Molecular signaling pathways that regulate prostate gland development.
Prostate gland development is a complex process that involves coordination of multiple signaling pathways including endocrine, paracrine, autocrine, juxtacrine and transcription factors. To put this into proper context, the present manuscript will begin with a brief overview of the stages of prostate development and a summary of androgenic signaling in the developing prostate, which is essential for prostate formation. This will be followed by a detailed description of other transcription factors and secreted morphogens directly involved in prostate formation and branching morphogenesis. Except where otherwise indicated, results from rodent models will be presented since studies that examine molecular signaling in the developing human prostate gland are sparse at the present time.


The total artificial heart in pediatrics: outcomes in an evolving field.
The use of the SynCardia temporary total artificial heart (TAH-t) in adults has increased with time. The development of the smaller, 50 cc TAH-t has expanded the potential applications of the device in children. We sought to describe the evolving use of the TAH-t over time and describe outcomes in the current era. The SynCardia database was queried to identify all pediatric patients ≤18 years of age implanted with the device between December 1985 and October 2019. Patient demographics, clinical outcome and support characteristics collected. Fifty-one children were supported, 36 with the 70 cc TAH-t and 15 with the 50 cc TAH-t with a total support time of 6,243 days. The number of implants has increased with time (19 between 2015 and 2019). A total of 13 patients have been converted to Freedom Driver support, seven 50 cc TAH-t and six 70 cc TAH-t. The majority of implants in the last 5 years (15/19, 79%) have been with the 50 cc TAH-t. The most common diagnosis was dilated cardiomyopathy [24 (47%)] and the average age at the time of implant was 16±2 years old. Overall survival for the patient cohort was 71%. The use of the SynCardia TAH-t to support children with end-stage heart failure has increased over time. Clinical outcomes with both the 50 cc and 70 cc TAH-t are similar to reported outcomes in adults who require TAH-t or other methods of biventricular support.


Immature angiomas: the importance of the Doppler exam in diagnosis and prognosis.
Immature angiomas are vascular hamartomatous malformations but clearly different from all other vascular, capillary, venous, arteriovenous, and lymphatic malformations, which, normally present at birth and established from a cellular viewpoint, grow because of the effect of hemodynamic stimuli and present no tendency toward spontaneous regression. The difference between immature angiomas and other hemangiomas has been demonstrated by investigations into cell dynamics. To facilitate a differentiated diagnosis and prognosis, the hemodynamics of the angiomas were studied with the Doppler flowmeter. The use of noninvasive techniques, such as those introduced by the Doppler flowmeter, permit a technical alternative and/or integration, giving results of equal relevance and importance, as well as the advantages of a more accessible and less expensive methodology.


Beyond single-level accounts: the role of cognitive architectures in cognitive scientific explanation.
We consider approaches to explanation within the cognitive sciences that begin with Marr's computational level (e.g., purely Bayesian accounts of cognitive phenomena) or Marr's implementational level (e.g., reductionist accounts of cognitive phenomena based only on neural-level evidence) and argue that each is subject to fundamental limitations which impair their ability to provide adequate explanations of cognitive phenomena. For this reason, it is argued, explanation cannot proceed at either level without tight coupling to the algorithmic and representation level. Even at this level, however, we argue that additional constraints relating to the decomposition of the cognitive system into a set of interacting subfunctions (i.e., a cognitive architecture) are required. Integrated cognitive architectures that permit abstract specification of the functions of components and that make contact with the neural level provide a powerful bridge for linking the algorithmic and representational level to both the computational level and the implementational level.


Dandruff is associated with disequilibrium in the proportion of the major bacterial and fungal populations colonizing the scalp.
The bacterial and fungal communities associated with dandruff were investigated using culture-independent methodologies in the French subjects. The major bacterial and fungal species inhabiting the scalp subject's were identified by cloning and sequencing of the conserved ribosomal unit regions (16S for bacterial and 28S-ITS for fungal) and were further quantified by quantitative PCR. The two main bacterial species found on the scalp surface were Propionibacterium acnes and Staphylococcus epidermidis, while Malassezia restricta was the main fungal inhabitant. Dandruff was correlated with a higher incidence of M. restricta and S. epidermidis and a lower incidence of P. acnes compared to the control population (p<0.05). These results suggested for the first time using molecular methods, that dandruff is linked to the balance between bacteria and fungi of the host scalp surface.


A descriptive analysis of spontaneous reports of antipsychotic-induced tardive dyskinesia and other extrapyramidal symptoms in the Japanese Adverse Drug Event Report database.
AimThe aim of this study is to summarize the spontaneous reports of tardive dyskinesia (TD) and extrapyramidal symptoms (EPSs) that occurred in Japan over the past decade. MethodsThe study analyzed TD and EPS cases reported in the Japanese Adverse Drug Event Report database between April 2011 and March 2021. The cases were stratified by the diagnoses of schizophrenia, bipolar disorders, and depressive disorders. ResultsIn total, 800 patients including a total of 171 TD cases and 682 EPS cases were reported in the JADER database across psychiatric diagnosis. The cases were caused by first-generation antipsychotics (FGA, TD: n = 105, EPS: n = 245) and second-generation antipsychotics (SGA, TD: n = 144, EPS: n = 598). The SGA were categorized based on Neuroscience-based Nomenclature (NbN) regarding pharmacological domain and mode of action, which were reported evenly as the offending agents. Among reported treatment and outcome in TD cases (n = 67, 37.6%) and EPS cases (n = 405, 59.3%), the relatively limited number of TD cases were reported as recovered/improved was also limited (n = 32, 47.8%) compared to those of EPS cases (n = 266, 65.7%). Some cases still had residual symptoms or did not recover fully (TD: n = 21, 31.3%, EPS: n = 77, 19.0%). CONCLUSION: Tardive dyskinesia and EPS have been widely reported in Japan over the past decade across psychiatric diagnoses and antipsychotic classes. LIMITATIONS: It is important to acknowledge the presence of reporting bias and the lack of comparators to accurately assess risks. Owing to the nature of spontaneous reporting, the estimation of prevalence is not feasible.


Reactions of sera from patients with rheumatoid arthritis, systemic lupus erythematosus and infectious mononucleosis to Epstein-Barr virus-induced polypeptides.
P3HR-1 and Ramos cells induced with sodium butyrate and 12-O-tetradecanoylphorbol 13-acetate were used in the protein immunoblot technique to identify Epstein-Barr virus (EBV)-specific antibodies present in sera from clinically normal individuals and patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and infectious mononucleosis (IM). Sixteen EBV-specific polypeptides were detected ranging in mol. wt. from 22,000 (22K) to 140K. Many of the sera contained antibodies to different subsets of these antigens, and a high proportion expressed autoantibodies which reacted with cellular components from an EBV genome-negative cell line. About 50% of the sera from each category reacted with the 44K to 48K and 36K and 38K early antigen (EA) components. A high proportion of the SLE sera (64%) were found to contain anti-EA antibodies, suggesting an association between EBV and SLE. Almost all of the EBV-seropositive sera examined contained antibodies against a 22K late antigen, but none of the sera from IM patients reacted with this polypeptide.


Perceived exertion and training load during self-selected and imposed-intensity resistance exercise in untrained women.
The purpose of the present study was to examine differences in ratings of perceived exertion (RPE) and the weight lifted (training load) during self-selected and imposed-intensity bouts of acute resistance exercise (RE). Nineteen untrained college-aged women completed 2 bouts of acute resistance exercise. During 1 session, 3 sets of 4 exercises were performed using a training load of 75% of 1 repetition maximum. Conversely, during the other session, each set and exercise were completed using a self-selected training load. Assessments of RPE and training load were obtained following each set during both imposed-intensity and self-selected-intensity sessions. Results of 2 (intensity) x 3 (set) repeated measures multivariate analyses of variance revealed that, when compared to self-selected RE, RPE and resistance used were significantly higher and the number of repetitions completed per set was significantly lower during imposed-intensity RE. These findings demonstrate that the training load and perceptions of effort elicited during conventional RE prescriptions differ from the level of exertion untrained women self-select. Additionally, it appears that untrained women may not self-select a relative intensity sufficient to stimulate meaningful improvements in muscular hypertrophy or strength. The implications of these findings for the adoption and maintenance of resistance exercise participation are discussed.


Resolving Dynamic Properties of Polymers through Coarse-Grained Computational Studies.
Coupled length and time scales determine the dynamic behavior of polymers and underlie their unique viscoelastic properties. To resolve the long-time dynamics it is imperative to determine which time and length scales must be correctly modeled. Here we probe the degree of coarse graining required to simultaneously retain significant atomistic details and access large length and time scales. The degree of coarse graining in turn sets the minimum length scale instrumental in defining polymer properties and dynamics. Using linear polyethylene as a model system, we probe how the coarse-graining scale affects the measured dynamics. Iterative Boltzmann inversion is used to derive coarse-grained potentials with 2-6 methylene groups per coarse-grained bead from a fully atomistic melt simulation. We show that atomistic detail is critical to capturing large-scale dynamics. Using these models we simulate polyethylene melts for times over 500 μs to study the viscoelastic properties of well-entangled polymer melts.


Combining Classical MD and QM calculations to elucidate complex system nucleation: a twisted, three-stranded, parallel β-sheet seeds amyloid fibril conception.
The crystal structure of the Sup35 prion segment, GNNQQNY, revealed precise side chain packing and an extensive H-bond network. However, the conformers and stabilizing interactions involved at nascent amyloid formation are still unclear. Here, long molecular dynamics simulations and quantum mechanical calculations have been utilized to study the conformation and energetics of the initial structure that acts to nucleate further growth. Considering all the plausible intermediates that may act as stepping stones, we find that the initial nucleus is a twisted single-layer, three-stranded parallel β-sheet. H-bonds between β-strands in this twisted sheet, some of which differ from those of the crystal structure's nontwisted β-strands, are key for the nucleus' formation and stability. High level theoretical calculations of these H-bonds' energetics can account for this amyloid-like trimer's remarkable stability. The intermeshing of facing sheets to form the dry interface provides less stability and would occur between two three-stranded β-sheets without metastable water nanowires.


