"But the moment they find out that you are MSM…": a qualitative investigation of HIV prevention experiences among men who have sex with men (MSM) in Ghana's health care system.
The prevalence of HIV in Ghana is 1.3%, compared to 17% among men who have sex with men (MSM). There is limited empirical data on the current health care climate and its impact on HIV prevention services for Ghanaian MSM. The purposes of this study were to investigate (1) MSM's experiences using HIV prevention resources, (2) what factors, including health care climate factors, influenced MSM's use of prevention resources and (3) MSM self-identified strategies for improving HIV/sexually transmitted infection (STI) prevention among MSM in Ghanaian communities. We conducted 22 focus groups (n = 137) with peer social networks of MSM drawn from three geographic communities in Ghana (Accra, Kumasi, Manya Krobo). The data were examined using qualitative content analysis. Interviews with individual health care providers were also conducted to supplement the analysis of focus group findings to provide more nuanced illuminations of the experiences reported by MSM. There were four major findings related to MSM experiences using HIV prevention resources: (1) condom quality is low, condom access is poor, and condom use is disruptive, (2) inaccurate information undermines HIV testing (3), stigma undermines HIV testing, and (4) positive attitudes towards HIV prevention exist among MSM. The main healthcare climate factors that affected prevention were that MSM were not free to be themselves, MSM were not understood by healthcare providers, and that MSM did not feel that healthcare providers cared about them. To improve HIV prevention MSM suggested increased education tailored to MSM should be provided to enable self-advocacy and that education and awareness are needed to protect human rights of MSM in Ghana. MSM in Ghana are exposed to negative health care climates. Health care spaces that are unsupportive of MSM's autonomy undermine the uptake of prevention measures such as condoms, HIV testing, and accurate sexual health education. These findings contribute to knowledge to inform development of HIV prevention interventions for MSM in Ghana, such as culturally appropriate sexual health education, and digital technology to connect individuals with resources supportive of MSM.


Perinatal outcomes among Asian-white interracial couples.
To investigate whether perinatal outcomes among interracial Asian-white couples are different than among Asian-Asian and white-white couples. This was a retrospective study of Asian, white, and Asian-white couples delivered at the Lucile Packard Children's Hospital from 2000-2005. Asian-white couples were subdivided into white-mother/Asian-father or Asian-mother/white-father. Perinatal outcomes included gestational diabetes, hypertensive disorders of pregnancy, preterm delivery, birth weight >4000 g and <2500 g, and cesarean delivery. In the study population of 868 Asian-white, 3226 Asian, and 5575 white couples there were significant outcome differences. Compared with white couples, Asian-white couples had an increased incidence of gestational diabetes (aOR 2.4 for white-mother/Asian-father and aOR 2.6 for Asian-mother/white-father), though not as high as Asian couples (aOR 4.7). Asian-white couples had larger babies (median 3360 g for Asian-mother/white-father and 3320 g for white-mother/Asian-father vs 3210 g for Asian, P < .001), but only Asian-mother/white-father couples had an increased rate of cesarean delivery (aOR 1.3-2.0). Significant differences in perinatal outcomes exist between Asian, white, and interracial Asian-white couples.


Compartments of tubulin and tubulin-like proteins in differentiating neubroblastoma cells.
Cytoplasmic, tubular and particulate fractions of differentiating neuroblastoma cells were prepared and the tubulin together with tubulin-like proteins was measured in each cell fraction during different stages of cell differentiation. In undifferentiated cells, 73%, 5% and 22% of the tubulin and tubulin-like proteins were contained in the cytoplasmic, tubular and particulate fractions, respectively. After 5 days of differentiation, the overall content of tubulin and tubulin-like proteins had increased by 73%. This corresponded to increases of 45%, 145% and 100% in the cytoplasmic, microtubular and particulate fractions, respectively. The increase in membrane-bound (particulate) tubulin and tubulin-like proteins was significantly greater than the total increase of proteins in the particulate fraction. Polyacrylamide gel electrophoresis of the proteins in each subcellular fraction revealed the presence of protein bands corresponding to the alpha and beta subunits of tubulin. Whereas these bands indicated equal amounts of protein in the alpha and beta positions for the tubular and particulate cell fractions, an analysis of the cytoplasmic fraction revealed much more protein migrating to the alpha-tubulin position than to the beta-tubulin position, especially during cell differentiation. Furthermore, two overlapping but distinct protein bands were demonstrable in the position of the alpha-tubulin from the cytoplasmic fraction. These bands were designated alpha 1 and alpha 2. The particulate fraction contained only the alpha 1 and the tubular fraction only the alpha 2 protein band. The addition of 1 mM dibutyryl cyclic AMP to the neuroblastoma cells, at the time when the serum was withdrawn, enhanced the rate of differentiation and the redistribution of tubulin and tubulin-like proteins within the 3 cellular compartments. These results are discussed as they relate to the regulation, biosynthesis, turnover and compartmentation of tubulin and tubulin-like proteins in differentiating neuroblastoma cells.


CAAC-IPr*: easily accessible, highly sterically-hindered cyclic (alkyl)(amino)carbenes.
IPr* (IPr* = 1,3-bis(2,6-bis(diphenylmethyl)-4-methylphenyl)imidazol-2-ylidene) has emerged as a powerful highly hindered and sterically-flexible ligand platform for transition-metal catalysis. CAACs (CAAC = cyclic (al-kyl)(amino)carbenes) have gained major attention as strongly electron-rich carbon analogues of NHCs (NHC = N-heterocyclic carbene) with broad applications in both industry and academia. Herein, we report a merger of CAAC ligands with highly-hindered IPr*. The efficient synthesis, electronic characterization and application in model Cu-catalyzed hydroboration of alkynes is described. The ligands are strongly electron-rich, bulky and flexible around the N-Ar wingtip. The availability of various IPr* and CAAC templates offers a significant potential to expand the existing arsenal of NHC ligands to electron-rich bulky architectures with critical applications in metal stabilization and catalysis.


The adaptation of a reflex response to the ongoing phase of locomotion in fish.
The reflex response to stimulation of the tail fin has been studied in the swimming fish, by bilateral electromyographical (EMG) recordings in several segments along the body. The response varies with the phase of swimming. When the muscles on one side (segment) are active, a large response will occur on this side but no response on the contralateral side at the same level. When the other side becomes active an identical stimulus will cause an activation of this side but no response on the previously active side. When the movements were filmed a powerful mechanical effect was demonstrated with an augmentation of the ongoing movement, that would result in an instantaneous increase in speed. The stimulus causes in addition a shortening of the duration of the swimming cycle and its components. Most of the results were obtained on spinal dogfish, which also exhibits spontaneous locomotion after a spinal transection. Mainly electrical bipolar stimulation of the tail fin was used. Identical stimuli applied in different phases on an ongoing movement, thus give a reflex response that changes dramatically with the phase of the movement. This phase dependent reflex reversal is functionally meaningful; it is fast and due to spinal mechanisms.


Growth and development of larvae and galls of Urophora cardui (Diptera, Tephritidae) on Cirsium arvense (Compositae).
The tephritid fly Urophora cardui induces a large multi-chambered gall within the stems of Cirsium arvense. Three distinct phases of gall development have been identified as initiation, growth, and maturation. During initiation the insect gains control of tissue development and during the gall's growth phase parenchyma cells proliferate rapidly surrounding the larvae with thick layers of cells. Patches of primary nutritive cells appear along the surface of larval chambers during the growth phase but few of these cells are consumed. In the gall's maturation phase, thick layers of secondary nutritive cells appear around the surface of larval chambers and the remaining gall parenchyma lignifies. Secondary nutritive cells are the primary food of U. cardui.The gall expands rapidly during the growth phase then abruptly slows at the beginning of the maturation phase. Rate of gall growth is dependent upon the number of larvae per gall but the number of larvae does not affect duration of this phase.Larvae remain in the second instar throughout the growth phase and grow slowly. Once the gall enters the maturation phase and the secondary nutritive cells appear, the larvae moult to the third instar and grow quickly. Larvace attain over 98% of their final weight during the maturation phase and consume all secondary nutritive cells.It is postulated that larvae do not feed extensively on primary nutritive cells since these cells play a key role in gall morphogenesis. The appearance of secondary nutritive cells stimulates larval feeding at a time when gall growth and development is finished.


Medical Treatments of Hidradenitis Suppurativa: More Options, Less Evidence.
Hidradenitis suppurativa is a common debilitating skin disease that has been neglected by science. The disease is getting more and more attention, reflected by the rising number of scientific publications. There is a clear need for effective treatment. We are still at the beginning of improving care for these patients as demonstrated by the low levels of evidence for the medical treatments. Many of these therapies showed promising results, but are still waiting to be validated in randomized, controlled trials. Much more research is needed to strengthen the Level of Evidence for these therapies and thus improve patient care.


Calcium regulates in vitro dimorphism in chromoblastomycotic fungi.
Cladosporium carrionii, Fonsecaea pedrosoi and Phialophora verrucosa, the three most important agents of chromoblastomycosis, produced large numbers of sclerotic bodies at 25 degrees C, and greater numbers at 37 degrees C, after inoculation into a defined pH 2.5 medium containing 0.1 mmol l-1 Ca2+. Higher concentrations of Ca2+ reversed this tendency and promoted maintenance of hyphal growth. Addition of the Ca2+ chelator EGTA to the same medium buffered at pH 6.5 also induced sclerotic bodies, but in a more concentration-dependent fashion. EGTA at 0.5-1.0 mmol l-1 induced maximum numbers of sclerotic bodies in Cl. carrionii, whereas 2 and 8 mmol l-1 concentrations were required for the same results with F. pedrosoi and P. verrucosa, respectively. These findings suggest that Ca2+ concentrations in human tissue may play a paramount role in the dimorphic switching between hyphae and sclerotic bodies among chromoblastomycotic agents during infection.


[Microsurgical bone replacement].
Microvascular bone transplantation has become a routine procedure. The iliac crest, scapula, and fibula are the most common donor sites. These are used for reconstruction of tumor-related defects or after osteoradionecrosis. But additional indications have been developed as defects after trauma, extreme atrophy, or hemifacial microsomia. In the future, three-dimensional techniques will improve transplantation surgery and will enable the prefabrication of transplants.


Transformation of the mycotoxin ochratoxin A in artificially contaminated vegetables and cereals.
The metabolism of the mycotoxin ochratoxin A (OTA) in intact vegetables and germinating cereals is described and compared with metabolism studies in cell suspension cultures. The metabolites formed in intact, OTA spiked vegetables were ochratoxin a and 4- hydroxyochratoxin A (dI) and II), which are also known from studies with plant cell suspension cultures.


