[Low dose of disulfiram and l-dopa evoked synergistic modification in behavior of Wistar and WAG/Rij rats].
Comparative analysis of behaviors of two rat strains, Wistar and WAG/Rij, was performed. No behavioral differences between Wistar and WAG/Rij were found in the emotional resonance test. Disulfiram injection produced similar effects in both rat strains. Animals of the first group (with slow acquisition of emotional resonance reaction) transformed into the animals of the second group (with fast acquisition). Passive avoidance conditioning was successfully reproduced in Wistar and was significantly impaired in WAG/Rij. A low dose of disulfiram injected before or immediately after conditioning substantially improved the reproduction to a greater extent in WAG/Rij than Wistar strains thus eliminating in interstrain differences. Active avoidance conditioning was more successful in WAG/Rij than in Wistar rats However, on the next day conditioning in WAG/Rij was substantially impaired. Administration of the low dose of disulfiram or L-DOPA prior to conditioning impaired the acquisition but improved the reproduction on the following day in both strains, but disulfiram injection after conditioning improved conditioning in WAG/Rij to a greater extent than in Wistar. Thus, the pharmacologic enhancement of the reward system substantially changed animal behavior and improved memory consolidation.


Trematode Metacercariae in Freshwater Fish from Water Systems of Hantangang and Imjingang in Republic of Korea.
The infection status of freshwater fish with digenetic trematode metacercariae was examined in water systems of Hantangang and Imjingang (River), the Republic of Korea. A total of 877 (594 from Hantangang and 283 from Imjingang) fishes were examined by the artificial digestion methods. Clonorchis sinensis metacercariae were detected in 7 (1.2%) fishes (in 3 spp.) from Hantangang in Cheorwon-gun, Gangwon-do, and 40 (14.1%) fishes (in 7 spp.) from Munsancheon in Paju-si, Gyeonggi-do. The average densities were 1.9 and 35.6 per fish infected, respectively. Metagonimus spp. metacercariae were detected in 312 (52.5%) and 113 (39.9%) fishes from Hantangang and Imjingang, and their average densities were 47.5 and 9.6 per fish infected, respectively. Centrocestus armatus metacercariae were found in 161 (27.1%) and 70 (24.7%) fishes from Hantangang and Imjingang, and their average number per fish infected was 694 and 82, respectively. Echinostoma spp. metacercariae were detected in 50 (8.4%) and 94 (33.2%) fishes from Hantangang and Imjingang, and their average densities were 9.6 and 23.1 per fish infected, respectively. The infection status of fishes with metacercariae of Stephanoprora spp., Diplostomum spp., Clinostomum complanatum, Metorchis orientalis, and Metorchis taiwanensis were analyzed by surveyed regions. Conclusively, it was confirmed that C. sinensis metacercariae were quite commonly detected in fishes from Munsancheon but rarely from other localities, whereas the metacercariae of other digenetic trematodes were relatively prevalent in fishes from water systems of Hantangang and Imjingang in Korea.


[The loss-grief reaction and coping behavior of a mother whose child died of a brain tumor].
This is a study on the loss-grief reaction and coping behavior of a mother whose child died of brain tumor. The researcher used field methods to collect data and analyze observations of mother-nurse interaction. The results showed that this mother had self-blame depression, and guilt feelings and affected the whole family. With the help of nurses and various supportive resources the mother was finally able to go through the grieving process smoothly.


Chlorambucil in the treatment of intractable Uveitis associated with juvenile chronic arthritis.
The response to prolonged low dose chlorambucil for chronic active uveitis in 6 patients with juvenile chronic arthritis and one patient with juvenile ankylosing spondylitis is described. Only 2 patients were judged to have had longterm benefit from treatment in both eyes and one had a transient benefit in one eye. Drug induced adverse effects occurred in 3 patients.


Nicotine deprivation influences P300 markers of cognitive control.
Studies suggest that reduced cognitive control due to nicotine withdrawal may have a critical role in promoting tobacco use. The P3 family of event-related brain potential (ERP) components is thought to serve as markers of cognitive control processes. Unfortunately, existing research that examines the effects of nicotine deprivation on P3 amplitude has been marred by small sample sizes and other design limitations. The present study sought to determine the effects of nicotine deprivation on P3b and P3a amplitudes, which index task relevant target detection and orienting responses to novelty, respectively. A secondary aim was to examine self-reported trait cognitive control as a moderator of nicotine deprivation-induced reductions in P3b and P3a amplitudes. In all, 121 nicotine-dependent smokers attended two experimental sessions following 12-h smoking/nicotine deprivation. In a counterbalanced manner, participants smoked nicotine cigarettes during one session and placebo cigarettes during the other session. Findings indicated that nicotine deprivation reduced P3b amplitude (p<0.00001) during a three-stimulus oddball task independent of trait cognitive control. In contrast, nicotine deprivation reduced P3a only among participants who scored lower on measures of trait cognitive control. Implications for conceptualizing risk for nicotine dependence, and its treatment, are discussed.


MMP-2, MMP-9, VEGF and CA 15.3 in breast cancer.
Matrix metalloproteinases (MMPs) are a family of extracellular matrix degrading proteinases. Owing to their matrix-degrading abilities and high expression in advanced tumours, MMPs were originally implicated in cancer progression, invasion and metastasis. In this study, the correlation was determined between the expression of gelatinases (MMP-2 and MMP-9) in the sera of breast cancer patients from zymographic analysis and serum concentrations of VEGF and CA 15.3, before surgery and after 1 and 6 months; the association of both markers with clinicopathological features including histological type, stage of disease and estrogen (ER) and progesterone (PgR) receptors status were also analysed. In all, 88 breast cancer patients and 20 healthy women were involved in this study. No statistically significant correlation between pro MMP-2, pro MMP-9, VEGF and CA 15.3 serum levels was found (p>0.05). In breast cancer patients, a significant decrease of the pro MMP-2 serum expression 1 month after surgery with respect to serum levels before surgery (p=0.0008) was evident, as well as of CA 15.3 serum levels at baseline and after 1 month (p=0.017). Moreover a strong decrease of pro MMP-9 serum levels was found in 88 breast cancer patients after 1 month (p=0.028) and after 6 months (p =0.009) from surgery. On the other hand, no significant differences in the serum levels of VEGF, CA 15.3, pro MMP-2 or pro MMP-9 between 88 breast cancer patients preoperatively and 20 healthy women as controls were found. Our findings did indicate a significant positive association between higher preoperative levels of CA 15.3 and progression of disease (p=0.03), as well as a longer disease-free survival in patients who exhibited a decrease of serum pro MMP-9 expression compared to other biomarkers. No relationship between these four markers and the main clinical and pathological parameters was found. The present study failed to demonstrate any association between serum levels of MMPs, VEGF and CA 15.3 and well-known clinicopathological characteristics of breast carcinoma, while demonstrating the prognostic value of CA 15.3 and pro MMP-9 in the follow-up of breast cancer patients.


[New approaches to the evaluation of functional state of afferent central nervous system pathways in patients with syringomyelia].
Functional state of both afferent and efferent pathways of CNS was studied with the method of magnetic stimulation (MS) in patients with syringomyelia. A control group contained 35 healthy individuals. The state of the efferent pathways was estimated by the time of the central motor conduction. The state of the afferent pathways of brain stem and spinal cord was analyzed by the latency of the motor responses of the orbicular muscle of the eye to MS of the spinal cord on the level of cervical and lumbar regions. The signs of the disorders in the conduction of the excitement through pyramidal pathways as well as through the afferent pathways of the spinal cord and the brain stem were registered in patients with syringomyelia. This observation allows to increase considerably the diagnostic range of MS.


TEL/AML1 fusion resulting from a cryptic t(12;21) is the most common genetic lesion in pediatric ALL and defines a subgroup of patients with an excellent prognosis.
The t(12;21)(p13;q22) is identified by routine cytogenetics in less than 0.05% of pediatric acute lymphoblastic leukemia (ALL) patients. This translocation encodes a TEL/AML-1 chimeric product comprising the helix-loop-helix domain of TEL, a member of the ETS-like family of transcription factors, fused to AML-1, the DNA-binding subunit of the AML-1/CBF beta transcription factor complex. Both TEL and AML-1 are involved in several myeloid leukemia-associated translocations with AML-1/CBF beta being altered in 20-30% of de novo acute myeloid leukemia (AML) cases. We now demonstrate that a TEL/AML1 chimeric transcript encoded by a cryptic t(12;21) is observed in 22% of pediatric ALL, making it the most common genetic lesion in these patients. Moreover, TEL/AML1 expression defined a distinct subgroup of patients characterized by an age between 1 and 10 years, B lineage immunophenotype, non-hyperdiploid DNA content and an excellent prognosis. These data demonstrate that molecular diagnostic approaches are invaluable in identifying clinically distinct subgroups, and that the AML1/CBF beta transcription complex is the most frequent target of chromosomal rearrangements in human leukemia.