Infection of HEp2 epithelial cells with Candida albicans: adherence and postadherence events.
We have previously observed that the infection of HEp2 epithelial cells with Candida albicans results in HEp2 cell actin rearrangement, and that a culture filtrate of C. albicans (Candida metabolite) caused the same changes and reduced membrane ruffling and motility. It was found that the Candida metabolite consisted of several proteins and nonproteinaceous components. In this study we report on the identity of three of the main proteins in the Candida metabolite, namely a secretory aspartate protease (Sap), an agglutinin-like adhesion sequence (Als) and a glucan 1,3-beta-glucosidase. The effect on HEp2 cells caused by the Candida metabolite, an inhibitor of the PKC MAP kinase signal pathway - bisindolylmaleimide (BIM), or the actin polymerization inhibitor - cytochalasin D (CyD) were studied alone and in combination. Exposure of HEp2 cells to the Candida metabolite, together with the BIM or CyD, had profound effects on HEp2 cell morphology, as compared to individually treated cells, and also reduced the adherence of the organisms to HEp2 cells. Our results show that the interaction of C. albicans with HEp2 cells is, not unexpectedly, complex, and involves changes in the host cell that may be related to the effect of Candida-secreted biomolecules.


Clinical evaluation of an improved cementation technique for implant-supported restorations: a randomized controlled trial.
Cement remnants were frequently associated with peri-implantitis. Recently, a shoulderless abutment was proposed, raising some concern about cement excess removal. To compare different cementation techniques for implant-supported restorations assessing the amount of cement remnants in the peri-implant sulcus. Additional aim was to compare the effect of these cementation techniques using two different abutment designs. Forty-six patients requiring double implant-supported restoration in the posterior maxilla were randomly divided in two groups according to the cementation modality: intraoral and extraoral. According to the abutment finishing line, implants in each patient were randomly assigned to shoulderless or chamfer subgroup. In the intraoral group, crowns were directly seated onto the titanium abutment. In the extraoral group, crowns were firstly seated onto a resin abutment replica and immediately removed, then cleansed of the cement excess and finally seated on the titanium abutment. After cement setting, in both groups, cement excess was carefully tried to remove. Three months later, framework/abutment complexes were disconnected and prepared for microscopic analysis: surface occupied by exposed cement remnants and marginal gaps were measured. Additionally, crown/abutment complexes were grinded, and voids of cement were measured at abutment/crown interface. Related-samples Friedman's two-way analysis of variance by ranks was used to detect differences between groups and subgroups (P ≤ 0.5). At the end of the study, a mean value of 0.45 mm2 (±0.80), 0.38 mm2 (±0.84), and 0.065 mm2 (±0.13) and 0.07 mm2 (±0.15) described surface occupied by cement remnants in shoulderless and chamfer abutment with intraoral cementation and shoulderless and chamfer abutment with extraoral cementation, respectively. A mean value of 0.40 mm2 (±0.377), 0.41 mm2 (±0.39) and 0.485 mm2 (±0.47) and 0.477 mm2 (±0.43) described cement voids at the abutment/crown interface; a mean value of 0.062 mm (±0.03), 0.064 mm (±0.35), 0.055 mm (±0.016) and 0.054 mm (±0.024) described marginal gaps. Statistics showed tendency of intraoral cementation to have significantly higher cement remnants compared with abutments with extraoral cementation groups. At the same time, the presence of voids was significantly higher in case of extraoral cementation. No significant differences between groups for the variable "gap". Despite the presence of more voids, extraoral cementation reduces cement excess. However, using low adhesivity cement and careful cement removal, a very limited quantity of cement remnants was observed also in the intraoral cementation.


Policresulen to treat hypergranulation tissue around drainage tubes.
To evaluate the efficacy of policresulen for the treatment of hypergranulation. This was a retrospective study of patients with percutaneous catheters. Inpatients from two hospitals and those from outpatient clinics were included. Approximately 2ml of 50% policresulen solution was applied to hypergranulation tissue, which was then immediately pressed with gauze for 1-3 minutes using light pressure. When haemostasis was achieved and the granulation tissue size decreased, the procedure was terminated. A total of eight patients (four females and four males) were included in this study. Effective haemostasis was achieved in all patients. The size of the hypergranulation tissue decreased with policresulen treatment, and resolved completely in one patient. There were no complications. Hypergranulation tissue recurred in one patient. Haemostasis was successfully achieved after repeated procedures. The findings of this study showed policresulen to be an inexpensive, easy treatment for hypergranulation at catheter insertion sites.


Swallowing dysfunction related to snoring: a videoradiographic study.
Biopsy studies of the soft palatal and oropharyngeal tissues in habitual snorers and patients suffering from obstructive sleep apnoea have shown signs of neurogenic lesions. These lesions might affect the pharyngeal swallowing function, which is dependent on adequate sensitivity. The objective of the present study was to test the hypothesis that snoring is associated with aberrant pharyngeal swallowing function. Forty-one consecutive patients without dysphagia, seeking medical attention because of heavy snoring and various degrees of daytime sleepiness, were prospectively selected. Fifteen non-snoring volunteers without dysphagia served as controls. Patients and volunteers were videoradiographically examined in lateral and posteroanterior views during the oral and pharyngeal phases of swallowing. The hypothesis was verified. Snoring patients demonstrated deviant pharyngeal swallowing function seven times more frequently than did the non-snoring volunteers. Deviant pharyngeal swallowing function was observed in 22 (54%) of the snorers compared with 1 (7%) of the non-snoring volunteers. Impaired bolus control with premature leakage of bolus into the pharynx and a delayed evocation of the swallowing reflex was the most common finding, followed by bolus residual in the pharynx and laryngeal penetration. The conclusion was that snoring is associated with subclinical pharyngeal swallowing dysfunction.


Developing Theory-Driven, Evidence-Based Serious Games for Health: Framework Based on Research Community Insights.
The idea of using serious games to effectuate better outcomes in health care has gained significant traction among a growing community of researchers, developers, and health care professionals. Many now recognize the importance of creating evidence-based games that are purposefully designed to address physical and mental health challenges faced by end users. To date, no regulatory resources have been established to guide the development of serious games for health (SGH). Developers must therefore look elsewhere for guidance. Although a more robust level of evidence exists in the research literature, it is neither structured nor is there any clear consensus. Developers currently use a variety of approaches and methodologies. The establishment of a well-defined framework that represents the consensus views of the SGH research community would help developers improve the efficiency of internal development processes, as well as chances of success. A consensus framework would also enhance the credibility of SGH and help provide quality evidence of their effectiveness. This research aimed to (1) identify and evaluate the requirements, recommendations, and guidelines proposed by the SGH community in the research literature, and; (2) develop a consensus framework to guide developers, designers, researchers, and health care professionals in the development of evidence-based SGH. A critical review of the literature was performed in October to November 2018. A 3-step search strategy and a predefined set of inclusion criteria were used to identify relevant articles in PubMed, ScienceDirect, Institute of Electrical and Electronics Engineers Xplore, CiteSeerX, and Google Scholar. A supplemental search of publications from regulatory authorities was conducted to capture their specific requirements. Three researchers independently evaluated the identified articles. The evidence was coded and categorized for analysis. This review identified 5 categories of high-level requirements and 20 low-level requirements suggested by the SGH community. These advocate a methodological approach that is multidisciplinary, iterative, and participatory. On the basis of the requirements identified, we propose a framework for developing theory-driven, evidence-based SGH. It comprises 5 stages that are informed by various stakeholders. It focuses on building strong scientific and design foundations that guide the creative and technical development. It includes quantitative trials to evaluate whether the SGH achieve the intended outcomes, as well as efforts to disseminate trial findings and follow-up monitoring after the SGH are rolled out for use. This review resulted in the formulation of a framework for developing theory-driven, evidence-based SGH that represents many of the requirements set out by SGH stakeholders in the literature. It covers all aspects of the development process (scientific, technological, and design) and is transparently described in sufficient detail to allow SGH stakeholders to implement it in a wide variety of projects, irrespective of discipline, health care segments, or focus.


Brain activation associated with motor skill practice in children with developmental coordination disorder: an fMRI study.
Children with developmental coordination disorder (DCD) have difficulty in learning new motor skills. At present, it is not known whether these children employ a different set of brain regions than typically developing (TD) children during skilled motor practice. Using functional magnetic resonance imaging, we mapped brain activity associated with skilled motor practice of a trail-tracing task in 7 children with DCD and 7 age-matched controls (aged 8-12 years). We indexed change in motor performance as a reduction in tracing error from early practice to retention. Children with DCD showed less blood-oxygen-level-dependent signal as compared to TD children in a network of brain regions associated with skilled motor practice: bilateral inferior parietal lobules (Brodmann Area (BA) 40), right lingual gyrus (BA 18), right middle frontal gyrus (BA 9), left fusiform gyrus (BA 37), right cerebellar crus I, left cerebellar lobule VI, and left cerebellar lobule IX. While no statistically significant differences were detected, effect size testing revealed that children with DCD demonstrated poorer tracing accuracy than TD children at retention (d=0.48). Our results suggest that, compared to TD peers, children with DCD demonstrate under-activation in cerebellar-parietal and cerebellar-prefrontal networks and in brain regions associated with visual-spatial learning. These data suggest a neurobiological correlation with impaired learning of motor skills in children with DCD, which will need to be confirmed with a larger sample.


Promoter hypermethylation of RASSF1A in esophageal squamous cell carcinoma.
The RAS association domain family 1A (RASSF1A) gene, a candidate tumor suppressor gene, is frequently inactivated by hypermethylation of its promoter region in several human cancers. The aim of this study was to evaluate the promoter methylation status of the RASSF1A in esophageal squamous cell carcinoma. We analyzed the methylation status of RASSF1A promoter by methylation-specific PCR in 23 esophageal squamous cell carcinoma cell lines and 48 primary tumors. Hypermethylation of RASSF1A was found in 74% of cell lines and 52% of primary tumors. The presence of hypermethylation was statistically associated with loss of RASSF1A mRNA expression in both cell lines (P = 0.007) and primary tumors (P = 0.003). There was a statistically significant correlation between the presence of hypermethylation and tumor stage (P = 0.009). Our findings suggest that epigenetic silencing of RASSF1A gene expression by promoter hypermethylation could play an important role in primary esophageal squamous cell carcinogenesis.


