Focused optical beams obtained at planar structures by an imaginary shift in position.
A theory for focused optical beams at planar structures is described. It is an extension of a previous theory based on summation of plane waves. The focused beam is obtained by an imaginary shift in the position vector of the plane waves. It is well suited for calculations of electromagnetic fields at planar surface plasmon resonance structures excited by a focused optical beam.


An audit of secondary peritonitis at a tertiary care university hospital of Sindh, Pakistan.
Peritonitis is the most common life threatening surgical emergency, which requires urgent surgical intervention and is a significant cause of morbidity and mortality. The objective of this study was to highlight the frequency of secondary peritonitis and to analyze the site and causes of perforation, in our tertiary care setup. A retrospective analysis of 311 patients of secondary peritonitis was done from July 2008 to June 2010 at Liaquat University Hospital Jamshoro, Hyderabad, Sindh, Pakistan. All cases found to have peritonitis as a result of perforation of any part of gastrointestinal tract at the time of surgery were included in the study. All cases with either primary peritonitis or that due to anastomotic dehiscence were excluded. A total of 311 patients were studied. Most of the patients were males (77%) and (89%) were in the third and fourth decades of life. Majority of the patients presented with pain (97%) associated with bowel symptoms. Most common site of perforation was small bowel (ileal 59%, jujenal 2%). In this series, most common risk factor of perforation was typhoid (43%). Ileostomy was the most commonly performed procedure. Overall morbidity was 48.5% and mortality was 17%. Considering the relatively higher rate of typhoid perforation quoted in this study, it is vital that typhoid fever ought to be eliminated by improved sanitation and immunizing programmes, otherwise surgeons will be confronted with its complications.


Enhancing liver tumor localization accuracy by prior-knowledge-guided motion modeling and a biomechanical model.
Pre-treatment liver tumor localization remains a challenging task for radiation therapy, mostly due to the limited tumor contrast against normal liver tissues, and the respiration-induced liver tumor motion. Recently, we developed a biomechanical modeling-based, deformation-driven cone-beam CT estimation technique (Bio-CBCT), which achieved substantially improved accuracy on low-contrast liver tumor localization. However, the accuracy of Bio-CBCT is still affected by the limited tissue contrast around the caudal liver boundary, which reduces the accuracy of the boundary condition that is fed into the biomechanical modeling process. In this study, we developed a motion modeling and biomechanical modeling-guided CBCT estimation technique (MM-Bio-CBCT), to further improve the liver tumor localization accuracy by incorporating a motion model into the CBCT estimation process. MM-Bio-CBCT estimates new CBCT images through deforming a prior high-quality CT or CBCT volume. The deformation vector field (DVF) is solved by iteratively matching the digitally-reconstructed-radiographs (DRRs) of the deformed prior image to the acquired 2D cone-beam projections. Using the same solved DVF, the liver tumor volume contoured on the prior image can be transferred onto the new CBCT image for automatic tumor localization. To maximize the accuracy of the solved DVF, MM-Bio-CBCT employs two strategies for additional DVF optimization: (I) prior-knowledge-guided liver boundary motion modeling with motion patterns extracted from a prior 4D imaging set like 4D-CTs/4D-CBCTs, to improve the liver boundary DVF accuracy; and (II) finite-element-analysis-based biomechanical modeling of the liver volume to improve the intra-liver DVF accuracy. We evaluated the accuracy of MM-Bio-CBCT on both the digital extended-cardiac-torso (XCAT) phantom images and real liver patient images. The liver tumor localization accuracy of MM-Bio-CBCT was evaluated and compared with that of the purely intensity-driven 2D-3D deformation technique, the 2D-3D deformation technique with motion modeling, and the Bio-CBCT technique. Metrics including the DICE coefficient and the center-of-mass-error (COME) were assessed for quantitative evaluation. Using limited-view 20 projections for CBCT estimation, the average (± SD) DICE coefficients between the estimated and the 'gold-standard' liver tumors of the XCAT study were 0.57±0.31, 0.78±0.26, 0.83±0.21, and 0.89±0.11 for 2D-3D deformation, 2D-3D deformation with motion modeling, Bio-CBCT and MM-Bio-CBCT techniques, respectively. Using 20 projections for estimation, the patient study yielded average DICE results of 0.63±0.21, 0.73±0.13 and 0.78±0.12, and 0.83±0.09, correspondingly. The MM-Bio-CBCT localized the liver tumor to an average COME of ~2 mm for both the XCAT and the liver patient studies. Compared to Bio-CBCT, MM-Bio-CBCT further improves the accuracy of liver tumor localization. MM-Bio-CBCT can potentially be used towards pre-treatment liver tumor localization and intra-treatment liver tumor location verification to achieve substantial radiotherapy margin reduction.


Cross-modal interactions in the experience of musical performances: physiological correlates.
This experiment was conducted to investigate cross-modal interactions in the emotional experience of music listeners. Previous research showed that visual information present in a musical performance is rich in expressive content, and moderates the subjective emotional experience of a participant listening and/or observing musical stimuli [Vines, B. W., Krumhansl, C. L., Wanderley, M. M., & Levitin, D. J. (2006). Cross-modal interactions in the perception of musical performance. Cognition, 101, 80--113.]. The goal of this follow-up experiment was to replicate this cross-modal interaction by investigating the objective, physiological aspect of emotional response to music measuring electrodermal activity. The scaled average of electrodermal amplitude for visual-auditory presentation was found to be significantly higher than the sum of the reactions when the music was presented in visual only (VO) and auditory only (AO) conditions, suggesting the presence of an emergent property created by bimodal interaction. Functional data analysis revealed that electrodermal activity generally followed the same contour across modalities of presentation, except during rests (silent parts of the performance) when the visual information took on particular salience. Finally, electrodermal activity and subjective tension judgments were found to be most highly correlated in the audio-visual (AV) condition than in the unimodal conditions. The present study provides converging evidence for the importance of seeing musical performances, and preliminary evidence for the utility of electrodermal activity as an objective measure in studies of continuous music-elicited emotions.


Predictors of long-term survival in Japanese patients with heart failure with reduced ejection fraction (HFrEF) treated with cardiac resynchronization therapy-defibrillators (CRT-D).
Reports on the factors predicting long-term survival of CRT-D cases from Western countries are increasing, however, those from Asia including Japan are still sparse. We aimed to clarify the factors predicting long-term survival of Japanese CRT-D cases. We retrospectively analyzed consecutive 133 patients who underwent CRT-D implantation between 2006 and 2021. We compared clinical factors between patients who died within 5 years after implantation (short-survival group: n = 31) and who had survived for more than 5 years (long-survival group: n = 36) after implantation. Major underlying heart diseases were dilated cardiomyopathy (45%) and ischemic heart disease (12%). There was no difference between the short-survival group and the long-survival group in incidence of CLBBB (32% vs. 30%), whereas CRBBB was more common in the short-survival group (26% vs. 0%, p = .004). Mechanical dyssynchrony at implantation was more frequent in the long-survival group (48% vs. 78%, p = .02). The incidence of response to CRT at 1 year after implantation was higher in long-survival group (19% vs. 50%, p = .02). Multiple logistic regression analysis identified NYHA class, mechanical dyssynchrony at implantation, and response at one year as predictors of long-term survival. In Japanese CRT-D cases, lower NHYA class, preexisting mechanical dyssynchrony, and 1-year response to CRT predict long-term survival.


Fracture displacement and screw cutout after open reduction and locked plate fixation of proximal humeral fractures [corrected].
Fixation of proximal humeral fractures is challenging. Locking plate technology offers mechanical advantages for treating unstable fractures in weak bone. In this study, we assessed the radiographic and clinical results of a single surgeon's experience treating proximal humeral fractures with a locked proximal humeral plate. Fifty-three adult patients with a displaced proximal humeral fracture were treated with a proximal humeral locking plate over a forty-five-month period. A standard postoperative rehabilitation regimen was followed. Radiographs were made at two weeks, six weeks, three months, six months, and one year and were examined for fracture alignment, fracture displacement, hardware position, and healing. Postoperative outcomes were collected with questionnaires. Fifty-two (98%) of the fifty-three fractures healed by six months. Nineteen patients (36%) had radiographic signs of a complication, including screw cutout with intra-articular displacement in twelve (23%), substantial (>10 degrees ) varus displacement in thirteen (25%), and osteonecrosis in two (4%). These radiographic signs of a complication occurred in twelve (57%) of twenty-one patients older than sixty years of age and in seven (22%) of thirty-two patients under sixty years of age (p = 0.0015). Screw cutout occurred in nine (43%) of the twenty-one patients older than sixty years. Patients with a complication had worse functional outcomes as measured with the Short Musculoskeletal Function Assessment (p < 0.05) and the Quick Disabilities of the Arm, Shoulder and Hand (p < 0.001) questionnaires. We were unable to demonstrate a relationship between fracture type and complications. Revision surgery was performed in seven (13%) of the fifty-three patients. There were no cases of infection, nerve injury, or hardware failure. The use of locking plates in the surgical treatment of proximal humeral fractures is associated with an unexpectedly high rate of screw cutout and revision surgery, especially in patients older than sixty years who have a three or four-part fracture. The indications for open reduction and internal fixation in these patients require continued analysis.


Biogas from mono- and co-digestion of microalgal biomass grown on piggery wastewater.
Biogas production has been suggested as a valid valorization solution for microalgal/bacteria biomass (MAB) grown on wastewater. This research is aimed at assessing the feasibility to use MAB grown in an outdoor raceway fed on piggery wastewater for biogas production. Batch and continuous anaerobic tests were conducted on the sole MAB and on a blend of MAB and carbonaceous substrates (deproteinated cheese whey and cellulose) to improve the carbon/nitrogen ratio. Results of batch biochemical methane potential tests confirmed that the sole microalgal/bacteria biomass was poorly degradable (119 NmLCH4·gCOD -1), while blending it with deproteinated cheese whey or cellulose (80% of carbonaceous material and 20% of MAB, as chemical oxygen demand (COD)) had no synergistic effects on the methane yield, although slight improvements in the degradation kinetics were observed. Continuous anaerobic degradation tests (at an organic loading rate of 1.5 gCOD·L-1·d-1, 35 °C and 30 days of hydraulic retention time) increased the overall methane yield from 81 NmLCH4·gCOD -1 (sole MAB) to 216 NmLCH4·gCOD -1 (MAB and deproteinated cheese whey) and 122 NmLCH4·gCOD -1 (MAB and cheese whey). However, data confirm that no evident synergistic effects were obtained.


