucleation or brachytherapy in the treatment of patients with intraocular malignant melanoma. Twenty-five patients with intraocular malignant melanomas were treated with ultrasonically induced hyperthermia. In 14 patients, hyperthermia was administered before enucleation (median follow-up period, 44 months), and in 11 patients, hyperthermia was used as an adjunct to brachytherapy (median follow-up period, 79 months). Patient survival in each group was compared with that of a control group treated with enucleation or brachytherapy alone, using Kaplan-Meier and Cox analysis. Taking into account the simultaneous effects of tumor size and location, the relative risk ratios and 95% confidence bounds associated with adjunctive hyperthermia were 1.68 (range, 0.60-4.72) and 0.68 (range, 0.16-2.89) for the enucleation and brachytherapy groups, respectively. Patients receiving adjunctive hyperthermia with brachytherapy showed increased survival, whereas those receiving hyperthermia before enucleation showed decreased survival. Neither trend was statistically significant in this small series. The synergism of hyperthermia with radiation may offer the possibility of improved tumor management.


Phentolamine blocks ATP sensitive potassium channels in cardiac ventricular cells.
The alpha adrenoceptor antagonist phentolamine prevents ischaemia related arrhythmias in rat, guinea pig, and cat heart. This effect has been related to the attenuation of ischaemia induced shortening of the action potential and has been ascribed to its alpha adrenoceptor antagonist properties. The aim of this study was to examine the effect of phentolamine on the ATP sensitive potassium channel (KATP), because this channel seems to be involved in action potential shortening during ischaemia. Single channel experiments were performed on inside-out and outside-out patches of isolated rabbit ventricular cells at room temperature. Cells were isolated with conventional isolation techniques. Pipette and bath solution contained (in mmol.litre-1): K-gluconate 140, KCl 10, and HEPES-KOH 10 (pH 7.4). Excision of the patch always resulted in KATP channel activity [single channel conductance 60(SD 2.8) pS n = 4], which could be completely blocked by 5 mM ATP. In 22 of 26 patches the addition of 5 microM phentolamine to the intracellular side of the membrane reduced KATP channel activity. In 17 of these patches the effect was reversible. In four patches no effect was observed. Open probability decreased by 94% (n = 12). Addition of 50 microM phentolamine resulted in the disappearance of channel activity in six of eight patches which was reversible in four patches. In outside-out patches 5 microM phentolamine was only effective in 50% of the patches, reducing open probability by 98 to 100%. Phentolamine blocks ATP sensitive potassium channels in rabbit ventricular cells independently of the alpha adrenoceptor. This blocking effect probably occurs at the intracellular side of the membrane. The antiarrhythmic effect of phentolamine may at least partially be explained by blockade of KATP channels and may thus partly be independent of its effects on the alpha adrenoceptor.


Linking structural and effective brain connectivity: structurally informed Parametric Empirical Bayes (si-PEB).
Despite the potential for better understanding functional neuroanatomy, the complex relationship between neuroimaging measures of brain structure and function has confounded integrative, multimodal analyses of brain connectivity. This is particularly true for task-related effective connectivity, which describes the causal influences between neuronal populations. Here, we assess whether measures of structural connectivity may usefully inform estimates of effective connectivity in larger scale brain networks. To this end, we introduce an integrative approach, capitalising on two recent statistical advances: Parametric Empirical Bayes, which provides group-level estimates of effective connectivity, and Bayesian model reduction, which enables rapid comparison of competing models. Crucially, we show that structural priors derived from high angular resolution diffusion imaging on a dynamic causal model of a 12-region network-based on functional MRI data from the same subjects-substantially improve model evidence (posterior probability 1.00). This provides definitive evidence that structural and effective connectivity depend upon each other in mediating distributed, large-scale interactions in the brain. Furthermore, this work offers novel perspectives for understanding normal brain architecture and its disintegration in clinical conditions.


Evaluation of repellency of some Chinese medicinal herbs essential oils against Liposcelis bostrychophila (Psocoptera: Liposcelidae) and Tribolium castaneum (Coleoptera: Tenebrionidae).
The screening for repellency against the booklouse, Liposcelis bostrychophila (Badonnel), and the red flour beetle, Tribolium castaneum (Herbst), from 14 Chinese medicinal herbs showed that the essential oils of Curcuma longa L., Epimedium pubescens Maximouwicz, Lindera aggregate (Sims) Kostermans, Nardostachys chinensis Battandier, Schizonepeta tenuifolia Briquet, Zanthoxylum schinifolium Sieber et Zuccarini, and Z. officinale Roscoe exhibited strong repellency against L. bostrychophila and T. castaneum. A total of 35 components of the essential oil of E. pubescens were identified by gas chromatography and gas chromatography-mass spectrometry. Beta-Eudesmol (14.89%), alpha-pinene (13.38%), borneol (9.56%), (R)-carvone (7.89%), and menthol (7.45%) were the main components of the essential oil of E. pubescens. From the essential oil of E. pubescens, four monoterpenoids and one sesquiterpenoid were isolated by bioassay-guided fractionation. The compounds were identified alpha-pinene, borneol, menthol, carvone, and beta-eudesmol. (R) -carvone, menthol, borneol, and beta-eudesmol were strongly repellent against L. bostrychophila at concentration of 8.5 nl/cm2 after 2 h exposure whereas alpha-pinene exhibited moderate repellency. (R)-carvone exhibited stronger repellency against the booklouse than the positive control, N, N-diethyl-3-methylbenzamide (DEET). Moreover, (R)-carvone also possessed stronger repellency against T. castaneum than DEET. The other four constituents, menthol, borneol, and beta-eudesmol also showed repellency against the red flour beetles but weaker than DEET at lower concentrations.


Hepatoportoenterostomy in Selective Obstructive Cholestasis - An New Experimental Model in the Rat.
Biliary atresia is the most frequent cause for neonatal obstructive cholestasis. Hepatoportoenterostomy (HPE) is the only method allowing survival until liver transplantation. For a maximum rate of success, the HPE procedure has to be performed within the 60 days of life. We aimed to create an experimental model for relieving obstructive cholestasis. In 20 Wistar rats selective bile duct obstruction was induced by the microsurgical ligature of the bile ducts corresponding to the median and left lateral liver lobes. After four weeks surgical re-intervention was carried out and HPE was performed microsurgically on the hilum of the median and left lateral liver lobes. One week after HPE, the integrity of the anastomosis and the hepatic changes were assessed. The survival rate throughout the study was 90%. The surgical re-intervention revealed hepatic-hilum adhesions, with fibrosis. Microscopically, an initial fibrogenic repair was identified, equivalent of moderate cholestasis. After the HPE, there was no bile leak from the anastomosis and no biliary peritonitis. The evolution was marked by a reduction in food intake. The experimental model we propose for the HPE is reliable by using microsurgical techniques. Based on it, one can study the changes induced by the bile duct obstruction.


Follistatin gene delivery enhances muscle growth and strength in nonhuman primates.
Antagonists of myostatin, a blood-borne negative regulator of muscle growth produced in muscle cells, have shown considerable promise for enhancing muscle mass and strength in rodent studies and could serve as potential therapeutic agents for human muscle diseases. One of the most potent of these agents, follistatin, is both safe and effective in mice, but similar tests have not been performed in nonhuman primates. To assess this important criterion for clinical translation, we tested an alternatively spliced form of human follistatin that affects skeletal muscle but that has only minimal effects on nonmuscle cells. When injected into the quadriceps of cynomolgus macaque monkeys, a follistatin isoform expressed from an adeno-associated virus serotype 1 vector, AAV1-FS344, induced pronounced and durable increases in muscle size and strength. Long-term expression of the transgene did not produce any abnormal changes in the morphology or function of key organs, indicating the safety of gene delivery by intramuscular injection of an AAV1 vector. Our results, together with the findings in mice, suggest that therapy with AAV1-FS344 may improve muscle mass and function in patients with certain degenerative muscle disorders.


Efficient Representation of Geometric Tree Models with Level-of-Detail Using Compressed 3D Chain Code.
In the paper, we present a method for space-efficient representation of geometric tree models, which are provided as skeletons with radii attached to individual branch segments. The proposed approach uses a new differential 3D chain code to encode orientation changes of consecutive branch segments, which allows optimizing chain code generation for increased compressibility while maintaining control over the model reconstruction error. The presented method is the first to encode the complete branching geometry including the branch radii and provides level-of-detail construction directly from the chain code. It is demonstrated that by using interpolative encoding of the resulting tree descriptors and radii sequences, the storage requirements for geometric description of a mixed all-aged forest can be reduced to less than 15 percent of its raw size while preserving the structural fidelity of tree models.