Metagenomic data on prokaryotic diversity of Kunashir island geothermal spring.
This is data on the microbial diversity of a geothermal spring located on the banks of the acidic creek of Kunashir Island. Data was obtained using 16s rRNA amplicon directed metagenomic sequencing on Illumina MiSeq. The raw sequence data used for analysis is available in NCBI under the Sequence Read Archive (SRA) with the BioProject No. PRJNA637298, PRJNA637447 and SRA accession number SRP265942, SRP266050. The data sequences of the 16s rRNA gene are presented at the accession numbers MT604934-MT604967, MT604911-MT604921 in NCBI GenBank database.


The epidemiology of dog walking: an unmet need for human and canine health.
To describe the prevalence of dog walking in New South Wales, and to identify potential health gains if more dogs were walked. Cross-sectional analytical survey. 894 adults in NSW in 1998 (among the owners of approximately two million domestic dogs in NSW who were potential participants in dog-walking behaviours). None yet. Dog walking hours per week; other DogEpi concepts to illustrate the public health gains include the DAF (dog attributable fraction), and the BBR (benefits to bites ratio). The response rate to the survey was 74%. 46% of households in NSW had a dog and, overall, dog owners walked 18 minutes per week more than non-dog owners. However, more than half of dog owners did not walk their dogs, and were less likely than non-owners to meet recommended levels of physical activity sufficient for health benefits. If all dog owners walked their dogs, substantial disease prevention and healthcare cost savings of $175 million per year might accrue. There are potential benefits of dog walking for human health; currently, among dog owners, much of this benefit remains to be realised. There are also likely benefits for canine health. Dog walking should be promoted through national strategies recommending "Walkies for all by the year 2010".


Study on the interaction of β-carotene and astaxanthin with trypsin and pepsin by spectroscopic techniques.
β-Carotene and astaxanthin are two carotenoids with powerful antioxidant properties, but the binding mechanisms of β-carotene/astaxanthin to proteases remain unclear. In this study, the interaction of these two carotenoids with trypsin and pepsin was investigated using steady-state and time-resolved fluorescence measurements, synchronous fluorescence spectroscopy, UV-vis absorption spectroscopy and circular dichroism (CD) spectroscopy. The experimental results indicated that the quenching mechanisms of trypsin/pepsin by the two carotenoids are static processes. The binding constants of trypsin and pepsin with these two carotenoids are in the following order: astaxanthin-trypsin > astaxanthin-pepsin > β-carotene-trypsin > β-carotene-pepsin, respectively. Thermodynamic investigations revealed that the interaction between the two carotenoids and trypsin/pepsin is synergistically driven by enthalpy and entropy, and hydrophobic forces and electrostatic attraction have a significant role in the reactions. In addition, as shown by synchronous fluorescence spectroscopy, UV-vis absorption spectroscopy and CD, the two carotenoids may induce conformational and microenvironmental changes in trypsin/pepsin. The study provides an accurate and full basic data for clarifying the binding mechanisms of the two carotenoids with trypsin/pepsin and is helpful in understanding their effect on protein function and their biological activity in vivo.


What happened and why? A programme theory-based qualitative evaluation of a healthcare-academia partnership reform in primary care.
There is increasing interest in and demands for partnerships between academia and healthcare practices. Few empirical studies have described the influence of such partnerships from a practice perspective. The purpose of this study was to evaluate the impact of a reform launched to increase integration between primary care and academia and to identify potential reasons for why the observed impact occurred in three areas targeted by the reform: research, student education, and continued professional development. The study was conducted in Stockholm County, the largest healthcare region in Sweden, at the introduction of a partnership between primary care and academia, including eight coordinating centres and approximately 500 surrounding primary care units. A programme theory-based qualitative approach to evaluation was used, building on document analysis, and in-depth interviews with the centre managers (n = 6) and coordinators (n = 8) conducted 42-66 months after the initiation of the reform. The analysis showed that the reform had some impact on all three areas targeted by the reform: research, student education, and continued professional development. The input that contributed most extensively to the impact was the establishment of facilitating roles. Most changes occurred at the coordinating centres and primarily in the area of student education. The effect on student education was primarily due to having prior experience in this area and perceptions of timely benefits of students to care practice. Partnerships between primary care and academia hold the potential of practice impact. To increase integration between primary care and academia, the components of the integration must be understandable and relevant for primary care practitioners, and importantly, compliant with delivery of primary care.


The neural signature of spatial frequency-based information integration in scene perception.
Spatial frequency-based information plays an important role in visual perception. By combining behavioral and electroencephalogram (EEG) measurements, we investigated the mechanisms of the interaction and information integration between different spatial frequency bands. The observers performed a scene categorization task on hybrid images that were generated by combining the low spatial frequency (LSF) component of one image with the high spatial frequency (HSF) component of another image. The results showed that the recognition of the HSF component was interfered by the non-attended LSF component at semantic level. The strength of the semantic interference was modulated by the physical similarity between the LSF and HSF components. Analyses of the EEG data revealed an early anterior N1 component (122 ms from stimulus onset) that was related to the observed interaction of the semantic and physical information between the LSF and HSF components. These findings demonstrate that the semantic information from different spatial frequency bands can be integrated at early stage of the perceptual processing. This early integration is likely to occur at frontal areas in order to initiate top-down facilitation.


Experimental evidence for large ring metallacycle intermediates in polyethylene chain growth using homogeneous chromium catalysts.
Deuterio-ethylene labeling studies on two homogeneous chromium ethylene oligomerization catalysts show that chain propagation proceeds via metallacyclic intermediates; reactions performed in the presence of 1-nonene show no incorporation of the higher olefin, strongly implicating the involvement of large ring metallacycles.


Role of the tear film in the optical quality of the human eye.
This paper reviews recent studies of the role of the tear film in the optical quality of the eye. Recent investigations focus on the dynamics of the tear film after a blink and its important role in the optical quality of the eye. The results in this review were used in an attempt to understand the optical and visual impact of tear-film breakup in normal eyes and dry eyes. It was noted that patients with dry-eye syndrome have large optical aberrations compared with those in normal eyes, which may be the cause of blurry vision associated with the syndrome. In addition, instillation of artificial tears reduces optical aberrations and thus improves the optical quality of vision in these patients.


Incidence of schizophrenia in Surinam.
More than one-third of the population of Surinam has migrated to The Netherlands in the 1970s and 1980s. If selective migration explains the increased incidence in these migrants, one expects to find a very low incidence of the disorder in Surinam. We examined the medical records of the sole psychiatric hospital in Surinam and found that the mean annual rate of first admissions for schizophrenia or schizophreniform disorder (DSM-III-R criteria) in 1992 and 1993 was 1.61 per 10,000 (95% Confidence interval: 1.24-1.98 per 10,000), a normal figure. These findings constitute a challenge to the hypothesis that selection explains the increased incidence in the migrants. The possibility of an increased incidence of the disorder in Surinam (which might also explain the increased incidence among migrants) has not been ruled out by the results of this study.


Degradation of di(2-ethyl hexyl) phthalate by Fusarium culmorum: Kinetics, enzymatic activities and biodegradation pathway based on quantum chemical modelingpathway based on quantum chemical modeling.
Di(2-ethylhexyl) phthalate (DEHP) is a plasticizer widely used in the manufacture of plastics, and it is an environmental contaminant. The specific growth rate (μ), maximum biomass (Xmax), biodegradation constant of DEHP (k), half-life (t1/2) of DEHP biodegradation and removal efficiency of DEHP, esterase and laccase specific activities, and enzymatic yield parameters were evaluated for Fusarium culmorum grown on media containing glucose and different concentrations of DEHP (0, 500 and 1000mg/L). The greatest μ and the largest Xmax occurred in media supplemented with 1000mg of DEHP/L. F. culmorum degraded 95% of the highest amount of DEHP tested (1000mg/L) within 60h of growth. The k and t1/2 were 0.024h(-1) and 28h, respectively, for both DEHP concentrations. The removal efficiency of DEHP was 99.8% and 99.9% for 1000 and 500mg/L, respectively. Much higher specific esterase activity than specific laccase activity was observed in all media tested. The compounds of biodegradation of DEHP were identified by GC-MS. A DEHP biodegradation pathway by F. culmorum was proposed on the basis of the intermolecular flow of electrons of the identified intermediate compounds using quantum chemical modeling. DEHP was fully metabolized by F. culmorum with butanediol as the final product. This fungus offers great potential in bioremediation of environments polluted with DEHP.


Equipercentile linking of the Brief Psychiatric Rating Scale and the Clinical Global Impression Scale in a catchment area.
Recent analyses tried to explain the meaning of the Brief Psychiatric Rating Scale total score (BPRS) and its percentage change from baseline by equipercentile linking with the Clinical Global Impression Scale (CGI). A major limitation was that they were conducted in clinical trial populations limiting generalisability to 'real-world' patients. We therefore replicated the findings in a large sample covering patients admitted to a state hospital with a catchment area. BPRS and CGI ratings at admission (n=1772) and at discharge from all patients with schizophrenic disorders (ICD-10 F20.0-F20.9) admitted between 2005 and 2008 were compared using equipercentile linking. Being considered "mildly ill" according to the CGI severity score approximately corresponded to a BPRS total score of 25, "moderately ill" to a BPRS of 33-35, "markedly ill" to a BPRS of 50 and severely ill to a BPRS of 70. To be "minimally improved" according to the CGI change score was associated with a mean BPRS reduction of 13%; and "much improved" with 50% BPRS reduction. The linking functions were not identical, but overall comparable to those in previous randomised trial samples. The suggestion that a 50% BPRS reduction from baseline is a clinically meaningful definition of response in acutely ill patients was reinforced.