Tuneable single-molecule electronic conductance of C60 by encapsulation.
It has been demonstrated that the single-molecule transport properties of fullerene C60 can be modulated by encapsulating endohedral species, i.e. Li+ and H2O, which exhibit different degrees of van der Waals interactions with the C60 cage. Single-molecule junctions were prepared between the gaps of Au electrodes using a break junction technique. Encapsulation of H2O inside the cage caused a slight decrease in the electronic conductivity relative to that of pristine C60. This is in sharp contrast to Li+ encapsulation, which results in a twofold-to-fourfold increase in the conductivity. The electronic couplings between the C60 cage and the Au electrodes were weakly dependent on the endohedral species in the cage, though the molecular orbital energy levels were remarkably modulated upon encapsulation.


Early warning technology for common characteristic resistances of lithium-ion batteries with thermal runaway.
A technology for early warning (of over 25 minutes) of thermal runaway in lithium-ion batteries based on common characteristic resistances supported by thermodynamic calculations was derived. With great potential in practical application for avoiding property losses and human casualties, this technology was proven to be efficient and accurate.


Differences between HA receptor-binding sites of avian influenza viruses isolated from Laridae and Anatidae.
A comparative study of the hemagglutinin (HA) receptor binding site (RBS) of a number of H13 influenza viruses isolated from Laridae family of birds (gulls) and other influenza viruses obtained from the Anatidae family (ducks) was conducted. The affinity of all viruses to alpha N-acetylneuraminic acid (Neu5Ac alpha), 3'sialyllactose (3'SL), and sialylglycopolymers bearing 3'-sialyl(N-acetyllactosamine) (3'SLN-PAA), [Neu5Ac alpha(2-3)Gal beta(1-4)][-Fuc alpha(1-3)]GlcNAc beta (SLe(x)-PAA), and [Neu5Ac alpha(2-3)Gal beta(1-3)][-Fuc alpha(1-4)]GlcNAc beta (SLe(a)-PAA), was determined. The last three polymer glycoconjugates were synthesized for determining the contribution of carbohydrate chains after the galactose link to the binding with the receptor. The difference in affinity between 3'SL and Neu5Ac alpha in all studied H13 viruses is small, which indicates a less significant role of the galactose moiety in the binding to the receptor. The results of virus binding with polymer sialylglycoconjugates indicates that the method of linking, the third monosaccharide moiety, and the presence of an extra fucose substitute in this moiety may influence the binding considerably. For viruses isolated from ducks, the suitable polymer is SLe(a)-PAA (i.e., a 1-3 linkage between galactose and glucosamine is optimal). This finding is in accord with the data that H13 viruses isolated from the gulls differ based on their ability to interact with polymer sialylglycoconjugates. The affinity to all three polymers is uniform, and the presence of GlcNAc-linked fucose does not prevent the binding. A comparative analysis of six sequenced HA H13 viruses and other subtype viruses showed presence of substantial differences in the composition of amino acids of this region in H13 viruses.


A Prospective cohort study of zoonotic cutaneous leishmaniasis in tunisia: Clinical and Immunological features and immune correlates of protection.
This study aimed to define immunological markers of exposure to L. major parasites and identify correlates of protection against infection. We analyzed a cohort of 790 individuals at risk of developing ZCL living in endemic areas with varying L. major infection prevalence. One area had a high infection prevalence indicated by high proportions of leishmanin skin test (LST) positive subjects, while the other areas were recent foci with lower infection prevalence. Blood samples were collected before the transmission season to measure Interferon gamma (IFN-γ), Interleukin 10 (IL-10), and Granzyme B (GrB) levels in response to parasite stimulation in peripheral blood mononuclear cells. A one-year follow-up period involved active detection of new ZCL cases to estimate disease incidence after a transmission season and identify immune correlates of protection. The study population showed heterogeneity in parasite contact, evident from specific scars and/or positive LST results, significantly higher in the old focus compared to recent foci. IFN-γ and GrB were markers of parasite exposure and reliable indicators of immunity to L. major. Positive correlations were observed between IFN-γ/IL-10 and GrB/IL-10 ratios and LST results. Unexpectedly, only 29 new ZCL cases (4%) appeared after a transmission season, with 27 cases reported in recent foci and 2 in the oldest focus. Our findings indicate that individuals in L. major endemic areas are likely to develop ZCL regardless of their LST status. We showed that high pre-transmission season levels of IFN-γ and GrB produced by PBMC, along with a high IFN-γ/IL-10 ratio, were associated with protection. This study on a large cohort at risk of ZCL confirmed IFN-γ and GrB as protective factors against the disease. A high IFN-γ/IL-10 ratio, but not GrB/IL-10 ratio was associated with resistance. These results are valuable for developing and evaluating of a vaccine against human leishmaniasis.


High incidence of human herpes virus 6-associated encephalitis/myelitis following a second unrelated cord blood transplantation.
Human herpes virus (HHV)6-associated limbic encephalitis and/or myelitis is one of the life-threatening central nervous system complications following allogeneic hematopoietic stem cell transplantation (HSCT). Recent reports have shown significant correlations of these complications with unrelated cord blood transplantation (UCBT). We retrospectively analyzed 228 allogeneic HSCT recipients in our single institution; 13 patients (5.7%) were diagnosed with HHV6-associated encephalitis/myelitis. This complication was documented in 8 of 51 UCBT recipients (15.7%) and 5 of 177 recipients (2.8%) transplanted with bone marrow or peripheral blood stem cells, indicating a higher incidence of this complication occurring in UCBT recipients (P = .0005). In addition, HHV6-associated encephalitis/myelitis occurred more frequently in recipients who underwent 2 or more HSCTs (7 of 59 recipients [11.9%]), compared to those who received only 1 HSCT (6 of 169 recipients [3.6%], P = .018). Of note, the incidence of this complication increased to 28.6% (6 of 21 recipients), when the analysis was restricted to a second or more UCBT recipients. All 13 patients presented preengraftment immune response prior to the onset of encephalitis. Two patients manifested typical symptoms at the onset of HHV6-associated encephalitis/myelitis, such as memory dysfunction, disorientation, and consciousness disturbance. However, 4 patients presented only with dysesthesia and pruritus, described as typical manifestations of patients with calcineurin-inhibitor-induced pain syndrome (CIPS), and the remaining 7 showed both symptoms, indicating that CIPS-like symptoms might be manifestations of HHV6-associated myelitis. Thus, physicians should be alert to this rare but often fatal complication, particularly for those who receive 2 or more HSCTs using UCB.


International guidelines for bioequivalence of systemically available orally administered generic drug products: a survey of similarities and differences.
The objective of this article is to discuss the similarities and differences among bioequivalence approaches used by international regulatory authorities when reviewing applications for marketing new generic drug products which are systemically active and intended for oral administration. We focused on the 13 jurisdictions and organizations participating in the International Generic Drug Regulators Pilot. These are Australia, Brazil, Canada, China, Chinese Taipei, the European Medicines Association, Japan, Mexico, Singapore, South Korea, Switzerland, the USA, and the World Health Organization. We began with a comparison of how the various jurisdictions and organizations define a generic product and its corresponding reference product. We then compared the following bioequivalence approaches: recommended bioequivalence study designs, method of pharmacokinetic calculations and bioequivalence acceptance limits, recommendations for modifying bioequivalence study designs and limits for highly variable drugs and narrow therapeutic index drugs, provisions for waiving bioequivalence study requirements (granting biowaivers), and implementation of the Biopharmaceutics Classification System. We observed that, overall, there are more similarities than differences in bioequivalence approaches among the regulatory authorities surveyed.


Environmental assessment and cost estimation of drinking water and wastewater systems for transition areas in Sweden.
In the Stockholm region there are around 90,000 households with single systems. These households cause larger phosphorus flows to the Baltic Sea than the 1.8 million people connected to four advanced large-scale treatment plants in the same region. According to city plans, some of these areas with on-site systems in transition to permanent living shall be connected to central systems. The problem is however that this sewer system will take decades to complete. It is also not ensured whether or not all peripheral areas with on-site systems could be connected to the central systems. To help support environmental decisions for the selection of wastewater systems for these areas, an Excel-based model has been developed where the cost for the systems can be assessed and evaluated in relation to their environmental impact. The model deals with two types of environmental issues: substance flow analysis and energy analysis. The cost part considers investigations, investments, design, operation, maintenance and supervision, and calculates total annual cost for the water and wastewater system per person.


Primary care experiences in 25 years of Journal Ciência & Saúde Coletiva: a review of the scientific literature.
The term "basic care" is restricted to a few countries like Brazil. Since the 1978 Alma-Ata Conference, "primary health care" (PHC) has been used to designate care at the first level. The paper summarizes the experiences of evaluation in primary health care, based on the review of the set of manuscripts published by Journal Ciência & Saúde Coletiva. A bibliographic search was made in the SciELO database in the 1996-2020 period. Several descriptors were selected in the spectrum of evaluation and basic care/primary care. The reviewed studies suggest the existence of two analytical periods over the 25 years of the Journal. The first, characterized by the 1996-2010 studies, had the studies of structure/process/results by Donabedian as its predominant theory. The second, from 2011-2020, was Billings' theories on Ambulatory Care Sensitive Conditions (ACSC) and Starfield's PHC attributes. The main dimensions presented in the studies refer to evaluations with a quantitative approach and are induced by the policies and public consultations of the Ministry of Health, and instruments referenced by it.


[Non-neoplastic enlargement of salivary glands: clinico-histologic analysis].
We carried out a retrospective study on non-neoplastic enlargement of the salivary glands at the Oral Histopathology Diagnostic Center of the Autonomous Metropolitan University at Xochimilco (UAM-Xochimilco) in Mexico during a period of 24 years (1979-2003). From 5,625 biopsies received and analyzed, a total of 461 (8.2%) were non-neoplastic enlargement of the salivary glands; for each case, we registered demographic data as well as clinic characteristics. These lesions were characterized as a heterogeneous group of pathologic entities among which we included local, obstructive, infectious, and immunopathologic lesions. The most frequent lesion was the extravasation cyst in 341 (74%) cases, followed by chronic sialoadenitis and Sjögren's syndrome with 54 (11.7%) and 41 (8.8%) cases, respectively, and at a lesser percentage mucous retention cyst, sialosis, benign lymphoepithelial lesions and those related with sialolytes. Females were affected more frequently; mean age was second to third life decades. These lesions were most frequently localized on inferior labial mucosa.