Optimal Timing of Mesenchymal Stem Cell Therapy for Neonatal Intraventricular Hemorrhage.
We recently showed that intraventricular transplantation of human umbilical cord blood (UCB)-derived mesenchymal stem cells (MSCs) significantly attenuated posthemorrhagic hydrocephalus (PHH) and brain injury after severe intraventricular hemorrhage (IVH) in newborn rat pups. The purpose of this study was to optimize the timing of MSC transplantation for severe IVH. Severe IVH was induced by injecting 100 µl of blood into each ventricle of Sprague-Dawley rats on postnatal day 4 (P4). Human UCB-derived MSCs (1 × 10(5) cells in 10 µl of normal saline) were transplanted intraventricularly under stereotaxic guidance either early at P6 or late at P11. Serial brain MRIs and behavioral function tests, such as negative geotaxis and rotarod tests, were performed. At P32, brain tissue samples were obtained for histological and biochemical analyses. Intracerebroventricular transplantation of MSCs significantly attenuated the development of PHH, behavioral impairment, increased apoptosis and astrogliosis, reduced corpus callosum thickness and brain myelination, and upregulated inflammatory cytokines including interleukin (IL)-1α, IL-1β, IL-6, and tumor necrosis factor-α (TNF-α) at P6 but not at P11 after induction of severe IVH. Intracerebroventricular transplantation of human UCB-derived MSCs attenuated PHH and brain injury after severe IVH in newborn rats in a time-dependent manner. Significant neuroprotection was only demonstrated when administered early at 2 days after induction but not late at 7 days after induction of severe IVH.


Influence of a fluoridated medium with different pHs on commercially pure titanium-based implants.
The objective of this study was to assess the influence of a fluoride medium with different pHs on the corrosion resistance of three commercially pure titanium-based dental implant commercial brands, under scanning electron microscopy (SEM) and EDS. Forty-two dental implants, from three commercial brands, were used. Five years of regular use of mouth rinsing, with NaF 1500 ppm content and two different pHs, were simulated by immersing the specimens into that medium for 184 hours. SEM and EDS analyses demonstrated no evidence of corrosion on the specimens' surfaces after being submitted to fluoride ions or incorporation of fluoride ions to the set surface. It was possible to conclude that both the fluoride concentration and the pH of the solutions did not exert any influence upon implant corrosion resistance.


Effect of intermittent administration of teriparatide on the mechanical and histological changes in bone grafted with β-tricalcium phosphate using a rabbit bone defect model.
Grafting β-tricalcium phosphate (TCP) is a well-established method for restoring bone defects; however, there is concern that the mechanical stability of the grafted β-TCP is not maintained during bone translation. Teriparatide has an anabolic effect, stimulating bone formation and increasing bone mineral density for the treatment of osteoporosis. The aim of the present study was to evaluate the effect of intermittent teriparatide treatment on changes in bone grafted with β-TCP using a rabbit bone defect model. Bone defects (5×15 mm) were created in the distal femoral condyle of Japanese white rabbits, and β-TCP granules of two different total porosities were manually grafted. Teriparatide (40 µg/kg) or 0.2% rabbit serum albumin solution as a vehicle control was subcutaneously injected three times per week following the surgery. At 4 or 8 weeks post-surgery, serum samples were obtained and the levels of γ-carboxylated osteocalcin (Gla-OC) were quantified using ELISA. Histomorphometry was also performed using sections of graft sites following staining for tartrate resistant acid phosphatase. Activity and mechanical strength (maximum shear strength, maximum shear stiffness and total energy absorption) were evaluated using an axial push-out load to failure test. Teriparatide treatment significantly increased (P<0.05) the serum levels of Gla-OC, a specific marker for bone formation, suggesting that teriparatide enhances bone formation in β-TCP-grafted rabbits. Furthermore teriparatide increased the degradation of β-TCP by bone remodeling (P<0.05) and promoted the formation of new bone following application of the graft compared with the control group (P<0.01). Furthermore, teriparatide suppressed the reduction in mechanical strength (P<0.05) during bone translation in bone defects grafted with β-TCP. The results of the present study demonstrate that teriparatide is effective in maintaining the mechanical stability of grafted β-TCP, possibly by promoting new bone formation.


Comparative study of clinical, histological, and immunological responses to interferon therapy in type non-A, non-B, and type B chronic hepatitis.
Nineteen patients with chronic non-A, non-B hepatitis (CH-NANB) and 24 patients with chronic hepatitis B (CH-B) were treated with interferons, and the therapeutic and biological responses of the two groups (CH-NANB and CH-B) were compared. All patients had had sustained elevations in serum glutamic pyruvic transaminase (sGPT) levels for more than 6 months and were proven to have chronic hepatitis by liver biopsy. alpha-Interferon (IFN-alpha) or beta-interferon (IFN-beta) was administered in low doses of 3 to 6 mega international units (MIU) daily for 4 wk. Liver biopsies were taken from 13 CH-NANB and 14 CH-B subjects just before and immediately after treatment, and histological findings were assessed by the histology activity index (HAI) score. SGPT levels decreased much more rapidly and markedly in CH-NANB than in CH-B during IFN therapy (p less than 0.01). The HAI score decreased 3.5 points in CH-NANB and 1.0 point in CH-B between pretreatment and posttreatment. Serum beta 2-microglobulin (beta 2-MG) increased in both types of chronic hepatitis during treatment, but the rate of elevation was significantly less in CH-NANB than in CH-B (p less than 0.001). beta 2-MG expression on hepatocytes stained by the PAP method was almost identical in CH-NANB before and after treatment, whereas it increased steadily in CH-B. The serum 2',5'-oligoadenylate synthetase level increased in both types of hepatitis on IFN administration. These results suggest that, in IFN treatment for CH-NANB, the antiviral actions of IFNs may play a very important role in reducing the activity of chronic hepatitis.


Mutation as a stress response and the regulation of evolvability.
Our concept of a stable genome is evolving to one in which genomes are plastic and responsive to environmental changes. Growing evidence shows that a variety of environmental stresses induce genomic instability in bacteria, yeast, and human cancer cells, generating occasional fitter mutants and potentially accelerating adaptive evolution. The emerging molecular mechanisms of stress-induced mutagenesis vary but share telling common components that underscore two common themes. The first is the regulation of mutagenesis in time by cellular stress responses, which promote random mutations specifically when cells are poorly adapted to their environments, i.e., when they are stressed. A second theme is the possible restriction of random mutagenesis in genomic space, achieved via coupling of mutation-generating machinery to local events such as DNA-break repair or transcription. Such localization may minimize accumulation of deleterious mutations in the genomes of rare fitter mutants, and promote local concerted evolution. Although mutagenesis induced by stresses other than direct damage to DNA was previously controversial, evidence for the existence of various stress-induced mutagenesis programs is now overwhelming and widespread. Such mechanisms probably fuel evolution of microbial pathogenesis and antibiotic-resistance, and tumor progression and chemotherapy resistance, all of which occur under stress, driven by mutations. The emerging commonalities in stress-induced-mutation mechanisms provide hope for new therapeutic interventions for all of these processes.


[The primary medical sanitary care and characteristics of drinking water supply of population].
The article considers characteristics of organization ofprimary medical sanitary care on territory with carcinogenic risks related to drinking water supply as exemplified by the Orlovskaia oblast. The importance of registration by local health authorities the sources of permanent chemical pollution of drinking water. The analysis of the State program of the Orlovskaia oblast "The development of health care in the Orlovskaia oblast in 2013-2020". The necessity of additional inclusion of issue related to healthy drinking water supply of population to prevent development of malignant neoplasms and prevalence of oncologic morbidity on oblast territory.


Microbiological quality of desiccated coconut.
A microbial survey of Sri Lankan desiccated coconut has been made on material purchased in supermarkets in Sheffield or on material obtained directly from the processing company. The total viable count (TVC) was reduced by spoilage and pasteurization from 10(4)/g to 10(3)/g. Most samples contained low levels of coagulase-positive Staphylococcus aureus suggesting that this commodity had been handled during production. One focus of contamination with Aspergillus flavus was found for each 8.34 g of desiccated coconut (mean contamination). The number of bacteria and moulds in spoiled coconut was significantly lower than that in coconut obtained from the processor or purchased from retail outlets. It is suggested that the accumulation of free fatty acids, aliphatic methyl ketones and secondary alcohols produced during fungal spoilage has had a bactericidal and fungicidal effect. The use of microbial specifications for foods is questioned in situations where there is evidence of microbial spoilage having taken place.


Phase diagram of softly repulsive systems: the Gaussian and inverse-power-law potentials.
We redraw, using state-of-the-art methods for free-energy calculations, the phase diagrams of two reference models for the liquid state: the Gaussian and inverse-power-law repulsive potentials. Notwithstanding the different behaviors of the two potentials for vanishing interparticle distances, their thermodynamic properties are similar in a range of densities and temperatures, being ruled by the competition between the body-centered-cubic (bcc) and face-centered-cubic (fcc) crystalline structures and the fluid phase. We confirm the existence of a reentrant bcc phase in the phase diagram of the Gaussian-core model, just above the triple point. We also trace the bcc-fcc coexistence line of the inverse-power-law model as a function of the power exponent n and relate the common features in the phase diagrams of such systems to the softness degree of the interaction.