Ultrastructural studies of glycoconjugates in brain micro-blood vessels and amyloid plaques of scrapie-infected mice.
Lectin or glycoprotein-gold complexes and samples of scrapie-infected mouse brain embedded in Lowicryl K4M were used for ultrastructural localization of glycoconjugates. The lectins tested recognize the following residues: beta-D-galactosyl [RCA, Ricinus communis agglutinin (aggl.) 120], N-acetyl and N-glycolyl neuraminic acid (LFA, Limax flavus aggl.), N-acetyl-D-glucosaminyl and sialyl (WGA, Wheat germ aggl.), N-acetyl-D-galactosaminyl (HPA, Helix pomatia aggl., and DBA, Dolichos biflorus aggl.), alpha-D-mannosyl/alpha-D-glucosyl (Con A, Concanavalin A), alpha-D-galactosyl and alpha-D-galactopyranoside (BSA, Bandeirea simplicifolia aggl., izolectin B4). Labeling of the majority of micro-blood vessels (MBVs) located outside the plaque area and in the remaining cerebral cortex was similar to that which has been previously observed in non-infected animals. Some MBVs, however, located inside the plaque area and surrounded directly by amyloid fibers showed attenuation of the endothelium, the surface of which was scarcely and irregularly decorated with RCA, LFA, WGA and Con A. These abnormalities in the composition of glycoconjugates can be associated with previously noted increased permeability of some MBVs in the brains of scrapie-infected mice. Some vessels in the plaque area were encapsulated by perivascular deposits of homogeneous or flocculogranular material containing several glycoconjugates. A very intimate structural relation between reactive (microglial-like) cells and amyloid fibers suggests the participation of these cells in elaboration of plaque material. Labeling of the cell surface and adjacent amyloid fibers with the same lectins (RCA, WGA, DBA, Con A) suggests the possibility that the glycosylation of these fibers occurs extracellularly. Only WGA and DBA were occasionally labeling some Golgi elements of the reactive cells.


Association between infestation by Lynxacarus radovskyi (Acari: Lystrophoridae) and the occurrence of Feline Eosinophilic Granuloma Complex.
Lynxacarus radovskyi are mites commonly found within domestic feline hair stems. The infested animal presents an opaque fur with a "salt and pepper" aspect. The contamination may occur by direct contact with other infected animals or by fomites, and the main diagnostic tool is the direct examination of the fur. The Feline Eosinophilic Granuloma Complex (FEGC) is a dermatological pattern of an immune answer against many types of injuries in felines, mainly during allergic reactions, and the treatment of choice are corticosteroids. The objective of this work was to document the linxcariosis cases at the Veterinary Hospital Professor Ricardo Alexandre Hippler-University of Vila Velha. Futhermore, the work also meant to research the association between the parasite contagion and the occurrence of FEGC injuries, which commonly occurred. Between April 2017 and August 2018, there were 8 reported cases of felines infested with L. radovskyi. The diagnoses were made with Acetate tape impression or by direct fur examination. Seven out of the eight cats presented with at least one characteristic injury of the FEGC. In all of them the chosen treatment was moxidectin or spot-on imidacloprid plus corticotherapy on the cats with FEGC, which were effective.


Metabolically conditioned media derived from bone marrow stromal cells or human skin fibroblasts act as effective chemoattractants for mesenchymal stem cells.
The main goal of bone tissue engineering has been the generation of healthy bone in order to replace affected tissue. Therefore, optimized biomaterials are needed which allow the survival and growth of mesenchymal stem cells. Until now the key challenge in the clinical application of cell-based tissue engineering bone implants was poor diffusion of oxygen into the tissue, making functional blood vessel networks a necessity. With their ability to evolve into different cell types, to expand extensively in vitro, and to release paracrine soluble factors, bone marrow stromal cells (BMSC) are highly attractive for tissue engineering. During the last years hypoxia became a proven method to control proliferation, differentiation, and pluripotency of BMSC. Here we applied different methods to characterize metabolically conditioned media (MCM) in comparison to hypoxia conditioned media (HCM) and evaluated their ability to attract BMSC in 2-D migration assays. BMSC and fibroblasts of human origin were isolated and cultivated to obtain HCM and MCM. Both media were characterized by angiogenesis arrays, cytokine arrays, and ELISA for selected factors. 2-D migration tests were performed with Corning Transwell®-96 permeable support chambers with porous polyester membranes with a pore size of 8.0 μm. Characterization of HCM and MCM revealed that the concentration of angiogenic factors was higher in MCM than in HCM. However, the chemoattractive capacity of MCM for BMSC was equivalent to that of HCM. HCM and MCM produced by human skin fibroblasts attracted human BMSC as efficiently as HCM and MCM produced by human BMSC. HCM and MCM have a high chemoattractive capacity for BMSC. Both conditioned media harbor high concentrations of angiogenic factors which are important for angiogenesis and cell migration. Both chemoattracting conditioned media can also be derived from skin fibroblasts which can easily be obtained from patients in individualized therapy approaches.


Ultrasonic examination of differences in bone density of chronic obstructive pulmonary disease (COPD) rats constructed by different methods.
Osteoporosis is one of the main complications of chronic obstructive pulmonary disease (COPD) patients. We investigated the bone density in rat model of COPD induced by different method. We developed seven distinct groups to evaluate the differences in bone density. Based on these seven different ways, rats were categorized into distinct groups in which simple cigarette inhalation, sulfur dioxide inhalation, lipopolysaccharide intubation, protease induction, bacterial nasal injection, smoking combined with endotoxin, smoking combined bacterial infection, and smoking combined with protease were tested. The results from the male Sprague-Dawley (SD) rats were used to construct the COPD model, and then the bone density of the rats' right femurs was examined by the ultrasonic bone density testing. The compound factor-induced COPD rat model provides a better simulation of the clinical characteristics and pathophysiological processes of COPD. Smoking combined with bacterial infection method has the most apparent effect on reducing bone density, with statistical differences (P<0.05). The COPD rat model constructed by the combination of smoking and bacterial infection method has a much lower bone density.


Phase I/II study of intraventricular and intrathecal ACNU for leptomeningeal neoplasia.
A total of 27 patients with leptomeningeal neoplasia were treated with the water-soluble nitrosourea ACNU given intraventricularly or intrathecally in a phase I/II study. Patients were entered in the study if they showed evidence of either a positive CSF cytology or neurodiagnostic evidence of leptomeningeal disease, or both. Patients were evaluated for toxicity and efficacy; additionally, in 13 patients ACNU pharmacokinetic studies were carried out. A variety of tumor types were represented in the study group, including primary and metastatic CNS tumors. Toxicity was mild and included pain at the injection site (four patients), transient radicular symptoms at a short distance from the injection site (three patients), and nausea and vomiting (one patient). No myelotoxicity was seen. Of 21 patients who presented with positive cytology, 8 (38%) had a conversion from positive to negative cytology, with a range of response durations from 1 to 20+ months. Of the remaining six patients with negative cytology but other neurodiagnostic evidence of leptomeningeal disease, one patient showed an improvement seen on the myelogram and one underwent a brief reduction in CSF protein. ACNU elimination from the ventricular system is rapid, with a beta slope of 0.028 min-1 and a computed elimination constant, Ko of 13 min. The mean clearance was 3.8 ml/min (range, 1.0-6.2 ml/min). Peak ACNU levels varied between 108 and 620 micrograms/ml, with the AUC being 1.4-14.7 mg.min/ml. The total dose of ACNU given was between 9 and 104 mg, and the single dose range was 4-16.5 mg. We conclude that ACNU can be given safely with minimal toxicity as intra-CSF therapy, that it demonstrates efficacy in some patients with leptomeningeal disease, and that further studies are warranted to evaluate more fully alternative dosing and drug delivery approaches.


AP2/ERF genes associated with superfast fig (Ficus carica L.) fruit ripening.
Fig fruits have significant health value and are culturally important. Under suitable climatic conditions, fig fruits undergo a superfast ripening process, nearly doubling in size, weight, and sugar content over three days in parallel with a sharp decrease in firmness. In this study, 119 FcAP2/ERF genes were identified in the fig genome, namely 95 ERFs, 20 AP2s, three RAVs, and one soloist. Most of the ERF subfamily members (76) contained no introns, whereas the majority of the AP2 subfamily members had at least two introns each. Three previously published transcriptome datasets were mined to discover expression patterns, encompassing the fruit peel and flesh of the 'Purple Peel' cultivar at six developmental stages; the fruit receptacle and flesh of the 'Brown Turkey' cultivar after ethephon treatment; and the receptacle and flesh of parthenocarpic and pollinated fruits of the 'Brown Turkey' cultivar. Eighty-three FcAP2/ERFs (68 ERFs, 13 AP2s, one RAV, and one soloist) were expressed in the combined transcriptome dataset. Most FcAP2/ERFs were significantly downregulated (|log2(fold change) | ≥ 1 and p-adjust < 0.05) during both normal fruit development and ethephon-induced accelerated ripening, suggesting a repressive role of these genes in fruit ripening. Five significantly downregulated ERFs also had repression domains in the C-terminal. Seven FcAP2/ERFs were identified as differentially expressed during ripening in all three transcriptome datasets. These genes were strong candidates for future functional genetic studies to elucidate the major FcAP2/ERF regulators of the superfast fig fruit ripening process.


Contrast-enhanced gray-scale harmonic ultrasound in the efficacy assessment of ablation treatments for hepatocellular carcinoma.
The aim of this study was to compare contrast-enhanced gray-scale harmonic ultrasound with multiphasic spiral computed tomography in the assessment of treatment efficacy of non-surgically treated HCC. We studied 56 HCCs treated by percutaneous ethanol injection (31 cases), radiofrequency ablation (three cases), trans-arterial chemoembolization (12 cases), and combined treatment (10 cases). The efficacy of therapies was blindly assessed by multiphasic computed tomography and gray-scale harmonic ultrasound with a second-generation contrast agent (sulfur hexafluoride). On computed tomography 30 tumors (53.6%) showed complete necrosis, while 26 lesions (45.4%) were still viable. On contrast-enhanced ultrasound examination 33/56 nodules (58.9%) had no contrast enhancement in the arterial phase, while 23/56 lesions (41.1%) were still vascularized. All the nodules assessed as completely necrotic on computed tomography did not show arterial enhancement on contrast-enhanced ultrasound and diagnostic agreement was found in 53/56 cases (94.6%) (P<0.001). Contrast-enhanced ultrasound demonstrated relative sensitivity and specificity of 87.0% and 98.4%. Contrast-enhanced harmonic ultrasound is promising in the efficacy evaluation of ablation treatments for HCC. Nodules vascularized in the arterial phase on contrast harmonic ultrasound should be considered still viable and addressed to additional treatment without further evaluation.


Suboptimal exposure to fluconazole in critically ill patients: Pharmacokinetic analysis and determinants.
This study aims at evaluating fluconazole exposure in critically ill patients and identifying variables associated with the latter. This was a 2-year (2018-2019) retrospective multicenter cohort study. Adult patients > 18 years-old with at least one fluconazole concentration measurement during their ICU stay were included. Twenty patients were included. Only 11 patients had a fluconazole trough concentration (Cmin) within the target range (≥15 mg/L). According to bivariable analysis, SOFA score, GGT, fluconazole clearance, Ke, and Vd, were independently associated with a decrease in fluconazole Cmin. The median loading dose required to achieve the Cmin target appeared to be greater in patients with higher SOFA or GGT level and in patients undergoing renal replacement therapy. This study supports recommendation for routine fluconazole therapeutic drug monitoring in ICU patients so as to avoid underexposure, especially if SOFA score is ≥ 7 and/or GGT is ≥ 100 U/L.