A simple way to indicate pulmonary nodules at thoracoscopic wedge resections.
Small pulmonary subpleural nodules are sometimes difficult to localise at thoracotomy. With the advent of minimal invasive surgery, thoracoscopic resection avoiding anterolateral thoracotomy is an attractive procedure. Since this technique does not allow manual palpation, preoperative indication of lesions is mandatory. A simple and cost-effective system for preoperative CT-guided localisation of small subpleural nodules before thoracoscopic resection is described. The system consists of a 0.2 mm steel wire 30-40 cm in length and a 0.9-mm biopsy needle. The tip of the wire is bent to a hook, and, guided by CT, it is placed in the vicinity of the lesion. The technique was tested in 8 cases. The procedure was possible to perform in 7 patients. In all instances the wire remained in place when the lung was collapsed during the thoracoscopic procedure. The staple resected part of the lung also contained the lesion when examined extracorporeally. This simple and inexpensive system was found to be useful for indication of pulmonary lesions at thoracoscopic wedge resections.


Water molecule ordering on the surface of an intrinsically disordered protein.
The dynamics and local structure of the hydration water on surfaces of folded proteins have been extensively investigated. However, our knowledge of the hydration of intrinsically disordered proteins (IDPs) is more limited. Here, we compare the local structure of water molecules hydrating a globular protein, lysozyme, and the intrinsically disordered N-terminal of c-Src kinase (SH4UD) using molecular dynamics simulation. The radial distributions from the protein surface of the first and the second hydration shells are similar for the folded protein and the IDP. However, water molecules in the first hydration shell of both the folded protein and the IDP are perturbed from the bulk. This perturbation involves a loss of tetrahedrality, which is, however, significantly more marked for the folded protein than the IDP. This difference arises from an increase in the first hydration shell of the IDP of the fraction of hydration water molecules interacting with oxygen. The water ordering is independent of the compactness of the IDP. In contrast, the lifetimes of water molecules in the first hydration shell increase with IDP compactness, indicating a significant impact of IDP configuration on water surface pocket kinetics, which here is linked to differential pocket volumes and polarities.


Finding the best estimates of metabolic rates in a coral reef fish.
Metabolic rates of aquatic organisms are estimated from measurements of oxygen consumption rates ( ) through swimming and resting respirometry. These distinct approaches are increasingly used in ecophysiology and conservation physiology studies; however, few studies have tested whether they yield comparable results. We examined whether two fundamental measures, standard metabolic rate (SMR) and maximum metabolic rate (MMR), vary based on the method employed. Ten bridled monocle bream (Scolopsis bilineata) were exercised using (1) a critical swimming speed (Ucrit) protocol, (2) a 15 min exhaustive chase protocol and (3) a 3 min exhaustive chase protocol followed by brief (1 min) air exposure. Protocol 1 was performed in a swimming respirometer whereas protocols 2 and 3 were followed by resting respirometry. SMR estimates in swimming respirometry were similar to those in resting respirometry when a three-parameter exponential or power function was used to extrapolate the swimming speed- relationship to zero swimming speed. In contrast, MMR using the Ucrit protocol was 36% higher than MMR derived from the 15 min chase protocol and 23% higher than MMR using the 3 min chase/1 min air exposure protocol. For strong steady (endurance) swimmers, such as S. bilineata, swimming respirometry can produce more accurate MMR estimates than exhaustive chase protocols because oxygen consumption is measured during exertion. However, when swimming respirometry is impractical, exhaustive chase protocols should be supplemented with brief air exposure to improve measurement accuracy. Caution is warranted when comparing MMR estimates obtained with different respirometry methods unless they are cross-validated on a species-specific basis.


Effect of aprotinin on Schistosoma mansoni miracidial penetration into biomphalaria Alexandrina.
The effect of aprotinin on Schistosoma mansoni miracidial penetration process, by its direct topical application on Biomphalaria alexandrina snails, was studied The snails were exposed to S. mansoni miracidial suspension which was mixed with aprotinin at concentrations ranging from 0.02 to 20 Kallikrein inactivator units (KIU)/ml of applied solution. Results showed that aprotinin had marked inhibitory effect on miracidial penetration of the snails. The concentration that resulted in 50% inhibition of the miracidial penetration into B. alexandrina snails (LD50) was 2.4 KIU/ml while (LD96) was 20 KIU/ml of the applied solution. Thus, aprotinin may be one of the important methods in the control of schistosomiasis.


Blueberry benefits to cognitive function across the lifespan.
It is well known that what we eat can influence our physical wellbeing, but interest is also increasing in the relationship between our diet and cognitive health. In recent years, blueberries have risen from relative obscurity to superfood status following a number of published epidemiological studies, rodent trials, and human RCTs, that suggest blueberries may convey benefits to cognition and mood. This commentary explores some of the evidence in humans, particularly during periods of cognitive development in the young and cognitive decline in the elderly. Evidence for possible mechanisms of action are also described. There is little doubt that blueberries convey a small, but tangible, benefit to cognitive function. Effects are seen following dose sizes easily achievable within a normal diet. Nevertheless, further research is needed on the cognitive domains influenced, additional benefits of longer-term supplementation, mechanisms of action responsible, and the real-world relevance of the cognitive benefits attained.


Resolution-adapted recombination of structural features significantly improves sampling in restraint-guided structure calculation.
Recent work has shown that NMR structures can be determined by integrating sparse NMR data with structure prediction methods such as Rosetta. The experimental data serve to guide the search for the lowest energy state towards the deep minimum at the native state which is frequently missed in Rosetta de novo structure calculations. However, as the protein size increases, sampling again becomes limiting; for example, the standard Rosetta protocol involving Monte Carlo fragment insertion starting from an extended chain fails to converge for proteins over 150 amino acids even with guidance from chemical shifts (CS-Rosetta) and other NMR data. The primary limitation of this protocol--that every folding trajectory is completely independent of every other--was recently overcome with the development of a new approach involving resolution-adapted structural recombination (RASREC). Here we describe the RASREC approach in detail and compare it to standard CS-Rosetta. We show that the improved sampling of RASREC is essential in obtaining accurate structures over a benchmark set of 11 proteins in the 15-25 kDa size range using chemical shifts, backbone RDCs and HN-HN NOE data; in a number of cases the improved sampling methodology makes a larger contribution than incorporation of additional experimental data. Experimental data are invaluable for guiding sampling to the vicinity of the global energy minimum, but for larger proteins, the standard Rosetta fold-from-extended-chain protocol does not converge on the native minimum even with experimental data and the more powerful RASREC approach is necessary to converge to accurate solutions.


The pharmacy as part of an integrated hospital information system: a focus on benefits.
An integrated hospital information system benefits not only the pharmacy but also each department within a hospital, including the physician and patient. The Composite Health Care System (CHCS) is a fully integrated healthcare information system that has been developed for the Department of Defense's medical treatment facilities. CHCS provides modules for Patient Administration, Patient Appointment Scheduling, Radiology, Laboratory, Pharmacy, and Physician/Nursing Order Entry and Results Retrieval, which serve to integrate inpatient wards, clinical services, administrative departments, and remote outpatient clinics. CHCS provides an integrated patient profile to care givers throughout the medical facility, improving the quality of their clinical decisions. The integrated hospital information system also helps to coordinate the delivery of patient care and automates many interdepartmental transactions, which allows for more efficient use of resources and increases the turnaround time for delivery of services. This article focuses on the system's pharmacy component to demonstrate the benefits realized with an integrated hospital information system.


The beta-strand D of transthyretin trapped in two discrete conformations.
Conformational changes in native and variant forms of the human plasma protein transthyretin (TTR) induce several types of amyloid diseases. Biochemical and structural studies have mapped the initiation site of amyloid formation onto residues at the outer C and D beta-strands and their connecting loop. In this study, we characterise an engineered variant of transthyretin, Ala108Tyr/Leu110Glu, which is kinetically and thermodynamically more stable than wild-type transthyretin, and as a consequence less amyloidogenic. Crystal structures of the mutant were determined in two space groups, P2(1)2(1)2 and C2, from crystals grown in the same crystallisation set-up. The structures are identical with the exception for residues Leu55-Leu58, situated at beta-strand D and the following DE loop. In particular, residues Leu55-His56 display large shifts in the C2 structure. There the direct hydrogen bonding between beta-strands D and A has been disrupted and is absent, whereas the beta-strand D is present in the P2(1)2(1)2 structure. This difference shows that from a mixture of metastable TTR molecules, only the molecules with an intact beta-strand D are selected for crystal growth in space group P2(1)2(1)2. The packing of TTR molecules in the C2 crystal form and in the previously determined amyloid TTR (ATTR) Leu55Pro crystal structure is close-to-identical. This packing arrangement is therefore not unique in amyloidogenic mutants of TTR.


Validation of the profile of female sexual function (PFSF) in surgically and naturally menopausal women.
The Profile of Female Sexual Function (PFSF) is a patient-based instrument for the measuring of loss of sexual function in menopausal women with low libido (hypoactive female sexual desire disorder). The instrument, which contains 37 items in seven domains (sexual desire, arousal, orgasm, sexual pleasure, sexual concerns, sexual responsiveness, and sexual self-image) and a single-item measure of overall satisfaction with sexuality, has been extensively developed and initially validated in over 500 oophorectomized women with low libido in North America, Europe, and Australia. Initial validation results showed the PFSF is capable of discriminating these patients from age-matched controls and produced consistent responses and sensitivity across geographies. The objective of this nonrandomized, parallel-group study was to examine the psychometric properties of the final PFSF in an independent group of surgically menopausal women with low libido and to extend validation to naturally menopausal women with low libido. Participants from 16 study centers in North America included surgically (n = 59) and naturally (n = 88) menopausal women with low libido and their age-matched control subjects, both premenopausal (n = 57) and naturally menopausal (n = 47), who reported no problems with libido. Subjects completed the PFSF at baseline and again 4 weeks later. Adjusted mean scores for each of the seven domains were statistically significantly lower (P < 0.0001) in surgically menopausal women with low libido compared with age-matched control women, and in naturally menopausal women with low libido compared with naturally menopausal control women, demonstrating excellent discriminant validity. Test-retest reliability ranged from 0.57 to 0.91 for the seven domain scores, whereas internal-consistency reliability ranged from 0.74 to 0.95. Results of this research support the conclusion that the PFSF is a valid and reliable instrument for measurement of loss of sexual function in both naturally and surgically menopausal women with low libido.