An overview of structurally diversified anticonvulsant agents.
There are several limited approaches to treat epilepsy in hospitals, for example, using medicines, surgery, electrical stimulation and dietary interventions. Despite the availability of all these new and old approaches, seizure is particularly difficult to manage. The quest for new antiepileptic molecules with more specificity and less CNS toxicity continues for medicinal chemists until a new and ideal drug arrives. This review covers new antiseizure molecules of different chemical classes, the exact mode of action of which is still unidentified. Newer agents include sulfonamides, thiadiazoles, semi- and thiosemicarbazones, pyrrolidine-2,5-diones, imidazoles, benzothiazoles and amino acid deriva tives. These new chemical entities can be useful for the design and development of forthcoming antiseizure agents.


Multibond dynamics of nanoscale friction: the role of temperature.
The main challenge in predicting sliding friction is related to the complexity of highly nonequilibrium processes, the kinetics of which are controlled by the interface temperature. Our experiments reveal a nonmonotonic enhancement of dry nanoscale friction at cryogenic temperatures for different material classes. Concerted simulations show that it emerges from two competing processes acting at the interface: the thermally activated formation as well as rupturing of an ensemble of atomic contacts. These results provide a new conceptual framework to describe the dynamics of dry friction.


Structure and expression of a human gene coding for a 71 kd heat shock 'cognate' protein.
In all eukaryotes examined so far, hsp70 gene families include cognate genes (hsc70) encoding proteins of about 70 Kd which are expressed constitutively during normal growth and development. We have investigated the structural relationship of heat-inducible and cognate members of the human hsp70 gene family. Among several human genomic clones isolated using Drosophila hsp/hsc70 probes, one contained an hsc70 gene. Its complete sequence is reported here. It is split by eight introns and encodes a predicted protein of 70899 d that would be 81% homologous to hsp70. Structural comparisons with corresponding genes from other species provide one of the most striking examples of gene conservation. Isolation of a corresponding cDNA clone, RNA-mapping and in vitro translation data demonstrate that the gene is expressed constitutively and directs the synthesis of a 71 kd protein. The latter is very likely to be identical to a clathrin uncoating ATPase recently identified as a member of the hsp70-like protein family.


Pragmatic Clinical Trials in CKD: Opportunities and Challenges.
Randomized controlled trials in CKD lag in number behind those of other chronic diseases, despite the high morbidity and mortality experienced by patients with kidney disease and the exorbitant costs of their health care. Observational studies of CKD frequently yield seemingly paradoxic associations of traditional risk factors with outcomes, making it difficult to extrapolate the results of trials conducted in people with normal kidney function to patients with CKD. However, many completed trials in CKD have been limited by intermediate outcomes of unclear clinical significance or narrow eligibility criteria that limit external validity, and implementation of proven therapies remains a challenge. It is therefore imperative that the nephrology community capitalize on recent interest in novel approaches to trial design, such as pragmatic clinical trials. These trials are meant to promote research within real world settings to yield clinically relevant results with greater applicability than those of traditional trials, while maintaining many advantages, such as controlling for potential sources of bias. We provide a description of pragmatic clinical trials and a discussion of advantages, disadvantages, and practical challenges inherent to this study design, in the context of specific scientific questions relevant to patients with CKD.


Cervical and peritoneal fluid cytology of uterine sarcomas.
To study the cytologic features of uterine sarcoma. The pathology records of 102 patients with uterine sarcoma were reviewed. Four patients, including one case of leiomyosarcoma (LMS), one high grade stromal sarcoma (HGSS) and two malignant mixed müllerian tumor (MMMT), had abnormal cervical and/or peritoneal cytologic findings. Three abnormal cervical smears and two abnormal peritoneal fluids from these patients, including immunohistochemically stained sections of cell block, were reviewed. The diagnostic cells appeared in clusters or in isolation. They had enlarged and hyperchromatic nuclei. Occasional mitotic figures were seen. The cells were considered suspicious for malignancy in cervical smears of HGSS and in the peritoneal fluid of LMS. Adenocarcinoma cells were identified in both the cervical smear and peritoneal fluid of one patient with MMMT. Atypical cells were found in another patient with MMMT. Positive cervical or peritoneal cytology is uncommonly detected in association with uterine sarcomas. Even when abnormal cells are found, it may be difficult to give a definitive diagnosis of uterine sarcoma based directly on the cytomorphologic characteristics of cervical or peritoneal smears. However, such a possibility should be kept in mind by the cytopathologist to avoid missing the diagnosis.


Glu-192----Gln substitution in thrombin mimics the catalytic switch induced by thrombomodulin.
In serine proteases, residue 192, three residues prior to the active site Ser-195, plays an important role in determining substrate specificity. In trypsin (EC 188.8.131.52) and most trypsin-like enzymes with relatively broad specificity, this position is occupied by Gln. In thrombin (EC 184.108.40.206), an enzyme with restricted specificity, position 192 is occupied by Glu. The potential importance of Glu-192 in restricting the specificity of thrombin was investigated by isosterically replacing Glu-192 with Gln. Unlike trypsin, thrombin cleavage of peptides with acidic residues in positions P3 and P'3 [where P3 and P'3 refer to three residues removed from the Arg (P1) cleavage site on the amino and carboxyl side, respectively] is inefficient. Protein C, an anticoagulant zymogen, has Asp residues in positions P3 and P'3. Thrombomodulin, an endothelial cell protein, complexes with thrombin to activate protein C rapidly thus altering the specificity of thrombin. Compared to thrombin, the Glu-192----Gln mutant thrombin activates protein C 22 times more rapidly and cleaves the P7-P'5 peptide from the protein C activation site 19 times faster. Enhanced protein C activation results primarily from an increase in the catalytic rate constant rather than an improved Michaelis constant, a property that is shared by the thrombin-thrombomodulin complex. The Glu-192----Gln mutation does not influence fibrinopeptide A release and only increases the rate of fibrinopeptide B release 2.7-fold. These results demonstrate that Glu-192 plays a critical role in restricting the specificity of thrombin and suggest that thrombomodulin may function in part by altering the enzyme-substrate interaction near residue 192 in thrombin.


Boule and the Evolutionary Origin of Metazoan Gametogenesis: A Grandpa's Tale.
The evolution of sex remains a hotly debated topic in evolutionary biology. In particular, studying the origins of the molecular mechanisms underlying sexual reproduction and gametogenesis (its fundamental component) in multicellular eukaryotes has been difficult due to the rapid divergence of many reproductive proteins, pleiotropy, and by the fact that only a very small number of reproductive proteins specifically involved in reproduction are conserved across lineages. Consequently, during the last decade, many efforts have been put into answering the following question: did gametogenesis evolve independently in different animal lineages or does it share a common evolutionary origin in a single ancestral prototype? Among the various approaches carried out in order to solve this question, the characterization of the evolution of the DAZ gene family holds much promise because these genes encode reproductive proteins that are conserved across a wide range of animal phyla. Within this family, BOULE is of special interest because it represents the most ancestral member of this gene family (the "grandfather" of DAZ). Furthermore, BOULE has attracted most of the attention since it represents an ancient male gametogenic factor with an essential reproductive-exclusive requirement in urbilaterians, constituting a core component of the reproductive prototype. Within this context, the aim of the present work is to provide an up-to-date insight into the studies that lead to the characterization of the DAZ family members and the implications in helping decipher the evolutionary origin of gametogenesis in metazoan animals.


Giant Aortic Arch Aneurysm and Cardio-vocal Syndrome: Still An Open-surgery Indication.
The Cardio-vocal Syndrome (Ortner's syndrome) is described as hoarseness due to the left recurrent laryngeal nerve palsy, caused by a specific cardiovascular pathology. In this case, we present a patient with a giant aortic arch aneurysm with an initial clinical presentation of Cardio-vocal Syndrome. The conventional open-surgery, instead of endovascular approach, was useful to control the morbidity from the compressive effect of adjacent structures, also preventing the aortic rupture. We strongly recommend analyzing carefully the individual case and the clinical targets to resolve, because the new technologies are not always the most effective therapeutic response.