Gene Expression Signature in Adipose Tissue of Acromegaly Patients.
To study the effect of chronic excess growth hormone on adipose tissue, we performed RNA sequencing in adipose tissue biopsies from patients with acromegaly (n = 7) or non-functioning pituitary adenomas (n = 11). The patients underwent clinical and metabolic profiling including assessment of HOMA-IR. Explants of adipose tissue were assayed ex vivo for lipolysis and ceramide levels. Patients with acromegaly had higher glucose, higher insulin levels and higher HOMA-IR score. We observed several previously reported transcriptional changes (IGF1, IGFBP3, CISH, SOCS2) that are known to be induced by GH/IGF-1 in liver but are also induced in adipose tissue. We also identified several novel transcriptional changes, some of which may be important for GH/IGF responses (PTPN3 and PTPN4) and the effects of acromegaly on growth and proliferation. Several differentially expressed transcripts may be important in GH/IGF-1-induced metabolic changes. Specifically, induction of LPL, ABHD5, and NRIP1 can contribute to enhanced lipolysis and may explain the elevated adipose tissue lipolysis in acromegalic patients. Higher expression of TCF7L2 and the fatty acid desaturases FADS1, FADS2 and SCD could contribute to insulin resistance. Ceramides were not different between the two groups. In summary, we have identified the acromegaly gene expression signature in human adipose tissue. The significance of altered expression of specific transcripts will enhance our understanding of the metabolic and proliferative changes associated with acromegaly.


Robotic single-site plus ONE port distal pancreatectomy.
Laparoscopic distal pancreatectomy is regarded as safe and effective surgical approach in benign and low-grade malignant tumor of the pancreas. With the advances of laparoscopic techniques and instruments, many efforts to reduce the number of the trocar site has been made. There are a few available surgical techniques of laparoscopic single-site (single port or reduced port) distal pancreatectomy, suggesting its safety and feasibility. However, it is true that laparoscopic single-site distal pancreatectomy is difficult and technically quite demanding. Robotic surgical system was introduced to overcome the limitation of conventional laparoscopic surgery. Recently, we experienced robotic single-site plus ONE port distal pancreatectomy in benign and low-grade malignant tumor of the pancreas. A 45-year-old male patient was incidentally found to have pancreatic mass in tail of the pancreas. October 6th 2015, robotic distal pancreatectomy was performed using the Da Vinci single-site surgical platform (DVSSP) with one additional port. Additional robotic 12-mm-port was placed left side of DVSSP, and robotic 3rd arm was used through this site. Usual robotic instruments such as hook, bipolar, vessel sealer, and endo-GIA with endo-wrist function could be used to facilitate effective surgical procedure. The general operation procedure was based on modified Lasso technique (isolation and ligation of splenic artery prior to Lasso technique). Resected specimen was delivered through umbilicus and drains were inserted through additional port site. Five consecutive clinical experiences were reviewed. This study was approved by institutional review board. Two patients were male and three were female with median age, 38 years (range 21-56). The distribution of the pathological diagnosis was 2 solid pseudopapillary tumors, 1 serous cystic neoplasm, 1 chronic pancreatitis, and 1 neuroendocrine tumor. Median operation time was 165 min (range 120-270 min), and intraoperative-estimated blood loss were median 5 ml (range 0-50 ml). One patient could preserve spleen by Warshaw procedure. One patient converted to conventional multi-port robotic distal pancreatectomy due to inter-arms collisions. There was no clinically relevant postoperative pancreatic fistula. Length of hospital stay was median 6 days after surgery (range 5-8 days). Robotic single-site plus ONE port distal pancreatectomy is safe and feasible with acceptable perioperative outcomes. Although, certain patients such as those with a hard pancreas need an amount of care due to the features of robotic GIA, currently available robotic single-site plus ONE port surgical system was thought to have potential role to make laparoscopic single-site distal pancreatectomy much easier and ergonomics, providing some room to expand more minimally invasive surgery. Further experiences are mandatory.


Bovine seminal ribonuclease is cytotoxic for both malignant and normal telomerase-positive cells.
Bovine seminal-ribonuclease (BS-RNase) is a member of the 'ribonucleases with special biological actions' family since it possesses specific anti-tumour, anti-spermatogenic and embryotoxic activities and exerts an immunosuppressive effect on T lymphocytes. In previous studies it was demonstrated that BS-RNase induced apoptosis in proliferating, malignant and normal cells and that telomerase activity loss also caused apoptotic death in neoplastic cells. Since an obvious relationship between cell proliferation and telomerase activity exists, the aim of this work was to study if the pro-apoptotic cytotoxic action exerted by BS-RNase on proliferating malignant cells (HT29) and proliferating normal cells (PHA-stimulated lymphocytes) could be linked to a possible BS-RNase effect on telomerase activity. In BS-RNase-treated HT29 cells (Na-butyrate-differentiated or not) and human lymphocytes (proliferating or not), we investigated cell vitality (MTT method) and morphology (SEM), BS-RNase localization (immunofluorescence), telomerase activity (TRAP-ELISA method), hTR mRNA expression (RT-PCR), and hTERT levels (western blot). While no BS-RNase effect was detectable on not proliferating cells, a clear relationship was noticed between the diminished number of vital elements of both proliferating cell populations after treatment (48 h and 72 h for HT29 and PHA-stimulated lymphocytes, respectively) with 50 microg/ml BS-RNase and the decrease of their telomerase activity. At the same time, we found that hTR levels, the RNA subunit of telomerase, in proliferation-inhibited BS-RNase-treated cells were diminished. Moreover, by immunofluorescence technique, we detected BS-RNase in the HT29 cell nucleolus after 3-h treatment. Therefore, as hTR has been recently proven to co-fractionate with nucleoli, we hypothesize that a BS-RNase direct action on the telomerase hTR subunit could be a possible mechanism of action by which BS-RNase exerts its pro-apoptotic effects only on proliferating cells.


Lebectin and lebecetin, two C-type lectins from snake venom, inhibit alpha5beta1 and alphaV-containing integrins.
Integrins are essential protagonists in the complex multistep process of cancer progression and metastasis. We recently reported that lebectin, a novel C-type lectin from Macrovipera lebetina venom, displays an anti-integrin activity. In this study, we extend this observation to lebecetin, a second C-type lectin isolated from the same venom and previously reported as a potent inhibitor of platelet aggregation. Both venom lectins appear to exert their effect on cell adhesion, migration, invasion and proliferation by inhibiting alpha5beta1 and alphav-containing integrins. Moreover, the inhibition of alpha5beta1 and alphav integrins is likely due to the binding of venom peptides, as both lebectin and lebecetin co-immunoprecipitate with these integrins. Lebectin and lebecetin are thus the first examples of venom C-type lectins inhibiting an integrin other than the collagen receptor alpha2beta1.


Evolutionary history of endemic Sulawesi squirrels constructed from UCEs and mitogenomes sequenced from museum specimens.
The Indonesian island of Sulawesi has a complex geological history. It is composed of several landmasses that have arrived at a near modern configuration only in the past few million years. It is the largest island in the biodiversity hotspot of Wallacea-an area demarcated by the biogeographic breaks between Wallace's and Lydekker's lines. The mammal fauna of Sulawesi is transitional between Asian and Australian faunas. Sulawesi's three genera of squirrels, all endemic (subfamily Nannosciurinae: Hyosciurus, Rubrisciurus and Prosciurillus), are of Asian origin and have evolved a variety of phenotypes that allow a range of ecological niche specializations. Here we present a molecular phylogeny of this radiation using data from museum specimens. High throughput sequencing technology was used to generate whole mitochondrial genomes and a panel of nuclear ultraconserved elements providing a large genome-wide dataset for inferring phylogenetic relationships. Our analysis confirmed monophyly of the Sulawesi taxa with deep divergences between the three endemic genera, which predate the amalgamation of the current island of Sulawesi. This suggests lineages may have evolved in allopatry after crossing Wallace's line. Nuclear and mitochondrial analyses were largely congruent and well supported, except for the placement of Prosciurillus murinus. Mitochondrial analysis revealed paraphyly for Prosciurillus, with P. murinus between or outside of Hyosciurus and Rubrisciurus, separate from other species of Prosciurillus. A deep but monophyletic history for the four included species of Prosciurillus was recovered with the nuclear data. The divergence of the Sulawesi squirrels from their closest relatives dated to ~9.7-12.5 million years ago (MYA), pushing back the age estimate of this ancient adaptive radiation prior to the formation of the current conformation of Sulawesi. Generic level diversification took place around 9.7 MYA, opening the possibility that the genera represent allopatric lineages that evolved in isolation in an ancient proto-Sulawesian archipelago. We propose that incongruence between phylogenies based on nuclear and mitochondrial sequences may have resulted from biogeographic discordance, when two allopatric lineages come into secondary contact, with complete replacement of the mitochondria in one species.


Follicular thyroid cancer.
Follicular thyroid cancer is the second most common thyroid malignancy after PTC. There are marked geographical variations in the relative proportions of FTC and PTC, most likely related to dietary iodine content. In iodine-deficient areas, the relative rate of FTC tends to be increased. Other risk factors for FTC include age over 50 years and female sex. Genetic factors may also have a role in determining disease susceptibility but remain ill-defined. Histologically, FTC is characterized by follicle formation and the absence of any papillary elements in the tumor. Differential diagnosis from a benign adenoma can be difficult. The degree of vascular invasiveness seems to correlate with tumor aggressiveness, and two histologic subtypes, oxyphilic FTC and insular FTC, may be associated with increased morbidity and mortality. Primary treatment for FTC is complete surgical tumor removal. Extensive bilateral surgery beyond this goal may not confer additional benefit but can facilitate adjuvant treatment and follow-up. Postoperative levothyroxine treatment is almost universally used, and patients deemed at high risk of recurrence may benefit from radioiodine remnant ablation. Treatment of metastatic disease involves operation, radioiodine, and, in selected cases, external beam radiation and chemotherapy. Prognosis for patients with metastatic disease is guarded, but most other patients have good outcomes comparable to that in PTC. For nonoxyphilic FTC, high-risk features other than initial metastases include advanced age, locally extensive disease, and the presence of marked angioinvasion. In oxyphilic FTC, DNA aneuploidy is also important. Follow-up should be most intense during the first 5 years after primary treatment and needs to be tailored to the patient's risk of disease progression. For patients at low risk of recurrence (young, small lesions, minimally invasive tumor), serum thyroglobulin measurements may largely suffice, whereas higher risk patients with elevated serum thyroglobulin levels and patients with significant titers of interfering anti-thyroglobulin autoantibodies may also need to undergo periodic diagnostic radioiodine scanning.