Midforehead lift.
Ptosis of the brow-glabellar tissues with or without vertical and horizontal wrinkling accompanies aging in other areas of the face. The direct browlift is effective in elevating and shaping brow tissues, but leaves a scar at the brow-forehead juncture and does little for glabellar deformity. The coronal forehead lift allows the correction of brow-glabellar ptosis and wrinkling with camouflage of the scar in the scalp. Male pattern hairline, thinning hair, or a high hairline may contraindicate this approach. Our technique for treating these patients is the midforehead lift. We review the anatomical considerations, patient selection, and surgical technique, showing representative cases.


Towards capability-adjusted life years in public health and social welfare: Results from a Swedish survey on ranking capabilities.
The aim of this study was to rank capabilities and suggest a relevant set of capabilities for the Swedish context to inform the development of capability-adjusted life years (CALYs). CALYs is a quality of life measure for policy making based on the capability approach by Amartya Sen. A Swedish governmental review proposed the following 10 relevant capabilities: time, financial situation, mental/physical health, political resources, knowledge, living environment, occupation, social relations, security, and housing. Researchers in health-related disciplines from 5 universities ranked these capabilities from 1 to 10 (most to least important) in a web-based cross-sectional survey; 115 of 171 responses were eligible. Health, social relations, and financial situation were deemed most important. Stratification by gender, research field, and age group revealed few differences. We found that it was possible to rank capabilities and that health, social relations, and financial situation were ranked highest by a non-representative sample of researchers and doctoral students from health-related disciplines at five Swedish universities. The revealed ranking is dependent on the metric and must be further explored. The findings support continued development of CALYs for monitoring and evaluating outcomes in public health and social-welfare interventions.


Comparative in silico analysis of SSRs in coding regions of high confidence predicted genes in Norway spruce (Picea abies) and Loblolly pine (Pinus taeda).
Microsatellites or simple sequence repeats (SSRs) are DNA sequences consisting of 1-6 bp tandem repeat motifs present in the genome. SSRs are considered to be one of the most powerful tools in genetic studies. We carried out a comparative study of perfect SSR loci belonging to class I (≥20) and class II (≥12 and <20 bp) types located in coding regions of high confidence genes in Picea abies and Pinus taeda. SSRLocator was used to retrieve SSRs from the full length CDS of predicted genes in both species. Trimers were the most abundant motifs in class I followed by hexamers in Picea abies, while trimers and hexamers were equally abundant in Pinus taeda class I SSRs. Hexamers were most frequent within class II SSRs followed by trimers, in both species. Although the frequency of genes containing SSRs was slightly higher in Pinus taeda, SSR counts per Mbp for class I was similar in both species (P-value = 0.22); while for class II SSRs, it was significantly higher in Picea abies (P-value = 0.00009). AT-rich motifs were higher in abundance than the GC-rich motifs, within class II SSRs in both the species (P-values = 10(-9) and 0). With reference to class I SSRs, AT-rich and GC-rich motifs were detected with equal frequency in Pinus taeda (P-value = 0.24); while in Picea abies, GC-rich motifs were detected with higher frequency than the AT-rich motifs (P-value = 0.0005). Our study gives a comparative overview of the genome SSRs composition based on high confidence genes in the two recently sequenced and economically important conifers and, also provides information on functional molecular markers that can be applied in genetic studies in Pinus and Picea species.


Graphene Oxide-ZnO Nanocomposites for Removal of Aluminum and Copper Ions from Acid Mine Drainage Wastewater.
Adsorption technologies are a focus of interest for the removal of pollutants in water treatment systems. These removal methods offer several design, operation and efficiency advantages over other wastewater remediation technologies. Particularly, graphene oxide (GO) has attracted great attention due to its high surface area and its effectiveness in removing heavy metals. In this work, we study the functionalization of GO with zinc oxide nanoparticles (ZnO) to improve the removal capacity of aluminum (Al) and copper (Cu) in acidic waters. Experiments were performed at different pH conditions (with and without pH adjustment). In both cases, decorated GO (GO/ZnO) nanocomposites showed an improvement in the removal capacity compared with non-functionalized GO, even when the pH of zero charge (pHPZC) was higher for GO/ZnO (5.57) than for GO (3.98). In adsorption experiments without pH adjustment, the maximum removal capacities for Al and Cu were 29.1 mg/g and 45.5 mg/g, respectively. The maximum removal percentages of the studied cations (Al and Cu) were higher than 88%. Further, under more acidic conditions (pH 4), the maximum sorption capacities using GO/ZnO as adsorbent were 19.9 mg/g and 33.5 mg/g for Al and Cu, respectively. Moreover, the removal percentages reach 95.6% for Al and 92.9% for Cu. This shows that decoration with ZnO nanoparticles is a good option for improving the sorption capacity of GO for Cu removal and to a lesser extent for Al, even when the pH was not favorable in terms of electrostatic affinity for cations. These findings contribute to a better understanding of the potential and effectiveness of GO functionalization with ZnO nanoparticles to treat acidic waters contaminated with heavy metals and its applicability for wastewater remediation.


Choroid Plexus Cyst in a Neonatal Burmeister's Porpoise (Phocoena spinipinnis).
Neuroectodermal developmental anomalies are reported rarely in cetaceans and central nervous system cysts are not described. We describe the gross, microscopical, histochemical and immunohistochemical features of a neuraxial myelencephalic cyst in a stranded neonatal Burmeister's porpoise (Phocoena spinipinnis). Grossly, a subdural, extra-axial, well-demarcated, yellow fluid-filled cystic structure (1.9 × 1.6 × 1 cm) expanded the left foramen of Luschka, the left caudolateral cerebellar recess and the left cranioventral myelencephalon. The cyst displaced the ipsilateral ventral paraflocculus and distended the underlying cranial nerves IX, X, XI and XII. Microscopically, the cystic structure was lined by a monolayer of low cuboidal to flattened epithelium supported by a thin fibrovascular matrix. Immunohistochemistry (IHC) revealed strong and diffuse expression of AE1/AE3 and focal positivity for vimentin. IHC for epithelial membrane antigen, glial fibrillary acid protein, synaptophysin and S100 was negative. Based on these findings, an extra-axial cyst of the choroid plexus of the fourth ventricle (CCPFV) was diagnosed. The pathological relevance of the CCPFV in this case is uncertain. The cause of death involved severe perinatal interspecific (shark) trauma. The present case provides the first evidence of a neuroepithelial cyst in cetacean species.


[A forgotten milestone of sanitation in Brazil: the water and sewage system of Ouro Preto (1887-1890)].
This article resurrects, contextualizes and characterizes the water and sewage system of Ouro Preto, created at the end of the 1880's in response to sanitary problems and the need to modernize the old capital of the Brazilian State of Minas Gerais. Based on documentary research undertaken in public archives, bibliographical reviews, interviews and field inspections, the text corrects mistakes regarding the authorship and construction date of the system. The need to restore the hundred year old sewage treatment station is emphasized, given its relevance in the history of Brazilian sanitation. Today, in contrast with the past, the city of Ouro Preto discharges its sewage in natura into the streams that gave it gold.


A Systematic Review of Physical Rehabilitation of Facial Palsy.
Background: Facial palsy is a frequent and debilitating sequela of stroke and brain injury, causing functional and aesthetic deficits as well as significant adverse effects on quality of life and well-being. Current literature reports many cases of acquired facial palsy that do not recover spontaneously, and more information is needed regarding the efficacy of physical therapies used in this population. Methods: A systematic search of eight electronic databases was performed from database inception to December 2018. Gray literature searches were then performed to identify additional articles. Studies were included if they addressed physical rehabilitation interventions for adults with acquired facial palsy. Reasons for exclusion were documented. Independent data extraction, quality assessment, and risk of bias assessment followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Results: Following abstract screening, a total of 13 full-text articles were identified for independent screening by two reviewers. This included four randomized control trials, two non-randomized control trials, one cohort study, and six prospective case series studies. Twelve out of the 13 included studies reported on facial palsy as a sequela of stroke. A total of 539 participants received intervention for facial palsy across the 13 included studies. Therapy design, length and frequency of intervention varied across the studies, and a wide range of outcome measures were used. Improvement on various outcome measures was reported across all 13 studies. The quality of the evidence was low overall, and most studies were found to have high risk of bias. Conclusions: All the studies in this review report improvement of facial movement or function following application of various methods of physical rehabilitation for facial palsy. Methodological limitations and heterogeneity of design affect the strength of the evidence and prevent reliable comparison between intervention methods. Strong evidence supporting physical rehabilitation was not found; well-designed rigorous research is required.


Minimally invasive endoscopic spinal cord untethering: case report.
Tethered cord syndrome is a constellation of symptoms and signs that include back and leg pain, bowel and bladder dysfunction, scoliosis and lower extremity weakness and deformity. Tethering may be due to a tight filum terminale or a form of spinal dysraphism. The authors present a case of a 40-year-old man who presented with symptoms of back pain, bilateral lower extremity radicular pain, and bowel and bladder dysfunction. Magnetic resonance imaging showed a sacral lipomyelomeningocele, with fat tracking superiorly to the conus, which was tethered at the L4-L5 level. A minimally-invasive surgical approach with endoscopic visualization and identification of the nerve roots and filum terminale was performed. The patient's postoperative clinical course was uneventful. This case highlights two important issues. First, minimally invasive spine techniques should be considered in the surgical treatment of tethered cord especially given the theoretical advantages of minimizing pain, spinal fluid leakage, and subsequent scarring. And second, endoscopic techniques are advancing. In the case presented here, endoscopic visualization and operative techniques made identification and transection of the filum terminale possible through a tiny dural opening. The small dural opening could theoretically pose the advantage of decreasing the risk of spinal fluid leakage. Clinicians should be aware that endoscopic visualization and techniques can serve as minimally-invasive adjuncts to enhance the traditional approach to many surgical pathologies.