Expression profiling of circulating miRNAs in mouse serum in response to Echinococcus multilocularis infection.
Echinococcus multilocularis is a most pathogenic zoonotic tapeworm that causes devastating echinococcosis in both humans and animals. Circulating microRNAs (miRNAs) are stably existed in the serum/plasma of mammalian hosts during helminthic infection. In this study, we compared the host-circulating miRNA expression in the sera from the E. multilocularis-infected and uninfected mice. A total of 58 host-origin serum miRNAs were differentially expressed (2 ⩾ fold change, P < 0·05), of which 21 were upregulated and 37 were significantly downregulated. Consistent with the sequencing data, quantitative polymerase chain reaction (PCR) results showed that the expression levels of four miRNAs were elevated gradually and one decreased gradually at the E. multilocularis infection time points. Moreover, seven of E. multilocularis specific miRNAs were identified in the sera. Real-time PCR analyses further demonstrated that only two parasite-derived miRNAs (emu-miR-10 and emu-miR-227) were specifically amplified in all the sera from mice infected with E. multilocularis. These findings will be helpful to understand the roles of miRNAs in host-parasite interaction and to potentiate serum miRNAs as diagnostic targets for echinococcosis.


Validation of the Canada Acute Coronary Syndrome Risk Score for Hospital Mortality in the Gulf Registry of Acute Coronary Events-2.
Several risk scores have been developed for acute coronary syndrome (ACS) patients, but their use is limited by their complexity. The new Canada Acute Coronary Syndrome (C-ACS) risk score is a simple risk-assessment tool for ACS patients. This study assessed the performance of the C-ACS risk score in predicting hospital mortality in a contemporary Middle Eastern ACS cohort. The C-ACS score accurately predicts hospital mortality in ACS patients. The baseline risk of 7929 patients from 6 Arab countries who were enrolled in the Gulf RACE-2 registry was assessed using the C-ACS risk score. The score ranged from 0 to 4, with 1 point assigned for the presence of each of the following variables: age ≥75 years, Killip class >1, systolic blood pressure <100 mm Hg, and heart rate >100 bpm. The discriminative ability and calibration of the score were assessed using C statistics and goodness-of-fit tests, respectively. The C-ACS score demonstrated good predictive values for hospital mortality in all ACS patients with a C statistic of 0.77 (95% confidence interval [CI]: 0.74-0.80) and in ST-segment elevation myocardial infarction and non-ST-segment elevation acute coronary syndrome patients (C statistic: 0.76, 95% CI: 0.73-0.79; and C statistic: 0.80, 95% CI: 0.75-0.84, respectively). The discriminative ability of the score was moderate regardless of age category, nationality, and diabetic status. Overall, calibration was optimal in all subgroups. The new C-ACS score performed well in predicting hospital mortality in a contemporary ACS population outside North America.


[Ureteral inverted papilloma: a case report].
A 43-year-old man presented with left hydronephrosis, incidentally found by ultrasonography. He had undergone transurethral bladder tumor resection when he was 29 years old. Cystoscopy revealed a tumor protruding from the left ureteral orifice. Left partial ureterectomy was performed, and its histopathological diagnosis was ureteral inverted papilloma. He has remained free of disease for 18 months after the surgery.


Sarcoidosis mimicking disseminated testicular cancer.
Sarcoidosis rarely involves the genitourinary system or the spinal cord. This report describes a case of sarcoidosis with a scrotal mass, a mass compressing the spinal cord, and lesions in the liver and spleen. This case illustrates an uncommon manifestation of sarcoidosis, which may mimic disseminated testicular cancer.


Callous-Unemotional Behaviors and Harsh Parenting: Reciprocal Associations across Early Childhood and Moderation by Inherited Risk.
Callous-unemotional (CU) behaviors increase children's risk for subsequent antisocial behavior. This risk process may begin in early childhood with reciprocal pathways between CU behaviors and harsh parenting. In a sample of 561 linked triads of biological mothers, adoptive parents, and adopted children, the present study examined bidirectional links between CU behaviors and harsh parenting across three time points from 18 to 54 months and investigated moderation by inherited risk for psychopathic traits. Child CU behaviors and harsh parenting were measured using adoptive mother and adoptive father reports, and biological mothers provided reports of their personality characteristics. Findings supported reciprocal associations between harsh parenting and CU behaviors during early childhood, especially during the transition from toddlerhood (27 months) to the preschool period (54 months). Moreover, multiple-group analyses showed that level of inherited risk moderated associations between CU behaviors and harsh parenting. Specifically, there were statistically reliable associations between CU behaviors at 27 months and adoptive mothers' harsh parenting at 54 months, and between adoptive fathers' harsh parenting at 27 months and CU behaviors at 54 months among children at higher inherited risk, but not among those at lower inherited risk. The findings illustrate the dynamic interplay between parenting, CU behaviors, and heritable risk.


Localization and phenotypic characterization of brainstem neurons activated by rimonabant and WIN55,212-2.
The mechanisms by which the CB1 receptor antagonist rimonabant exerts its appetite-suppressing and energy-dissipating effects are still incompletely resolved. To shed further light on the central pathways influenced by CB1 receptor modulation we examined the expression of the immediate early gene c-fos in male Sprague-Dawley rats at 60, 120 and 240 min after intraperitoneal administration of the CB1R antagonist rimonabant (10 mg/kg) and the CB1R agonist WIN55,212-2 (3 mg/kg). Perfusion-fixed brains were processed for immunohistochemistry and the localization of c-Fos immunoreactive neuronal profiles was assessed qualitatively throughout the brain. Nine areas, including specific hypothalamic and brainstem nuclei known to be involved in appetite regulation, were selected for quantitative analyses. Whereas WIN55,212-2 induced c-Fos immunoreactivity in a time-specific manner in the striatum, the central nucleus of amygdala, the hypothalamic paraventricular nucleus and the arcuate nucleus, no significant increases in c-Fos positive nuclei were found in any forebrain areas following rimonabant administration. In contrast, rimonabant and WIN55,212-2 were both found to significantly increase c-Fos immunoreactivity in the brainstem lateral parabrachial nucleus, the nucleus of the solitary tract and the area postrema. To characterize the phenotype of activated neurons in the nucleus of the solitary tract, a triple immunohistochemical staining technique was used to simultaneously label c-Fos protein and tyrosine hydroxylase (TH), GLP-1 or CART. Interestingly, rimonabant was found to significantly increase c-Fos protein expression in TH-positive neurons. Collectively, these results suggest that brainstem areas including ascending catetholaminergic A2/C2 neurons could play a role in rimonabant-induced inhibition of food intake.


In vivo multiplexed interrogation of amplified genes identifies GAB2 as an ovarian cancer oncogene.
High-grade serous ovarian cancers are characterized by widespread recurrent copy number alterations. Although some regions of copy number change harbor known oncogenes and tumor suppressor genes, the genes targeted by the majority of amplified or deleted regions in ovarian cancer remain undefined. Here we systematically tested amplified genes for their ability to promote tumor formation using an in vivo multiplexed transformation assay. We identified the GRB2-associated binding protein 2 (GAB2) as a recurrently amplified gene that potently transforms immortalized ovarian and fallopian tube secretory epithelial cells. Cancer cell lines overexpressing GAB2 require GAB2 for survival and show evidence of phosphatidylinositol 3-kinase (PI3K) pathway activation, which was required for GAB2-induced transformation. Cell lines overexpressing GAB2 were as sensitive to PI3K inhibition as cell lines harboring mutant PIK3CA. Together, these observations nominate GAB2 as an ovarian cancer oncogene, identify an alternative mechanism to activate PI3K signaling, and underscore the importance of PI3K signaling in this cancer.


Drug-related mortality and its impact on adult mortality in eight European countries.
To estimate the mortality rates from drug-related deaths and other causes among problem drug users and population attributable risk of death due to opiate use in eight study sites in Europe. Opiate users were recruited from drug treatment centres during the period 1990-1998 and deaths followed up through national or local mortality registries. Gender-specific overall mortality rate, proportion of deaths by cause (drug-related, HIV, other), standardized mortality ratios (SMRs), and the attributable risk fraction (ARF) were estimated. Crude mortality rates varied from 1 per 100 person-years in the Dublin and London cohorts to 3.8 per 100 person-years in Barcelona. The highest drug-related mortality rate was 10 per 1,000 person-years in Barcelona; the rates were approximately 7 per 1,000 person-years in Denmark, London, Rome, and Vienna, and <3.5 per 1,000 person-years for the others cohorts. The mortality rate for AIDS was <2 per 1,000 person-years in all the cohorts except Lisbon, Rome, and Barcelona, for which it was approximately 6 per 1,000 person-years. The highest SMR among males was 21.1 in Barcelona, and among females the highest SMRs were 53.7 and 37.7 in Barcelona and Rome, respectively. In Denmark the ARF was 5%, whereas it was >10% in all other study sites and 24% in Barcelona. Cohort mortality studies, especially in combination with estimates of prevalence, provide useful insights into the impact of opiate use on mortality across European countries and emphasize how preventing overall and drug-related deaths among opiate users can significantly improve the health of the population.