Nonpharmacological interventions for the prevention of type 2 diabetes mellitus.
During the past decade, improved understanding of the pathophysiological mechanisms of diabetes development has resulted in advances in therapeutic concepts, but has also supported the potential for diabetes prevention through nonpharmacological means. At the beginning of the century, we experienced a shift in paradigm, as landmark studies have shown that diabetes mellitus is preventable with lifestyle intervention; moderate changes in diet and physical activity produce a substantial and sustained reduction in the incidence of type 2 diabetes mellitus (T2DM) for individuals with impaired glucose tolerance. This evidence must now be translated into clinical and public-health practice, but translational studies have varied in their ability to replicate the results of clinical trials. This variation reflects a number of challenging barriers for diabetes prevention in real-world clinical practice, which makes it necessary to focus on identifying efficient intervention methods and delivery mechanisms. Research is now focusing on these mechanisms, as well as on developing efficient screening and risk-identification strategies and realistic scenarios for public-health policy to implement diabetes prevention programs. In this Review, we will discuss these mechanisms and will consider the implications of diabetes prevention for public-health strategy and policy.


The ecological distribution of C4 and C3 grasses in the Hawaiian Islands.
Nearly two-thirds of both the native and exotic grasses of the Hawaiian Islands are C4 species. Elevational gradients on the island of Hawaii demonstrate that C4 taxa dominate both species composition and coverage of grasses up to 1,000 m, while C3 taxa predominate above 1,400 m. The elevational transition of dominance between the two metabolic systems is much sharper on a coverage than on a floristic composition basis. Despite the shaded characteristic of the habitat, C4 grasses are the most important group in wet forests at intermediate elevations. The 1,400 m elevation of floristic balance between C4 and C3 grasses corresponds to a low monthly mean minimum temperature of approximately 9° C and a mean maximum temperature for the warmest month of about 21° C. These temperatures are considerably lower than those reported for a latitudinal point of floristic balance in North America, but similar to those indicated by other studies of elevational distributions of tropical grasses.


Non-operative management of solid organ injuries in a middle-income country, how does it stack up?
The first trauma surgery unit in Malaysia was established in 2011. After 10 years, we examine our experience in the management, and outcomes of blunt liver, spleen, and kidney injuries. This is a cross-sectional study of patients with blunt liver, spleen, and kidney injuries in a level 1 trauma centre in Malaysia between January 2018 to June 2021. Patients' characteristics, new injury severity score, organ-specific AAST injury score, type of primary management (operative management [OM], non-operative management [NOM]), causes of failed NOM, management of failed NOM, and outcome of treatment were recorded and analysed. Among 448 patients, 83.9% were male and in the working-age range of 15-64 years old (93.5%). Road traffic crashes made up 92.0% of blunt trauma resulting in 65.5% of isolated organ injuries and 34.5% combined injuries. An overwhelming 84.2% of the patients had major trauma (NISS>15). Three hundred and thirty-four patients (74.6%) underwent initial non-operative management. Patients in the OM group showed lower mean GCS scores (p = 0.022) and higher NISS scores (p < 0.001). High-grade liver and kidney injuries were mostly treated with NOM (p < 0.001). In contradistinction, patients with high-grade spleen injuries had more OM performed (p < 0.001). NOM had been successful in 325 patients (97.3%) with 9 failures. Underlying causes for NOM failure were hemodynamic instability due to secondary bleeding and infectious complications. Overall mortality was 11.2%, which was significantly higher in the OM group (23.7%) than in the NOM group (6.9%). This study represents one of the largest single centre experiences on the blunt liver, spleen, and kidney injuries in Malaysia and South-East Asia. With good selection and adequate resources, non-operative management of blunt liver, spleen, and kidney injuries is a safe and effective therapeutic approach with a high success rate of 97.3%, avoiding the morbidity of unnecessary laparotomies.


Effects of sex hormones on costimulatory molecule expression in multiple sclerosis.
Sex hormones play a central role as modulators of immune responses and autoimmune diseases. We hypothesized that suppression of MS disease during pregnancy may be mediated by sex steroid hormones via regulation of costimulatory molecules such as CD40L or CD80/CD86 (B7-1/B7-2). We tested two sex hormones that are implicated in immune suppression during pregnancy: estriol and progesterone. We also examined whether this regulation is gender-specific or disease-related. PBMC from untreated relapsing remitting multiple sclerosis (RR MS) patients and controls were examined for expression of T cell and monocyte costimulatory molecules following mitogen stimulation in the presence or absence of sex hormones. In the absence of hormones, we confirmed that mitogen stimulation induced significantly more CD40L on the surface of CD4(+)T cells in MS patients compared to controls, and we extend these findings by showing there were no gender differences in induction of CD40L. Although supra-physiologic doses of hormones mildly suppressed CD40L expression on activated T cells, in vitro exposure to typical pregnancy-related physiologic doses of estriol or progesterone showed very little or no suppression of CD40L. On monocytes, neither estriol nor progesterone significantly altered the expression of CD80/CD86. These results suggest that physiologic doses of estriol or progesterone cannot alter CD40L on T cells or CD80/CD86 on monocytes sufficiently to explain the improvement observed in MS during pregnancy. Thus, although amelioration of MS and other autoimmune diseases during pregnancy is thought to be due to increased sex hormones, the present results do not support a role for suppression of costimulation via estriol or progesterone.


Epitope specific immunity elicited by a synthetic streptococcal antigen without carrier or adjuvant.
A polypeptide fragment of type 24 streptococcal M protein (pep M24) has been shown to raise protective anti-streptococcal antibodies in rabbits and humans when administered with adjuvants. More recently, such protective antibodies were shown to be evoked by a synthesized 35-residue sub-peptide fragment (S-CB7 synthetic cyanogen bromide fragment 7) of pep M24. We now show that the weak pep M24 immunogen induces high titers of long lasting antibodies when associated with murabutide, a synthetic derivative of MDP (NAcMur-L-Ala-D-Gln-n-butyl-ester) which is currently undergoing clinical trials. We demonstrate also that the polymerized synthetic S-CB7 administered without adjuvant or carrier evokes a strong epitope specific, protective immune response in mice primed with the parent pep M24. A booster dose of polymerized S-CB7 induced antibodies directed specifically against the S-CB7 structure whereas a booster dose of pep M24 evoked antibodies recognizing additional determinants of the whole pep M24 molecule.


Ultrastructural researches on rabbit myxomatosis. Lymphnodal lesions.
Ultrastructural examination of head and neck lymph nodes in rabbits with spontaneous subacute myxomatosis showed fusion of immature reticuloendothelial cells which lead to the formation of polykarocytes. There was no ultrastructural evidence of viral infection of these polykaryocytes. Histiosyncytial lymphadenitis can be considered a specific lesion of myxomatosis.


Newborn screening for Pompe disease in Japan.
Pompe disease is caused by a deficiency of acid alpha-glucosidase (GAA) that results in glycogen accumulation, primarily in muscle. Newborn screening (NBS) for Pompe disease has been initiated in Taiwan and is reportedly successful. However, the comparatively high frequency of pseudodeficiency allele makes NBS for Pompe disease complicated in Taiwan. To investigate the feasibility of NBS for Pompe disease in Japan, we obtained dried blood spots (DBSs) from 496 healthy Japanese controls, 29 Japanese patients with Pompe disease, and five obligate carriers, and assayed GAA activity under the following conditions: (1) total GAA measured at pH 3.8, (2) GAA measured at pH 3.8 in the presence of acarbose, and (3) neutral glucosidase activity (NAG) measured at pH 7.0 without acarbose. The % inhibition and NAG/GAA ratio were calculated. For screening, samples with GAA<8% of the normal mean, % inhibition>60%, and NAG/GAA ratio>30 were considered to be positive. Two false positive cases (0.3%) were found, one was a healthy homozygote of pseudodeficiency allele (c.1726G>A). The low false-positive rate suggests that NBS for Pompe disease is feasible in Japan.


Echocardiography of the aortic root.
The anterior and posterior walls of the aortic root are recognized as a pair of parallel linear signals which move anteriorly in systole and posteriorly in diastole. Valve cusps appear as thin lines which move briskly toward the periphery of the aortic lumen in systole and coapt in the middle in diastole producing a box-like configuration. Cusp calcification results in the appearance of multiple, linear echoes within the aortic root. Mild aortic stenosis is characterized by lightly calcified leaflets whereas heavy calcification, which completely obscures cusp motion, signifies severe stenosis. Aortic aneurysms produce significant enlargement of the aortic root image; marked widening of the aortic walls indicates the presence of aortic root dissection, but there are important limitations and pitfalls in the diagnosis of this condition. A markedly eccentric diastolic cusp position within the aortic lumen resulting in asymmetric images of the leaflets in systole is the hallmark of a bicuspid aortic valve. An abrupt premature closure of the valve leaflets in early systole is typical of subaortic membranous stenosis. In tetralogy of Fallot the aortic root is dilated and overrides the ventricular septum.


A novel algorithm for precise identification of spikes in extracellularly recorded neuronal signals.
The spike represents the fundamental bit of information transmitted by the neurons within a network in order to communicate. Then, given the importance of the spike rate as well as the spike time for coding the activity generated at the level of a cell assembly, a relevant issue in extracellular electrophysiology is the correct identification of the spike in multisite recordings from brain areas or neuronal networks. In this paper, we present a novel spike detection algorithm, named Precise Timing Spike Detection (PTSD), aimed at (i) reducing the number of false positives and false negatives, in order to optimize the rate code, and (ii) improving the time precision of the identified spike, in order to optimize the spike timing. The PTSD algorithm considers consecutive portions of the signal and looks for the Relative Maximum/Minimum whose peak-to-peak amplitude is above a defined differential threshold and responds to specific requirements. To validate the algorithm, the presented spike detection has been compared with other methods either commercially available or proposed in the literature by using two benchmarking procedures: (i) visual inspection by a group of experts of a portion of signal recorded from a rat cortical culture and (ii) detection of the spikes generated by a realistic neuronal network model. In both cases our algorithm produced the best performances in terms of efficiency and precision. The ROC curve analysis further proved that the best results are reached by the application of the PTSD.