Role of porins for uptake of antibiotics by Mycobacterium smegmatis.
The outer membrane of mycobacteria presents an effective permeability barrier for many antibiotics. Transport pathways across this membrane are unknown for most drugs. Here, we examined which antibiotics utilize the porin pathway across the outer membrane of the model organism Mycobacterium smegmatis. Deletion of the porins MspA and MspC drastically increased the resistance of M. smegmatis ML10 to beta-lactam antibiotics, while its beta-lactamase activity remained unchanged. These results are consistent with the ninefold-reduced outer membrane permeability of the M. smegmatis porin mutants for cephaloridine and strongly indicate that beta-lactam antibiotics rely on the porin pathway. The porin mutant ML10 accumulated less chloramphenicol and norfloxacin and was less susceptible to these antibiotics than wild-type M. smegmatis. These results demonstrated that small and hydrophilic antibiotics use the Msp porins for entering the cell. In contrast to norfloxacin, the hydrophobic moxifloxacin was 32-fold more effective in inhibiting the growth of M. smegmatis, presumably because it was able to diffuse through the lipid membrane. Structural models indicated that erythromycin, kanamycin, and vancomycin are too large to move through the MspA channel. This study presents the first experimental evidence that hydrophilic fluoroquinolones and chloramphenicol diffuse through porins in mycobacteria. Thus, mutations resulting in less efficient porins or lower porin expression levels are likely to represent a mechanism for the opportunistic pathogens M. avium, M. chelonae, and M. fortuitum, which have Msp-like porins, to acquire resistance to fluoroquinolones.


Pathogens that cause travelers' diarrhea in Latin America and Africa.
With the advent of rapid and convenient means of transportation, millions of persons travel each year from industrialized to developing countries in the tropics and subtropics. These travelers are at risk for a variety of infectious diseases that are endemic in these areas; the most frequently occurring of these is diarrhea. Studies of groups of travelers to Latin America and Africa have found that approximately one-half develop diarrhea during their stay abroad. Etiologic investigations of these illnesses have demonstrated that the important agents that cause travelers' diarrhea are similar to those that cause diarrhea in children in the developing countries. One-third of the cases are associated with enterotoxin-producing strains of Escherichia coli. Smaller proportions appear to be due to rotavirus, Norwalk virus, Shigella, Salmonella, Giardia lamblia, and Entamoeba histolytica. Although they have not been fully evaluated in travelers' illnesses in Latin America or Africa, Campylobacter jejuni, Aeromonas hydrophila, other viruses, and Cryptosporidium probably cause some of the currently unexplained cases of diarrhea.


Ticarcillin plus clavulanic acid in the treatment of patients with cancer.
Since the combination of ticarcillin with clavulanic acid is active against many otherwise resistant organisms that commonly affect patients with cancer, a therapeutic trial with ticarcillin disodium plus clavulanate potassium for treating infections in cancer patients was conducted. A total of 127 evaluable patients were treated with this antibiotic. Of these, 63 percent were women with breast carcinoma, 28 percent were patients with leukemia, and the remainder were patients with sarcomas and lung cancer. The median duration of therapy was 7.7 days. There were 63 documented infections, with bacteriologic documentation in 39 episodes. Because of the high incidence of gram-positive infections and after the failure of ticarcillin plus clavulanate potassium in two of these episodes, vancomycin was added to the regimen. The overall response rate was 75 percent. In microbiologically proved infections, the response rate was 79 percent. Thirteen of 17 gram-negative infections responded (76 percent), including four of four episodes caused by Pseudomonas aeruginosa. The only failures in this group were two episodes with Klebsiella species, one episode with Escherichia coli, and one episode with Enterobacter species. Of the gram-positive infections treated without vancomycin, five of eight (63 percent) responded and only two episodes due to Staphylococcus aureus and one due to JK diphtheroid bacteria failed. All episodes treated with the combination of ticarcillin plus clavulanate potassium and vancomycin responded. Seven of eight (88 percent) polymicrobial infections and 73 percent of those infections without identified organisms responded as well. The overall response rates for septicemia, pneumonia, soft tissue infections, and urinary tract infections were 71, 50, 71, and 83 percent, respectively. Of five microbiologically proved superinfections, three were fungal, and one each was due to Klebsiella species and S. aureus. No toxicity was observed. For 12 organisms, the minimal inhibitory concentration was lower for ticarcillin plus clavulanate potassium than for ticarcillin alone; in six it was identical. Five organisms were resistant to both, and three that were resistant to ticarcillin were sensitive to ticarcillin plus clavulanate potassium. Ticarcillin plus clavulanate potassium is a safe drug with an expanded spectrum of activity. More therapeutic trials need to be conducted to better define its role in the therapy of serious infections in cancer patients.


A strategy toward reconstructing the healthcare system of a unified Korea.
This road map aims to establish a stable and integrated healthcare system for the Korean Peninsula by improving health conditions and building a foundation for healthcare in North Korea through a series of effective healthcare programs. With a basic time frame extending from the present in stages towards unification, the roadmap is composed of four successive phases. The first and second phases, each expected to last five years, respectively, focus on disease treatment and nutritional treatment. These phases would thereby safeguard the health of the most vulnerable populations in North Korea, while fulfilling the basic health needs of other groups by modernizing existing medical facilities. Based on the gains of the first two phases, the third phase, for ten years, would prepare for unification of the Koreas by promoting the health of all the North Korean people and improving basic infrastructural elements such as health workforce capacity and medical institutions. The fourth phase, assuming that unification will take place, provides fundamental principles and directions for establishing an integrated healthcare system across the Korean Peninsula. We are hoping to increase the consistency of the program and overcome several existing concerns of the current program with this roadmap.


Age-related clinical and biological features of PTEN abnormalities in T-cell acute lymphoblastic leukaemia.
The tumour suppressor gene PTEN is commonly altered in T-cell acute lymphoblastic leukaemia but its prognostic impact is still debated. We screened a cohort of 573 fully characterised adult and paediatric T-cell acute lymphoblastic leukaemia (T-ALL) patients for genomic PTEN abnormalities. PTEN-inactivating mutations and/or deletions were identified in 91 cases (16%), including 18% of paediatric (49/277) and 14% of adult cases (42/296). Thirty-four patients harboured only mutations, 12 cases demonstrated only large deletions and 9 only microdeletions. About 36 patients had combined alterations. Different mechanisms of PTEN inactivation predicted differences in the clinical outcome for both adult and paediatric patients treated according to the GRAALL03/05 and FRALLE2000 protocols. Whereas large deletions predicted lower 5-year overall survival (P=0.0053 in adults, P=0.001 in children) and disease-free survival (P=0.0009 in adults, P=0.0002 in children), mutations were not associated with a worse prognosis. The prognostic impact of PTEN loss is therefore linked to the underlying type of genomic abnormality, both in adult and paediatric T-ALLs, demonstrating that detailed analysis of the type of abnormality type would be useful to refine risk stratification.


[Population difference of polypores in northwest and southeast of China].
Polypores are an important group of wood-rotting fungi and play a key role in decomposing wood in the forest ecosystem. Based on field investigations and laboratory analysis, fungal flora and diversity composition of polypores in Tianshan Moutains, Qilian Mountains, Baotianman Nature Reserve and Wuyi Mountains were analyzed. In total, 72 polypore species were found in Tianshan Mountains, 99 in Qilian Mountains, 124 in Baotianman Nature Reserve and 156 in Wuyi Mountains. There were fourteen common species in the four zones. The biogeography could be divided into 4 groups at genera level of the four zones, the important elements were North temperate element and cosmopolitan element, and floristic analysis showed a distinct north temperate character. The proportion of white rot polypores in the four zones increased from northwest to southeast of China, while the proportion of brown rot polypores decreased. Polypores preferentially grew on angiosperm trees compared to gymnosperm trees. Among the four zones, polypores in Baotianman had the highest proportion of species living on angiosperm trees. Rare and threatened species in Tianshan Mountains and Qilian Mountains were mainly found on conifer trees, while in the other two zones, most rare and threatened species were found on broadleaf trees. Generally, the distinctions of these four areas were mainly affected by the forest type.


[Cooperation in health from the bioethical perspective].
This study considers the scenario of international relations in the transition to the twenty-first century as a backdrop for reflection on the bioethical perspective of international cooperation in health. It presents an exploratory analysis of the interdisciplinary scientific production in bioethics and public health in the international context, revealing that the focus and confluence of both issues has scant coverage in terms of diplomatic relations. It describes the methodology used to select publications cataloged in this interdisciplinary area from two bibliographic sources available on the web (93 articles in BVS/BIREME and 161 in PubMed), pointing to difficulties in locating this literature. The potential of the epistemological approach that flourished in Latin America under the guise of the Bioethics of Intervention in addressing the challenges that confront the international cooperation system, identified as the benchmark for analysis of South-South cooperation in health, is recommended. It concludes by proposing systematization and broadening of knowledge at the intersection of bioethics, public health and diplomacy, whose projection in the political and institutional field can contribute to reducing inequalities in health conditions among nations.


Oral administration of probiotic Escherichia coli after birth reduces frequency of allergies and repeated infections later in life (after 10 and 20 years).
The development of allergies is a complex in which both composition and influence of the intestinal flora play an important role. We observed in earlier studies that the presence of an orally administered probiotic Escherichia coli strain in the intestine stimulated both a serum and local antibody response, decreased the presence of pathogens, the number of infections and the need for antibiotics. The preventive effect of oral colonization after birth with a probiotic E. COLI strain was assessed by evaluating the results of a questionnaire both 20 years (150 full-term infants) and 10 years (77 preterm infants) after colonization. Differences in occurrence of allergies in colonized and control subjects were statistically significant both after 10 and 20 years (p < 0.01). Specific serum IgE antibodies confirmed the presence of allergies in 100% of 10-year-old and 91% of 20-year-old patients with clinical symptoms of allergy. Ten years after colonization, the occurrence of repeated infections was significantly lower in colonized subjects than it was in controls (p < 0.01); 20 years later, no differences were found in these groups. Intentional colonization of the intestine with E. coli after birth (offering the advantage of the first colonizer) was found to decrease the incidence of allergies and repeated infections in later life.