Histopathological causes of late liver allograft dysfunction: analysis at a single institution.
We summarize our experience in the pathological diagnosis of late complications of liver transplantation (LT) to better understand the causes of late allograft dysfunction in a population mostly composed of patients with hepatitis B virus (HBV) infection. We reviewed 361 post-transplant liver biopsies from 174 patients who underwent LT and first presented with liver function abnormalities 3 months post-procedure. The underlying diseases included HBV-associated liver disease (77%), toxic or alcoholic liver disease (10.3%), hepatitis C virus (HCV)-associated liver disease (8.6%), primary biliary cirrhosis (1.2%), primary sclerosing cholangitis (1.2%), and metabolic disease (1.7%). The three most common late complications were acute rejection (32.5%), recurrent disease (19.1%), and biliary complication (17.1%). Patients who underwent LT for HBV infection or for drug- or alcohol-related liver disease had a lower incidence of recurring disease than those who underwent transplantation for HCV infection. During post-transplantation months 3-12, acute rejection was the most common cause of allograft dysfunction and recurring disease was the leading cause for allograft dysfunction (p=0.039). The two primary causes of late allograft dysfunction have overlapping histological features, although acute rejection more frequently showed bile duct damage and vascular endothelialitis than recurring HBV infection, and recurring HBV infection had more frequent lobular activity and piecemeal necrosis. The causes of late liver allograft dysfunction are closely associated with the original liver diseases and the period after LT. Careful attention is required for differential diagnosis between acute rejection and recurrent HBV.


Pelvic trauma: WSES classification and guidelines.
Complex pelvic injuries are among the most dangerous and deadly trauma related lesions. Different classification systems exist, some are based on the mechanism of injury, some on anatomic patterns and some are focusing on the resulting instability requiring operative fixation. The optimal treatment strategy, however, should keep into consideration the hemodynamic status, the anatomic impairment of pelvic ring function and the associated injuries. The management of pelvic trauma patients aims definitively to restore the homeostasis and the normal physiopathology associated to the mechanical stability of the pelvic ring. Thus the management of pelvic trauma must be multidisciplinary and should be ultimately based on the physiology of the patient and the anatomy of the injury. This paper presents the World Society of Emergency Surgery (WSES) classification of pelvic trauma and the management Guidelines.


Spatial Heterogeneity in Particle-Associated, Light-Independent Superoxide Production Within Productive Coastal Waters.
In the marine environment, the reactive oxygen species (ROS) superoxide is produced through a diverse array of light-dependent and light-independent reactions, the latter of which is thought to be primarily controlled by microorganisms. Marine superoxide production influences organic matter remineralization, metal redox cycling, and dissolved oxygen concentrations, yet the relative contributions of different sources to total superoxide production remain poorly constrained. Here we investigate the production, steady-state concentration, and particle-associated nature of light-independent superoxide in productive waters off the northeast coast of North America. We find exceptionally high levels of light-independent superoxide in the marine water column, with concentrations ranging from 10 pM to in excess of 2,000 pM. The highest superoxide concentrations were particle associated in surface seawater and in aphotic seawater collected meters off the seafloor. Filtration of seawater overlying the continental shelf lowered the light-independent, steady-state superoxide concentration by an average of 84%. We identify eukaryotic phytoplankton as the dominant particle-associated source of superoxide to these coastal waters. We contrast these measurements with those collected at an off-shelf station, where superoxide concentrations did not exceed 100 pM, and particles account for an average of 40% of the steady-state superoxide concentration. This study demonstrates the primary role of particles in the production of superoxide in seawater overlying the continental shelf and highlights the importance of light-independent, dissolved-phase reactions in marine ROS production.


The Fos complex and Fos-related antigens recognize sequence elements that contain AP-1 binding sites.
The Fos protein complex and several Fos-related antigens bind directly or indirectly to a common sequence element that is similar to the consensus binding site for HeLa cell activator protein 1 (AP-1). This element is present in a negative regulatory sequence in the differentiation-sensitive adipocyte gene, aP2; in a transcriptional enhancer for the Gibbon ape leukemia virus; and in a region of the human immunodeficiency virus (HIV) long terminal repeat partially characterized as a negative regulatory element. The protein level and binding activity of Fos and Fos-related antigens increase rapidly after calcium ionophore treatment of a CD4+ human lymphoblast cell line, H9. These data suggest that several proteins may associate with the AP-1 binding site. Moreover, temporally regulated control of the level of each protein could represent a mechanism for modulation of these putative mediators of gene expression.


Social inequalities in sleep-disordered breathing: Evidence from the CoLaus|HypnoLaus study.
Sleep-disordered breathing is a common condition, related to a higher cardiometabolic and neurocognitive risk. The main risk factors for sleep-disordered breathing include obesity, craniofacial characteristics, male sex and age. However, some studies have suggested that adverse socioeconomic circumstances and lifestyle-related behaviours such as smoking and alcohol use, may also be risk factors for sleep-disordered breathing. Here, we investigate the associations between socioeconomic status and sleep-disordered breathing, as measured by sleep apnea-hypopnea and oxygen desaturation indexes. Furthermore, we assess whether these associations are explained by lifestyle-related factors (smoking, sedentary behaviour, alcohol use and body mass index [BMI]). We used data from the CoLaus|HypnoLaus study, a population-based study including 2162 participants from Lausanne (Switzerland). Socioeconomic status was measured through occupation and education. Sleep-disordered breathing was assessed through polysomnography and measured using the apnea-hypopnea index (AHI: number of apnea/hypopnea events/hr: ≥15/≥30 events), and the ≥3% oxygen desaturation index (ODI: number of oxygen desaturation events/hr: ≥15/≥30 events). Lower occupation and education were associated with higher AHI and ODI (occupation: AHI30, odds ratio (OR) = 1.88, 95% confidence interval (CI) [1.07; 3.31]; ODI30, OR = 2.29, 95% CI [1.19; 4.39]; education: AHI30, OR = 1.21, 95% CI [0.85; 1.72]; ODI30, OR = 1.26, 95% CI [0.83; 1.91]). BMI was associated with socioeconomic status and AHI/ODI, and contributed to the socioeconomic gradient in SDB, with mediation estimates ranging between 43% and 78%. In this Swiss population-based study, we found that low socioeconomic status is a risk factor for sleep-disordered breathing, and that these associations are partly explained by BMI. These findings provide a better understanding of the mechanisms underlying social differences in sleep-disordered breathing and may help implement policies for identifying high-risk profiles for this disorder.


Nonprofit Human Milk Banking in the United States.
Human milk, widely understood to be beneficial for infants, can be lifesaving for preterm neonates, especially in reducing the risk of necrotizing enterocolitis. Donor human milk (DHM) is an option when mothers are unable to provide milk or have an inadequate supply for their infants. Nonprofit donor human milk banks are established to provide safe, processed human milk from milk donated by healthy lactating mothers who have undergone a rigorous screening process. These milk banks, operating under the auspices of the Human Milk Banking Association of North America, obtain, process, and dispense human milk under strict guidelines set by the association. Increasing the supply of donor human milk to meet a dramatic increase in demand poses a significant challenge for nonprofit milk banks. Efforts to increase supply nationwide include education of providers, use of social media to engage potential donors, and outreach to news media. In parallel, milk banks are establishing regional depots to collect donations, and additional milk banks are being developed. This article describes the current nonprofit milk bank industry in the United States, its challenges, and its future prospects.


Expression of transient receptor potential vanilloid channels TRPV5 and TRPV6 in retinal pigment epithelium.
Hydration and ionic composition of the subretinal space (SRS) is modulated by the retinal pigment epithelium (RPE). In particular calcium concentration (Ca(2+)) in the SRS varies with light exposure, and although this change is regulated by RPE transport activity, the specific transport proteins involved have yet to be defined. Two members of the transient receptor potential vanilloid family, TRPV5 and TRPV6, are calcium selective ion channels and are known to be expressed in calcium-transporting epithelial tissues. The present work characterizes of TRPV5 and TRPV6 in RPE. Reverse transcriptase PCR was used to examine the presence of TRPV5 and TRPV6 mRNA in cultured human RPE. Protein expression was assessed by western blotting using TRPV5- and TRPV6-specific antibodies. Immunocytochemistry was employed to examine subcellular localization of TRPV5 and TRPV6 in frozen, formaldehyde-fixed sections of native RPE-choroid tissue and in cultured human RPE monolayers. Finally, TRPV5/TRPV6 activity was assessed in cultured RPE, using Ca(2+) indicator dyes to follow [Ca(2+)](i) as a function of changes in [Ca(2+)](o) with and without addition of the TRPV5/TRPV6 inhibitor ruthenium red. Direct sequencing of PCR DNAs documented the presence of TRPV5 and TRPV6 transcripts in human RPE. Immunocytochemistry showed that TRPV5 and TRPV6 are expressed in native RPE-choroid tissue with strong immunoreactivity for both channels on the apical as well as the basal plasma membranes. Immunostaining for both channels was also positive in monolayers of cultured RPE cells. In cultured cells subcellular localization was variable with immunoreactivity present in the cytoplasmic domain as well as on the plasma membrane. Plasma membrane staining was increased with phagocytosis. The reported molecular weight of the core protein for both TRPV5 and TRPV6 is about 75 kDa, with the expected size of the glycosylated proteins in the range of 85-100 kDa. Western blot analysis of TRPV6 in RPE detected a distinct band at approximately 85 kDa, with another strong band at approximately 60 kDa. A similar pattern was seen for TRPV5, with strong bands at 82 kDa and 71 kDa. In live-cell imaging experiments, [Ca(2+)](i) was lower in the presence of the TRPV5/TRPV6 inhibitor ruthenium red. RPE expresses the epithelial calcium channels TRPV5 and TRPV6, the most calcium-selective channels of the TRP superfamily. Present findings suggest that these channels could function in RPE to mediate calcium influx from SRS and thus regulate changes in SRS calcium composition that accompany light/dark transitions.


Income inequality and adolescent fertility in low-income countries.
: The well-known socioeconomic gradient in health does not imply that income inequality by itself has any effect on well-being. However, there is evidence of a positive association between income inequality and adolescent fertility across countries. Nevertheless, this key finding is not focused on low-income countries. This study applies a multilevel logistic regression of country-level adolescent fertility on country-level income inequality plus individual-level income and controls to the Demographic and Health Surveys data. A negative association between income inequality and adolescent fertility was found among low-income countries, controlling for income (OR = 0.981; 95%CI: 0.963-0.999). Different measures and different subsamples of countries show the same results. Therefore, the international association between income inequality and adolescent fertility seems more complex than previously thought.