[Proprotein convertase subtilisin/kexin type 9 (PCSK9) and inhibitors].
Hypercholesterolemia is a major risk factor for atherosclerosis. Low-density lipoprotein cholesterol (LDL-C) lowering drugs reduce cardiovascular morbidity and mortality. However, many individuals treated with statins do not achieve their target levels of LDL-C. So, there is great need for new drugs to reduce cholesterol in those patients who have not achieved target levels with statins as well as those who are statin intolerant. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a novel agent, which plays an important role in the regulation of cholesterol metabolism. It increases degradation of the low-density lipoprotein receptor, modulates cholesterol metabolism, and transport. This review will address new therapeutic strategies targeting PCSK9, including monoclonal antibodies, small interfering RNAs, and other small molecule inhibitors.


Length polymorphisms in human proline-rich protein genes generated by intragenic unequal crossing over.
Southern blot hybridization analysis of genomic DNAs from 44 unrelated individuals revealed extensive insertion/deletion polymorphisms within the BstNI-type loci (PRB1, PRB2, PRB3 and PRB4) of the human proline-rich protein (PRP) multigene family. Ten length variants were cloned, including alleles at each of the four PRB loci, and in every case the region of length difference was localized to the tandemly repetitious third exon. DNA sequences covering the region of length variation were determined for seven of the alleles. The data indicate (1) that the PRB loci can be divided into two subtypes, PRB1 plus PRB2, and PRB3 plus PRB4, and (2) that the length differences result from different numbers of tandem repeats in the third exons. Variant chromosomes were also identified with different numbers of PRP loci resulting from homologous but unequal exchange between the PRB1 and PRB2 loci. The overall data are compatible with the observed length variants having been generated via homologous but unequal intragenic exchange. The results also indicate that these crossover events are sensitive to the amount of homology shared between the interacting DNA strands. Allelic length variants have arisen independently at least 20 times at the PRB loci, but only one has been detected at a PRH locus. Comparison of the detailed structures of the repetitious regions in PRB and PRH loci shows that the repeats in PRB genes are very similar to each other in sequence and in length. The PRH genes contain fewer repeats, which differ considerably in their individual lengths. These differences suggest that the larger number of length variants in PRB genes is related to their greater ease of homologous but unequal pairing compared to PRH genes.


Streamlining gene expression analysis: integration of co-culture and mRNA purification.
Co-culture of multiple cell types within a single device enables the study of paracrine signaling events. However, extracting gene expression endpoints from co-culture experiments is laborious, due in part to pre-PCR processing of the sample (i.e., post-culture cell sorting and nucleic acid purification). Also, a significant loss of nucleic acid may occur during these steps, especially with microfluidic cell culture where lysate volumes are small and difficult to access. Here, we describe an integrated platform for performing microfluidic cell culture and extraction of mRNA for gene expression analysis. This platform was able to recover 30-fold more mRNA than a similar, non-integrated system. Additionally, using a breast cancer/bone marrow stroma co-culture, we recapitulated stromal-dependent, estrogen-independent growth of the breast cancer cells, coincident with transcriptional changes. We anticipate that this platform will be used for streamlined analysis of paracrine signaling events as well as for screening potential drugs and/or patient samples.


Ultraviolet-induced paramagnetic centers and absorption changes in singlemode Ge-doped optical fibers.
We investigated the laser-energy-density dependence of absorption changes and paramagnetic centers induced by a cw Ar(+)laser operating at 5.1 eV, in both unloaded and H(2)-loaded singlemode Ge-doped optical fibers. The induced absorption is measured in the blue and near ultraviolet spectral range by using the 3.1 eV photoluminescence, ascribed to Ge lone pair center (GLPC), as an in situ probe source. We find that the Ge(1) center (GeO-(4) ) is induced upon UV exposure by electron trapping on GeO(4) precursors, where the free electrons are most likely produced by ionization of GLPC. Ge(1) is responsible of optical transmission loss of the fiber in the investigated range. Hydrogen loading strongly influences the generation efficiency of the several observed paramagnetic defects, leading in particular to passivation of radiation-induced Ge(2) centers.


A new look at the 5alpha-reductase inhibitor finasteride.
Finasteride is the first 5alpha-reductase inhibitor that received clinical approval for the treatment of human benign prostatic hyperplasia (BPH) and androgenetic alopecia (male pattern hair loss). These clinical applications are based on the ability of finasteride to inhibit the Type II isoform of the 5alpha-reductase enzyme, which is the predominant form in human prostate and hair follicles, and the concomitant reduction of testosterone to dihydrotestosterone (DHT). In addition to catalyzing the rate-limiting step in the reduction of testosterone, both isoforms of the 5alpha-reductase enzyme are responsible for the reduction of progesterone and deoxycorticosterone to dihydroprogesterone (DHP) and dihydrodeoxycorticosterone (DHDOC), respectively. Recent preclinical data indicate that the subsequent 3alpha-reduction of DHT, DHP and DHDOC produces steroid metabolites with rapid non-genomic effects on brain function and behavior, primarily via an enhancement of gamma-aminobutyric acid (GABA)ergic inhibitory neurotransmission. Consistent with their ability to enhance the action of GABA at GABA(A) receptors, these steroid derivatives (termed neuroactive steroids) possess anticonvulsant, antidepressant and anxiolytic effects in addition to altering aspects of sexual- and alcohol-related behaviors. Thus, finasteride, which inhibits both isoforms of 5alpha-reductase in rodents, has been used as a tool to manipulate neuroactive steroid levels and determine the impact on behavior. Results of some preclinical studies and clinical observations with finasteride are described in this review article. The data suggest that endogenous neuroactive steroid levels may be inversely related to symptoms of premenstrual and postpartum dysphoric disorder, catamenial epilepsy, depression, and alcohol withdrawal.


Drug-induced hypertension: an unappreciated cause of secondary hypertension.
A myriad variety of therapeutic agents or chemical substances can induce either a transient or persistent increase in blood pressure, or interfere with the blood pressure-lowering effects of antihypertensive drugs. Some agents cause either sodium retention or extracellular volume expansion, or activate directly or indirectly the sympathetic nervous system. Other substances act directly on arteriolar smooth muscle or do not have a defined mechanism of action. Some medications that usually lower blood pressure may paradoxically increase blood pressure, or an increase in pressure may be encountered after their discontinuation. In general, drug-induced pressure increases are small and transient: however, severe hypertension involving encephalopathy, stroke, and irreversible renal failure have been reported. The deleterious effect of therapeutic agents is more pronounced in patients with preexisting hypertension, in those with renal failure, and in the elderly. Careful evaluation of a patient's drug regimen may identify chemically induced hypertension and obviate unnecessary evaluation and facilitate antihypertensive therapy. Once chemical-induced hypertension has been identified, discontinuation of the causative agent is recommended, although hypertension can often be managed by specific therapy and dose adjustment if continued use of the offending agent is mandatory. The present review summarizes the therapeutic agents or chemical substances that elevate blood pressure and their mechanisms of action.


Diagnostic accuracy of a pH stick, modified to detect gastric lipase, to confirm the correct placement of nasogastric tubes.
The correct placement of a nasogastric feeding tube is usually confirmed by establishing that an aspirate is acidic using a pH stick. However, antacid medication and achlorhydria can cause false negative pH tests that may delay feeding and increase resource use. The purpose of this study was to evaluate a modified pH stick designed to detect gastric lipase and therefore reduce false negative tests. In this prospective observational study, a convenience sample of adult patients who had either gastric and oesophageal samples taken during routine diagnostic gastroscopy (n=97) or bronchial and saliva samples taken during a bronchoscopy (n=106). The samples were tested by blinded observers using the modified and standard pH sticks. The sensitivities and specificities of the two pH sticks in identifying gastric and non-gastric aspirates were compared using the pH cut-off ≤5.5. The sensitivities of a pH≤5.5 to correctly identify gastric samples were 66% (95% CI 56 to 75) and 68% (95% CI 57 to 77) for the modified and the standard pH, respectively. The specificities were 81% (95% CI 76 to 85) and 79% (95% CI 74 to 84). There were no significant differences in the distribution of the discordant results between the paired gastric and non-gastric samples for both the modified and standard pH sticks at pH≤5.5 (both McNemar's tests, p≥0.05). There were no significant differences between the paired modified and standard pH tests for the gastric samples. Due to the limited accuracy of pH sticks, further research is required to identify accurate and cost-effective bedside methods to confirm the correct placement of nasogastric tubes.


Scientific Findings of the Southern and Central Africa International Center of Excellence for Malaria Research: Ten Years of Malaria Control Impact Assessments in Hypo-, Meso-, and Holoendemic Transmission Zones in Zambia and Zimbabwe.
For a decade, the Southern and Central Africa International Center of Excellence for Malaria Research has operated with local partners across study sites in Zambia and Zimbabwe that range from hypo- to holoendemic and vary ecologically and entomologically. The burden of malaria and the impact of control measures were assessed in longitudinal cohorts, cross-sectional surveys, passive and reactive case detection, and other observational designs that incorporated multidisciplinary scientific approaches: classical epidemiology, geospatial science, serosurveillance, parasite and mosquito genetics, and vector bionomics. Findings to date have helped elaborate the patterns and possible causes of sustained low-to-moderate transmission in southern Zambia and eastern Zimbabwe and recalcitrant high transmission and fatality in northern Zambia. Cryptic and novel mosquito vectors, asymptomatic parasite reservoirs in older children, residual parasitemia and gametocytemia after treatment, indoor residual spraying timed dyssynchronously to vector abundance, and stockouts of essential malaria commodities, all in the context of intractable rural poverty, appear to explain the persistent malaria burden despite current interventions. Ongoing studies of high-resolution transmission chains, parasite population structures, long-term malaria periodicity, and molecular entomology are further helping to lay new avenues for malaria control in southern and central Africa and similar settings.