Deep venous thrombosis.
Venous thromboembolism (VTE), manifested as either deep venous thrombosis (DVT) or pulmonary embolism (PE), is an extremely common medical problem, occurring either in isolation or as a complication of other diseases or procedures. Yet, despite its frequency, much remains to be learned regarding the pathogenic mechanisms that initiate VTE, about tailoring its treatment to the individual with her/his specific set of risk factors for recurrence, and about its medical management when associated with specific disease entities, such as cancer. These three topics are addressed in this chapter. In Section I, Drs. López and Conde discuss the mechanisms by which venous thrombi may be initiated on the vessel wall in the absence of anatomically overt vessel wall injury. The authors propose a model whereby tissue factor (TF)-bearing microvesicles that arise from cells of monocyte/macrophage lineage can fuse with activated endothelial cells in regions of vessel activation or inflammation and initiate blood coagulation. Key components of this model include docking of the microvesicles to the stimulated endothelium through P-selectin glycoprotein ligand-1 on their surfaces binding to either P-selectin or E-selectin on the endothelium, and the role of hypoxia during blood stasis in initiating local endothelial activation. Elevations in the levels of TF-bearing microvesicles associated with inflammatory conditions would help to explain the increased risk of thrombosis associated with infections and inflammatory states such as inflammatory bowel disease. In Section II, Dr. Clive Kearon discusses the risk factors for recurrent thrombosis and strategies for determining length of therapy and tailoring specific therapies through risk stratification. Those patients who experience VTE in association with a major reversible risk factor such as surgery are much less likely to experience a recurrence when anticoagulation is discontinued than are patients with a persistent risk factor, such as thrombophilia or cancer unresponsive to therapy. Those with a minor reversible risk factor, such as prolonged air travel, have an intermediate risk of recurrence after discontinuance of anticoagulant therapy. The author provides an algorithm for using risk assessment as a means of determining the length and type of therapy to be used to minimize the rate of recurrence while simultaneously diminishing the risk of bleeding associated with anticoagulation. In Section III, Dr. Agnes Lee updates the topic of VTE associated with malignancy. Patients with cancer make up approximately 20% of those presenting with first time VTE, and the presence of VTE forebodes a much poorer prognosis for patients with cancer, likely because of the morbidity associated with VTE itself and because VTE may herald a more aggressive cancer. Recent evidence indicates that low-molecular weight heparins (LMWHs) improve survival in patients with advanced cancer through mechanisms beyond their effect as anticoagulants. Because of their improved efficacy and safety and potential anti-neoplastic effect, the LMWHs have become the anticoagulants of choice for treating VTE associated with cancer.


A meta-analytic investigation of the impact of mindfulness-based interventions on ADHD symptoms.
Mindfulness-based interventions (MBIs) have been reported to be efficacious in treating attention deficit hyperactivity disorder (ADHD). However, the value of the control effect of MBIs on ADHD core symptoms remains controversial. To clarify the literature on the control effect of MBIs on the symptoms of ADHD and guide future researches, an effect-size analysis was conducted. A systematic search in PubMed, Embase, Web of Science, Medline, Cochrane Library, China National Knowledge Infrastructure, and Wangfang Data databases was performed up to January 11, 2019. The overall effect size of MBIs on ADHD core symptoms (ie, inattention and hyperactivity/impulsivity) was recorded by the metric of Hedges' g with 95% confidence interval, Z-value, and P-value. Eleven eligible studies featuring 682 participants were included in the meta-analysis. The overall results indicated that MBIs had large effects on inattention (Hedges' g = -0.825) and hyperactivity/impulsivity (Hedges' g = -0.676) relative to the control group. Results from subgroup analyses between self- and observer rating on ADHD symptoms revealed that the effect of MBIs both remained in a large range and self-rated ADHD core symptom had a greater impact on heterogeneity across the studies. Meta-regression found that the overall effect might be moderated by participant age group and control condition. The present meta-analysis suggested that MBIs had large effects in reducing ADHD core symptoms in comparison with the control group. Future researches are needed to assess follow-up effects of MBIs on ADHD core symptoms and explore the correlation between the individual level of mindfulness and reduction of ADHD symptoms.


Problems of confidentiality in reporting morbidity and causes of death.
The author stresses that in the reporting of morbidity and causes of death, the confidential nature of the medical records must be respected, while at the same time sufficient and accurate information must be given for statistical purposes. Various practical measures are described. Where possible, data indispensable for general administration should be filed separately from those of exclusively statistical interest, for which it should also be possible to give a reasonable guarantee that their publication will not lead to any infringement of secrecy. Where guarantees cannot be given that confidentiality will be respected, medical practitioners may be reluctant to file a full report.


Epidemiology of mouth cancer in 1989: a review.
The oral cavity and pharynx combined is the sixth commonest site of cancer in both sexes. In many countries the mortality rate is increasing among younger men born since approximately 1910-1920. A causal role in the aetiology of mouth cancer has been established for tobacco use, both smoking and chewing, separately and in conjunction with betel-quid chewing; with alcohol consumption and, less certainly, with other factors such as poor oral hygiene, nutritional factors and certain occupational exposures. In Western countries, there is convincing evidence that a large attributable risk can be ascribed to the joint habits of cigarette smoking and alcohol consumption. In Asian societies, a high attributable risk can be ascribed to cigarette smoking and betel chewing. Mouth cancer is at the same time an important form of cancer, and one for which practical prospects for prevention already exist. Against this background of a continually increasing trend among younger persons, it seems essential to engage upon programmes of prevention, including increasing awareness for early detection, against mouth cancer at the present time.


Liposome-Based Carriers for CRISPR Genome Editing.
The CRISPR-based genome editing technology, known as clustered regularly interspaced short palindromic repeats (CRISPR), has sparked renewed interest in gene therapy. This interest is accompanied by the development of single-guide RNAs (sgRNAs), which enable the introduction of desired genetic modifications at the targeted site when used alongside the CRISPR components. However, the efficient delivery of CRISPR/Cas remains a challenge. Successful gene editing relies on the development of a delivery strategy that can effectively deliver the CRISPR cargo to the target site. To overcome this obstacle, researchers have extensively explored non-viral, viral, and physical methods for targeted delivery of CRISPR/Cas9 and a guide RNA (gRNA) into cells and tissues. Among those methods, liposomes offer a promising approach to enhance the delivery of CRISPR/Cas and gRNA. Liposomes facilitate endosomal escape and leverage various stimuli such as light, pH, ultrasound, and environmental cues to provide both spatial and temporal control of cargo release. Thus, the combination of the CRISPR-based system with liposome delivery technology enables precise and efficient genetic modifications in cells and tissues. This approach has numerous applications in basic research, biotechnology, and therapeutic interventions. For instance, it can be employed to correct genetic mutations associated with inherited diseases and other disorders or to modify immune cells to enhance their disease-fighting capabilities. In summary, liposome-based CRISPR genome editing provides a valuable tool for achieving precise and efficient genetic modifications. This review discusses future directions and opportunities to further advance this rapidly evolving field.


A circulating TH2 cytokines profile predicts survival in patients with resectable pancreatic adenocarcinoma.
Surgery is the only potentially curative option for patients with pancreatic ductal adenocarcinoma (PDAC), but metastatic relapse remains common. We hypothesized that the expression levels of inflammatory cytokines could predict recurrence of PDAC, thus allowing to select patients who most likely could benefit from surgical resection. We prospectively collected plasma at diagnosis from 287 patients with pancreatic resectable neoplasms. The expression levels of 23 cytokines were measured in 90 patients with PDAC by using a multiplex analyte profiling assay. Levels higher than cutoff identified of the TH2 cytokines interleukin (IL)4, IL5, IL6 of macrophage inflammatory protein (MIP)1α, granulocyte-macrophage colony-stimulating factor (GM-CSF), and monocyte chemoattractant protein (MCP)1, and of IL17α, IFNγ-induced protein (IP)10, and IL1b were significantly associated with a shorter median OS. In particular, levels of IL4 and IP10 higher than cutoff identified, and level of TH1 cytokines TNFα and INFγ, and of IL9 and IL1Rα lower than cutoff identified were significantly associated with a shorter DFS. In the multivariate analysis, high IP10 was confirmed as negatively associated with OS (HR = 3.097, p = 0.014) and IL4 and TNFα remain negatively (HR = 2.75, p = 0.002) and positively (HR = 0.224, p = 0.049) associated with DFS, respectively. Simultaneous expression of low IL4 and high TNFα identified patients with best prognosis (HR = 0.313, p < 0.0001). In conclusion, we demonstrated that, among a series of cytokines, IL4 is the most significant independent prognostic factor for DFS in resectable PDAC patients, and it could be useful to select patients with high risk of early recurrence who may avoid an unnecessary resection.


Hyper-CVAD regimen in routine management of adult acute lymphoblastic leukemia: a retrospective multicenter study.
Treatment of acute lymphoblastic leukemia is unsatisfactory in adults due to disease and patient-related factors and probably because adult chemotherapy regimens are weaker than pediatric protocols. Worries about inadequacy of adult regimens urged many hematologists, including us, to reconsider their routine treatment practices. In this retrospective multicenter study, we aimed to evaluate results of hyper-CVAD treatment in comparison to other intensive protocols. All patients aged ≤65 years who were commenced on intensive induction chemotherapy between 1999 and 2011 were included in the study. Sixty-eight of 166 patients received hyper-CVAD, 65 were treated with CALGB-8811 regimen and 33 with multiple other protocols. Limited number of patients who were treated with other intensive protocols and mature B-acute lymphoblastic leukemia cases who were mostly given hyper-CVAD were eliminated from the statistical analyses. In spite of a favorable complete remission rate (84.2%), overall (26.3 vs. 44.2% at 5 years, p = 0.05) and disease-free (24.9 vs. 48.2%, p = 0.001) survival rates were inferior with hyper-CVAD compared to CALGB-8811 due to higher cumulative nonrelapse mortality risk (29.7 vs. 5.9%, p = 0.003) and no superiority in cumulative relapse incidence comparison (45% for both arms, p = 0.44). Hyper-CVAD, in its original form, was a less favorable regimen in our practice.