Neurobiology of ADHD From Childhood to Adulthood: Findings of Imaging Methods.
To review the pattern of morphological and functional brain changes in both children and adults with ADHD that emerges from the recent literature. In addition, the task of the present review is to explore how to understand the nature of the brain changes. Literature review. Neuroimaging studies provide a multitude of information that currently allows us to expand the notions of ADHD neurobiology beyond its traditional understanding as a manifestation of frontostriatal dysfunction. They point to disorders of several other areas of the brain, particularly the anterior cingulum, the dorsolateral as well as ventrolateral prefrontal cortex, the orbitofrontal cortex, the superior parietal regions, the caudate nucleus, the thalamus, the amygdala and the cerebellum. Imaging studies point to the persistence of changes in both brain structure and function into adulthood, although there might be a tendency for improvement of caudate nucleus pathology. Changes in neuronal (dendritic) plasticity, which are under the modulatory influence of the dopaminergic system, may be in the background of disorders of brain morphology and anatomical connectivity with subsequent brain dysfunction. Growing evidence suggest that methylphenidate treatment can lead to improvement of brain changes seen in neuroimaging by its positive effect on neuroplasticity. Changes in neuronal plasticity may be behind persisting brain changes in ADHD. Current treatment approaches seem to improve these neuroplastic processes, and, therefore, may have a positive effect on the neuropathology of ADHD.


Anti-Inflammatory Effects of OxPAPC Involve Endothelial Cell-Mediated Generation of LXA4.
Oxidation of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (OxPAPC) generates a group of bioactive oxidized phospholipid products with a broad range of biological activities. Barrier-enhancing and anti-inflammatory effects of OxPAPC on pulmonary endothelial cells are critical for prevention of acute lung injury caused by bacterial pathogens or excessive mechanical ventilation. Anti-inflammatory properties of OxPAPC are associated with its antagonistic effects on Toll-like receptors and suppression of RhoA GTPase signaling. Because OxPAPC exhibits long-lasting anti-inflammatory and lung-protective effects even after single administration in vivo, we tested the hypothesis that these effects may be mediated by additional mechanisms, such as OxPAPC-dependent production of anti-inflammatory and proresolving lipid mediator, lipoxin A4 (LXA4). Mass spectrometry and ELISA assays detected significant accumulation of LXA4 in the lungs of OxPAPC-treated mice and in conditioned medium of OxPAPC-exposed pulmonary endothelial cells. Administration of LXA4 reproduced anti-inflammatory effect of OxPAPC against tumor necrosis factor-α in vitro and in the animal model of lipopolysaccharide-induced lung injury. The potent barrier-protective and anti-inflammatory effects of OxPAPC against tumor necrosis factor-α and lipopolysaccharide challenge were suppressed in human pulmonary endothelial cells with small interfering RNA-induced knockdown of LXA4 formyl peptide receptor-2 (FPR2/ALX) and in mFPR2-/- (mouse formyl peptide receptor 2) mice lacking the mouse homolog of human FPR2/ALX. This is the first demonstration that inflammation- and injury-associated phospholipid oxidation triggers production of anti-inflammatory and proresolution molecules, such as LXA4. This lipid mediator switch represents a novel mechanism of OxPAPC-assisted recovery of inflamed lung endothelium.


Extraarticular villonodular synovitis of the tendoachilles: a case report.
Extraarticular form of pigmented villonodular synovitis is rare and usually presents as an extension of a primary intraarticular process. Purely extraarticular lesions are even less common. Pigmented villonodular synovitis involving the synovium around the tendoachilles has not been reported. We report a unique case in a healthy 22-year-old male who presented with a swelling around the tendoachilles for a year. It became painful following a traumatic event 4 weeks prior to consultation. Magnetic resonance imaging (MRI) revealed an extraarticular soft tissue mass moulded to the posterior surface of the calcaneum. It was excised and histology revealed pigmented villonodular synovitis.


Prevalence of antibodies to Toxoplasma gondii in wolverines from Nunavut, Canada.
The prevalence of antibodies to Toxoplasma gondii was determined in blood and tissue exudates recovered from the spleens of 41 wolverines (Gulo gulo) collected in Nunavut, Canada, using a modified agglutination test (MAT). Antibodies to T. gondii were found in 17 (41.5%) of the 41 wolverines with MAT titers of 1:25 in 1, 1:50 in 4, 1:100 in 5, 1:200 in 6, and 1:400 in 1. This is the first report of antibodies to T. gondii in wolverines, and the results indicate that exposure is common.


Whole cell patch-clamp recordings of rat midbrain dopaminergic neurons isolate a sulphonylurea- and ATP-sensitive component of potassium currents activated by hypoxia.
The effects of brief (2-4 min) hypoxia on presumed dopaminergic "principal" neurons of the rat ventral mesencephalon were investigated by using either intracellular or whole cell patch-clamp recordings in in vitro conditions. Under single-electrode voltage clamp, with sharp microelectrode (Vh -60 mV), a brief hypoxia caused an outward current (hypoOUT) of 110.2 +/- 15.2 (SE) pA (n = 18), which was followed by a posthypoxic outward current (posthypoOUT) of 149.6 +/- 10.6 pA (n = 18). Although the hypoOUT reversed at -83.7 +/- 3.8 mV (n = 18), the posthypoOUT did not reverse. The K+ATP-blocking sulphonylureas tolbutamide (100 microM) and glibenclamide (30 microM), significantly reduced the peak of the hypoOUT by 47.6 +/- 7.7% (n = 16) and 54.18 +/- 7.5% (n = 3), respectively. In contrast, they did not affect the posthypoOUT. Extracellular barium (300 microM to 1 mM) almost abolished the hypoOUT, leaving the posthypoOUT unchanged. The large K+ channel blocker charybdotoxin (10-50 nM), depressed the hypoOUT after tolbutamide treatment. To investigate whether or not cytosolic factors might control the development of the hypoOUT, we dialyzed the principal neurons by patch-clamp recordings (Vh -60 mV). Under whole cell recordings hypoxia evoked an hypoOUT of 70.2 +/- 14.5 pA that reversed polarity at -87.9 +/- 5.1 mV (n = 8). A small posthypoxic response was detected upon reoxygenation in a few neurons (4 out of 14). Three different sulphonylureas, tolbutamide (100 microM), glibenclamide (10-30 microM), and glipizide (100 nM) completely blocked the hypoOUT in patch-clamped neurons. The hypoOUT was also abolished by extracellular BaCl2 (300 microM). When the content of ATP in the dialyzate was raised from 2 to 10 mM no outward current/hyperpolarization was evoked by hypoxia. These data suggest that the hypoOUT, in principal neurons, is a complex response sustained by at least two barium-sensitive components: 1) an ATP-dependent, sulphonylurea-sensitive K+ conductance which could be isolated by the patch-clamp techniques and 2) a K+ conductance remaining after tolbutamide in intracellularly recorded neurons, which is sensitive to charybdotoxin and dependent on dialyzable cytosolic factors.


Human gene MOB: structure specification and aspects of transcriptional activity.
Prior investigation of human brain cDNA libraries revealed an evolutionarily conserved gene MOB that has been cloned in silico on chromosome 10. To elucidate its biological role, we performed structural and functional analysis of its transcripts. Applying an expressed sequence tag (EST) approach, we specified the sequence of the predicted MOB transcript and found another four exons to belong to the 5'- end of the MOB gene; the newly constructed MOB transcript was detected in vitro. Here, we report MOB to comprise at least 11 exons and 10 introns and to span more than 320 kb of the genomic sequence. We propose complex regulation of MOB gene activity at a transcriptional level, based on its expression pattern. Thus, in the human cerebellum, we discovered multiple alternatively spliced products of MOB differing in their coding portion; one of the alternative transcripts was demonstrated to lack the longest coding exon VII. MOB was expressed at very low levels in a wide spectrum of human tissues: most abundantly in the brain and in the kidney. Two transcription initiation sites were found for MOB and two alternative promoters were suggested to govern its expression. We believe that MOB activity is also regulated at the posttranscriptional level. In the constructed MOB transcript, the extended multiexon 5'-untranslated region (UTR) together with the weak context of the translation start ATG codon are considered as potent translator inhibitors. Modulation of MOB translation efficiency is proposed based on the appropriate alternative splicing events within the 5'-UTR. The MOB 3'-UTR is anticipated to mediate message instability. We thus suggest that this MOB transcript may be a labile short-lived molecule with strong regulation of its translational efficiency. We believe that MOB gene activity is controlled at least at the transcriptional and the posttranscriptional levels, strictly regulating the amount of the encoded protein product.


Teaching-Service integration within the National Professional Health Education Reorientation Program.
This integrative literature review aimed at identifying the characteristics and describing how teaching-service integration is expressed in studies on Pró-Saúde (Charitable institution for social and hospital assistance) published in Brazil in the period 2007-2012. For the search, the term National Professional Health Education Reorientation Program was entered in the following databases: Virtual Health Library (BVS), Google Scholar and the Bank of Theses of the Coordination for the Improvement of Higher Education Personnel (CAPES). Forty-one publications were selected with the following inclusion criteria: scientific papers; theses and dissertations; studies in English, Portuguese or Spanish. The critical review of studies was performed through a comprehensive reading of the texts. Outcomes are presented in two categories: Dialogue and partnership as tools for teaching-service integration and Movements of change in teaching-service through Pró-Saúde. Studies have shown that changes in professional education and practice are possible and necessary, especially when supported by strategies that encourage active participation of subjects and confirm teaching-service integration as opportunity for dialogue, promoted by this inducing policy.