Proprioception in the posterior cruciate ligament deficient knee.
This study was undertaken to evaluate knee proprioception in patients with isolated unilateral posterior cruciate ligament (PCL) injuries. Eighteen subjects with isolated PCL tears were studied 1-234 months after injury. The threshold to detect passive motion (TTDPM) was used to evaluate kinesthesia and the ability to passively reproduce passive positioning (RPP) to test joint position sense. Two starting positions were tested in all knees: 45 degrees (middle range) and 110 degrees (end range) to evaluate knee proprioception when the PCL is under different amounts of tension. TTDPM and RPP were tested as the knee moved into flexion and extension from both starting positions. A statistically significant reduction in TTDPM was identified in PCL-injured knees tested from the 45 degrees starting position, moving into flexion and extension. RPP was statistically better in the PCL-deficient knee as tested from 110 degrees moving into flexion and extension. No difference was identified in the TTDPM starting at 110 degrees or in RPP with the presented angle at 45 degrees moving into flexion or extension. These subtle but statistically significant findings suggest that proprioceptive mechanoreceptors may play a clinical role in PCL-intact and PCL-deficient patients. Further, it appears that kinesthesia and joint position sense may function through different mechanisms.


Nutrition intervention for high-risk auto workers: results of the Next Step Trial.
The Next Step Trial tested interventions encouraging prevention and early detection practices in automotive-industry employees at increased colorectal cancer risk. This article describes results of the nutrition intervention promoting low-fat, high-fiber eating patterns. Twenty-eight worksites (5,042 employees at baseline) were randomized to a 2-year nutrition intervention including classes, mailed self-help materials, and personalized dietary feedback. Control worksites received no intervention. Nutrition outcomes were assessed by mailed food frequency questionnaires (FFQs) Primary nutrition outcomes included percentage energy from fat and fiber density (g/1,000 kcal) at 1 year postrandomization. Secondary outcomes included servings of fruits/vegetables and dietary measures at 2 years postrandomization. Analyses were adjusted for within worksite correlations and baseline covariates. Fifty-eight percent of employees returned FFQs. At 1 year, there were modest but statistically significant intervention effects for fat (-0.9 %en), fiber (+0.5 g/1,000 kcal), and fruits/vegetables (+0.2 servings/day) (all P < 0.007). At 2 years, due to significant positive changes in control worksites, intervention effects were smaller, significant for fiber only. Intervention effects were larger in younger (<50 years), active employees and class attendees. The nutrition intervention produced significant but modest effects on dietary fat and fiber and fruits/vegetables in these high-risk employees. Age and dose effects suggest younger employees may be more responsive to this intervention.


History and therapeutic rationale of long acting antipsychotics.
Despite their widespread use, long acting antipsychotics, are often regarded with prejudice, due to fears of punishment, control and insufficient evolution towards psychosocial development of psychotic patients raised by their improper utilization. Another major shortcoming of long-acting antipsychotics is the impossibility of altering their dosage if side-effects appear. However, long-acting antipsychotics proved effective in schizophrenia and other severe psychotic disorders as a consequence of stable dose administration, leading to reduction of relapses and increased treatment adherence. Therapeutic opportunities have also risen after introduction of newer long acting second generation antipsychotics in recent years. Newer long-acting antipsychotics were developed to tackle the need for pharmacotherapy enhancing adherence in integrated rehabilitation programmes. This review is an outline of the development and introduction of older and newer long-acting antipsychotics in the treatment of schizophrenia and other psychoses, with considerations on past and present pharmacological and therapeutic issues.


Animal intelligence as encephalization.
There is no consensus on the nature of animal intelligence despite a century of research, though recent work on cognitive capacities of dolphins and great apes seems to be on one right track. The most precise quantitative analyses have been of relative brain size, or structural encephalization, undertaken to find biological correlates of mind in animals. Encephalization and its evolution are remarkably orderly, and if the idea of intelligence were unknown it would have to be invented to explain encephalization. The scientific question is: what behaviour or dimensions of behaviour evolved when encephalization evolved? The answer: the relatively unusual behaviours that require increased neural information processing capacity, beyond that attributable to differences among species in body size. In this perspective, the different behaviours that depend on augmented processing capacity in different species are evidence of different intelligences (in the plural) that have evolved.


Ionic liquid near a charged wall: structure and capacitance of electrical double layer.
We study the effects of ion size asymmetry and short-range correlations on the electrical double layer in ionic liquids: we perform molecular dynamics simulations of a model ionic liquid between two "electrodes" and calculate the differential capacitance of each as a function of the electrode potential. The capacitance curve has an asymmetric "bell-shape" character, in qualitative agreement with recent experiments and the mean- field theory (MFT) which takes into account the limitation on the maximal local density of ions. The short-range ionic correlations, not included in the MFT, lead to an overscreening effect which changes radically the structure of the double layer at small and moderate charging. With the radius of cations taken to be twice as large as anions, the position of the main capacitance maximum is shifted positively from the potential of zero charge (PZC), as predicted by MFT. An extension of the theory (EMFT), however, reproduces the simulated capacitance curve almost quantitatively. Capacitance curves for real ionic liquids will be affected by nonspherical shape of ions and sophisticated pair potentials, varying from liquid to liquid. But understanding the capacitance behavior of such model system is a basis for rationalizing those more specific features.


Organ/Tissue-Specific Vascular Endothelial Cell Heterogeneity in Health and Disease.
The vascular system forms the largest surface in our body, serving as a critical interface between blood circulation and our diverse organ/tissue environments. Thus, the vascular system performs a gatekeeper function for organ/tissue homeostasis and the body's adjustment to pathological challenges. The endothelium, as the most inner layer of the vasculature, regulates the tissue microenvironment, which is critical for development, hemostatic balance, inflammation, and angiogenesis, with a role as well in tumor malignancy and metastasis. These multitudinous functions are primarily mediated by organ/tissue-specifically differentiated endothelial cells, in which heterogeneity has long been recognized at the molecular and histological level. Based on these general principles of vascular-bed heterogeneity and characterization, this review largely covers landmark discoveries regarding organ/tissue microenvironment-governed endothelial cell phenotypic changes. These involve the physical features of continuous, discontinuous, fenestrated, and sinusoidal endothelial cells, in addition to the more specialized endothelial cell layers of the lymphatic system, glomerulus, tumors, and the blood brain barrier (BBB). Major signal pathways of endothelial specification are outlined, including Notch as a key factor of tip/stalk- and arterial-endothelial cell differentiation. We also denote the shear stress sensing machinery used to convey blood flow-mediated biophysical forces that are indispensable to maintaining inert and mature endothelial phenotypes. Since our circulatory system is among the most fundamental and emergent targets of study in pharmacology from the viewpoint of drug metabolism and delivery, a better molecular understanding of organ vasculature-bed heterogeneity may lead to better strategies for novel vascular-targeted treatments to fight against hitherto intractable diseases.


[Attention and neglect: neurological basis, assessment and disorders].
Attention phenomenology is a wide subject, in this revision we will explain attention and its relationship with behavioral neglect. Selective attention is the ability to throw the focus of awareness toward behaviorally relevant events in the personal and extrapersonal space. Severe alteration of these mechanisms constitutes unilateral neglect in patients with contralateral brain damage. Unilateral neglect is one of the most behaviorally devastating syndrome. There are different behavioral neglect: attentional (perceptual), intentional (motor), motivational and representational aspects of unilateral neglect. Left side neglect after right hemisphere lesions is more common (31 to 46%) than right sided neglect following lesions in the left hemisphere (2 to 12%). One year after a cerebrovascular accident only 1/3 of the patients with unilateral neglect persist with this handicap.


An observational study of physical activity in parks in Asian and Pacific Islander communities in urban Honolulu, Hawaii, 2009.
Research on park use among Asians and Pacific Islanders is limited. This study examined use and conditions of 6 urban parks, varying in size, location, and neighborhood income level, in predominantly Asian and Pacific Islander communities in Honolulu, Hawaii. Sociodemographic predictors of park use were also identified. Observations were conducted from June through October 2009. Raters used the System for Observing Play and Recreation in Communities to count the number of people in predesignated zones and to code their physical activity level as sedentary, moderate, or vigorous. Raters coded park conditions on the basis of accessibility and usability, whether equipment and supervision were provided, and whether organized activities were occurring. Differences associated with sex and age of park users and income level of the neighborhood were examined by using χ² and logistic regression. Raters observed 6,477 park users, most of whom were men. Approximately 60% of users were sedentary, 26% were engaged in moderate activities, and 14% performed vigorous activities. Women and girls were less active than men and boys. More users were present in the evenings, but morning users were more active. Although park users in low-income neighborhoods were more active than users in high-income neighborhoods, fewer people used the low-income parks. Most parks were accessible and usable but few provided equipment and supervision. Organized activities were rarely observed. More efforts should be made to promote parks as a physical activity resource in Asian and Pacific Islander communities, particularly for women, girls, and low-income residents. More research should be conducted to identify barriers and facilitators to park use, especially among underrepresented populations.


[Alcohol consumption in pupils of Compulsory Secondary Education].
The consumption of addictive substances by adolescents is a growing problem with a considerable social and health impact, with alcohol being the drug of greatest consumption. The aim of this paper is to analyse the consumption of alcohol in pupils attending Compulsory Secondary Education in our health care milieu in order to understand the dimension of the problem in our context. Randomized distribution, stratified by school year, of a semi-quantitative questionnaire on the frequency of consumption of alcoholic drinks. Distributed to 406 pupils in Compulsory Secondary Education: 194 males and 212 females, with ages between 13 and 16 years. Alcohol consumption increased with school year (p<0.05), with differences existing between the two sexes. From figures for consumption in the 1st year of Compulsory Secondary Education of 27.8% in males and 11.4% in females (p<0.05), figures were reached in the 4th school year of 81.5% in males and 54.7% in females (p<0.05). The regular consumption of alcohol (at least once a week) in males rose from 8.4% (1st school year) to 53.7% (4th school year); and in females from 5.8% (1st school year) to 24.6% (4th school year). In the 4th year of Compulsory Secondary Education, amongst the males who consumed alcohol, 18.2% did so on a daily basis, 47.7% at the weekend, and the remaining 34.1% occasionally; and amongst the females, 6.9% did so on a daily basis, 37.9% at the weekend, and the remaining 55.2% occasionally. In the 4th year of Compulsory Secondary Education, the average quantity of alcohol ingested by the males at the weekend was 130.7 grams, and by the females 98.8 grams. In both sexes, the proportional contribution to the total ingestion of alcohol was in the majority of cases by consumption of spirits (46.1% in males and 55.4% in females) and beer (30.9% in males and 31.6% in females). The prevalence of alcohol consumption amongst Secondary School pupils is very high, especially starting in the 3rd year of Compulsory Secondary Education in males and the 4th school year in females. On the completion of studies in Compulsory Secondary Education, there is a generalised consumption of alcohol amongst our adolescents that is mainly circumscribed to the weekend, although there is an important and relevant number of pupils who refer to daily consumption.