Screening of respiratory pathogens by Respiratory Multi Well System (MWS) r-gene™ assay in hospitalized patients.
Novel respiratory viruses have been identified as possible agents of upper and lower respiratory tract infections. Multiplex real-time PCRs have been developed to identify clinically relevant respiratory pathogens. In this study, 178 respiratory samples already screened for influenza virus types A and B by Flu A/B ASR real-time PCR kit were retrospectively analyzed with the Respiratory Multi Well System (MWS) r-gene™ real-time PCR kit which detects a wide spectrum of respiratory pathogens. The goal was to demonstrate the importance of a wide spectrum screening compared to a single diagnostic request. The Flu A/B ASR kit detected influenza B virus in 1.7% of the samples (3/178) and no influenza A virus. The MWS r-gene™ kit detected influenza virus in 6.7% (12/178) of samples (0.6% influenza A, and 6.2% influenza B), while the overall detection rate for respiratory pathogens was 54% (96/178). Co-infections were detected in 8/178 (4.5%) samples. Adenovirus was the infectious agent detected most frequently, followed by respiratory syncytial virus. The risk of being infected by respiratory syncytial virus is almost threefold higher in patients older than 65 years compared to the younger age group (OR:2.7, 95% CI: 1.2-6.2). Wide spectrum screening of respiratory pathogens by real-time PCR is an effective means of detecting clinically relevant viral pathogens.


[Morphological changes in prostatic tissue of patients with benign prostatic hyperplasia treated with permixon].
A pilot trial has been performed to assess effects of permixon on prostatic tissue in patients with benign prostatic hyperplasia (BPH). A total of 49 BPH and control patients entered the trial. 36 patients of the study group were randomized into 3 subgroups of 12 patients each. Permixon was taken in a standard dose of 320 mg/day for 3, 6 and 12 months, respectively. Mean duration of BPH was 3.7 years (0-8 years). Mean value of PCA was 6.0 ng/ml. The control group of 13 patients were not given permixon. Multifocal prostatic biopsy was performed in all the patients before and after the treatment or follow-up. Stromal-parenchymatous correlation in the study group significantly increased (by 59%)--from 3.28 (0.25-9.61) to 5.22 (1.20-10.67) (p = 0.0002). For the control group this correlation was insignificant. Permixon-treated patients demonstrated inhibition of prostatic epithelium proliferative activity by 32% (p = 0.0001) and a rise in the stage of proliferative centers development from stage II-III to IV-V. Intensity of inflammation in prostatic tissue decreased by 53% in the study group and insignificantly in the control group. Thus, permixon treatment of BPH leads to a significant rise in stromal-parenchymatous correlation due to inhibition of proliferative activity of prostatic epithelium and attenuation of inflammation.


Infrastructural considerations of implementing gene therapy for hemophilia in the Nordic context.
Despite improvements in hemophilia care, challenges remain, including treatment burden and impaired quality of life. Gene therapy may overcome these. However, its introduction presents a challenge. To outline a function-based gene therapy working model describing critical milestones associated with gene therapy handling, administration, and follow-up to facilitate and implement an effective infrastructure for gene therapy introduction. Literature review and consensus discussion among Hemophilia Comprehensive Care centers (HCCCs) in the Nordic region. Representatives from six HCCCs sought to pinpoint milestones and key stakeholders for site readiness at the pre-, peri-, and post-infusion stages, including authority and genetically modified organism (GMO) product requirements, awareness, medical eligibility, logistics and product handling for infusion, laboratory monitoring, and follow-up. A gene therapy transit map was developed with key stakeholders identified. The approach to prepare the vector will differ between the Nordic centers, but the contracted pharmacy unit will be a key stakeholder. Therefore, a pharmacy checklist for the implementation of gene therapy was developed. For the future, Advanced Therapy Medicinal Product centers will also be implemented. Patients' expectations, commitments, and concerns need to be addressed repeatedly and education of patients and the expanded health-care professionals team will be the key to successful and optimal clinical management. Eligibility testing according to the product's summary of product characteristics and frequent follow-up and monitoring post-infusion according to the World Federation of Hemophilia chart will be crucial. The approach to deliver gene therapy in the Nordic region will differ partly between the hemophilia centers, but the defined road map with checklists for the implementation of this advanced therapy will be applicable to all. The map may also serve as a platform for the use of future GMO product options both within and outside the area of hemophilia.


Gamma knife radiosurgery for acromegaly: outcomes after failed transsphenoidal surgery.
This study evaluates the safety and efficacy of gamma knife radiosurgery (GKRS) in patients with a growth hormone-secreting adenoma. A retrospective review of data collected from a prospective database of GKRS patients between January 1988 and September 2006 was performed in patients with acromegaly. Successful endocrine outcome was defined as normalization of the insulin-like growth factor level. Tumor volume was also assessed. At least 18 months of follow-up was available in 95 patients who received radiosurgery during the study period. Mean endocrine follow-up was 57 months (range, 18-168 mo). Normal insulin-like growth factor levels were achieved in 50 patients (53%) at an average time of 29.8 months after radiosurgery (median, 23.5 mo). A decrease in tumor volume control was achieved in 83 (92%) of 90 patients. Five patients (6%) had no change in tumor volume, and two patients (2%) had an increase in tumor volume. New endocrine deficiencies developed in 32 patients (34%). Four patients developed new-onset partial visual acuity deficits; three of these patients had received previous conventional fractionated radiation therapy. GKRS is a complementary treatment for recurrent or residual growth hormone-secreting pituitary adenomas. Although infrequent, tumor growth, new-onset pituitary hormone deficiency, recurrence, and neurological dysfunction require careful clinical, radiological, and endocrinological follow-up.


Case Report: Rare presentation of adult intussusception at Orotta National Referral Hospital, Eritrea.
A 38-year-old woman presented at Orotta National Referral Hospital emergency department in May 2017 with pain in the epigastric region and vomiting. Physical examination revealed no pertinent findings. Blood and urine tests were normal, and erect abdominal x-ray revealed a distended small intestine with multiple layers of "air-fluid levels". CT scan and MRI were not done due to their temporary unavailability. During laparotomy a large mass of 20x20 cm in size was detected in the mid-jejunum of the small intestine. This leading tumor caused intussusception and coiling of the small intestine. As there are no typical symptoms of intussusception, it is very important to do CT scan for patients with long-standing abdominal pain and vomiting to achieve a definitive diagnosis of intussusception.


The use of complementary and alternative therapies by cancer patients in northern Israel.
The use of complementary and alternative medicine has increased over the last decade in the western world. To evaluate the extent and characteristics of CAM use among cancer patients in northern Israel. Telephone interviews were conducted with 2,176 newly registered cancer patients or their family members, at least 1 year following referral. The rates of CAM use varied significantly according to demographic characteristics and chemotherapy treatment, from 3% in the basically educated elderly group up to 69% of educated Israeli-born Jews younger than 70 years receiving chemotherapy. The overall rate of CAM use was 17%. The most influential factors determining CAM use were academic or high school education, chemotherapy treatment, Israel as country of birth, and age 41-50 years. All patients used CAM in addition to conventional therapies. Less than half of them reported it to their physicians. The most frequently used treatments were various chemical, biological, botanic and homeopathy remedies. Friends and relatives were the main recommenders of CAM. Most CAM users reported that they used CAM because they believed it "strengthens the immune system," alleviates side effects of chemotherapy, improves quality of life, and helps to overcome pain and stress; 62% of them reported subjective beneficial effects. A predicting module of CAM user patients was built that may help physicians initiate conversations with their patients on CAM use. Expanding physicians' knowledge on CAM methods will encourage them to provide additional advice, promote the use of beneficial therapies, and inform patients about potentially harmful methods.


Using heterozygosity-fitness correlations to study inbreeding depression in an isolated population of white-tailed deer founded by few individuals.
A heterozygosity-fitness correlations (HFCs) may reflect inbreeding depression, but the extent to which they do so is debated. HFCs are particularly likely to occur after demographic disturbances such as population bottleneck or admixture. We here study HFC in an introduced and isolated ungulate population of white-tailed deer Odocoileus virginianus in Finland founded in 1934 by four individuals. A total of 422 ≥ 1-year-old white-tailed deer were collected in the 2012 hunting season in southern Finland and genotyped for 14 microsatellite loci. We find significant identity disequilibrium as estimated by g 2. Heterozygosity was positively associated with size- and age-corrected body mass, but not with jaw size or (in males) antler score. Because of the relatively high identity disequilibrium, heterozygosity of the marker panel explained 51% of variation in inbreeding. Inbreeding explained approximately 4% of the variation in body mass and is thus a minor, although significant source of variation in body mass in this population. The study of HFC is attractive for game- and conservation-oriented wildlife management because it presents an affordable and readily used approach for genetic monitoring that allowing identification of fitness costs associated with genetic substructuring in what may seem like a homogeneous population.


Clinical Characteristics and Self-Harm in Forensic Psychiatric Patients.
Self-harm, comprising non-suicidal self-injury, and suicide attempts, is a serious and potentially life-threatening behavior that has been associated with poor life quality and an increased risk of suicide. In forensic populations, increased rates of self-harm have been reported, and suicide is one of the leading causes of death. Aside from associations between self-harm and mental disorders, knowledge on self-harm in forensic psychiatric populations is limited. The purpose of this study was to characterize the clinical needs of a cohort of forensic psychiatric patients, including self-harm and possible risk factors thereof. Participants (N = 98) were consecutively recruited from a cohort of forensic psychiatric patients in Sweden from 2016 to 2020. Data were collected through file information, self-reports, and complemented with semi-structured interviews. Results showed that self-harm was common among the participants, more than half (68.4%) of whom had at some point engaged in self-harm. The most common methods of non-suicidal self-injury were banging one's head or fist against a wall or other solid surface and cutting, and the most common method of suicide attempt was hanging. The most prominent functions of non-suicidal self-injury among the participants were intrapersonal functions such as affect regulation, self-punishment, and marking distress. Self-harm in general was associated to neurodevelopmental disorders (p = 0.014, CI = 1.23-8.02, OR = 3.14) and disruptive impulse-control and conduct disorders (p = 0.012, CI = 1.19-74.6, OR = 9.41), with reservation to very wide confidence intervals. Conclusions drawn from this study are that self-harm was highly prevalent in this sample and seems to have similar function in this group of individuals as in other studied clinical and non-clinical groups.