Physostigmine: improvement of long-term memory processes in normal humans.
Nineteen normal male subjects received 1.0 milligram of physostigmine or 1.0 milligram of saline by a slow intravenous infusion on two nonconsecutive days. Physostigmine significantly enhanced storage of information into long-term memory. Retrieval of information from long-term memory was also improved. Short-term memory processes were not significantly altered by physostigmine.


Ultrasensitive Quantitation of Plasma Membrane Proteins via isRTA.
Quantitation of plasma membrane proteins (PMPs) is fundamental and frequently performed daily in the lab. However, challenged by the inherent/interacting heterostructures and complex surroundings of the PMPs in lipid membrane, quantitative techniques for PMP often require complex treatments (e.g., labeling, isolation, purification, and determination), and the sensitivity is usually not satisfactory. To address this problem, we have proposed a novel method that enables quantitation of PMPs with extremely high sensitivity, in an easier-to-manipulate and more streamlined way. This method is based on the design of an in situ rolling cycling replication-templated amplification strategy (isRTA). In fact, two rounds of DNA cascade isothermal amplifications have been conducted. The first round of amplification can provide templates for the second round of amplification; thus, significant enhancement of quantitative signals can be achieved. In this way, PMPs are quantified with ultrahigh sensitivity; as few as 25 copies of PMPs can be detected per cell. Moreover, the advantages of isRTA have been demonstrated by simultaneous identification of several PMP biomarkers (MUC1, EpCAM, and HER2) that are expressed over a wide distribution range on breast cancer cells. The precise typing of breast cancer cell subsets is thus possible because of the "quantitative-to-qualitative" strategy. Therefore, the unprecedented sensitivity and high usability of the isRTA method may present significant prospects for delving into membrane proteins and their related biofunctions in many research fields.


Gene expression profiling of breast cancer in relation to estrogen receptor status and estrogen-metabolizing enzymes: clinical implications.
Interactions between luminal epithelial cells and their surrounding microenvironment govern the normal development and function of the mammary gland. Estradiol plays a key role in abnormal intracellular signaling, which contributes to the development and progression of breast tumors. The present article summarizes the results from a microarray whole genome gene expression analysis as well as a quantitative analysis of the mRNA expression of members of the estradiol metabolic and signaling pathways in the tumors of postmenopausal breast cancer patients. The analysis of the variation in whole genome gene expression resulted in a tumor classification comprising several distinct groups with distinct expression of the estrogen receptor (ER). The parallel study on the expression of only nine mRNA transcripts of members of the estradiol pathways resulted in two main clusters, representing ER- and ER tumors. The mRNA expression of the estradiol-metabolizing enzymes did not follow the expression of the ER in all cases, leading to the recognition of several further subclasses of tumors. When the tumor classes obtained by whole genome gene expression analysis were compared with those obtained by independent quantitation of the estradiol-metabolizing enzymes, a statistically significant association between both classification groups was observed. These findings point to a possible association between development of a tumor with a particular expression profile and its capacity to synthesize estradiol as measured by the expression of the transcripts for the necessary key enzymes. Further, whole genome expression patterns were studied in 12 patients treated with anastrozole. Using significance analysis of microarrays, we identified 298 genes significantly differently expressed between partial response and progressive disease groups.


Results Following Stent-Graft Coverage of the Hypogastric Artery in the Management of Aortoiliac Aneurysms in Endovascular Aneurysm Repair.

Aim: The aim of our study was to assess the outcomes of stent-graft coverage of the hypogastric artery in the management of aortoiliac aneurysms with endovascular aneurysm repair (EVAR).

Material and methods: From January 2013 to March 2017, a total of 93 patients with aortoiliac aneurysms were treated with EVAR, which required occlusion of one or both of the hypogastric arteries. The patients of the Department of General, Vascular, Endocrine and Transplant Surgery were included in the study continuously and all procedures were elective.

Results: A total of 93 patients with aortoiliac aneurysms required a unilateral or bilateral procedure. Six patients were excluded from our study because they did not appear at their follow-up appointments. The study included 87 patients (80 men; mean age 71.9 (7.9) years, range 54-88), of which 30 had a unilateral procedure and 57 had a bilateral procedure. In 8 procedures (5.55%, n = 7) there was a type II endoleak that resolved during follow-up and required no surgical intervention. In 10 procedures (6.94%, n = 10) there was a type IB endoleak, with 8 procedures requiring surgical re-intervention in the form of an extension. In 12 procedures (8.33%, n = 9), the hypogastric artery thrombosed.

Conclusion: Coverage of the hypogastric artery by stent-graft has been proven to be a safe procedure, but there is still a risk of type II endoleak. Although 5.55% (n = 7) of the procedures in our study had a type II endoleak, none required surgical intervention.</br&gt.


Changes in liver function parameters after occlusion of gastrorenal shunts with balloon-occluded retrograde transvenous obliteration.
To evaluate the effects of portal blood flow on liver function, this pilot study investigated the correlation between changes in portal blood flow as measured by image-directed Doppler ultrasonography and liver function tests in nine patients with cirrhosis who were treated with balloon-occluded retrograde transvenous obliteration. All patients had large gastric varices and prominent gastrorenal shunts. Treatment caused a significant increase (p < 0.01) in portal blood flow; we documented reversion from hepatofugal to hepatopetal portal flow in one patient and increases in hepatopetal flow from 5.4 +/- 1.1 to 7.85 +/- 1.4 cm/s (mean +/- SD) in eight patients. All patients showed decreases in gastric variceal size. However, portal pressure rose significantly in all patients after treatment from 25.4 +/- 7.6 to 30.7 +/- 5.8 mmH2O (n = 7, mean +/- SD), and two of nine patients had worsening of esophageal varices. All nine patients showed improvement in the 15-min retention rate of indocyanine green from 31.8 +/- 16.1 to 21.8 +/- 12.4% (mean +/- SD, p < 0.01), whereas seven patients showed increased serum albumin levels after treatment. These results suggest balloon-occluded retrograde transvenous obliteration increases hepatic portal blood flow, which may be accompanied by improvements in liver function.


The optical properties of CuA in bovine cytochrome c oxidase determined by low-temperature magnetic-circular-dichroism spectroscopy.
The visible-near-i.r.-region m.c.d. (magnetic-circular-dichroism) spectrum recorded at low temperature in the range 450-900 nm is reported for oxidized resting mammalian cytochrome c oxidase. M.c.d. magnetization curves determined at different wavelengths reveal the presence of two paramagnetic species. Curves at 576, 613 and 640 nm fit well to those expected for an x,y-polarized haem transition with g values of 3.03, 2.21 and 1.45, i.e. cytochrome a3+. The m.c.d. features at 515, 785 and 817 nm magnetize as a S = 1/2 paramagnet with average g values close to 2, and simulated m.c.d. magnetization curves obtained by using the observed g values of CuA2+, i.e. 2.18, 2.03 and 1.99, fit well to the experimental observations. The form of the m.c.d. magnetization curve at 466 nm is curious, but it can be explained if CuA2+ and cytochrome a3+ contribute with oppositely signed bands at this wavelength. By comparing the m.c.d. spectrum of the enzyme with that of extracted haem a-bisimidazole complex it has been possible to deconvolute the m.c.d. spectrum of CuA2+, which shows transitions throughout the spectral region from 450 to 950 nm. The m.c.d.-spectral properties of CuA2+ were compared with those of a well-defined type I blue copper centre in azurin isolated from Pseudomonas aeruginosa. The absolute intensities of the m.c.d. signals at equal fields and temperatures for CuA2+ are 10-20-fold greater than those for azurin. The optical spectrum of CuA2+ strongly suggests an assignment as a d9 ion rather than Cu(I) bound to a thiyl radical.


Parent-offspring conflict and cost-benefit analysis in adolescent suicidal behavior : Effects of birth order and dissatisfaction with mother on attempt incidence and severity.
Data on birth order and parent-offspring relations for 1,601 adolescents participating in the National Longitudinal Study of Adolescent Health were used to test hypotheses about the role of adolescent suicidal behavior in parent-offspring conflict. Among adolescents highly dissatisfied with their mothers, the odds that middleborns would make at least one suicide attempt was 23% that of first- and lastborns (p<.001), but their odds of receiving medical treatment for their attempts was 8.5 times greater than the odds for first- and lastborns (p=.032). The results are tentatively interpreted as supporting the hypothesis that adolescents use suicide attempts to leverage investment from their parents.


Factors associated with stigma and depressive symptoms in family members of patients with epilepsy.
Literature regarding family stigma related to epilepsy is scarce. This study investigated the prevalence of family stigma and depressive symptoms and the associated factors among the family members of patients with epilepsy. In a cross-sectional study, Stigma Scale-Revised score ≥ 4 and Patient Health Questionnaire-9 score ≥ 10 were considered indicative of moderate-to-severe stigma and depressive symptoms, respectively. Stepwise logistic regression analyses were performed. Of the 482 family members, a mean age was 47.1 ± 9.4 years, and 73.4% were female. Of the patients, a mean age was 25.5 ± 16.7 years, and 45.0% were female. Idiopathic generalized epilepsy and focal epilepsy were noted in 22.4% and 65.6% of patients, respectively. Family stigma and depressive symptoms were noted in 10.0% and 11.2% of family members, respectively. Family stigma was significantly associated with high seizure frequency and being a sibling or offspring of a patient independent of their depressive symptoms. By contrast, depressive symptoms in family members were significantly associated with polytherapy, being parents of a patient, and neurological comorbidities independent of family stigma. In a subset of patients and their family, patients had higher proportion of stigma and depressive symptoms than their family. Depressive symptoms and stigma among patients were significantly correlated with those among parents, but not spouse. Family stigma is common in families with epilepsy and is closely related to depressive symptoms. Frequent seizures, polytherapy, neurological comorbidities, and the relationship to a patient may be factors that are independently associated with family stigma and depressive symptoms in family members.