[Hypertension as a biological marker of systemic atherosclerotic disease].
There is a close link between hypertension and atherosderosis. Hypertension causes atherosclerotic damage of several organs, called target organs and the risk factors for hypertension and atherosderosis are very similar. The risk of mortality associated to hypertension increases with blood pressure values below the cutoff point of normality (140/90 mm Hg), even below 130/85 mm Hg, and includes a stage called pre hypertension. Moreover, the initial damage of the arterial walls and target organs are present before there is a significant elevation of blood pressure. Therefore, hypertension could become a biological marker of the evolution of an underlying atherosclerotic process. A new pathophysiological paradigm has been proposed in which the severity of hypertension is not classified according to blood pressure values, but rather on the initiation and progression of vascular damage among target organs. These alterations determine the prognosis and management of systemic vascular damage that can be called "hypertensive atherosclerotic disease" or simply systemic atherosclerotic disease.


Energy liberation and chemical change in frog skeletal muscle during single isometric tetanic contractions.
Recent data obtained from Rana temporaria sartorius muscles during an isometric tetanus indicate that the time-course of phosphocreatine (PC) splitting cannot account for the total energy (heat + work) liberation (Gilbert et al. 1971. J. Physiol. (Lond.) 218:)63). As this conclusion is important to an understanding of the chemical energetics of contraction, similar experments were performed on unpoisoned, oxygenated Rana pipiens sartorius muscles. The muscles were tetanized (isometrically) at 0 degrees C for 0.6, 1, or 5 s; metabolism was rapidly arrested by freezing the muscles with a specially designed hammer apparatus, and the frozen muscles were chemically analyzed. Comparable myothermal measurments were made on frogs from the same batch. Results of these experiments indicate: (a) The energy liberation parallels the PC and ATP breakdown with a proportionality constant of 10.7 kcal/mol; (b) comparably designed experiments with sartorius muscles of R. temporaria revealed that the ratio of energy liberation to PC splitting was significantly greater than that observed in R. pipiens sartorius muscles; (c) there is no systematic difference between experiments in which metabolism was arrested by the hammer apparatus and others using a conventional immersion technique.


Getting the timing right: antler growth phenology and sexual selection in a wild red deer population.
There has been growing interest in the determinants of the annual timing of biological phenomena, or phenology, in wild populations, but research on vertebrate taxa has primarily focused on the phenology of reproduction. We present here analyses of the phenology of the annual growth of a secondary sexual characteristic, antlers in red deer (Cervus elaphus) males. The long-term individual-based data from a wild population of red deer on the Isle of Rum, Scotland allow us to consider ecological factors influencing variation in the phenology of growth of antlers, and the implications of variation in antler growth phenology with respect to the phenotype of antler grown (antler mass) and annual breeding success. The phenology of antler growth was influenced by local environmental conditions: higher population density delayed both the start date (during spring) and the relative end date (in late summer) of antler growth, and warmer temperatures in the September and April prior to growth advanced start and end dates, respectively. Furthermore, there was variation between individuals in this phenotypic plasticity of start date, although not in that of end date of growth. The phenology of antler growth impacted on the morphology of antlers grown, with individuals who started and ended growth earliest having the heaviest antlers. The timing of antler growth phenology was associated with breeding success in the following mating season, independently of the mass of antlers grown: an earlier start of antler growth was associated with siring a higher number of the calves born the following spring. Our results suggest that the phenology of traits that are not directly correlated with offspring survival may also regularly show correlations with fitness.


Association of beta-blocker therapy at discharge with clinical outcomes in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention.
This study sought to investigate the association of beta-blocker therapy at discharge with clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI) after primary percutaneous coronary intervention (PCI). Limited data are available on the efficacy of beta-blocker therapy for secondary prevention in STEMI patients. Between November 1, 2005 and September 30, 2010, 20,344 patients were enrolled in nationwide, prospective, multicenter registries. Among these, we studied STEMI patients undergoing primary PCI who were discharged alive (n = 8,510). We classified patients into the beta-blocker group (n = 6,873) and no-beta-blocker group (n = 1,637) according to the use of beta-blockers at discharge. Propensity-score matching analysis was also performed in 1,325 patient triplets. The primary outcome was all-cause death. The median follow-up duration was 367 days (interquartile range: 157 to 440 days). All-cause death occurred in 146 patients (2.1%) of the beta-blocker group versus 59 patients (3.6%) of the no-beta-blocker group (p < 0.001). After 2:1 propensity-score matching, beta-blocker therapy was associated with a lower incidence of all-cause death (2.8% vs. 4.1%, adjusted hazard ratio: 0.46, 95% confidence interval: 0.27 to 0.78, p = 0.004). The association with better outcome of beta-blocker therapy in terms of all-cause death was consistent across various subgroups, including patients with relatively low-risk profiles such as ejection fraction >40% or single-vessel disease. Beta-blocker therapy at discharge was associated with improved survival in STEMI patients treated with primary PCI. Our results support the current American College of Cardiology/American Heart Association guidelines, which recommend long-term beta-blocker therapy in all patients with STEMI regardless of reperfusion therapy or risk profile.


Superinfection exclusion of alphaviruses in three mosquito cell lines persistently infected with Sindbis virus.
Three Aedes albopictus (mosquito) cell lines persistently infected with Sindbis virus excluded the replication of both homologous (various strains of Sindbis) and heterologous (Aura, Semliki Forest, and Ross River) alphaviruses. In contrast, an unrelated flavivirus, yellow fever virus, replicated equally well in uninfected and persistently infected cells of each line. Sindbis virus and Semliki Forest virus are among the most distantly related alphaviruses, and our results thus indicate that mosquito cells persistently infected with Sindbis virus are broadly able to exclude other alphaviruses but that exclusion is restricted to members of the alphavirus genus. Superinfection exclusion occurred to the same extent in three biologically distinct cell clones, indicating that the expression of superinfection exclusion is conserved among A. albopictus cell types. Superinfection of persistently infected C7-10 cells, which show a severe cytopathic effect during primary Sindbis virus infection, by homologous virus does not produce cytopathology, consistent with the idea that cytopathology requires significant levels of viral replication. A possible model for the molecular basis of superinfection exclusion, which suggests a central role for the alphavirus trans-acting protease that processes the nonstructural proteins, is discussed in light of these results.


Par-3-mediated junctional localization of the lipid phosphatase PTEN is required for cell polarity establishment.
PDZ domain-containing scaffold protein Par-3 is the central organizer of the evolutionarily conserved cell polarity-regulatory Par-3.Par-6.atypical protein kinase C complex. The PDZ domains of Par-3 have also been implicated as potential phosphoinositide signaling integrators, since its second PDZ domain binds to phosphoinositides, and the third PDZ interacts with phosphoinositide phosphatase PTEN. However, the molecular basis of Par-3/PTEN interaction is still poorly understood. Additionally, it is not known whether the regulatory function of PTEN in cell polarity is specifically mediated by its interaction with Par-3. The structures of Par-3 PDZ3 in both its free and PTEN tail peptide-bound forms determined in this work reveal that Par-3 PDZ3 binds to PTEN with two discrete binding sites: a canonical PDZ-ligand interaction site and a distal, opposite charge-charge interaction site. This distinct target recognition mechanism confers the interaction specificity of the Par-3.PTEN complex. We show that the Par-3 PDZ3-PTEN binding is required for the enrichment of PTEN at the junctional membranes of Madin-Darby canine kidney cells. Finally, we demonstrate that the junctional membrane-localized PTEN is specifically required for the polarization of Madin-Darby canine kidney cells. These results, together with earlier data, firmly establish that Par-3 functions as a scaffold in integrating phosphoinositide signaling events during cellular polarization.


Mutational analysis of potential zinc-binding residues in the active site of the enterococcal D-Ala-D-Ala dipeptidase VanX.
VanX, one of the five proteins required for the vancomycin-resistant phenotype in clinically pathogenic Enterococci, is a zinc-containing d-Ala-d-Ala dipeptidase. To identify potential zinc ligands and begin defining the active site residues, we have mutated the 2 cysteine, 5 histidine, and 4 of the 28 aspartate and glutamate residues in the 202 residue VanX protein. Of 10 mutations, 3 cause inactivation and greater than 90% loss of zinc in purified enzyme samples, implicating His116, Asp123, and His184 as zinc-coordinating residues. Homology searches using the 10 amino acid sequence SxHxxGxAxD, in which histidine and aspartate residues are putative zinc ligands, identified the metal coordinating ligands in the N-terminal domain of the murine Sonic hedgehog protein, which also exhibits an architecture for metal coordination identical to that observed in thermolysin from Bacillus thermoproteolyticus. Furthermore, this 10 amino acid consensus sequence is found in the Streptomyces albus G zinc-dependent N-acyl-d-Ala-d-Ala carboxypeptidase, an enzyme catalyzing essentially the same d-Ala-d-Ala dipeptide bond cleavage as VanX, suggesting equivalent mechanisms and zinc catalytic site architectures. VanX residue Glu181 is analogous to the Glu143 catalytic base in B. thermoproteolyticus thermolysin, and the E181A VanX mutant has no detectable dipeptidase activity, yet maintains near-stoichiometric zinc content, a result consistent with the participation of the residue as a catalytic base.