Automatic containment sampling of recombinant escherichia coli fermentations.
A containment sampling system for shake flasks and fermentors has been developed from a blood collection system used in hospitals. The core of the system is a collection vial with a vacuum inside. When a needle connected to the fermentation fluid penetrates a rubber seal on the vial, a sample is withdrawn. The system has been developed in two versions, a manual method for shake flasks, and an automated version for fermentors including cool storage of samples. The sampling system offers the same safety for fermentation containment as the original system offers safety for patients and hospital staff.


Occult tumor cells in the lymph nodes of patients with pathological stage I malignant melanoma. An immunohistological study.
We examined 2,227 lymph nodes from 100 patients with clinical Stage I cutaneous melanoma for the presence of microscopic deposits of tumor. On examination of hematoxylin-and-eosin-stained sections, none had melanoma. Sixteen nodes from 14 patients had melanoma detectable by an antiserum to S-100 protein in a peroxidase-antiperoxidase (PAP) assay. The melanomatous nature of these cells was confirmed by their reaction with the melanoma-directed monoclonal antibody NKl/C3. The incidence of occult nodal metastases was highest in patients with deeply invasive and micrometrically thick primary tumors. The incidence of occult melanoma was not increased where additional serial sections were cut and semiserial sections examined. Pitfalls in the identification of occult melanoma cells (OMC) include S-100 protein-positive interdigitating dendritic cells, capsular nevus cells, a minority of sinus "macrophages," and the Schwann cells of node-associated nerves. Thus, we conclude that the incidence of early melanoma metastases in the regional lymph nodes of patients with clinical Stage I melanoma is greater than has previously been appreciated on the basis of assessment of routine hematoxylin-and-eosin-stained sections. Six of the 14 patients with OMC died of melanoma (41%), as compared to only 18 of 86 patients without OMC (21%; 0.10 greater than P greater than 0.05).


New aliphatic alcohol and (Z)-4-coumaric acid glycosides from Acanthus ilicifolius.
From the aerial parts of Acanthus ilicifolius, a new aliphatic alcohol glycoside (ilicifolioside C) and two new (Z)-4-coumaric acid glycosides, (Z)-4-coumaric acid 4-O-beta-D-glucopyranoside and (Z)-4-coumaric acid 4-O-beta-D-apiofuranosyl-(1"-->2')-O-beta-D-glucopyranoside were isolated. The structural elucidations were based on the analyses of spectroscopic data. Z-Form 4-coumaric acid glycosides were first isolated from plant.


The breeding systems and floral visitors of two widespread African dry forest species of ethnobotanical significance.
Forest products derived from woody trees, such as fruits, seeds, honey, wood and others, are important resources for supporting rural livelihoods. However, little is known about the breeding systems or floral visitors of trees that provide these resources, often due to the difficulty of accessing tree canopies. This study addresses key knowledge gaps from a data poor region, providing information on the breeding systems and contribution of biotic pollination to two trees abundant in south-central Africa, that provide forest product supports for rural livelihoods: Julbernardia paniculata (Benth.) Troupin and Syzygium guineense (Willd.) subsp. barotsense F. White (Fabaceae and Myrtaceae respectively). The breeding systems of these species were assessed by conducting controlled pollination experiments, and then measuring the effects on reproductive success to determine the degree of self-compatibility and pollen limitation. Floral visitors and their behaviour were observed to provide preliminary information on possible pollinator groups. S. guineense appeared to be self-compatible, while J. paniculata showed signs of both self-incompatibility and pollen limitation. Floral visitors of both species were dominated by bees, with native honeybees (Apis mellifera) providing the highest visitation rates. These insights provide the first steps for understanding the reproductive ecology of these key tree species and can help to inform sustained management and conservation aimed at protecting forests and supporting rural livelihoods, as well as broaden the understanding of the floral visitors, and contribution of biotic pollination to forest tree reproductive success.


Melanin-concentrating hormone receptor subtypes 1 and 2: species-specific gene expression.
To assess the contribution of potential central nervous system pathways implicated in the control of appetite regulation and energy metabolism, it is essential to first identify appropriate animal models. Melanin-concentrating hormone (MCH), a conserved cyclic neuropeptide implicated in the modulation of food intake, has been shown to bind and activate two G-protein-coupled receptors, called GPR24 and MCHR2, expressed in human brain and other tissues. Here we show that several non-human species (rat, mouse, hamster, guinea pig, and rabbit) do not have functional MCHR2 receptors, or encode a nonfunctional MCHR2 pseudogene while retaining GPR24 expression. We identified three species for further evaluation that express both MCH receptor subtypes. We cloned and functionally characterized dog, ferret, and rhesus GPR24 and MCHR2 in mammalian cells and studied their brain distribution patterns by in situ hybridization. The homology, expression profile, and functional similarity of the receptors in the dog, ferret, and rhesus to that of human support the potential use of these species as preclinical animal models in the development of therapeutic agents for obesity or other MCH-mediated disorders.


Complications after Radiofrequency Ablation of 233 Hepatic Tumors.
The only curative treatment for primary and secondary hepatic malignancies is surgery and liver transplantation. Thus, the majority of the patients are not candidates for resection, and there is a lack of organs. For these reasons, alternative treatment modalities such as radiofrequency ablation (RFA) are employed. The objective of this paper is to evaluate the incidence and types of complications related to open and percutaneous RFA. This is a retrospective study of patients with hepatic malignancies treated by RFA. Tumor size, location, numbers of nodules, approach, histology and associated procedures were analyzed and correlated to complications. A total of 151 patients with primary and secondary hepatic malignancies were included: 58 with hepatocellular carcinoma (HCC), 68 with metastases from colorectal cancer and 25 with other types of tumors. Complications occurred in 24.5% of the patients, mostly (58.9%) in those with HCC. Ascites was the most common complication, followed by wound infection. The only two significant factors associated with complications were the presence of HCC (p = 0.0087) and two or more lesions (p = 0.0323). The mortality rate was 0.69%. RFA is a safe technique, but complications may occur and are multifactorial. Appropriate patient selection, early complication recognition and adequate treatment are essential.


Understanding and managing respiratory infections in children and young adults with neurological impairment.
Patients with neurocognitive impairment (NI) have multiple medical needs, with respiratory problems leading to an important reduction in quality of life and life expectancy. We aimed to explain that the origin of chronic respiratory symptoms in patients with NI is multifactorial. In people with NI there is a high prevalence of swallowing dysfunction and hypersalivation inducing aspiration; cough efficacy is decreased resulting in chronic lung infection; sleep-disordered breathing is frequent and muscle mass is abnormal due to malnutrition. Technical investigations are not always specific and sensitive enough to better diagnose the causes of the respiratory symptoms; moreover, they can sometimes be difficult to perform in this vulnerable patient population. We provide a clinical pathway to adopt to identify, prevent, and treat respiratory complications in children and young adults with NI. A holistic approach in discussion with all care providers and the parents is highly recommended. The care for people with NI and chronic respiratory problems is challenging. The interplay between several causative factors may be difficult to entangle. Well-performed clinical research in this field is largely missing and should be encouraged. Only then, evidence-based clinical care will become possible for this vulnerable patient group.


Cardiac sarcoidosis: epidemiology, characteristics, and outcome over 25 years in a nationwide study.
This study was designed to assess the epidemiology, characteristics, and outcome of cardiac sarcoidosis (CS) in Finland. We identified in retrospect all adult (>18 years of age) patients diagnosed with histologically confirmed CS in Finland between 1988 and 2012. A total of 110 patients (71 women) 51±9 years of age (mean±SD) were found and followed up for outcome events to the end of 2013. The annual detection rate of CS increased >20-fold during the 25-year period, reaching 0.31 in 1×10(5) adults between 2008 and 2012. The 2012 prevalence of CS was 2.2 in 1×10(5). Nearly two thirds of patients had clinically isolated CS. Altogether, 102 of the 110 patients received immunosuppressive therapy, and 56 received an intracardiac defibrillator. Left ventricular function was impaired (ejection fraction <50%) in 65 patients (59%) at diagnosis and showed no overall change over 12 months of steroid therapy. During follow-up (median, 6.6 years), 10 patients died of a cardiac cause, 11 patients underwent transplantation, and another 11 patients suffered an aborted sudden cardiac death. The Kaplan-Meier estimates for 1-, 5-, and 10-year transplantation-free cardiac survival were 97%, 90%, and 83%, respectively. Heart failure at presentation predicted poor outcome (log-rank P=0.0001) with a 10-year transplantation-free cardiac survival of only 53%. The detection rate of CS has increased markedly in Finland over the last 25 years. With current therapy, the prognosis of CS appears better than generally considered, but patients presenting with heart failure still have poor long-term outcome.