Fine particulate matter exposure and incidence of stroke: A cohort study in Hong Kong.
We aimed to assess the association of long-term residential exposure to fine particulate matter (PM) with aerodynamic diameter less than 2.5 μm (PM2.5) with the incidence of stroke and its major subtypes. We ascertained the first occurrence of emergency hospital admission for stroke in a Hong Kong Chinese cohort of 66,820 older people (65+ years) who enrolled during 1998-2001 (baseline) and were followed up to December 31, 2010. High-resolution (1 × 1 km) yearly mean concentrations of PM2.5 were predicted from local monitoring data and US National Aeronautics and Space Administration satellite data using linear regression. Baseline residential PM2.5 exposure was used as a proxy for long-term exposure. We used Cox proportional hazards to evaluate the risk of incident stroke associated with PM2.5 exposure adjusted for potential confounders, including individual and neighborhood factors. Over a mean follow-up of 9.4 years, we ascertained 6,733 cases of incident stroke, of which 3,526 (52.4%) were ischemic and 1,175 (17.5%) were hemorrhagic. The hazard ratio for every 10 μg/m3 higher PM2.5 concentration was statistically significant at 1.21 (95% confidence interval [CI] 1.04-1.41) for ischemic and non-statistically significant at 0.90 (95% CI 0.70-1.17) for hemorrhagic stroke in fully adjusted model 3. The estimates for ischemic stroke were higher in older participants (>70 years), less educated participants, and in men for current smokers. Long-term PM2.5 exposure was associated with higher risk of incident ischemic stroke, but the association with incident hemorrhagic stroke was less clear.


Cellular lipid composition influences stress activation of the yeast general stress response element (STRE).
The heat inducibility of the yeast heat-shock response (HSR) pathway has been shown to be critically dependent on the level of unsaturated fatty acids present in the cell. Here the inducibility by heat or salt of the independently regulated general stress response (GSR) pathway is shown to be affected in the same way. An increase in the percentage of unsaturated fatty acids in heat- or salt-acclimated cells correlated with a decrease in the induction of a general stress-response-promoter-element (STRE)-driven reporter gene by either stress. Despite inducing reporter gene expression, sorbic acid treatment did not confer salt cross-tolerance on the cells. This failure correlated with a failure to increase the percentage of unsaturated fatty acids in the cells, suggesting that GSR pathway induction, in the absence of lipid changes, is insufficient for the induction of cross-tolerance. Cells grown with fatty acid supplements under anaerobic conditions provided further evidence for a potential role for lipids in the acquisition of stress resistance. These cells contained different fatty acid profiles depending on the fatty acid supplement supplied, exhibited differential sensitivity to both heat and salt stress, but had not undergone STRE induction. These results suggest that heat- and salt-stress induction of the GSR are sensitive to the level of unsaturated fatty acids present in the cell and that stress cross-tolerance may be a lipid-mediated phenomenon. Given that an increased level of unsaturated fatty acids also down-regulates heat induction of the HSR pathway, these observations lead to the provocative hypothesis that lipid modifications, rather than HSR or GSR pathway induction, are a major contributor to the induced heat and salt tolerance of yeast cells.


Effects of ACTH (corticotropin) analogues on steroidogenesis and cyclic AMP in rat adrenocortical cells. Evidence for two different steroidogenically responsive receptors.
Comparative studies on the mechanism of action of ACTH1-39 and ACTH5-24 [corticotropin-(1-39)- and corticotropin-(5-24)-peptides] on isolated rat adrenal cells were performed. The relationship between stimulated steroidogenesis and cyclic AMP was very different, suggesting that cyclic AMP does not play the same role in mediating the action of the two agonists. Data from three separate experiments showed that the competitive antagonist ACTH6-24 [corticotropin-(6-24)-peptide] had mean inhibitor constants of 13.4 +/- 3.1 nM against ACTH1-39 and 3.4 +/- 1.0 nM against ACTH5-24, indicating that the steroidogenic actions of these two agonists are mediated by two different receptor types. We conclude that there are two possible mechanisms for corticotropin action, only one of which involves the necessary production of cyclic AMP.


Is the routine measurement of ionized calcium worthwhile in patients with cancer?
This study was undertaken to analyse the relationship between total calcium (TCa) and ionized calcium (ICa) in patients with cancer, and to assess the clinical value of routine measurements of ICa in these patients. Serum TCa, ICa, albumin, proteins and creatinine were measured in 188 adult patients with solid malignant tumours. Most of them were out-patients, the Karnofsky score being 80 or above in 67%. The correlation coefficient between ICa and TCa was 0.85 (P less than 0.001) and did not improve after correcting TCa for protein concentration with several published formulae. Although TCa measurements had a global diagnostic accuracy (percent of patients correctly classified) of 90%, they failed to identify a substantial proportion of patients with increased levels of ICa (57% for uncorrected TCa, and 27-57% for protein-corrected TCa). However, the finding of slightly increased ICa levels did not seem to predict the development of frank hypercalcaemia and did not impair the prognosis. According to these results, the routine measurement of ICa in unselected patients with cancer has no clinical usefulness.


Serum Androgens Are Independent Predictors of Insulin Clearance but Not of Insulin Secretion in Women With PCOS.
In insulin-resistant individuals, hyperinsulinemia is a key compensatory mechanism, aimed at maintaining glucose homeostasis. Increased secretion and reduced clearance of insulin may both potentially contribute to this phenomenon. Insulin resistance and hyperinsulinemia are common findings in women with polycystic ovary syndrome (PCOS). While there is some information on insulin secretion, very few studies have investigated metabolic clearance rate of insulin (MCRI) in these women. Moreover, there is paucity of data on the relationships between MCRI and the pathophysiological characteristics of PCOS. The aim of the study was to explore these issues. One hundred ninety women with PCOS, diagnosed according to the Rotterdam criteria, with normal glucose tolerance. Assessment of MCRI and clinical, hormonal, and metabolic characteristics of subjects. MCRI and insulin sensitivity were measured by the hyperinsulinemic euglycemic clamp. Serum androgens were assessed by liquid chromatography-mass spectrometry and equilibrium dialysis. A historical sample of healthy women was used to define the corresponding reference intervals. MCRI was impaired in about two-thirds of women with PCOS. Subjects with low MCRI differed from those with normal MCRI for a number of anthropometric, metabolic, and endocrine features. In multivariate analysis, the degree of adiposity, estimates of insulin secretion, and serum androgen concentrations were independent predictors of MCRI. Conversely, age, adiposity, MCRI, and insulin sensitivity, but not serum androgens, were independent predictors of insulin secretion. In women with PCOS, metabolic clearance of insulin is reduced, contributing to generating hyperinsulinemia. Serum androgens are independent predictors of this phenomenon.


CYP2C19 activity comparison between Swedes and Koreans: effect of genotype, sex, oral contraceptive use, and smoking.
To compare CYP2C19 enzyme activity between Swedes and Koreans controlling for the effect of CYP2C19 genotype, sex, oral contraceptive use, and smoking habits. CYP2C19 activity was determined in 185 healthy Swedish and 150 Korean subjects as the omeprazole/5-hydroxyomeprazole ratio (metabolic ratio; MR) using high-performance liquid chromatography. Genotyping was performed by PCR using Taqman assay. As expected, a higher incidence of poor metabolizers (PM) was found in Koreans (14%) compared with Swedes (3.8%) and the frequency of the CYP2C19 17 allele was very low in Koreans (0.3%). Among subjects homozygous for CYP2C19 1, Koreans displayed significantly lower CYP2C19 enzyme activity than Swedes (p < 0.000001). Interestingly, in Koreans a pronounced gender difference was apparent: females (n = 24) had significantly lower MR than males (n = 30; p < 0.0001), but such a gender difference was not seen among Swedes. Swedish OC users had a higher MR than non-users (p < 0.00001), whereas OC was only used by one Korean. No effects of smoking were observed. We find specific gender-dependent effects of CYP2C19 activity in Koreans, but not in Swedes. Controlling for the effect of genotype and sex, Koreans display lower CYP2C19 activity than Swedes. The genetic, epigenetic or environmental basis for this difference remains to be identified.


Racial diversity with high nucleated cell counts and CD34 counts achieved in a national network of cord blood banks.
Banked, unrelated, partially HLA-matched, umbilical cord blood is an alternative stem cell source for patients in need of transplantation therapy who lack traditionally matched donors. A presumed advantage of cord blood is the ability to increase recruitment of donors of minority ethnic backgrounds. The American Red Cross Cord Blood Program was established in 1999 with 6 banks and 10 collection sites throughout the country. Cord blood donors self-report racial designations on questionnaires, and donor race was collected from each site. Postprocessing nucleated cell counts and CD34(+) counts were obtained on the cord blood units, and results from each racial group (white, black, Asian, Hispanic, and Native American) were compared in the natural logarithmic scale by using analysis of variance. A total of 18878 donors consented: 64% white, 16% black, 12% Hispanic, 4% Asian, 1% Native American, and 3% other. The Detroit area consented the highest percentage of black donors (87%), San Diego consented the highest percentage of Hispanic donors (59%), and Oakland consented the highest percentage of Asian donors (15%). Seven thousand eight hundred sixty-six cord blood units have been banked for transplantation. The mean preprocessing nucleated cell count was 1220 x 10(6) (range, 327-7300 x 10(6)). There was no difference among racial groups when controlled for site (P =.395). The mean CD34(+) count was 3.28 x 10(6). Blacks had a significantly lower CD34(+) count than the other racial/ethnic groups in the Midwest, Northwest, and North Carolina collection sites. A racially diverse cord blood bank can be achieved. Nucleated cell counts were similar among the different racial/ethnic groups. CD34(+) counts were lower for blacks in some collection sites.