Propagation of human hepatitis A virus in African green monkey kidney cell culture: primary isolation and serial passage.
Human hepatitis A virus (HAV) was propagated in primary African Green Monkey (Cercopithecus aethiops) kidney (AGMK) cell cultures. Three strains of HAV were used: MS-1, SD-11, and HM-175. Cells were inoculated with marmoset-passaged material or human clinical specimens and were stained by direct immunofluorescence to establish the identity of the virus. Both clinical samples and marmoset-passaged material produced immunofluorescence. HAV antigen was found scattered throughout the cytoplasm of inoculated cultures. The HM-175 strain produced the most intense immunofluorescence. This strain of HAV had been serially passaged in cell culture seven times. Blocking experiments with paired human sera from naturally acquired HAV infections and hyperimmune chimpanzee serum from an experimentally infected animal established that the immunofluorescence was specific. The viral antigen was found to be exclusively intracellular. The interval to maximum HAV antigen expression was decreased by serial passage. The HAV strain described herein, which was recovered directly from the stool specimen of a patient with HAV in primary AGMK cell culture, may prove useful as a source of antigen for serological tests and as a candidate vaccine strain.


Feasibility and pharmacokinetics of carbamazepine oral loading doses.
The pharmacokinetics and adverse effects of an oral loading dose of carbamazepine administered in tablet or suspension form were studied. Patients on a hospital epilepsy unit who were to receive carbamazepine as a discharge medication were randomly assigned to receive either an oral 8-mg/kg loading dose of the tablet formulation or the same dose of the suspension on an empty stomach. Blood samples were drawn before and at intervals up to 12 hours after the loading dose. Adverse effects were evaluated subjectively and objectively. Total and free serum carbamazepine and carbamazepine-10, 11-epoxide (CBZE) concentrations were determined by high-performance liquid chromatography. Six adult patients were enrolled in and completed the study. All the patients achieved therapeutic total carbamazepine levels; the suspension group did so within two hours and the tablet group within five hours. Maximum serum carbamazepine concentrations ranged from 7.10 to 9.92 mg/L, area under the concentration-versus-time curve from 54.85 to 82.23 micrograms.hr/L, and terminal elimination half-life from 14.05 to 15.71 hours. Adverse effects were mild, few, and short-lived; none of the patients developed gastrointestinal toxicity. Adverse effects were not associated with total or free carbamazepine and CBZE concentrations or with total or free CBZE:carbamazepine ratios. An oral loading dose of carbamazepine 8 mg/kg achieved therapeutic levels within two hours when given as a suspension and within five hours when given as tablets and was well tolerated in all patients.


Strategies for ensuring good hydration in the elderly.
Dehydration is a frequent etiology of morbidity and mortality in elderly people. It causes the hospitalization of many patients and its outcome may be fatal. Indeed, dehydration is often linked to infection, and if it is overlooked, mortality may be over 50%. Older individuals have been shown to have a higher risk of developing dehydration than younger adults. Modifications in water metabolism with aging and fluid imbalance in the frail elderly are the main factors to consider in the prevention of dehydration. Particularly, a decrease in the fat free mass, which is hydrated and contains 73% water, is observed in the elderly due to losses in muscular mass, total body water, and bone mass. Since water intake is mainly stimulated by thirst, and since the thirst sensation decreases with aging, risk factors for dehydration are those that lead to a loss of autonomy or a loss of cognitive function that limit the access to beverages. The prevention of dehydration must be multidisciplinary. Caregivers and health care professionals should be constantly aware of the risk factors and signs of dehydration in elderly patients. Strategies to maintain normal hydration should comprise practical approaches to induce the elderly to drink enough. This can be accomplished by frequent encouragement to drink, by offering a wide variety of beverages, by advising to drink often rather than large amounts, and by adaptation of the environment and medications as necessary.


[Role of ocular ischaemic syndrome in establishing indications for revasculization of the carotid basin in stenotic lesions of extracranial portions of carotid arteries].
The article is dedicated to the problem concerning indications for revascularization of the carotid basin. The aim was to determine significance of ocular ischaemic syndrome in establishing indications for revascularization of the carotid basin in stenotic lesions of extracranial portions of carotid arteries.


Sterol regulatory element-binding protein (SREBP)-1-mediated lipogenesis is involved in cell senescence.
Increased cell mass is one of the characteristics of senescent cells, but this event has not been clearly defined. When subcellular organellar mass was estimated with organelle-specific fluorescence dyes, we observed that most membranous organelles progressively increase in mass during cell senescence. This increase was accompanied by an increase in membrane lipids and augmented expression of lipogenic enzymes, such as fatty acid synthase (FAS), ATP citrate lyase, and acetyl-CoA carboxylase. The mature form of sterol regulatory element-binding protein (SREBP)-1 was also elevated. Increased expression of these lipogenic effectors was further observed in the liver tissues of aging Fischer 344 rats. Ectopic expression of mature form of SREBP-1 in both Chang cells and primary young human diploid fibroblasts was enough to induce senescence. Blocking lipogenesis with FAS inhibitors (cerulenin and C75) and via siRNA-mediated silencing of SREBP-1 and ATP citrate lyase significantly attenuated H(2)O(2)-induced senescence. Finally, old human diploid fibroblasts were effectively reversed to young-like cells by challenging with FAS inhibitors. Our results suggest that enhanced lipogenesis is not only a common event, but also critically involved in senescence via SREBP-1 induction, thereby contributing to the increase in organelle mass (as a part of cell mass), a novel indicator of senescence.


Assessing the Influence of Visual-Taste Congruency on Perceived Sweetness and Product Liking in Immersive VR.
This study was designed to assess whether the combined effect of taste-congruent and incongruent extrinsic visual cues presented in virtual reality (VR) influences the perception of sweetness and product liking. Three VR environments (sweet-congruent, sweet-incongruent, and neutral) were created based on the evidence in existing literature. Participants tasted the same beverage in three VR environments and evaluated the environment and beverage liking, as well as perceived taste intensity (sweetness, sourness, and bitterness), congruency, comfort, and environment vividness. Frontal EEG alpha asymmetry (FAA) was also recorded as a complementary physiological measurement of overall liking. The results showed that the perceived sweetness of the beverage was significantly elevated in a sweet-congruent environment versus the other environments. Visual-taste congruency did not seem to have an effect on beverage liking and overall liking, whereas an increase in environment liking was found in the incongruent environment versus the other environments. These findings confirmed the significant influence of taste-specific visual cues on flavour perception, while the successful use of VR in the study provided insight into future applications of taste-specific VR environment in the modulation of flavour perception and sugar reduction.


Some new approaches to the management of hepatocellular carcinoma.
A concordance of multiple advances is changing the management of hepatocellular carcinoma (HCC). These include: (1) identification of preventable and treatable causal factors, including hepatitis B and obesity (non-alcoholic steatotic hepatitis [NASH]); (2) description of molecular and proteomic profiles for HCC prognosis, disease subtyping, and drug selection; (3) identification of circulating tumor cells for non-invasive molecular typing; (4) identification of tumor stem cells, for HCC subtyping and as treatment targets; (5) large numbers of multi-kinase inhibitors that are currently undergoing clinical trial assessment and comparison; (6) an array of newer therapies of different drug classes, aimed at a wide range of targets in cell growth, apoptosis, autophagy, and tumor invasion pathways; (7) newer regional chemotherapy and radiotherapy regimens and delivery systems; (8) the extension of liver transplantation to larger HCCs and its wider availability through use of living-related organ donors; (9) new radiological techniques to assess the changes in HCC vascularity associated with angiogenic drug actions; (10) re-evaluation of the importance of tumor biopsy to obtain molecular signatures; (11) recognition of the importance of non-tumor liver parenchyma for tumor growth control and as a source of prognostic profiling in HCC patients; (12) the evaluation of kinase- and other inhibitors in neo-adjuvant and adjuvant therapy associated with resection and liver transplant and minimization of transplant waiting list drop-out; (13) re-evaluation of the role or limitation of tumor responses, since kinase inhibitors can enhance survival without HCC size responses; and (14) the development of combination therapies to enhance tumor control rates, either using drugs targeting differing pathways, or kinase-inhibitors combined with either chemotherapy drugs or yttrium 90.


Dynamic and accretive composition of patient engagement instruments for personalized plan generation.
Patient engagement is important to help patients become more informed and active in managing their health. Effective patient engagement demands short, yet valid instruments for measuring self-efficacy in various care dimensions. However, the static instruments are often too lengthy to be effective for assessment purposes. Furthermore, these tests could neither account for the dynamicity of measurements over time, nor differentiate care dimensions that are more critical to certain sub-populations. To remedy these disadvantages, we devise a dynamic instrument composition approach that can model the measurement of patient self-efficacy over time and iteratively select critical care dimensions and appropriate assessment questions based on dynamic user categorization. The dynamically composed instruments are expected to guide patients through self-management reinforcement cycles within or across care dimensions, while tightly integrated into clinical workflow and standard care processes.


Genetic evidence that relative synaptic efficacy biases the outcome of synaptic competition.
Synaptic activity drives synaptic rearrangement in the vertebrate nervous system; indeed, this appears to be a main way in which experience shapes neural connectivity. One rearrangement that occurs in many parts of the nervous system during early postnatal life is a competitive process called 'synapse elimination'. At the neuromuscular junction, where synapse elimination has been analysed in detail, muscle fibres are initially innervated by multiple axons, then all but one are withdrawn and the 'winner' enlarges. In support of the idea that synapse elimination is activity dependent, it is slowed or speeded when total neuromuscular activity is decreased or increased, respectively. However, most hypotheses about synaptic rearrangement postulate that change depends less on total activity than on the relative activity of the competitors. Intuitively, it seems that the input best able to excite its postsynaptic target would be most likely to win the competition, but some theories and results make other predictions. Here we use a genetic method to selectively inhibit neurotransmission from one of two inputs to a single target cell. We show that more powerful inputs are strongly favoured competitors during synapse elimination.