Differential-pulse polarographic determination of zinc and manganese in various pharmaceutical and biological samples after adsorption of their morpholine-4-carbodithioates on microcrystalline naphthalene.
A highly selective, sensitive, rapid and economical differential-pulse polarographic method was developed for the simultaneous determination of trace amounts of zinc and manganese in various standard alloys and pharmaceutical, biological and environmental samples after adsorption of their morpholine-4-carbodithioates on microcrystalline naphthalene in the pH range 4.1-9.0 for manganese and 6.5-10.2 for zinc. After filtration, the metal complexes are shaken with 10 ml of 1 mol l-1 HCl and determined simultaneously using a differential-pulse polarograph. There is no need to remove naphthalene from the solution. Dissolved oxygen is removed by adding a few millilitres of 4% NaBH4 solution. The detection limits are 0.06 ppm for Mn and 0.1 ppm for Zn (signal-to-noise ratio = 2). Linearity is maintained in the concentration ranges 0.06-10 ppm for Mn and 0.1-12 ppm for Zn with a correlation factor of 0.9997 and relative standard deviations of 0.95 and 0.81%, respectively. The characterization of the electroactive process included an examination of the degree of reversibility. Various parameters such as the effect of pH, volume of aqueous phase and interference of a number of metal ions on the determination of manganese and zinc were studied in detail to optimize the conditions for their simultaneous determination (based on the large difference in their Ep values) in various biological, pharmaceutical and environmental samples.


An ordered sequence of events is required before BALB/c-3T3 cells become committed to DNA synthesis.
An ordered sequence of events must be completed before cells become committed to synthesize DNA. A platelet-derived growth factor (PDGF), present in heated (100 degrees ) extracts of human platelets, induces density-inhibited BALB/c-3T3 cells to become competent to proliferate. Platelet-poor plasma induces these competent cells to leave the competence point, progress through G(0)/G(1), and enter the S phase. Treatment of G(0)-arrested, incompetent cells with plasma, before the addition of PDGF, did not shorten the latent period for DNA synthesis or increase the rate of entry into the S phase. Growth arrest points in the plasma-dependent progression sequence were detected in G(0)/G(1). PDGF-treated competent cells were exposed to an optimal concentration of plasma (5%) for various lengths of time and were then transferred to medium lacking plasma; the subsequent readdition of plasma stimulated the cells to enter the S phase. The lag period until DNA synthesis, in such experiments, was dictated by the length of the initial exposure to plasma. PDGF-treated competent cells that were incubated with plasma for 5 hr during the initial exposure did not leave the competence point; they began DNA synthesis 12 hr after the readdition of plasma. However, a population of cells treated with plasma for 10 hr became arrested at a point 6 hr before DNA synthesis, whereas a population treated with plasma for 12-15 hr became arrested at a point immediately before DNA synthesis. Cells remained arrested at this latter point for as long as 24 hr, and these arrested cells were not committed to DNA synthesis. The addition of plasma induced immediate entry into the S phase with an apparent first-order rate of entry being determined by the plasma concentration. This plasma-dependent commitment (transition) to DNA synthesis was blocked by cycloheximide but not by hydroxyurea. Removal of the hydroxyurea allowed cells to enter the S phase synchronously in the absence of plasma.


High molecular weight fibroblast growth factor-2 as a promising prognostic biomarker to predict the occurrence of heart failure in atrial fibrillation patients.
Heart failure (HF) has a significant effect on the prognosis of the patients with atrial fibrillation (AF), and also it is an important risk factor for overall mortality. High molecular weight fibroblast growth factor-2 (Hi-FGF-2) is emerging as a prognostic marker with HF and AF. The aim of this study was to prove that Hi-FGF-2 would predict occurrence of HF in the patients with AF. Subjects diagnosed with paroxysmal AF (Group paAF), persistent AF (Group peAF) and sinus rhythm (Group SR) were enrolled in the study. Serum Hi-FGF-2 concentration was measured by ELISA at baseline. Multivariable logistic models and receiver operating characteristic (ROC) curve analysis were established to predict the prognosis of AF subjects. 260 patients were enrolled in the study: 104 (40.0%) admitted for sinus rhythm (Group SR) and 156 (60.0%) with AF (Group paAF and Group peAF). The Hi-FGF-2 levels were much lower in the Group SR (58.2 ± 27.1 ng/L) than in the Group AF. Furthermore, the Group peAF (84.3 ± 34.1 ng/L) had higher Hi-FGF-2 levels than the Group paAF (72.9 ± 35.8 ng/L). Serum Hi-FGF-2 levels were classified into trisection in the multivariable logistic model (T1 < 57.3 ng/L, 57.3 < T2 < 86.5 ng/L, and T3 > 86.5 ng/L). Hi-FGF-2 showed good predictive ability for new-onset HF in the patients with AF. The occurrence of HF was associated significantly with increased tertile of serum Hi-FGF-2 levels (T2: OR 5.922, 95% CI 1.109-31.626, P = 0.037 and T3: OR 8.262, 95% CI 1.735-39.343, P = 0.008). ROC curve analysis showed that the area under curves for Hi-FGF-2 were 0.720 (P < 0.0001). Hi-FGF-2 has a significant meaning in AF subjects. Further to this, higher circulating Hi-FGF-2 was highly related to persistent AF, and Hi-FGF-2 may be an independent risk factor of occurrence HF in AF subjects.


Acute Effect of Atrial Fibrillation on Circulating Natriuretic Peptides: The Influence of Heart Rate, Rhythm Irregularity, and Left Atrial Pressure Overload.
Plasma natriuretic peptides (NPs) are increased in patients with atrial fibrillation (AF) compared with the patients with sinus rhythm. This study investigated whether this phenomenon is intrinsic to heart rhythm irregularity and independent of the heart rate and left atrial pressure (LAP) overload. We investigated 46 patients (age: 59 ± 10 years, male gender: 77%) with non-valvular paroxysmal AF who were scheduled for catheter ablation and had documented stable sinus rhythm for at least 18 hours before the procedure. All patients underwent direct measurement of right atrial pressure and LAP, simultaneously with assessment of plasma B-type NP, N-terminal pro-brain NP, and mid-regional pro-atrial NP. The baseline measurement was followed by induction of AF by rapid atrial pacing in the first 24 patients and by regular pacing from the coronary sinus at 100/min (corresponding to the mean heart rate during induced AF) in the latter 22 patients. Hemodynamic assessment and blood sampling were repeated after 20 min of the ongoing AF or fast regular paging. The baseline characteristics and hemodynamic measurements were comparable between study groups; however, patients in the regular atrial pacing group had a higher body mass index and a larger left atrial diameter compared with the induced AF group. Plasma levels of all 3 NPs increased significantly during induced AF but not during fast regular pacing, and the increase of NPs was independent of right atrial pressure and LAP. Baseline concentrations of NPs and heart rhythm irregularity were the only independent predictors of increased NPs.


Effectiveness of bee venom acupuncture for patients suffering from periarthritis humeroscapularis.
To evaluate the efficacy of bee venom acupuncture in humeroscapularis (PHS) patients. One hundred and twenty patients diagnosed with PHS were assigned into four groups: BV1 (0.01 mg/kg), BV2 (0.005 mg/kg), BV3 (0.0025 mg/kg), and control group (vitamin B1 plus novocain 3% injection) with 15 d of treatment. The outcomes of the study including visual analogue scale (VAS) score and β-endorphin, inflammatory cytokines including interleukin-10 (IL-10), IL-1β and tumor necrosis factor α (TNF-α) and shoulder function score were assessed at baseline, after 10 and 15 d of treatment. All four groups reported statistically significant improvement in VAS score, motion range, and shoulder function score ( < 0.01), only the BV3 group showed significant increase of anti-inflammatory (IL-10) and decrease of pro-inflammatory (IL-1β, TNF-α) cytokines after treatment ( < 0.05). The BV3 group presented a significant difference between all outcomes compared to the control and other groups. BV3 groups showed better recovery including reduced pain, improved motor function and normalized inflammatory cytokines than current therapy used in Vietnam and other groups.


Hepatobiliary effects of obesity and weight-reducing surgery.
Obesity clearly increases the risk of gallstone formation. The role of nucleating factors may be most decisive in transforming merely saturated bile into a gallstone-forming solution. Weight loss in the short run may promote stone formation but in the long run may be beneficial if it is maintained. UDCA appears to be a promising prophylactic agent against gallstone formation during weight loss regardless of whether it is achieved by diet alone, by jejunoileal bypass, or by gastric restriction surgery.


TBIs: an emerging risk for health systems.
Healthcare providers should take eight steps to ensure their organizations are prepared for the potential risks associated with traumatic brain injuries: Review current procedures. Educate parents and caregivers. Create targeted programs for seniors. Adopt standard written protocols for providers for identification and treatment. Ensure proper and periodic follow-up with all patients at risk. Add a question about recent falls and head injuries to the patient intake discussion sheet. Conduct thorough debriefings and analyses following confirmed TBIs. Evaluate the organization's current insurance policy to ensure it provides the coverage needed.