Molecular analysis of the SLC22A12 (URAT1) gene in patients with primary gout.
To analyse the SLC22A12 (URAT1) gene in primary gout patients, first-grade relatives and healthy controls and the possible association of them with demographic and clinical data. We included 69 consecutive patients with diagnosis of primary gout, as well as 29 first-grade relatives and 120 healthy volunteers. Demographic and clinical data were obtained from the patients and relatives. DNA was purified from peripheral blood and all 10 exons of the SLC22A12 (URAT1) gene were sequenced. We found six different mutations in the SLC22A12 gene in 16 out of 69 (23%) patients with primary gout. Five mutations were in exon 5 and one in exon 4; five out of six mutations were heterozygous (one compound heterozygous) and one homozygous. The C850G mutation (exon 5) was found in 11 gout patients, these patients have lower levels of triglycerides than the rest of the group: 160 +/- 56 vs 292 +/- 203 mg/dl (P = 0.038). In one family, we found SLC22A12 mutations in three relatives within exon 5. We did not find mutations in the other exons studied (1-3 and 6-10), nor in any of the 10 exons of the 120 healthy volunteers. We found several mutations in SLC22A12 gene associated with primary gout, the definite role of these mutations in URAT1 activity needs to be further studied.


Factors associated with Salmonella shedding among equine colic patients at a veterinary teaching hospital.
To evaluate factors potentially associated with fecal Salmonella shedding among equine patients hospitalized for colic at a veterinary teaching hospital and to determine the effects of probiotic treatment on fecal Salmonella shedding and clinical signs. Longitudinal study and controlled trial. 246 equine colic patients. History and medical information were obtained from patient records. Fecal and environmental samples were submitted for aerobic bacterial culture for Salmonella enterica. Fifty-one patients were treated with a commercially available probiotic; 46 were treated with a placebo. Logistic regression was used to evaluate data. Salmonella organisms were detected in feces from 23 (9%) patients at least once during hospitalization. Patients were more likely to shed Salmonella organisms if diarrhea was evident < or = 6 hours after hospitalization and duration of hospitalization exceeded 8 days (odds ratio [OR], 20.3), laminitis developed during hospitalization (OR, 12.0), results of nasogastric intubation were abnormal (OR, 4.9), leukopenia was evident < or =6 hours after hospitalization (OR, 4.6), or travel time to the teaching hospital exceeded 1 hour (OR, 3.5). Horses treated with the probiotic did not differ from control horses in regard to likelihood of fecal Salmonella shedding (OR, 1.5) or prevalence of clinical signs. Results suggest that certain risk factors are associated with fecal shedding of S enterica among equine patients hospitalized at a veterinary teaching hospital because of colic and that pathogen monitoring in patients and the hospital environment and use of barrier nursing precautions for equine colic patients are beneficial.


Colonization and persistence of Escherichia coli in axenic and monoxenic turkeys.
Sites of colonization and persistence of virulent (O78) and avirulent (O2) Escherichia coli were determined in 3-week-old axenic turkeys. Colonization of O78 in turkeys infected with Streptococcus faecalis was also determined. Colonization and persistence of E coli in the intestinal tract and lung were not correlated with virulence. Both serotypes persisted in high titer in crop, ileum, ceca, colon, and lung. Persistence of E coli in the liver was positively correlated with virulence, although both serotypes were recovered from the liver in the absence of bacteremia, indicating possible intestinal translocation of E coli to the liver. A reduction in intestinal colonization and translocation of O78 was determined in monoxenic turkeys infected with S faecalis. In contrast, S faecalis had no effect on lung titers of O78. Air sacculitis, pericarditis, and pneumonia were observed in axenic and monoxenic turkeys infected with O78. Bacteremia was detected in a turkey exposed to O78.


High-resolution sonography of the palmar cutaneous branch of the median nerve.
The aim of this study was to describe the potential value of high-resolution sonography for evaluation of the palmar cutaneous branch of the median nerve (MN). The volar wrists of 12 healthy volunteers and 22 consecutive patients with sensory deficit in the palmar triangle and thenar eminence suggesting neuropathy of the palmar cutaneous branch of the MN were examined with high-frequency sonography. Nine patients underwent carpal tunnel release, five had a history of penetrating trauma, six had symptoms suggesting concurrent carpal tunnel syndrome, one received surgery for palmaris tendon transfer, and one underwent resection of a ventral carpal ganglion cyst. Correlative 1.5-T MRI was performed in six patients. In 83% of the healthy volunteers, 17-5-MHz sonography was able to identify the palmar cutaneous branch of the MN from its origin down to slightly distal to the wrist crease. In the patient group, sonography allowed detection of nerve abnormalities in 55% of the cases. Focal hypoechoic swelling of the nerve at the fascial crossing was observed in patients who had either concurrent carpal tunnel syndrome (four cases) or previous carpal tunnel release (three cases). Sonography performed after a penetrating trauma revealed nerve encasement by scar tissue (two cases) or complete transection of the nerve ending in a terminal neuroma (one case). Nerve transection secondary to resection of a ventral carpal ganglion cyst (one case) or to carpal tunnel release (one case) was also observed. Sonography can identify the palmar cutaneous branch of the MN and characterize its abnormalities, providing unique information about this small nerve branch.


Return-to-Sport and Performance After Anterior Cruciate Ligament Reconstruction in National Basketball Association Players.
Anterior cruciate ligament (ACL) rupture is a significant injury in National Basketball Association (NBA) players. NBA players undergoing ACL reconstruction (ACLR) have high rates of return to sport (RTS), with RTS the season following surgery, no difference in performance between pre- and postsurgery, and no difference in RTS rate or performance between cases (ACLR) and controls (no ACL tear). Case-control. NBA players undergoing ACLR were evaluated. Matched controls for age, body mass index (BMI), position, and NBA experience were selected during the same years as those undergoing ACLR. RTS and performance were compared between cases and controls. Paired-sample Student t tests, chi-square, and linear regression analyses were performed for comparison of within- and between-group variables. Fifty-eight NBA players underwent ACLR while in the NBA. Mean player age was 25.7 ± 3.5 years. Forty percent of ACL tears occurred in the fourth quarter. Fifty players (86%) RTS in the NBA, and 7 players (12%) RTS in the International Basketball Federation (FIBA) or D-league. Ninety-eight percent of players RTS in the NBA the season following ACLR (11.6 ± 4.1 months from injury). Two players (3.1%) required revision ACLR. Career length following ACLR was 4.3 ± 3.4 years. Performance upon RTS following surgery declined significantly (P < 0.05) regarding games per season; minutes, points, and rebounds per game; and field goal percentage. However, following the index year, controls' performances declined significantly in games per season; points, rebounds, assists, blocks, and steals per game; and field goal and free throw percentage. Other than games per season, there was no significant difference between cases and controls. There is a high RTS rate in the NBA following ACLR. Nearly all players RTS the season following surgery. Performance significantly declined from preinjury level; however, this was not significantly different from controls. ACL re-tear rate was low. There is a high RTS rate in the NBA after ACLR, with no difference in performance upon RTS compared with controls.


Designing a competency-based orientation for critical care nurses.
A competency-based approach to staff nurse orientation can assist critical care units in more nearly achieving what orientation is really intended to accomplish. In so doing, entry level standards of nursing performance are founded, and critically ill patients and the public can be better assured of receiving the quality of nursing care that they deserve.


Variability in responsiveness to clopidogrel in patients with intermittent claudication.
The concept of clopidogrel resistance is frequently evoked in the cardiac literature. The variability of antiplatelet response in patients with intermittent claudication has not been investigated. The aim of this study was to describe the effect of the addition of clopidogrel to aspirin using ex vivo measures of platelet activation in patients with life-style limiting intermittent claudication. Data from randomised controlled trial. Data from 67 patients with intermittent claudication taking part in a randomised controlled trial and who received clopidogrel in addition to aspirin was analysed. Platelet activation was measured using whole-blood flow cytometric measurement of ADP-stimulated fibrinogen binding at baseline and 12h after administration of a loading dose of 300 mg clopidogrel. Patients continued to receive 75 mg clopidogrel daily for 30 days and platelet activation was again measured at day 30. Compliance with treatment was assessed by counting returned tablets. Six patients were excluded from analysis because of incomplete compliance with treatment. Six of the sixty-one patients (9.8%) showed no reduction in platelet activation 12h after administration of the loading dose of clopidogrel. At 30 days these six patients still showed no response to clopidogrel. Amongst the remaining 55 patients, the mean reduction in fibrinogen binding after clopidogrel administration was 51.5% (95% CI: 43.8-59.2). Amongst responders there was a wide variability in reduction of fibrinogen binding in response to clopidogrel (range 8.11-97.7%). Four of these patients (6.6%) showed a reduction of more than 95% in fibrinogen binding. Patients with intermittent claudication show a wide variability in their response to clopidogrel. While a small proportion of these patients shows no response at all, another small group appears to respond excessively to clopidogrel. Clinical studies are required to identify whether hyper-responders are at increased risk of bleeding complications and whether hyporesponders are at a higher risk of thrombotic events.