Extraction and characterization of a cytochemically assayable Na+/K+-ATPase inhibitor/glucose-6-phosphate dehydrogenase stimulator in the hypothalamus and plasma of man and the rat.
Some physicochemical properties of partially purified hypothalamic material from the spontaneously hypertensive rat, and of plasma from man and the rat, have been characterized using a validated cytochemical bioassay which measures the ability of biological fluids to stimulate fresh guinea-pig kidney glucose-6-phosphate dehydrogenase (G6PD) after 2 min of exposure to the test substance, as an indication of their ability to inhibit Na+/K+ adenosine triphosphatase (Na+/K+-ATPase) after 4-6 min of exposure. The G6PD-stimulating activity of both hypothalamic extract and plasma is soluble in water and insoluble in chloroform. During electrophoresis the activity from both sites appears in the same fractions and travels considerably further than lysine. After high-pressure liquid chromatography the activity of hypothalamic extract appears in a discreet fraction which does not absorb u.v. light. The activity of both the hypothalamic extract and plasma survives boiling and acid hydrolysis, but is substantially inhibited by prior incubation with digoxin antibody. From ultrafiltration studies, the substance responsible for the ability to stimulate G6PD appears to have a molecular weight of less than 500. The G6PD-stimulating activity of hypothalamic extracts was destroyed by ashing and by base hydrolysis. The ability of plasma of high activity to stimulate G6PD is considerably increased by incubating at 37 degrees C for 15 min and destroyed by incubation for 45 min. It is concluded that these and several other previously noted similarities suggest that the cytochemically assayable Na+/K+-ATPase-inhibiting/G6PD-stimulating activity in the plasma and hypothalamus may be due to the same ouabain-like substance.


Beyond ADA Accessibility Requirements: Meeting Seniors' Needs for Toilet Transfers.
To identify the optimal spatial and dimensional requirements of grab bars that support independent and assisted transfers by older adults and their care providers. Although research has demonstrated that toilet grab bars based on the Americans with Disabilities Act (ADA) Accessibility Standards do not meet the needs of older adults, the specific dimensional requirements for alternative configurations are unknown. A two-phased study with older adults and care providers in residential facilities was conducted to determine the optimal requirements for grab bars. Seniors and caregivers in skilled nursing facilities performed transfers using a mock-up toilet. In Phase 1, participants evaluated three grab bar configurations to identify optimal characteristics for safety, ease of use, comfort, and helpfulness. These characteristics were then validated for using ability-matched samples in Phase 2. The optimal configuration derived in Phase 1 included fold-down grab bars on both sides of the toilet (14" from centerline [CL] of toilet, 32" above the floor, and extended a minimum of 6" in front of the toilet) with one side open and a sidewall 24" from CL of toilet on the other. Phase 2 feedback was significantly positive for independent and one-person transfers and somewhat lower, albeit still positive, for two-person transfers. The study provides substantial evidence that bilateral grab bars are significantly more effective than those that comply with current ADA Accessibility Standards. Findings provide specific spatial and dimensional attributes for grab bar configurations that would be most effective in senior facilities.


How the measurement of residual volume developed after Davy (1800).
H. Davy measured the residual volume of his own lungs in 1800, by inhaling a hydrogen mixture contained in a mercurial air holder. Using the same principle, Nestor Grehant determined the functional residual capacity, and the volume of the dead space, in 1864. Both used a forced breathing method, that was substituted by a prolonged dilution method by D.D. Van Slyke and C.A.L. Binger in 1923. It was in 1941 that G.R. Meneely and M.L. Kaltreider replaced hydrogen with helium. The open circuit nitrogen washout method was proposed by R.E. Darling, A. Cournand and D.W. Richards in 1940, and the body plethysmograph by A.B. DuBois et al. in 1956. So the three methods, still in common use today for measuring the static lung volumes, had been described by the mid-1950s.


T-type Ca2+ current as a trigger for Ca2+ release from the sarcoplasmic reticulum in guinea-pig ventricular myocytes.
1. We have investigated whether Ca2+ entry through T-type Ca2+ channels participates in triggering Ca2+ release from the sarcoplasmic reticulum (SR) in single guinea-pig ventricular myocytes (whole-cell voltage clamp, K5fura-2 as [Ca2+]i indicator; all monovalent cations replaced by impermeant ions to record uncontaminated Ca2+ currents; T = 23 or 36 degrees C). 2. T-type Ca2+ currents were elicited from a holding potential of -90 mV during steps to -50 to -20 mV. For steps to -50 mV, very small [Ca2+]i transients could be recorded with high loading of the SR (peak Delta[Ca2+]i, 67 +/- 41 nM; n = 9). 3. For steps to -40, -30 and -20 mV, we compared the amplitude of Ca2+ release for a holding potential of -50 mV with L-type Ca2+ current only to Ca2+ release for a holding potential of -90 mV with both T- and L-type Ca2+ current. Significantly more Ca2+ release was observed with T-type current present, and both the T-type current and the additional Ca2+ release were suppressed by 50 microM NiCl2. 4. Ca2+ influx through T-type Ca2+ channels triggered less Ca2+ release than a comparable Ca2+ influx through L-type Ca2+ channels. 5. Rapid block of T-type Ca2+ current during the action potential (50 microM NiCl2 during steady-state stimulation at 1 or 2 Hz) did not immediately reduce Ca2+ release, although a small decrease was observed after longer application. 6. We conclude that T-type Ca2+ current can trigger Ca2+ release from the SR albeit less efficiently than L-type Ca2+ current. T-type current is most likely to provide only a small contribution to the trigger for Ca2+ release in normal conditions. These results support the hypothesis that L-type Ca2+ channels have a privileged role in excitation-contraction coupling.


A kinetic isotope effect study and transition state analysis of the S-adenosylmethionine synthetase reaction.
The biosynthesis of S-adenosylmethionine occurs in a unique enzymatic reaction in which the synthesis of the sulfonium center results from displacement of the entire polyphosphate chain from MgATP. The mechanism of S-adenosylmethionine synthetase (ATP:L-methionine s-adenosyltransferase) from Escherichia coli has been characterized by kinetic isotope effect and substrate trapping measurements. Replacement of 12C by 14C at the 5' carbon of ATP yields a primary Vmax/Km isotope effect (12C/14C) of 1.128 +/- 0.003 in the absence of added monovalent cation activator (K+). At saturating K+ concentrations (10 mM) the primary isotope effect diminishes slightly to 1.108 +/- 0.003, indicating that the step in the mechanism involving bond breaking at the 5' carbon of MgATP has a small commitment to catalysis at conditions near Vmax. No alpha-secondary 3H isotope effect from [5'-3H]ATP was detected, (1H/3H) = 1.000 +/- 0.002, even in the absence of KCl. There was no significant primary sulfur isotope effect from [35S]methionine at KCl concentrations from 0 to 10 mM. Substitution of the methyl group of methionine with tritium yielded a beta-secondary isotope effect (CH3/C3H3) = 1.009 +/- 0.008 independent of KCl concentration. The reaction of selenomethionine and [5'-14C]ATP gave a primary isotope effect of 1.097 +/- 0.006, independent of KCl concentration. Substrate trapping experiments demonstrated that the step in the mechanism involving bond making to sulfur of methionine does not have a significant commitment to catalysis at 0.25 mM KCl, therefore intrinsic isotope effects were observed. Substrate trapping experiments indicated that the step involving bond breaking at carbon 5' of MgATP has a 10% commitment to catalysis at 0.25 mM KCl. The isotope effects are interpreted in terms of an Sn2-like transition state structure in which bonding of the C5' is symmetric with respect to the departing tripolyphosphate group and the incoming sulfur of methionine. With selenomethionine as substrate an earlier transition state is implicated.


Acceptance and adoption of biofortified crops in low- and middle-income countries: a systematic review.
Biofortification of staple crops is a promising strategy for increasing the nutrient density of diets in order to improve human health. The willingness of consumers and producers to accept new crop varieties will determine whether biofortification can be successfully implemented. This review assessed sensory acceptance and adoption of biofortified crops and the determining factors for acceptance and adoption among consumers and producers in low- and middle-income countries. PubMed, Scopus, and Web of Science were searched for published reports. Unpublished studies were identified using an internet search. From a total of 1669 records found, 72 primary human research studies published in English or Spanish met the criteria for inclusion. : Data were extracted from each identified study using a standardized form. Sensory acceptability (n = 40) was the most common topic of the studies, followed by determinants of acceptance (n = 25) and adoption (n = 21). Of crops included in the studies, sweet potato and maize were the most studied, whereas rice and pearl-millet were the least investigated. Overall, sensory acceptance was good, and availability and information on health benefits of the crops were the most important determinants of acceptance and adoption. : Changes to the sensory qualities of a crop, including changes in color, did not act as an obstacle to acceptance of biofortified crops. Future studies should look at acceptance of biofortified crops after they have been disseminated and introduced on a wide-scale.


Giant trichobezoar of duodenojejunal flexure: a rare entity.
Bezoars are concretions of undigested material in the gastrointestinal tract, most commonly in the stomach. Duodenojejunal localization of bezoars is exceptional. We report a case of a 27-year-old woman who experienced nausea, vomiting and severe abdominal pain for one week. By palpation a mobile and sensitive mass, 15 Chi 15 cm, was detected, which filled the upper quadrant. Results of gastric endoscopy were normal. X-ray and ultrasonography suggested a bezoar. A laparotomy revealed that the jejunum was fissured by the trichobezoar ball. This trichobezoar mass was totally excised by intestinal resection. To our knowledge, this is the first reported case of duodenojejunal fissuration caused by trichobezoar in an adult. Among patients with high subocclusif syndrome, duodenojejunal bezoar should remain a possibility in differential diagnosis.


[Determining factors of effectiveness of extracorporeal shock wave lithotripsy in ureteral stones: results of own investigation].
The purpose of the present study is to investigate main determining factors of effectiveness of extracorporeal shock wave lithotripsy (ESWL) in urethral stones and the influence of these factors on the number of necessary sessions of ESWL procedure. The problem presents a special interest for insurance medicine, as the number of sessions has a direct impact on the cost and length of treatment. The present investigation included 162 patients with urolithiasis having stones in urethra. To find out determining factors of effectiveness of ESWL in urethral stones the following factors were considered: size, localization, radioopacity of stone, its duration of stay in urethra, the degree of dilation of upper urinary tract. The influence of mentioned factors on the number of necessary ESWL sessions was investigated. On the basis of the present study a conclusion can be made that the principal factors determining the clinical efficacy of ESWL in urethral stones are the stone size, condition of upper urinary tract and radioopacity of stone. The level of localization of the stone in urethra has no influence on ESWL efficacy. Therefore in case of large size stones, their long stay in urethra and significant disorders of urodynamics in upper urinary tract, in marked radioopacity of stones more than one session of ESWL is required. In such cases, we recommend to consider other less invasive methods of treatment of urethral stones (ureterorenoscopy or percutaneous urethra lithotripsy).