Efficacy and Safety of Paliperidone Palmitate Treatment in Patients With Schizophrenia: A Real-World Multicenter, Retrospective, Mirror-Image Study.
The aim of the study was to assess efficacy and safety of paliperidone palmitate (PP) in schizophrenic patients using real-life data. This national, multicenter, retrospective, and mirror-image study was performed reviewing the medical records of patients in 18 centers. Adult schizophrenic patients receiving PP treatment (n = 205) were enrolled. Patients' data covering the last 12 months before the initial PP injection and the period until the end of study with at least 12 months after the initial PP injection were evaluated. Patients' characteristics, scale scores, and adverse events were recorded. Nonadherence to prior medication was the most frequent reason for switching to PP treatment. Comparing with the period before PP treatment, the rate of patients visiting the hospital for relapse (79.5% vs 28.9%, P < 0.001) and the median number of hospitalizations (2 vs 0, P < 0.001) were lower during PP treatment. During PP treatment, the Positive and Negative Syndrome Scale score decreased by 20% or more (response to treatment) in 75.7% of the patients. The frequency of adverse events did not differ between the period before and during PP treatment. Improvement in functionality was higher in those with disease duration of 5 years or less. Paliperidone palmitate is effective and safe in treatment of schizophrenic patients and in switching to PP treatment in patients with schizophrenia, which reduced the percentage of patients admitted to the hospital for relapse and the median number hospitalization, and has positive effects on functionality.


Transdermal fentanyl and its use in ovine surgery.
Fentanyl delivered via a transdermal patch has the potential to decrease the need for post-operative handling of sheep undergoing surgical procedures. Two studies were performed to test: (1) the ideal timing for the application of pre-emptive analgesic patches and (2) the efficacy of a 2 µg/kg/h dose, as extrapolated from other species. The first study had sheep divided into two groups. Group 1 had a fentanyl patch applied for 24 h prior to a patch change and group 2 had a fentanyl patch applied 72 h prior to a change. The second study applied the results obtained in the first and tested the efficacy of 2 µg/kg/h as an effective dose in an orthopaedic surgical environment. Results indicated that the ideal time for pre-emptive fentanyl patch administration is 24-36 h prior to surgery and that 2 µg/kg/h is an effective minimum therapeutic dose rate for the use of fentanyl as an analgesic in an orthopaedic surgical environment.


Short-term clinical and osteoimmunological effects of scaling and root planing complemented by simple or repeated laser phototherapy in chronic periodontitis.
The aim of this study was to evaluate the clinical, anti-inflammatory, and osteoimmunological benefits of the single (PT) and repeated laser phototherapy (rPT) as an adjunctive treatment of inflamed periodontal tissue. Twenty-seven patients with chronic periodontitis were randomly divided into three groups of nine patients each in order to undergo scaling and root planing (SRP), SRP followed by one session of adjunctive PT (Day 1; SRP + PT), or SRP followed by adjunctive repeated PT five times in 2 weeks (Days 1, 2, 4, 7, and 11; SRP + rPT). For phototherapy session, a diode laser (λ = 670 nm, 200 mW, 60 s/tooth) was applied into the sulcus. Clinical parameters, including full-mouth plaque score, full-mouth bleeding score, probing pocket depth, and clinical attachment level were recorded. Samples of gingival crevicular fluid (GCF) were taken at baseline, 4, and 8 weeks after treatment. Interleukin 1 beta (IL-1β), tumor necrosis factor alpha (TNF-α), receptor activator of nuclear factor κΒ ligand (RANKL), and osteoprotegerin (OPG) levels in the collected GCF were measured. PT used in a single or repeated doses, does not produce a significant reduction in the clinical parameters essayed (p > 0.05). Levels of IL-1β in GCF were significantly reduced in SRP + PT and SRP + rPT groups compared with the SRP group (p < 0.05). However, the SRP + rPT group showed a significant reduction of pro-inflammatory cytokine TNF-α and RANKL/OPG ratio at 4 weeks post-treatment compared with the SRP + PT and SRP groups (p < 0.05). SRP + PT group also showed a significant reduction in TNF-α and RANKL/OPG ratio at 8 weeks post-treatment compared with the SRP group (p < 0.05). PT exerts a biostimulative effect on the periodontal tissue. Multiple sessions of PT showed a faster and greater tendency to reduce proinflammatory mediators and RANKL/OPG ratio.


Effects of statins beyond lipid lowering: potential for clinical benefits.
The role of statin drugs in the reduction of serum lipids has been well documented. More recently, evidence suggesting that statins may positively impact many organ systems and disease states independent of lipid reduction has emerged. The term "pleiotropic effects" has been used to refer to these properties. We reviewed the evidence exploring such potential effects. A search of the MEDLINE database was conducted for articles published between 1985 to 2005 on the pleiotropic and the lipid-lowering independent effects of statin drugs. The search terms "statin", "HMG-CoA reductase inhibitor", "pleiotropic effects", and "inflammation" were used. English language articles were selected for inclusion along with selected cross-references. Numerous animal and clinical studies support the presence of a spectrum of beneficial effects for statins that are independent of their lipid-lowering properties. These effects are mediated by a variety of mechanisms and they suggest that the therapeutic role of statins may expand. Statins have shown great promise beyond their lipid-lowering effects. Ongoing and future studies will help to further clarify the potential clinical impact of these "pleiotropic effects".


Biphasic changes in the levels of poly(ADP-ribose) polymerase-1 and caspase 3 in the immature brain following hypoxia-ischemia.
Poly(ADP-ribose) polymerase-1 (PARP-1) is a DNA repair-associated enzyme that has multiple roles in cell death. This study examined the involvement of PARP-1 in ischemic brain injury in the 7-day old rat, 0.5-48 h after unilateral carotid artery ligation and 2 h of 7.8% oxygen. This experimental paradigm produced a mild to moderate injury; 40-67% of animals in the ligated groups had histological evidence of neuronal death. Ipsilateral cortical injury was seen at all survival times, while mild contralateral cortical injury was seen only at the 1h survival time. Hippocampal injury was delayed relative to the cortex and did not show a biphasic pattern. Immunohistochemical staining for PARP showed bilateral increased staining as early as 1 h post-hypoxia. PARP staining at early time periods was most intense in layer V of cortex, but did not demonstrate a pattern of cell clusters or columns. Ipsilateral PARP-1 levels quantified by western blotting showed a biphasic pattern of elevation with peaks at 0.5 and 12 h post-hypoxia. Contralateral PARP-1 levels were also elevated at 0.5 and 24 h. PARP activity as determined by immunoreactivity for poly(ADP-ribose) (PAR) was increased ipsilaterally at 0.5, 2 and 12 h survival times. Cortical caspase 3-activity was increased ipsilaterally at 6, 12, and 24 h and contralaterally at 0.5, 1, 2 and 6 h post-hypoxia. There are three main findings in this study. First, changes in the distribution and amount of cell death correlate well with measured PARP-1 levels after hypoxia-ischemia, and both display biphasic characteristics. Second, there are significant early, transient morphological and biochemical changes in the contralateral cortex after neonatal hypoxia-ischemia due to unilateral permanent occlusion of a carotid artery followed by 2 h of systemic hypoxia. Third, variability in the responses of individual pups to hypoxia-ischemia suggests the presence of unidentified confounding factors.


Can multiple sclerosis be cured? A case of highly active relapsing multiple sclerosis treated with autologous hematopoietic stem-cell transplantation 13 years ago.
A 26-year-old man, with five years of highly active deteriorating relapsing multiple sclerosis (MS), unresponsive to conventional therapy, was treated with autologous hematopoietic stem-cell transplantation (AHSCT) 13 years ago. Since then the patient had no clinical or neuroradiological disease activity and disability progression was halted. Repeated analysis of CSF revealed reduced levels of inflammatory biomarkers and the neurofilament light protein level was normalized indicating no further axonal degeneration. The patient is socio-economic independent, is working full time, and has become a father. Measures of quality of life and cognition did not indicate further deterioration. Long-term follow-up has not shown any signs of active disease suggesting that AHSCT may be a cure for MS.


Cryo-EM structure of phosphodiesterase 6 reveals insights into the allosteric regulation of type I phosphodiesterases.
Cyclic nucleotide phosphodiesterases (PDEs) work in conjunction with adenylate/guanylate cyclases to regulate the key second messengers of G protein-coupled receptor signaling. Previous attempts to determine the full-length structure of PDE family members at high-resolution have been hindered by structural flexibility, especially in their linker regions and N- and C-terminal ends. Therefore, most structure-activity relationship studies have so far focused on truncated and conserved catalytic domains rather than the regulatory domains that allosterically govern the activity of most PDEs. Here, we used single-particle cryo-electron microscopy to determine the structure of the full-length PDE6αβ2γ complex. The final density map resolved at 3.4 Å reveals several previously unseen structural features, including a coiled N-terminal domain and the interface of PDE6γ subunits with the PDE6αβ heterodimer. Comparison of the PDE6αβ2γ complex with the closed state of PDE2A sheds light on the conformational changes associated with the allosteric activation of type I PDEs.


Pyrolytic carbon proximal interphalangeal joint resurfacing arthroplasty.
To evaluate the clinical results of a pyrolytic carbon resurfacing proximal interphalangeal joint (PIPJ) arthroplasty in patients with osteoarthritis. A retrospective review of 18 PIPJ arthroplasties in 8 women with severe osteoarthritis performed by a single surgeon was completed with an average follow-up period of 13 months. Clinical assessment included range of motion (ROM), stability, and deformity. Radiographs were reviewed for evidence of loosening, subsidence, fracture, and osseointegration. Six patients, representing 16 joints, answered a questionnaire regarding pain relief, appearance, and overall satisfaction with the arthroplasty. Complications also were recorded. The average preoperative ROM was 10 degrees to 63 degrees, and the average postoperative ROM was 18 degrees to 71 degrees. Although the average arc of motion was unchanged, 9 joints had an increase in ROM and 9 joints had a decrease in ROM. All joints were stable laterally. Radiographic review indicated 2 joints with loosening at 4 months after surgery. Complications included 8 squeaky joints, 5 joint contractures, and 2 dislocations. Pain was relieved completely in 8 joints, and the pain rating on a visual analog scale was 3.6 out of 10 for the 8 patients who had residual pain. Patients were satisfied completely with the results of 9 joints. Although there was residual deformity in 4 joints, patients believed that 15 of 16 joints had improved in appearance. Five of 6 patients responded that they would have the surgery again. There have been no secondary procedures performed by us. The insertion of pyrolytic carbon implants for PIPJ arthroplasty is a technically demanding procedure, but it has the potential to achieve pain relief, stability, satisfactory ROM, and correction of the deformity; however, the results in this review were unpredictable and may not be superior to those achieved with other methods of arthroplasty. Therapeutic, Level IV.