Person-centred psychopharmacotherapy: what is it? Each patient is a unique, responsive and responsible subject.
Modern psychopharmacotherapy is currently in contention both outside and within the field of psychiatry. Conventional psychopharmacology paradigms focusing just on a disease perspective, biological narrative and a "one fits all" treatment are often regarded as inadequate and disjunctive. A significant proportion of psychiatric patients achieve no improvement or only partial improvement in their symptoms, while many of them suffer adverse and even toxic effects of medications. Psychopharmacotherapy as a sole form of treatment may carry the wrong message that patients don't have to change their life style and don't have to learn any new skills, they just have to receive their medication on time because the only problem is in brain chemistry. Evidence-based psychopharmacotherapy and person-centered narrative psychopharmacotherapy are not competitors but a complementuary duality, as intimately connected as brain and soul. Narrative preserves individuality, distinctivenesss and therapeutic context, whereas quantitative methods and evidence-based guidelines offer a solid foundation for what is reliably and generally correct. The purpose of person-centered psychopharmacotherapy is to empower the patients to control their disease, to re-author their problematic life story, to obtain full personal recovery and to regain control over their life.


Spectral cues for sound localization in cats: a model for discharge rate representations in the auditory nerve.
Neural representations of pinna-based spectral cues for sound localization were modeled by simulating auditory nerve discharge rates to noise bursts that had been shaped by filtering properties of the cat's head-related transfer functions (HRTFs) at 179 locations in the frontal field. The auditory nerve model transformed spectral differences between HRTFs into simulated neural rate differences. Linear equations for this transformation were developed from actual auditory nerve responses to a limited subset of HRTF-filtered noise bursts [Rice et al., J. Acoust. Soc. Am. 97, 1764-1776 (1995)]. Signal detection methods were used to investigate simulated neural responses to pairwise changes between HRTFs. The quality of neural representation for these changes, in terms of d' values, declined when the reference HRTF was moved from a central location (0 degree AZ, 0 degree EL) to a large positive azimuth in the horizontal plane (75 degrees AZ, 0 degree EL) or a high elevation in the median plane (0 degree AZ, 75 degrees EL). Most simulated responses exhibited large d' values for comparisons of contralateral versus ipsilateral azimuths, or eccentric versus frontal elevations. This rate information resulted from directionally dependent changes in the overall gain of HRTFs. In addition, fibers with best frequency (BF: the frequency of greatest sensitivity for individual fibers) between 5 and 18 kHz showed large d' values for HRTF contrasts in the immediate frontal field because of the effects of spectral notches (i.e., sharp drops in gain over a narrow frequency range). Spectral notches also played a prominent role in simulations that required identification of HRTF location in the absence of a fixed reference stimulus. These modeling results correspond well with previously described patterns in the cat's localization behaviors.


Two distinct interacting classes of nuclear envelope-associated coiled-coil proteins are required for the tissue-specific nuclear envelope targeting of Arabidopsis RanGAP.
Ran GTPase plays essential roles in multiple cellular processes, including nucleocytoplasmic transport, spindle formation, and postmitotic nuclear envelope (NE) reassembly. The cytoplasmic Ran GTPase activating protein RanGAP is critical to establish a functional RanGTP/RanGDP gradient across the NE and is associated with the outer surface of the NE in metazoan and higher plant cells. Arabidopsis thaliana RanGAP association with the root tip NE requires a family of likely plant-specific nucleoporins combining coiled-coil and transmembrane domains (CC-TMD) and WPP domain-interacting proteins (WIPs). We have now identified, by tandem affinity purification coupled with mass spectrometry, a second family of CC-TMD proteins, structurally similar, yet clearly distinct from the WIP family, that is required for RanGAP NE association in root tip cells. A combination of loss-of-function mutant analysis and protein interaction data indicates that at least one member of each NE-associated CC-TMD protein family is required for RanGAP targeting in root tip cells, while both families are dispensable in other plant tissues. This suggests an unanticipated complexity of RanGAP NE targeting in higher plant cells, contrasting both the single nucleoporin anchor in metazoans and the lack of targeting in fungi and proposes an early evolutionary divergence of the underlying plant and animal mechanisms.


Immune thrombotic thrombocytopenic purpura: Spotlight on long-term outcomes and survivorship.
Advances in diagnosis and treatment have dramatically improved survival of acute immune thrombotic thrombocytopenic purpura (iTTP) and iTTP has evolved from an acute fatal condition to a chronic relapsing disorder. In addition to the risk of iTTP relapse, iTTP survivors are at risk of multiple adverse health outcomes including higher than expected rates of all-cause mortality, increased rates of stroke and other cardiovascular disease, and higher rates of morbidities such as obesity, hypertension, and autoimmune disorders. iTTP survivors also report neurocognitive impairment, depression, and reduced quality of life. Women with iTTP are at risk for recurrent iTTP, preeclampsia, and other maternal and fetal complications in subsequent pregnancies. ADAMTS13 activity during clinical remission has emerged as an important targetable risk factor for iTTP relapse and other outcomes including stroke and all-cause mortality. This review summarizes current literature regarding the epidemiology and potential mechanisms for adverse long-term sequelae of iTTP, outlines current best practices in iTTP survivorship care, and highlights a research agenda to improve long-term iTTP outcomes.


A review of case-control studies on the risk factors for the development of autoimmune blistering diseases.
Autoimmune blistering diseases (AIBD) are a group of rare but potentially fatal diseases characterized by the production of autoantibodies directed against the structural proteins of the skin. Much has been published on the clinical manifestation and interventional options for AIBD, especially on the more common subtypes such as bullous pemphigoid, pemphigus vulgaris (PV) and pemphigus foliaceus (PF). However, the aetiology of AIBD remains unknown. We aim to provide an overview of published case-control studies focussing on the non-genetic aetiological factors of bullous pemphigoid, PV and/or PF. The relevant studies were appraised for their validity and results. Our results showed that a large proportion of the studies had inconclusive results due to compromised study methodologies. Moreover, there were no identified case-control studies that investigated the possible associations between bullous pemphigoid and patient environment, or the potential links between pemphigus and drugs. Hence, a case-control study with a higher quality design addressing these shortcomings would contribute greatly to our knowledge of AIBD.


Comment on Roy's "Alcohol misuse and posttraumatic stress disorder (delayed): an alternative interpretation of the data".
The statistical methods used by Roy to compare veterans who served in Vietnam with Vietnam-era veterans who did not serve there are questionned. His method of pooling means is considered improper and his data are considered incomplete because they do not relate to alcohol use in veterans with posttraumatic stress disorder. Roy's argument that the military is not liable for problems caused by predispositions is questioned.


Hyperthermic intraperitoneal chemotherapy with melphalan: a summary of clinical and pharmacological data in 34 patients.
Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is a treatment option for peritoneal metastases. The optimal agents for HIPEC have not been established. Melphalan is a drug with broad activity and a favorable profile for intraperitoneal application. The purpose of this study is to review our experience using melphalan for HIPEC. Pharmacologic data was obtained. Thirty four patients who underwent CRS for peritoneal metastases received melphalan for HIPEC between 2003 and 2011. The first 10 patients received 70 mg/m(2); subsequent 24 received 60 or 70 mg/m(2). The mean PCI was 21 ± 7. Twenty-eight patients (83%) had a CC score of 1 or 2. The mean length of stay was 18 ± 2 days. Nine patients (26%) had a grade 3 and 6 (17%) had grade 4 morbidity. There were no postoperative deaths. The pharmacologic analysis of plasma to peritoneal fluid levels of melphalan showed an AUC ratio of 33 while the tumor nodules to peritoneal ratio was 8. Melphalan is an acceptable agent for use in HIPEC. The morbidity of intraperitoneal melphalan at the dose of 60-70 mg/m(2) appears acceptable. Further studies comparing the effectiveness of melphalan and other HIPEC agents are needed.


Hunting for predictive computational drug-discovery models.
The Keystone Symposium on Computer-Aided Drug Design was held at Steamboat Springs (CO, USA), from March 29th to the 3rd of April, 2008. The organizers brought together approximately 180 participants, representing a cross-section of viewpoints from academia and the pharmaceutical industry. Since it is a young discipline, it was a privilege to have a keynote introduction from one of the original pioneers of the field, Irwin Kuntz. By avoiding pitfalls, and addressing active debates, the young field can become more reliably predictive. Accordingly, this report focuses on best practices. As reliability improves, drug-discovery programs will increasingly use models to determine which high-throughput screens to run.


pH Dependence of catalysis by Pseudomonas aeruginosa isochorismate-pyruvate lyase: implications for transition state stabilization and the role of lysine 42.
An isochorismate-pyruvate lyase with adventitious chorismate mutase activity from Pseudomonas aerugionsa (PchB) achieves catalysis of both pericyclic reactions in part by the stabilization of reactive conformations and in part by electrostatic transition-state stabilization. When the active site loop Lys42 is mutated to histidine, the enzyme develops a pH dependence corresponding to a loss of catalytic power upon deprotonation of the histidine. Structural data indicate that the change is not due to changes in active site architecture, but due to the difference in charge at this key site. With loss of the positive charge on the K42H side chain at high pH, the enzyme retains lyase activity at ∼100-fold lowered catalytic efficiency but loses detectable mutase activity. We propose that both substrate organization and electrostatic transition state stabilization contribute to catalysis. However, the dominant reaction path for catalysis is dependent on reaction conditions, which influence the electrostatic properties of the enzyme active site amino acid side chains.