[Distribution and changes in properties of ferromagnetic iron particles administered to the animal body].
The registration of ESR signals of organs and tissues in the wide range of temperatures permits to study properties and distribution of ferromagnetic particles in animal organisms. High dispersed powder (HDP) of iron (particle dimension--50-100 nm) was administered subcutaneously to mice in the doses 2 and 100 mg/kg weight of animals. One week after the administration HDP was accumulated in the animal organs under study. Two weeks after the treatment of mice with HDP in the dose of 2 mg/kg the ESR signals with g = 2.1 appeared in the animal tissues: liver, spleen, kidney, heart and lungs. Six weeks after the treatment the ESR signals of the studied tissues did not differ from those in control animals.


RAS blockade with ARB and ACE inhibitors: current perspective on rationale and patient selection.
Cardiovascular disease represents a continuum that starts with risk factors such as hypertension and progresses to atherosclerosis, target organ damage, and ultimately to myocardial infarction, heart failure, stroke or death. Renin-angiotensin system (RAS) blockade with angiotensin converting enzyme (ACE) inhibitors or angiotensin AT(1)-receptor blockers (ARBs) has turned out to be beneficial at all stages of this continuum. Both classes of agent can prevent or reverse endothelial dysfunction and atherosclerosis, thereby reducing the risk of cardiovascular events. Such a reduction has been shown mainly for ACE inhibitors in patients with coronary artery disease, but recent studies revealed that ARBs are not inferior in this respect. However, no such data are currently available on the combination of these drugs. Both ACE inhibitors and ARBs have been shown to reduce target organ damage in organs such as the kidney, brain and heart, and to decrease cardiovascular mortality and morbidity in patients with congestive heart failure. Experimental data point to an influence of ACE inhibitors and ARBs on the number and function of endothelial progenitor cells revealing additional mechanisms of action of these drugs. The VALIANT trial has shown equivalent effects of ARB valsartan and the ACE-inhibitor captopril in patients post myocardial infarction, but the dual RAS-blockade, compared to monotherapy, did not further reduce events. In secondary prevention, the most-recently published ONTARGET study provides evidence that on top of a better tolerability AT(1)-receptors antagonists are equal to ACE inhibitors in the prevention of clinical endpoints like cardiovascular mortality and morbidity, myocardial infarction and stroke. The combined RAS blockade, however, achieved no further benefits in vascular high-risk patients and was associated with more adverse events. In chronic heart failure, ValHeFT and CHARM-ADDED have shown that combined RAS inhibition with ACE inhibitor and valsartan or candesartan reduced morbidity and mortality in certain patient subgroups. Accumulating evidence also points to benefits of the combination therapy in individuals with proteinuric nephropathies. In conclusion, while combined RAS-inhibition is not generally indicated in patients along the cardio-reno-vascular continuum, it has already proven to be effective in heart failure patients with incomplete neuroendocrine blockade. In secondary prevention, monotherapy with either RAS inhibitor is equally efficacious. Furthermore, novel pharmacologic agents such as renin inhibitors may prove useful in preventing common side effects of RAS blockade such as angiotensin escape and AT(1)-receptor upregulation, giving clinicians additional therapeutic tools to optimally treat the individual patient.


Surviving niche busters: Main strategies employed by Canadian private insurers facing the arrival of high cost specialty drugs.
The Canadian patchwork system of prescription drug coverage and the employer sponsored private health benefits group plans appear vulnerable to cost growth due to insufficient balance of power between fragmented public and private buyers, and pharmaceutical manufacturers. The emergence of "bad" insurance risks caused by new and very expensive treatments featuring high cost specialty medicines - also known as niche buster drugs - exposes this vulnerability. This study fills a gap in knowledge by seeking to better understanding how Canadian private insurers face the arrival of specialty pharmaceuticals. It completes an overview of a body of grey literature composed of publicly available online articles from the employment benefits and group insurance consulting and administration industry; online documents from group benefits sector conferences; and online or on demand materials from Canadian life and health insurers. Claims for high cost specialty drugs generate new bad insurance risks that Canadian health insurers attempt to mitigate through isolated corporate initiatives, industry-wide strategies and calls for universal, public catastrophic coverage. The outcomes of these strategies are limited cost-control measures as well as risk and cost transfers onto plan sponsors, patients and provincial public programs.


Pathological study of the 2019 novel coronavirus disease (COVID-19) through postmortem core biopsies.
Data on pathologic changes of the 2019 novel coronavirus disease (COVID-19) are scarce. To gain knowledge about the pathology that may contribute to disease progression and fatality, we performed postmortem needle core biopsies of lung, liver, and heart in four patients who died of COVID-19 pneumonia. The patients' ages ranged from 59 to 81, including three males and one female. Each patient had at least one underlying disease, including immunocompromised status (chronic lymphocytic leukemia and renal transplantation) or other conditions (cirrhosis, hypertension, and diabetes). Time from disease onset to death ranged from 15 to 52 days. All patients had elevated white blood cell counts, with significant rise toward the end, and all had lymphocytopenia except for the patient with leukemia. Histologically, the main findings are in the lungs, including injury to the alveolar epithelial cells, hyaline membrane formation, and hyperplasia of type II pneumocytes, all components of diffuse alveolar damage. Consolidation by fibroblastic proliferation with extracellular matrix and fibrin forming clusters in airspaces is evident. In one patient, the consolidation consists of abundant intra-alveolar neutrophilic infiltration, consistent with superimposed bacterial bronchopneumonia. The liver exhibits mild lobular infiltration by small lymphocytes, and centrilobular sinusoidal dilation. Patchy necrosis is also seen. The heart shows only focal mild fibrosis and mild myocardial hypertrophy, changes likely related to the underlying conditions. In conclusion, the postmortem examinations show advanced diffuse alveolar damage, as well as superimposed bacterial pneumonia in some patients. Changes in the liver and heart are likely secondary or related to the underlying diseases.


Regional specificity in anatomy at the lamina cribrosa.
Specimens cut in cross section at the level of the lamina cribrosa in normal primate eyes are examined by light microscopy. The density of structural elements, consisting of crosswise-oriented connective-tissue trabeculae, is examined in different regions of the nerve head. It is noted that nasal more than temporal more than superior or inferior regions of the lamina cross section contain increased connective-tissue elements. This regional variation in nerve head anatomy is contrasted with susceptibility patterns of nerve head tissue to pressure elevation in both experimental and clinical glaucoma.


Assessing the Effects of One-Time Praziquantel Treatment on Urogenital Lesions Detected by Ultrasound in Schistosoma haematobium-Infected Individuals in Chad.
The objective was to determine the impact of a single dose of praziquantel on urogenital lesions caused by Schistosoma haematobium. Ultrasound (US) was performed on three age groups of subjects with a positive test for hematuria, with the first examination performed in November 2017 and a follow-up visit 7 months later. None of the subjects had previously received treatment. The participants were categorized into three distinct age groups: group 1 = 1-15 years, group 2 = 15-30 years, and group 3 = ≥ 30 years. A total of 250 people from these three groups underwent screening: 99 in group 1, 90 in group 2, and 61 in group 3, among whom 131 (52.4%) had at least one detectable lesion of the urogenital tract on US. Follow-up US after 7 months was possible in 60%, 67%, and 77% of the respective groups (with lesions). The anomalies disappeared in 80% of individuals in group 1, 76% of those in group 2, and 65% in group 3. With the exception of calcifications, most visible anomalies had been resolved. The total number of anomalies is low. Severe obstructive uropathy was not detected. We can conclude that single treatment with praziquantel is able to cure visible anomalies, with the exception of calcifications. The low rate of anomalies, compared with levels in the literature, is speculated to be due to undetected death by obstructive uropathy caused by S. haematobium. This requires further investigation.


ROS signaling in systemic and cellular responses to chronic intermittent hypoxia.
Chronic intermittent hypoxia (CIH) is a common and life-threatening condition that occurs in many different diseases, including sleep-disordered breathing manifested as recurrent apneas. Reactive oxygen species (ROS) have been identified as one of the causative factors in a variety of morbidities. The purpose of this article is to present a brief overview of recent studies implicating a critical role of ROS in evoking phenotypic adverse effects in experimental models of CIH and in patients with recurrent apneas. In experimental models, CIH activates ROS signaling that contributes to several systemic and cellular responses that include (a) altered carotid body function, the primary chemoreceptor for sensing changes in arterial blood O2; (b) elevated blood pressures; (c) enhanced release of transmitters and neurotrophic factors; (d) altered sleep and cognitive behaviors; and (e) activation of second-messenger pathways and transcriptional factors. Considerable evidence indicates elevated ROS levels in patients experiencing CIH as a consequence of recurrent apneas. Antioxidants not only prevent many of the CIH-evoked physiologic and cellular responses in experimental settings, but more important, they also offer protection against certain phenotypic adverse effects in patients with recurrent apneas, suggesting their potential therapeutic value in alleviating certain morbidities associated with recurrent apneas.


What do measurements of molecular biomarkers in different body fluids really tell us?
Molecular or biochemical biomarkers of joint metabolism offer promise in helping us understand joint pathology, its detection and treatment. But they have often been studied alone and in only one body fluid. Although the synovial joint is usually the focus of most arthritis pathology, it is often difficult, for a variety of reasons, to obtain synovial fluid that should best reflect changes in biomarkers related to pathology. It is therefore very important to see whether analyses of more readily obtainable sera and urine also reflect changes in synovial fluid. Catterall and colleagues, in a paper in Arthritis Research & Therapy that examines very early biomarker changes following joint injury, provide us with some insights into these important questions. As the study was very small and examined very early changes following joint injury, prior to onset of any recognisable pathology, we look forward to future larger biomarker studies of this kind in patients with clinically defined arthritic changes to which we can relate biomarker data.