Influence of the interface on the optical activity of confined glucose films.
We report on the time evolution of the optical activity of a thinning liquid film containing glucose, and confined between two glass slides. This dynamics strongly depends on the presence of surfactant molecules. With sodium dodecyl sulfate (SDS), we evidence favorable interactions of sugar molecules with the sulfate group. As previously observed for a freely suspended soap film in the air (see Emile et al., 2013), this corresponds to an anchoring of glucose molecules at the interface. For glucose alone, we also highlight a molecular rearrangement that is not instantaneous and occurs after several minutes. This interfacial organization leads to an unusual giant optical activity that is different with or without SDS. Molecular simulations confirm the anchoring of the glucose molecules at the glass/liquid interface, and show a different molecular orientation in each case.


Investigation of FRMPD4 variants associated with X-linked epilepsy.
The etiology of unexplained epilepsy in most patients remains unclear. Variants of FRMPD4 are suggested to be associated with neurodevelopmental disorders. Therefore, we screened for disease-causing FRMPD4 variants in patients with epilepsy. Trios-based whole-exome sequencing was conducted on a cohort of 85 patients with unexplained epilepsy, their parents, and extended family members. Additional cases with FRMPD4 variants were identified from the China Epilepsy Gene Matching Platform V.1.0. The frequency of variants was analyzed, and their subregional effects were predicted using in silico tools. The genotype-phenotype correlation of the newly defined causative genes and protein stability were analyzed using I-Mutant V.3.0 and Grantham scores. Two novel missense variants of FRMPD4 were identified in two families. Using the gene matching platform, we identified three additional novel missense variants. These variants presented at low or no allele frequencies in the gnomAD database. All the variants were located outside the three FRMPD4 main domains (WW, PDZ, and FERM). In silico analyses revealed that the variants were damaging and were predicted to be the least stable. All patients eventually became seizure-free. Eight of the 21 patients with FRMPD4 variants had epilepsy, of which five (63%) had missense variants located outside the domains, two had deletions involving exon 2, and one had a frameshift variant located outside the domains. Patients with epilepsy caused by missense variants were often free of intellectual disabilities (4/5), whereas patients with epilepsy caused by truncated variants had intellectual disabilities and structural brain abnormalities (3/3). The FRMPD4 gene is potentially associated with epilepsy. The genotype-phenotype correlation of FRMPD4 variants indicated that differences in variant types and locations of FRMPD4 may explain their phenotypic variation.


Male aromatase-knockout mice exhibit normal levels of activity, anxiety and "depressive-like" symptomatology.
It is well known that estradiol derived from neural aromatization of testosterone plays a crucial role in the development of the male brain and the display of sexual behaviors in adulthood. It was recently found that male aromatase knockout mice (ArKO) deficient in estradiol due to a mutation in the aromatase gene have general deficits in coital behavior and are sexually less motivated. We wondered whether these behavioral deficits of ArKO males could be related to changes in activity, exploration, anxiety and "depressive-like" symptomatology. ArKO and wild type (WT) males were subjected to open field (OF), elevated plus maze (EPM), and forced swim tests (FST), after being exposed or not to chronic mild stress (CMS). CMS was used to evaluate the impact of chronic stressful procedures and to unveil possible differences between genotypes. There was no effect of genotype on OF, EPM and FST behavioral parameters. WT and ArKO mice exposed to CMS or not exhibited the same behavioral profile during these three types of tests. However, all CMS-exposed mice (ArKO and WT) spent less time in the center of the EPM. Additionally, floating duration measured in the FST increased between two tests in both WT and ArKO mice, though that increase was less prominent in mice previously subjected to CMS than in controls. Therefore, both ArKO and WT males displayed the same behavior and had the same response to CMS however CMS exposure slightly modified the behavior displayed by mice of both genotypes in the FST and EPM paradigms. These results show that ArKO males display normal levels of activity, exploration, anxiety and "depressive-like" symptomatology and thus their deficits in sexual behavior are specific in nature and do not result indirectly from other behavioral changes.


STING-IRG1 inhibits liver metastasis of colorectal cancer by regulating the polarization of tumor-associated macrophages.
The liver is the main site of colorectal cancer (CRC) metastasis. Tumor-associated macrophages (TAMs) play a key role in tumor metastasis. Therefore, modulating the function of tumor-associated macrophages is a potential therapeutic strategy to control tumor metastasis. We found in vivo experiments that the activation of STING inhibited CRC liver metastasis in model mice and affected the macrophage phenotype in the tumor microenvironment. Mechanistically, STING affects TAM polarization and regulates macrophage function through IRG1. And STING activates IRG1 to promote the nuclear translocation of TFEB, affecting the ability of macrophages to suppress tumor metastasis.Therefore, this study highlights the critical role of the STING-IRG1 axis on TAM reprogramming and its role in the process of tumor liver metastasis, which may provide a promising therapeutic strategy for CRC liver metastasis.


Effects of atropine and propranolol on the respiratory, circulatory, and ECG responses to high altitude in man.
In order to analyze the respiratory, cardiovascular, and ECG responses to acute hypoxic hypoxia, three experimental series were carried out in a randomized manner on 11 healthy, unacclimatized volunteers at rest during standardized stepwise exposure to 6000 m (PAO2 35.2 +/- 2.9 mmHg/4.7 +/- 0.4 kPa) in a low-pressure chamber a) without (control), b) with propranolol, and c) with atropine combined with propranolol. The results show that hypoxic hyperventilation and alveolar gases are not affected by activation of the sympatho-adrenal axis or by parasympathetic withdrawal. Sympathetic activity, however, increases heart rate, stroke volume (pulse pressure), estimated cardiac output and systolic blood pressure, whereas decreased parasympathetic activity increases heart rate and estimated cardiac output, but lowers stroke volume. The fall in peripheral resistance, observed during progressive hypoxia in all three groups, is thought to be due to hypoxia-induced depression of the vasomotor center. At altitude catecholamine secretion and vagal withdrawal synergistically account in the ECG for the R-R shortening, the relative Q-T lengthening, the elevation of the P wave and the ST-T flattening. Probable direct hypoxic effects on the heart are the increase in P-Q duration and the minor but still significant depression of the T wave. It is concluded that at altitude increased sympatho-adrenal and decreased parasympathetic activity is without effect on hypoxic hyperventilation, but accounts for most of the cardiovascular and ECG changes. Diminution of sympathetic activity and imminent vagotonia arising after acute ascent to 6000 m probably reflect hypoxia of the central nervous system.


Effect of prostaglandins on cyclic nucleotide levels in cultured keratinocytes.
Ginea pig ear epidermal cells (keratinocytes) were established in primary cultures using trypsin, and treated in their proliferative phase of growth with prostaglandins E1, D1, F1 alpha, E2, D2, or F2 alpha. This phase is induced by the addition of retinoic acid during cell plating. Intracellular content of cAMP and cGMP was measured by radioimmunoassay at various times after treatment. Maximum stimulation of cAMP levels was observed with PGD2, smaller increases with PGE2 and relatively transient rises with PGF2 alpha which were of low significance, but confirm earlier data. Similar results were observed with PGD1, PGE1, and PGF1 alpha with smaller increases. The effects of D and E PGs were biphasic. Significant increases in cGMP were immediately observed with PGD2 and PGE2. With PGF2 alpha, maximum cGMP levels were noted after some delay. All PGs tested showed some effect in elevating cyclic nucleotides in keratinocytes. The most striking result was the increase in cAMP on PGD2 treatment.


Evaluation of speech disorders in children with cleft lip and palate.
We investigated the reliability of nasopharyngoscopy and auditory perception, two common clinical methods employed in examining the speech pathology of children with cleft lip and palate. Nasopharyngoscopy was performed to assess velopharyngeal closure function and nasopharyngeal morphology. The auditory examination evaluated nasality and other speech disorders such as articulatory tension, shift in articulation, and sigmatism. The study was based on the audio and video recordings of twelve patients (9.5 +/- 0.5 years) after surgical rehabilitation of their cleft lip and palate. The speech sample consisted of reading a standardized sequence of words. The recordings were analyzed by several examiners with different experience in the evaluation procedure at two time-points. Inter-rater and intra-rater reliability was determined by Cohen's Kappa coefficient and by estimation of the 95% intervals of confidence. Analysis of the visual and auditory-perceptual findings by the experienced raters was highly reliable. However, the less experienced raters' results showed greater variability, as did morphological evaluation in both groups. Comparison between visual and auditory evaluations concerning hypernasality resulted in little correlation. These two subjective methods of evaluation are recommended because of their high reliability with experienced raters. Our results suggest that "experience" is an essential criterion in determining the structural quality of the morphological and functional assessment of typical speech pathologies in children with cleft lip and palate. In addition, the data demonstrate the necessity of special multidisciplinary rehabilitation teams in so-called cleft centers.


Age as a moderator in the interplay among locus of control, coping, and quality of life of people with chronic pain.
Identifying the factors that determine the quality of life of patients with chronic pain is an integral part of developing interventions to reduce the negative impact of persistent pain. Locus of control (LoC) could play an important role in adaptation to prolonged pain, but the results of studies are inconsistent. We examined the link between pain LoC and quality of life. Moreover, we investigated whether the relationship between LoC and quality of life is mediated by passive and active coping, and whether age moderates the LoC-coping relationship. The study was cross-sectional, and variables (internal, chance and powerful-others LoC, pain coping strategies, average pain intensity, and quality of life) were assessed via questionnaires in a sample of 594 individuals (67% females) with chronic pain who were 18-72 (mean: 36) years of age. Mediation and moderated mediation analyses were conducted. Internal and external LoC were associated, respectively, with better and with worse quality of life. Passive coping mediated the association between the powerful-others dimension of LoC and poor quality of life. Additionally, indirect effects of internal LoC on quality of life via passive and active coping were found. The relationship between the powerful-others dimension of LoC and coping was stronger for middle-aged and older individuals than for younger individuals. This study contributes to a better understanding of the mechanisms linking LoC with quality of life of patients with chronic pain. Depending on the age, control beliefs might translate differently into strategies used to cope with pain, and thus into quality of life.