Multilevel factors influencing hepatitis B screening and vaccination among Vietnamese Americans in Atlanta, Georgia.
Chronic hepatitis B virus (HBV) infection may lead to liver cirrhosis, chronic liver disease, and liver cancer. Immunization rates are suboptimal among Asian Americans/Pacific Islanders (AAPIs), who remain disproportionately affected by these illnesses. We investigated socioecological factors affecting HBV prevention among 316 Vietnamese Americans in Atlanta, Georgia. Social and community support of HBV vaccination was associated with screening (OR=1.69, 95% CI [1.21,2.38]), vaccination (OR=1.89, [1.27,2.81]), and intent to vaccinate (OR=1.77, [1.13,2.78]). Misconceptions decreased screening likelihood (OR=0.67, [0.46,0.99]) and vaccination (OR=0.55, [0.35,0.86]). Those able to pay for medical treatment (OR=1.23, [1.01,1.50]) were also more likely immunized, and greater transportation access (OR=1.42, [1.07,1.87]) was associated with greater intention to vaccinate. Multi-level factors facilitated HBV vaccination in this population. Tailored, culturally appropriate communication strategies will positively influence immunization uptake.


Evolution of pseudorabies virions containing genomes with an invertible long component after repeated passage in chicken embryo fibroblasts.
The genome of pseudorabies virus consists of two components, short (S) and long (L). Only the S component is bracketed by inverted repeats, and only the S component inverts itself relative to the L component, giving rise to two isomeric forms of the genome. An attenuated vaccine strain of pseudorabies virus (Norden), however, has a genome which is found in four isomeric forms (B. Lomniczi, M. L. Blankenship, and T. Ben-Porat, J. Virol. 49:970-979, 1984). To determine the basis for the atypical structure of the genome of the Norden strain, we examined more than 40 field isolates of pseudorabies virus; all contained genomes in which the L component was fixed in only one orientation relative to the S component. Several independently generated vaccine strains which have been passaged extensively in chicken embryos and chicken embryo fibroblast (CEF) cell cultures were also analyzed; they possessed an invertible L component. Furthermore, emergence of pseudorabies virus variants with an invertible L component was observed after passage of the virus in CEF, but not in rabbit kidney or pig kidney, cells. The invertibility of the L component was associated consistently with a translocation of sequences from the left end of the genome to a position next to the inverted repeat sequence of the S component. Three observations indicate that genomes with an invertible L component (and the translocation) have a selective growth advantage over standard pseudorabies virus when grown in CEF. The proportion of virions with such genomes does not increase linearly as would be expected if the translocation events occurred repeatedly, most genomes eventually experiencing the translocation. Instead, after a lag, the proportion of such virions in the population increases relatively rapidly. The genome structures that are generated upon independent passage in CEF of each virion population were relatively homogeneous. Some heterogeneity was observed at relatively early stages of the emergence of the genomes carrying the translocation; at later stages, virions with genomes with a specific size translocation predominated in the virus population. Parallel passages in CEF of the same pseudorabies virus strain resulted in the emergence of populations of virions with genomes with different size translocations. However, in each of the passaged populations of virions the majority of virions had genomes with the same size translocation. The most likely interpretation of these results is that virions with genomes carrying the translocations that emerge upon passage of the virus in CEF have a selective advantage when grown in these cells.


Understanding the grapefruit-drug interaction.
The inhibitory interaction of grapefruit juice and CYP3A4 medication metabolism was discovered in 1989. CYP3A4 enzymes are responsible for the metabolism of more than 60% of orally-administered drugs. Grapefruit components inhibit CYP3A4 drug oxidation and P-glycoprotein transportation, allowing more systemic drug bioavailability. This inhibitory interaction should be kept in mind when prescribing drugs that are metabolized by CYP3A4, such as orally administered midazolam, triazolam, and diazepam.


[Validation of a screening method for occupational bladder cancer].
Transitional bladder cancer is the most frequent malignant urinary neoplasm. Occupational exposure to aromatic amines and to polycyclic aromatic hydrocarbons are the main risk factors, in addition to cigarette smoking, recurrent inflammatory diseases of the urinary tract, consumption of certain drugs and a positive family history. Nevertheless cases of work-related bladder cancer are poorly identified in Italy. The aim of this study is to assess the screening accuracy of a short structured interview to detect suspected cases of occupational bladder cancer, which may be confirmed in a second step assessment by an occupational physician. The study sample consisted of 94 transitional bladder cancer patients, first hospitalised in 2004 and 2005 at the Department of Urology of the Ospedale di Circolo - Fondazione Macchi, in Varese, Italy. Based on data collected through a simple structured interview, it was possible to estimate two occupational exposure indices: one taking into account only the length of employment in industrial settings (DS Index) and the other considering job title in addition (DSM Index). For all cases a second-step assessment by an occupational physician (gold standard) made it possible to establish the occupational origin of cancer and to assess accuracy. Satisfactory values of the area under the ROC curve were found for both indices (AUC 0,81 for DS and 0,87 for DSM). In particular at the same level of sensitivity (90%), the DSM Index showed a better specificity (72%) in comparison to the DS Index (64%). The short structured interview proposed here proved to be a valuable tool for general practitioners and urologists to detect cases of bladder cancer of suspected occupational aetiology, which can be referred to an occupational physician for further investigations.


Antitumor Activity of Ferulic Acid Against Ehrlich Solid Carcinoma in Rats via Affecting Hypoxia, Oxidative Stress and Cell Proliferation.
Background Ferulic acid is a natural compound commonly found in fruits and vegetables like tomatoes, sweet corn, rice bran, and dong quai. It has various beneficial effects on the body, such as anti-inflammatory, anti-apoptotic, hepatoprotective, cardioprotective, and neuroprotective properties. Aims We conducted a study to investigate the antitumor activity of ferulic acid against Ehrlich solid carcinoma (ESC), specifically by affecting hypoxia-inducible factor (HIF)-1α and its subsequent effects on other factors like nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), cellular Myc (cMyc), cyclin D1, mammalian target of rapamycin (mTOR), and signal transducer and activator of transcription 3 (STAT3). Materials and methods The study involved implanting rats with ESC cells and administering 50 mg/kg of ferulic acid orally daily for eight days. Sections of the muscles with ESC were stained with toluidine blue or immunostained with anti-HIF-1α antibodies. The tumor samples were used to evaluate the expression of HIF-1α, Nrf2, HO-1, cMyc, cyclin D1, mTOR, and STAT3. Results Ferulic acid increased mean survival time, reduced tumor volume and weight, and improved the appearance of the tumor tissue. Furthermore, ferulic acid significantly elevated the expression of Nrf2 and HO-1, while reducing the expression of HIF-1α, Nrf2, HO-1, cMyc, cyclin D1, mTOR, and STAT3. Conclusions Ferulic acid can reduce tumor size and weight while improving the structure of muscle cells, suggesting it may have antineoplastic activity against ESC. Further investigation revealed that ferulic acid downregulates HIF-1α, increasing the expression of antioxidant proteins Nrf2 and HO-1. Additionally, ferulic acid decreases the expression of proliferation markers cMyc and cyclin D1 and downregulates cellular regulators mTOR and STAT3.


Effect of alpha 1-adrenoceptor antagonists on urinary bladder function in urethane-anesthetized rats.
1. We investigated the effects of selective alpha 1-adrenoceptor antagonists on rhythmic bladder contraction and cystometrograms as representative of urinary bladder function in urethane-anesthetized rats. 2. The selective alpha 1-adrenoceptor antagonists tamsulosin (0.03-3 micrograms/kg IV), prazosin (0.03-3 micrograms/ kg IV) and bunazosin (0.03-3 micrograms/kg IV) exerted little effect on the amplitude and frequency of rhythmic bladder contraction in anesthetized rats. In contrast, the antipollakiuria agent flavoxate (5 and 10 mg/kg IV) induced a dose-dependent disappearance in frequency without affecting the amplitude of the contractions. 3. Tamsulosin (1 and 3 micrograms/kg IV), prazosin (1 and 3 micrograms/kg IV), and bunazosin (1 and 3 micrograms/kg IV) exerted no effect on the cystometrogram, either. However, flavoxate (5 and 10 mg/kg IV) raised the micturition threshold pressure and prolonged the time to micturition. 4. These results suggest that the alpha 1-adrenoceptor plays little role in urinary bladder contraction in anesthetized rats.