In situ hybridization for human papillomavirus.
There is increasing molecular and epidemiologic evidence that human papillomavirus (HPV) is associated with distinct subset of head and neck lesions. The aim of the present study was to evaluate a possible relationship between the presence of HPV DNA and morphological signs of HPV infections in twenty-six formalin-fixed, paraffin-embedded cases of laryngeal squamous cell carcinomas and seventeen cases of sinonasal inverted papillomas, retrieved from archival material. Ten out of twenty-six cases of cancers and eleven out of seventeen sinonasal inverted papillomas showed morphological signs of HPV infections. All cases have been analyzed using in situ hybridization. The expression of HPV DNA was noted in both examined groups of squamous cell carcinomas and in group of sinonasal inverted papillomas when the morphological signs of HPV infections were present. No significant differences in the frequency of HPV DNA expression were noted in both examined groups of cancers and inverted papillomas (with and without morphological signs of HPV infection). In conclusion, our study confirms the role of HPVs in pathogenesis of inverted papillomas and laryngeal squamous cell carcinomas. However, there is no relevant relationship between the presence of HPV DNA and morphological signs of HPV infections in studied cases.


Surfactant status assessment and personalized therapy for surfactant deficiency or dysfunction.
Surfactant is a pivotal neonatal drug used both for respiratory distress syndrome due to surfactant deficiency and for more complex surfactant dysfunctions (such as in case of neonatal acute respiratory distress syndrome). Despite its importance, indications for surfactant therapy are often based on oversimplified criteria. Lung biology and modern monitoring provide several diagnostic tools to assess the patient surfactant status and they can be used for a personalized surfactant therapy. This is desirable to improve the efficacy of surfactant treatment and reduce associated costs and side effects. In this review we will discuss these diagnostic tools from a pathophysiological and multi-disciplinary perspective, focusing on the quantitative or qualitative surfactant assays, lung mechanics or aeration measurements, and gas exchange metrics. Their biological and technical characteristics are described with practical information for clinicians. Finally, available evidence-based data are reviewed, and the diagnostic accuracy of the different tools is compared. Lung ultrasound seems the most suitable tool for assessing the surfactant status, while some other promising tests require further research and/or development.


Hyperlipidemia and long-term outcomes in nondiabetic chronic kidney disease.
Dyslipidemia confers a paradoxical survival advantage in patients with kidney failure. Data are limited in the earlier stages of chronic kidney disease (CKD). This was a cohort study in 840 subjects with stage 3 to 4 CKD enrolled in the Modification of Diet in Renal Disease study. Cox models were used to examine the relationship of total cholesterol (TC), non-HDL-cholesterol (NHDL-C), triglycerides (TG), and HDL-cholesterol (HDL-C) with all-cause and cardiovascular disease (CVD) mortality and progression to kidney failure. During a mean follow-up of 10 years, there were 208 deaths, 128 deaths from CVD, and 554 subjects reached kidney failure. There was no association between tertiles of any of the lipid variables and mortality; the lowest HDL-C tertile (1.44, 1.18 to 1.78) had increased risk of kidney failure but covariate adjustment abolished this association. In analyses with lipids as continuous variables, there was a significant association with all-cause mortality for TC (hazard ratio [HR] per 10-mg/dl increase, 95% confidence intervals [CI] = 1.03, 1.0 to 1.06) that disappeared with covariate adjustment; there was no association of TG, HDL-C, and NHDL-C as continuous variables with all-cause or CVD mortality. There was a significant inverse association between HDL-C and kidney failure (HR = 0.93, CI = 0.87 to 0.99) in an unadjusted Cox model that was attenuated after adjustment for covariates (HR = 0.98 CI = 0.91 to 1.06). In this cohort, with predominantly nondiabetic CKD patients, hyperlipidemia is not an independent predictor of long-term outcomes.


Nucleolin down-regulation is involved in ADP-induced cell cycle arrest in S phase and cell apoptosis in vascular endothelial cells.
High concentration of extracellular ADP has been reported to induce cell apoptosis, but the molecular mechanisms remain not fully elucidated. In this study, we found by serendipity that ADP treatment of human umbilical vein endothelial cells (HUVEC) and human aortic endothelial cells (HAEC) down-regulated the protein level of nucleolin in a dose- and time-dependent manner. ADP treatment did not decrease the transcript level of nucloelin, suggesting that ADP might induce nucleolin protein degradation. HUVEC and HAEC expressed ADP receptor P2Y13 receptor, but did not express P2Y1 or P2Y12 receptors. However, P2Y1, 12, 13 receptor antagonists MRS2179, PSB0739, MRS2211 did not inhibit ADP-induced down-regulation of nucleolin. Moreover, MRS2211 itself down-regulated nucleolin protein level. In addition, 2-MeSADP, an agonist for P2Y1, 12 and 13 receptors, did not down-regulate nucleolin protein. These results suggested that ADP-induced nucleolin down-regulation was not due to the activation of P2Y1, 12, or 13 receptors. We also found that ADP treatment induced cell cycle arrest in S phase, cell apoptosis and cell proliferation inhibition via nucleolin down-regulation. The over-expression of nucleolin by gene transfer partly reversed ADP-induced cell cycle arrest, cell apoptosis and cell proliferation inhibition. Furthermore, ADP sensitized HUVEC to cisplatin-induced cell death by the down-regulation of Bcl-2 expression. Taken together, we found, for the first time to our knowledge, a novel mechanism by which ADP regulates cell proliferation by induction of cell cycle arrest and cell apoptosis via targeting nucelolin.


R-U policy frontiers for health data de-identification.
The Health Insurance Portability and Accountability Act Privacy Rule enables healthcare organizations to share de-identified data via two routes. They can either 1) show re-identification risk is small (e.g., via a formal model, such as k-anonymity) with respect to an anticipated recipient or 2) apply a rule-based policy (i.e., Safe Harbor) that enumerates attributes to be altered (e.g., dates to years). The latter is often invoked because it is interpretable, but it fails to tailor protections to the capabilities of the recipient. The paper shows rule-based policies can be mapped to a utility (U) and re-identification risk (R) space, which can be searched for a collection, or frontier, of policies that systematically trade off between these goals. We extend an algorithm to efficiently compose an R-U frontier using a lattice of policy options. Risk is proportional to the number of patients to which a record corresponds, while utility is proportional to similarity of the original and de-identified distribution. We allow our method to search 20 000 rule-based policies (out of 2(700)) and compare the resulting frontier with k-anonymous solutions and Safe Harbor using the demographics of 10 U.S. states. The results demonstrate the rule-based frontier 1) consists, on average, of 5000 policies, 2% of which enable better utility with less risk than Safe Harbor and 2) the policies cover a broader spectrum of utility and risk than k-anonymity frontiers. R-U frontiers of de-identification policies can be discovered efficiently, allowing healthcare organizations to tailor protections to anticipated needs and trustworthiness of recipients.


[Microsurgical elimination of foot soft tissue defects with free vascularized flaps].
The results of 40 microsurgical transplantations of complex flaps in 37 patients with cicatricial-ulcerous foot deformations are analysed. The surgery was indicated in cicatricial soft tissues defects, unhealing trophic ulcers, inability to use local tissues for plastic surgery. The scapular flap was used in 34 cases, thoraco-dorsal flap in 5 cases, deltoid flap in 1 case. It was necessary to increase the square of the scapular flap in case of a vast cicatricial soft tissue defect of the talocrural joint and dorsal surface of the foot and the sole. A special expander was used for this purpose. The importance of ultrasound methods for evaluation of the vessels supplying the sole, as well as the state of the microvascular anastomoses in postoperative period is stressed. The long-term results were followed up for 1.5 to 5 years in 29 of 37 patients. The good results was noted in 18 patients, satisfactory in 7 patients, complications (unhealed trophic ulcers) in 4 patients. The complications were caused by calcanel tuber deformation with osteophyte, osteomyelitis, inradically removed scars.


Bacteriology of the Buttonhole Cannulation Tract in Hemodialysis Patients: A Prospective Cohort Study.
The buttonhole cannulation technique for arteriovenous fistulas is widely used, but has been associated with an increased rate of vascular access-related infections. We describe the frequency and type of bacterial colonization of the buttonhole tract over time and associated clinical infections. A prospective observational cohort study with 9 months of follow-up. 84 in-center hemodialysis patients using the buttonhole cannulation technique at 2 Danish dialysis centers. Bacterial growth from the buttonhole tract and dialysis cannula tip and clinically important infections during follow-up. On 3 occasions 1 month apart, cultures before dialysis (from the skin surrounding the buttonhole before disinfection and from the cannulation tract after disinfection and scab removal) and the cannula tip after dialysis. Patients with positive cultures from the buttonhole tract or cannula tip had repeat cultures within 1 week, along with blood cultures. Growth from the cannulation tract and/or cannula tip at each of the 3 monthly sets of cultures was found in 18%, 20%, and 17% of patients, respectively. 38% of patients had at least 1 positive culture from the buttonhole tract. Sustained growth was detected in 11% of patients, whereas asymptomatic bacteremia was seen in 30% of those with positive buttonhole cultures. Staphylococci species were the most common pathogens (Staphylococcus aureus, 25%; and Staphylococcus epidermidis, 41%). Colonization-positive buttonholes had more localized redness and slightly more tenderness. During follow-up, significantly more access-related infections were diagnosed among those with positive buttonhole cultures (P<0.001). No comparison to area puncture cannulation technique. Blood cultures were obtained only from patients with positive buttonhole bacteriology. Transient or sustained colonization of the buttonhole tract by staphylococci and asymptomatic bacteremia is common in hemodialysis patients, implying a substantial risk for access-related infections among patients using a buttonhole cannulation technique. These findings suggest the possible value of surveillance of buttonhole colonization.