The vascular orienting response and the law of initial values.
Vascular responses following exposure to the experimental situation (a type orienting reflex) were evaluated in 6 male subjects. Bilateral skin temperature was recorded from the head and finger regions for the duration of the experimental session. The interaction of Location X Trial (p less than or equal to 0.002) showed reliable differences between the head and finger sites and the left and right forehead sites early in the session followed by differential rates of change during the session across sites. The results support the recent claim for the importance of the law of initial values in finger temperature research and extend the findings to multiple site comparisons in the absence of hemispheric task demands. The vascular orienting reflex to the experimental context may augment initial value differences among recording sites.


A study of yeasts during the delignification and fungal transformation of wood into cattle feed in Chilean rain forest.
In Chilean rain forest the presence and distribution of yeasts were studied during the fungal transformation of wood, producing a partially delignified material used as cattle feed ("huempe"). A total of 68 yeast species was reported, including a noticeable proportions of basidiomycetous and xylose-assimilating strains, the latter related to the increased availability of this sugar in the decayed wood. The results of the mathematic comparison of taxonomic data of 327 strains showed a delimitation of sharp clusters corresponding to different species, including several new species described from this substrate, and genera, as Rhodotorula and Cryptococcus. At the initial stages of wood decay, characterized by the presence of Candida species, yeast diversity was low. The highest values were found in the medium stage of decay, used as feed, with an important presence of the genera Apiotrichum, Rhodotorula, Cryptococcus and Schizoblastosporion. After establishing a non-linear ordination from Euclidean distances between samples, based on yeast abundances, a relationship was observed between the populations developing at the different stages of wood decay by Ganoderma applanatum. A succession of yeast species was demonstrated during wood degradation by this white-rot fungus.


Enhanced taupathy and AD-like pathology in aged primate brains decades after infantile exposure to lead (Pb).
Late Onset Alzheimer Disease (LOAD) constitutes the majority of AD cases (∼90%). Amyloidosis and tau pathology, which are present in AD brains, appear to be sporadic in nature. We have previously shown that infantile lead (Pb) exposure is associated with a change in the expression and regulation of the amyloid precursor protein (APP) and its beta amyloid (Aβ) products in old age. Here we report that infantile Pb exposure elevated the mRNA and protein levels of tau as well as its transcriptional regulators namely specificity protein 1 and 3 (Sp1 and Sp3) in aged primates. These changes were also accompanied by an enhancement in site-specific tau phosphorylation as well as an increase in the mRNA and protein levels of cyclin dependent kinase 5 (cdk5). There was also a change in the protein ratio of p35/p25 with more Serine/Threonine phosphatase activity present in aged primates exposed to Pb as infants. These molecular alterations favored abundant tau phosphorylation and immunoreactivity in the frontal cortex of aged primates with prior Pb exposure. These findings provide more evidence that neurodegenerative diseases may be products of environmental influences that occur during the development.


Exchange of cytochrome b5 between phospholipid vesicles.
Detergent-extracted cytochrome b5, which binds readily to phosphatidylcholine vesicles, has been shown to exchange between vesicles by the following experiments. When preformed cytochrome b5-vesicle complexes are incubated with fresh vesicles a new species arises which sediments in the analytical ultracentrifuge with a rate intermediate between those of the original components. When the same mixture is subjected to free boundary electrophoresis no slow moving component corresponding to pure vesicles is seen. The results of sucrose density gradient centrifugation are also consistent with the conclusion that cytochrome b5 exchanges between vesicles. The possibility that the above results were produced by vesicle fusion or aggregation was eliminated by light-scattering studies and a direct assay for vesicle fusion. The ability of cytochrome b5 to exchange between lipid structures has important implications not only in the cytochrome b5-lipid system but also in enzymatic reactions in which cytochrome b5 is involved.


Strategies for addressing long-term issues after institutionalization.
As a result of their preadoptive histories and experiences, internationally adopted children, especially those with a history of institutionalization, can present with a complex profile of developmental and behavioral issues. Although many children demonstrate significant recovery and resilience after joining their adoptive homes, others go on to have mild or sometimes more severe developmental and behavioral issues. This high-risk population requires comprehensive evaluation, monitoring, and interventions by professionals with expertise in child development and knowledge of the impact of institutionalized care to support optimal developmental and behavioral outcomes for children and their families. This article focuses on strategies for evaluation and management of long-term developmental and/or behavioral difficulties exhibited by postinstitutionalized children.


Cell-shape assemblage and nanostructure of akaganéite bioformed in FeCl2 solutions.
Akaganéite (β-FeOOH) with a tunnel structure typically occupied by chloride can undergo anion-exchange reactions in aqueous solutions for pollutant removal. In this work, we studied bioformation of akaganéite in FeCl2 solutions with Acidithiobacillus ferrooxidans cells at pH 2.9, during 36-h incubation. The obtained products were analyzed and characterized by XRD, FTIR, EDS, FETEM, and HRTEM. Results showed that in acidic media with pH 2.9, the cells facilitated ferrous biooxidation and ferric precipitation. The resulting ferric precipitates were identified as polycrystalline akaganéite powders and had a morphology of nanospindles with a length of less 100 nm. The correlatively chemical formula for akaganéite collected at 1 h was reckoned as Fe8O8(OH)6.71(Cl)1.29 with 6.6% Cl. It was observed that ferric precipitates along exterior structures of cells or their extruded organic polymers grew and assembled into cellular shape. The evolved cell-shape akaganéite assemblages were twice of cells (about 2 µm) in size. These results could contribute to understanding of laboratorial bioformation of akaganéite and its biomineralization in acidic environments and promoting its practical applications.


Parecoxib sodium administered over several days reduces pain after gynecologic surgery via laparotomy.
To assess the analgesic efficacy of a multidose, multiday regimen of intravenous (IV) parecoxib sodium (parecoxib). Multicenter, randomized, double-blind, placebo-controlled, parallel-group trial. Postoperative recovery area and inpatient care facility. 422 patients who had undergone gynecologic surgery via laparotomy participated (day 1), and 414 patients were randomized (day 2). After surgery on day 1, all patients received parecoxib 40 mg (IV), followed by 20 mg (IV) one to 12 hours later; patients were then randomized to receive parecoxib 20 mg (IV) twice daily (n = 211) or placebo (IV) twice daily (n = 203) on days 2 to 5. Patients were permitted rescue medication as needed. Primary efficacy measures were summed pain intensity through 24 hours (SPI-24) and Patient's Global Evaluation of Study Medication on days 2 and 3. In the parecoxib treatment group, 24-hour summed pain intensity scores were significantly lower than in the placebo treatment group (P < 0.001) on days 2 and 3. More patients in the parecoxib treatment group rated their treatment as "excellent" or "good" using the Patient's Global Evaluation of Study Medication (P < 0.001) on days 2 and 3. Patients treated with parecoxib had lower pain intensity and consumed less rescue medication compared with the placebo-treated patients. Multidose parecoxib was well tolerated over several days and provided improved pain control after gynecologic surgery.


Estimated Cost-effectiveness of Medical Therapy, Sleeve Gastrectomy, and Gastric Bypass in Patients With Severe Obesity and Type 2 Diabetes.
Bariatric surgery is recommended for patients with severe obesity (body mass index ≥40) and type 2 diabetes (T2D). However, the most cost-effective treatment remains unclear and may depend on the patient's T2D severity. To estimate the cost-effectiveness of medical therapy, sleeve gastrectomy (SG), and Roux-en-Y gastric bypass (RYGB) among patients with severe obesity and T2D, stratified by T2D severity. This economic evaluation used a microsimulation model to project health and cost outcomes of medical therapy, SG, and RYGB over 5 years. Time horizons varied between 10 and 30 years in sensitivity analyses. Model inputs were derived from clinical trials, large cohort studies, national databases, and published literature. Probabilistic sampling of model inputs accounted for parameter uncertainty. Estimates of US adults with severe obesity and T2D were derived from the National Health and Nutrition Examination Survey. Data analysis was performed from January 2020 to August 2021. Medical therapy, SG, and RYGB. Quality-adjusted life-years (QALYs), costs (in 2020 US dollars), and incremental cost-effectiveness ratios (ICERs) were projected, with future cost and QALYs discounted 3.0% annually. A strategy was deemed cost-effective if the ICER was less than $100 000 per QALY. The preferred strategy resulted in the greatest number of QALYs gained while being cost-effective. The model simulated 1000 cohorts of 10 000 patients, of whom 16% had mild T2D, 56% had moderate T2D, and 28% had severe T2D at baseline. The mean age of simulated patients was 54.6 years (95% CI, 54.2-55.0 years), 61.6% (95% CI, 60.1%-63.4%) were female, and 65.1% (95% CI, 63.6%-66.7%) were non-Hispanic White. Compared with medical therapy over 5 years, RYGB was associated with the most QALYs gained in the overall population (mean, 0.44 QALY; 95% CI, 0.21-0.86 QALY) and when stratified by baseline T2D severity: mild (mean, 0.59 QALY; 95% CI, 0.35-0.98 QALY), moderate (mean, 0.50 QALY; 95% CI, 0.25-0.88 QALY), and severe (mean, 0.30 QALY; 95% CI, 0.07-0.79 QALY). RYGB was the preferred strategy in the overall population (ICER, $46 877 per QALY; 83.0% probability preferred) and when stratified by baseline T2D severity: mild (ICER, $36 479 per QALY; 73.7% probability preferred), moderate (ICER, $37 056 per QALY; 85.6% probability preferred), and severe (ICER, $98 940 per QALY; 40.2% probability preferred). The cost-effectiveness of RYGB improved over a longer time horizon. These findings suggest that the effectiveness and cost-effectiveness of bariatric surgery vary by baseline severity of T2D. Over a 5-year time horizon, RYGB is projected to be the preferred treatment strategy for patients with severe obesity regardless of baseline T2D severity.


Ultrasound Evaluation in Female Infertility: Part 2, the Uterus and Implantation of the Embryo.
This article discusses the role of ultrasound in assessing endometrial and uterine factors affecting the implantation of the embryo. Modern ultrasound equipment includes advanced Doppler and three-dimensional facilities that refine our understanding of factors that affect implantation such as endometrial blood flow. Three dimensional scanning is principally used to define the relationship of fibroids to the endometrial cavity, the position of polyps and other anatomic structures relative to the implantation site, to diagnose adenomyosis, to reveal and classify congenital uterine malformations and in the differential diagnosis od ovarian and extraovarian cystic structures in the pelvis.


Effect of mannitol-based reduced-volume hydration on kidney function in concomitant cisplatin-based chemoradiation for head-and-neck squamous cell carcinoma.
Nephrotoxicity is frequent in cisplatin-based chemoradiation of head and neck squamous cell carcinoma (HNSCC). Toxicity outcomes and achieved cisplatin-doses after change of departmental hydration policy are presented. We performed a retrospective time-series analysis of HNSCC patients undergoing chemoradiation with conventional hydration (CH) between 01/2017 and 09/2018 versus shorter hydration with mannitol (SHM) between 09/2018 and 08/2019 to compare the rate of acute kidney injury (AKI) and cumulative cisplatin dose. Among 113 HNSCC patients, SHM (n = 35) in comparison to CH (n = 78) correlated with less AKI (54.3% vs. 74.4%; p = 0.034) and higher cisplatin doses (82.9% vs. 61.5% ≥200 mg/m2 ; p = 0.025). AKI ≥grade 2 was lower with SHM (2.9% vs. CH: 22.8%; p = 0.01). AKI occurred more frequently in females (92.6% vs. males: 60.5%, p = 0.002). Females received lower cumulative cisplatin doses (51.9% vs. males: 73.3%; p = 0.037). We observed less AKI and higher cumulative chemotherapy doses with SHM. Female patients were at higher risk of AKI.


Identification of D-sorbitol 3-phosphate in the normal and diabetic mammalian lens.
The 31P NMR spectra of mammalian lenses show, in addition to previously identified compounds such as ATP, Pi, glycerophosphorylcholine, and alpha-glycerophosphate, an unusual phosphorylated metabolite resonating at 6.5 ppm. The concentration of this compound increases manyfold in the lenses of diabetic rats concomitant with activation of the aldose reductase pathway. We have purified this material and have identified it as D-sorbitol 3-phosphate. It appears likely that this unusual metabolite of sorbitol may reflect or be part of the metabolic aberration of diabetes in the lens.


Laparoscopic adjustable gastric banding: 1,014 consecutive cases.
The purpose of this study was to examine 1,014 consecutive laparoscopic adjustable gastric banding (LAGB) procedures with up to 48 months of followup, including evolution and changes in surgical technique, learning curve issues, weight loss outcomes, and complications. Between October 2000 and December 2004, 1,014 consecutive patients (81.8% women, mean age 42.3 years, mean body mass index 47.7 +/- 8.6 kg/m(2)) underwent LAGB operation at our center. Perigastric dissection was used in the first 44 patients; pars flaccida technique was used for the latter 970 patients. Fluoroscopy-guided adjustments were performed and patients received intensive followup. Excess weight loss at 12, 24, 36, and 48 months was 40.5 +/- 17%, 52.9 +/- 19.5%, 62 +/- 20.9%, and 64.3 +/- 19%, respectively, with data available in > 85% of patients who had reached each of the time intervals. Patients with lower preoperative body mass index had higher excess weight loss initially, but this difference was not apparent at 3 and 4 years' followup. At 36 and 48 months, respectively, 73.5% and 75% of patients had > 50% excess weight loss. Perigastric dissection led to 9 of 44 (20.5%) slippages, compared with 14 of 970 (1.4%) with pars flaccida technique. Other complications included 2 erosions (0.2%), 5 tubing breaks (0.5%), 7 access port problems (0.7%), and 14 acute stoma obstructions (1.4%). Eight (0.8%) bands were explanted. No deaths occurred. LAGB can achieve effective and safe weight loss. Change from perigastric to pars flaccida technique reduced slippage rate. Preoperative body mass index alone was not found to be a predictor of effective weight loss in the longterm.


A global view of undergraduate education in pharmacovigilance.
The aim of this study was to gain insight in current pharmacovigilance educational activities and to gather information on which topics should be included in the undergraduate pharmacovigilance core curriculum. A web-based questionnaire was carried out containing 45 questions divided over four sections between 28 October 2014 and 31 January 2015. Potential participants working in pharmacovigilance and/or providing training in this field were invited via email and a widespread web link and snowball sampling was used to recruit additional participants. The questionnaire was filled out by 307 respondents from 88 different countries with a response rate of 29.3% for the email invitation and an unknown rate for the web link. Respondents were mainly pharmacists and physicians. Currently, lectures are the largest proportion of educational activities and all healthcare profession curricula have a mode of 2 h as number of contact hours per course. Respondents rated clinical aspects as the most important subdomain to be included in the core curriculum with prevention of adverse drug reactions as the most important subtopic. This was followed by communication aspects between parties, with communication between regulatory authorities and healthcare professionals, methodological aspects with causality assessment, and regulatory aspects with benefit-risk assessment. This is similar to subjects addressed in current educational activities with little difference between medical and pharmacy curricula. This study gave a good general impression in current educational activities and the respondents' needs and wishes for future activities worldwide, which both will be used for the development of the undergraduate pharmacovigilance core curriculum.


Audit of internal quality control practice and processes in the south-east of England and suggested regional standards.
Internal quality control (IQC) has a long and well-established role in clinical biochemistry laboratories. However, despite the duration of use, and the publication of several articles detailing best practice, the implementation and use of IQC vary significantly between institutions. Consequently, the North Thames Audit and Quality Assurance Group undertook a region-wide audit of current IQC practice in 2006. On aspects of IQC testing, interpretation and laboratory processes, 54 laboratories in the region were audited. Audit data showed significant variability in all aspects of practice, including IQC frequency, use of appropriate material, statistical processing and grades of staff involved. Some of the variation in practice may affect the effectiveness of laboratory IQC, and thus the adequacy of a laboratory to monitor system performance. Consequently, a set of proposed regional standards have been developed and disseminated, prior to re-audit at a future date.


Transdiaphragmatic intercostal hernia following blunt trauma.
We report a rare case of traumatic transdiaphragmatic intercostal hernia (TDIH) in an 85-year-old women who was transported to our hospital by ambulance after blunt trauma caused by the involvement in a motor vehicle accident. Chest and abdominal computed tomography (CT) revealed a left diaphragmatic rupture with a chest wall hernia involving loops of small intestine. An emergency operation was performed and led to a diagnosis of TDIH. Surgery via a thoracoabdominal incision in the left side was performed to reduce the hernia contents, and the diaphragmatic and intercostal defects were reconstructed by direct suture. CT scans were very helpful in detecting TDIH in this case.


Seasonal activity of ticks on small ruminants in Tamil Nadu State, India.
The seasonal activity of ticks on sheep and goat populations was examined from December 2000 to November 2001 in the state of Tamil Nadu, India. This longitudinal study spread over four seasons and seven agroclimatic zones took into consideration the spectrum of species involved, the levels of infestations, the seasonal epidemiology of ticks and the associated management practices. The most common species of tick spread throughout the state was Haemaphysalis bispinosa followed by Rhipicephalus haemaphysaloides, Hyalomma marginatum isaaci and Hyalomma anatolicum anatolicum with mixed infestations being the rule. Although the infestations were found throughout the year, they were greater during the rainy season and rainfall seemed to be the most important climatic factor affecting seasonal variation. In general, most of the small-ruminant populations carried moderate tick burdens with mixed infestations and this varied with the management practices.


Mipomersen and lomitapide: Two new drugs for the treatment of homozygous familial hypercholesterolemia.
Familial hypercholesterolemia (FH) is a disease associated with very high plasma concentrations of low-density lipoprotein cholesterol (LDL-C) and premature cardiovascular disease. It is difficult in these high risk patients, exposed lifelong to very high LDL-C, to reach target LDL-C concentrations, which require >50% LDL-C reduction, even when on maximally tolerated statin therapy and on apheresis if available. Therefore, there is an unmet need for new therapeutic options for these patients. In 2013 two new drugs were approved for the treatment of homozygous FH, namely the apolipoprotein B synthesis inhibitor mipomersen and the microsomal transfer protein inhibitor lomitapide. Objective of this narrative review is to discuss the available evidence on the safety and efficacy profile of these new drugs.


[Cervical tumoration as consultation symptom. Our experience].
A cervical tumoration is a frequent symptom presented by patients of different ages. Analyse the clinical, diagnostical and treatment aspects of patients affected by cervical tumoration. Retrospective study of a serie of cases during 10 years. A total of 182 patients, affected by cervical tumoration, were analysed. The 60% were men and the 40% women with 45 years average. The benign pathology more frequent was the branchial cyst and the malign were the metastasis of epidermoide carcinoma. The diagnostic and therapeutic procedures utilized are analysed. An anamnesis and a minoutious exploration diminish in great measure the diagnostic possibilities. The TAC and the PAAF are diagnostic methods of great value in the study of a cervical tumoration and facilitate an adequate scheme of treatment, that is essential for a good prognosis.


Detection of inflammation from finger temperature profile in rheumatoid arthritis.
Rheumatoid arthritis (RA) is a chronic inflammatory tissue disease that leads to cartilage, bone, and periarticular tissue damage. This study aimed to investigate whether the use of infrared thermography and measurement of temperature profiles along the hand fingers could detect the inflammation and improve the diagnostic accuracy of the cold provocation test (0 °C for 5 s) and rewarming test (23 °C for180 s) in RA patients. Thirty RA patients (mean age = 49.5 years, standard deviation = 13.0 years) and 22 controls (mean age = 49.8 years, standard deviation = 7.5 years) were studied. Outcomes were the minimal and maximal: baseline temperature (T1), the temperature post-cooling (T2), the temperature post-rewarming (T3), and the Tmax-Tmin along the axis of each finger. The statistical significance was observed for the thumb, index finger, middle finger, and ring finger post-cooling and post-rewarming. Receiver operating characteristics (ROC) analysis to distinguish between the two groups revealed that for the thumb, index finger, middle finger, and ring finger, the area under the ROC curve was statistically significantly (p < 0.05) post-cooling. The cold provocation test used in this study discriminates between RA patients and controls and detects an inflammation in RA patients by the measurement of temperature profiles along the fingers using an infrared camera. Graphical abstract.


Anastrozole.
Recent trials have indicated that the aromatase inhibitors (anastrozole, letrozole, exemestane) are more effective than tamoxifen, the standard adjuvant treatment for estrogen receptor-positive breast cancer, both in adjuvant and first-line advanced settings. This paper reviews the mode of action and the main clinical trials done with anastrozole, the only aromatase inhibitor currently licensed for use in the adjuvant setting in estrogen receptor-positive tumors. Results from studies using anastrozole as a first-line treatment in advanced disease strongly suggest that this drug should now be considered as an alternative first-line therapy to tamoxifen in postmenopausal women with estrogen receptor-positive advanced breast cancer. As a second-line treatment in tamoxifen failures, anastrozole has shown a better survival rate and a better side-effect profile than megestrol acetate. Similarly, the use of anastrozole in the adjuvant setting has shown a significantly prolonged disease-free survival time and improved tolerability compared to tamoxifen in postmenopausal breast cancer survivors.