Validity of self-reported waist and hip circumferences in men and women.
Recent epidemiologic evidence indicates an association between fat distribution and many diseases. To assess the validity of circumference measurements obtained by self-report, the authors analyzed data from 123 men aged 40-75 years and 140 women aged 41-65 years, drawn from two large ongoing prospective studies. On mailed questionnaires, subjects were asked to measure and record their weight and waist and hip circumferences. These data were compared with standardized measurements taken approximately six months apart by technicians who visited participants at their homes. Crude Pearson correlations between self-reported waist circumferences and the average of two technician-measured waist circumferences were 0.95 for men and 0.89 for women. Similar correlations for hip measurements were 0.88 for men and 0.84 for women, and for waist-to-hip ratios, 0.69 for men and 0.70 for women. After adjusting for age and body mass index (kg/m2), correlations for waist-to-hip ratios were 0.55 for men and 0.58 for women. Correlations became stronger after correcting for random within-person variability from daily or seasonal fluctuations. Self-reported and measured weights were highly correlated: 0.97 for men and 0.97 for women. Self-reported waist, hip, and weight measurements appear reasonably valid. The moderate degree of measurement error for the ratio of self-reported waist and hip circumferences, however, implies that previously reported associations based on self-report of these measures may have been appreciably underestimated.


Evaluation of shared genetic aetiology between osteoarthritis and bone mineral density identifies SMAD3 as a novel osteoarthritis risk locus.
Osteoarthritis (OA) is a common complex disease with high public health burden and no curative therapy. High bone mineral density (BMD) is associated with an increased risk of developing OA, suggesting a shared underlying biology. Here, we performed the first systematic overlap analysis of OA and BMD on a genome wide scale. We used summary statistics from the GEFOS consortium for lumbar spine (n = 31,800) and femoral neck (n = 32,961) BMD, and from the arcOGEN consortium for three OA phenotypes (hip, ncases=3,498; knee, ncases=3,266; hip and/or knee, ncases=7,410; ncontrols=11,009). Performing LD score regression we found a significant genetic correlation between the combined OA phenotype (hip and/or knee) and lumbar spine BMD (rg=0.18, P = 2.23 × 10-2), which may be driven by the presence of spinal osteophytes. We identified 143 variants with evidence for cross-phenotype association which we took forward for replication in independent large-scale OA datasets, and subsequent meta-analysis with arcOGEN for a total sample size of up to 23,425 cases and 236,814 controls. We found robustly replicating evidence for association with OA at rs12901071 (OR 1.08 95% CI 1.05-1.11, Pmeta=3.12 × 10-10), an intronic variant in the SMAD3 gene, which is known to play a role in bone remodeling and cartilage maintenance. We were able to confirm expression of SMAD3 in intact and degraded cartilage of the knee and hip. Our findings provide the first systematic evaluation of pleiotropy between OA and BMD, highlight genes with biological relevance to both traits, and establish a robust new OA genetic risk locus at SMAD3.


Prevalence and risk factors for lens opacities in Nigeria: results of the national blindness and low vision survey.
Investigate prevalence and risk factors for lens opacities among a nationally representative sample of Nigerians aged ≥ 40 years. Across 305 clusters, 13,591 adults were examined. Every seventh participant (n = 1722) was sampled systematically and examined in detail, including lens opacity grading. Lenses were examined at the slit-lamp with pupil dilation and graded using the World Health Organization (WHO) system. Significant opacities were defined as nuclear, cortical, or posterior subcapsular opacity of WHO grade >1, or hyper/mature cataract. The category "Any Opacity" included hyper/mature opacity and aphakia/pseudophakia/couching. Data were collected on sociodemographic and environmental factors, including height and weight. A total of 1631/1722 (95%) in the normative subsample had their lenses graded. Prevalence of "Any Opacity" was 19.8% (95% confidence interval [CI]: 7.9-21.7) the prevalence of all types increased with age, and was higher in females and those not literate. Prevalence of nuclear, cortical, and posterior subcapsular were 8.8% (95% CI: 7.5-10.1); 11.7% (95% CI: 10.0-13.3); and 2.9% (95% CI: 2.1-3.8), respectively. In multivariate analysis, age was an independent risk factor for all types. Nuclear opacity was also associated with female sex (odds ratio [OR] 2.4; 95% CI: 1.5-3.6); lean body mass index (BMI; OR 2.0; 95% CI: 1.1-3.5); and the Igbo ethnic group (OR 4.4; 95% CI: 2.3-8.4). Cortical opacity was also associated with female sex (OR 2.1; 95% CI: 1.5-3.0) and the Yoruba (OR 0.45; 95% CI: 0.3-0.8), but not with BMI. "Other Lens Opacities," which includes couching, was significantly lower in the Guinea savannah region (OR 0.4; 95% CI: 0.2-0.9), while living in rain forest areas was protective for posterior subcapsular cataracts (OR 0.3; 95% CI: 0.1-0.7). A fifth of Nigerian adults have some degree of lens opacity. Further studies are needed to investigate the role of ethnicity, climate variables, and other risk factors.


Exercise capacity and paroxysmal atrial fibrillation in patients with hypertrophic cardiomyopathy.
Atrial fibrillation (AF) is the most common arrhythmia among patients with hypertrophic cardiomyopathy (HCM). The relationship between paroxysmal AF and exercise capacity in this population is incompletely understood. Patients with HCM underwent symptom-limited cardiopulmonary testing with expired gas analysis at Stanford Hospital between October 2006 and October 2012. Baseline demographics, medical histories and resting echocardiograms were obtained for all subjects. Diagnosis of AF was established by review of medical records and baseline ECG. Those with paroxysmal AF were in sinus rhythm at the time of cardiopulmonary testing with expired gas analysis. Exercise intolerance was defined as peak VO2<20 mL/kg/min. We used multivariate logistic regression to evaluate the association between exercise intolerance and paroxysmal AF. Among the 265 patients recruited, 55 had AF (28 paroxysmal and 27 permanent). Compared with those without AF, subjects with paroxysmal AF were older, more likely to use antiarrhythmic and anticoagulant medications, and had larger left atria. Patients with paroxysmal AF achieved lower peak VO2 (21.9±9.2 mL/kg/min vs 26.9±10.8 mL/kg/min, p=0.02) and were more likely to have exercise intolerance (61% vs 28%, p<0.001) compared with those without AF. After adjustment for age, sex and body mass index (BMI) exercise intolerance remained significantly associated with paroxysmal AF (OR 4.65, 95% CI 1.83 to 11.83, p=0.001). Patients with HCM and paroxysmal AF demonstrate exercise intolerance despite being in sinus rhythm at the time of exercise testing.


The use of the 13C-dextromethorphan breath test for phenotyping CYP2D6 in breast cancer patients using tamoxifen: association with CYP2D6 genotype and serum endoxifen levels.
Adjuvant therapy with tamoxifen significantly reduces breast cancer recurrence and mortality in estrogen receptor positive disease. CYP2D6 is the main enzyme involved in the activation of the prodrug tamoxifen into the anti-estrogen endoxifen. Endoxifen is thought to be a main determinant for clinical efficacy in breast cancer patients using tamoxifen. As the large interindividual variation in endoxifen levels is only partly explained by CYP2D6 genotype, we explored the use of the (13)C-dextromethorphan breath test (DM-BT) for phenotyping CYP2D6 and to predict serum steady-state endoxifen levels as a marker for clinical outcome in breast cancer patients using tamoxifen. In 65 patients with early breast cancer using tamoxifen, CYP2D6 phenotype was assessed by DM-BT. CYP2D6 genotype using Amplichip and serum steady-state levels of endoxifen were determined. Genotype was translated into the gene activity score and into ultrarapid, extensive, heterozygous extensive, intermediate or poor metabolizer CYP2D6 predicted phenotype. CYP2D6 phenotype determined by the DM-BT explained variation in serum steady-state endoxifen levels for 47.5% (R(2) = 0.475, p < 0.001). Positive and negative predictive values for a recently suggested threshold serum level of endoxifen (5.97 ng/mL) for breast cancer recurrence rate were 100 and 90%, respectively, for both CYP2D6 phenotype by DM-BT (delta-over-baseline at t = 50 min (DOB(50)) values of 0.7-0.9) and genotype (CYP2D6 gene activity score of 1.0). DM-BT might be, along with CYP2D6 genotyping, of value in selection of individualized endocrine therapy in patients with early breast cancer, especially when concomitant use of CYP2D6 inhibiting medication alters the phenotype.


Acceptability and Feasibility of Wearable Transdermal Alcohol Sensors: Systematic Review.
Transdermal alcohol sensors (TASs) have the potential to be used to monitor alcohol consumption objectively and continuously. These devices can provide real-time feedback to the user, researcher, or health professional and measure alcohol consumption and peaks of use, thereby addressing some of the limitations of the current methods, including breathalyzers and self-reports. This systematic review aims to evaluate the acceptability and feasibility of the currently available TAS devices. A systematic search was conducted in CINAHL, EMBASE, Google Scholar, MEDLINE, PsycINFO, PubMed, and Scopus bibliographic databases in February 2021. Two members of our study team independently screened studies for inclusion, extracted data, and assessed the risk of bias. The study's methodological quality was appraised using the Mixed Methods Appraisal Tool. The primary outcome was TAS acceptability. The secondary outcome was feasibility. The data are presented as a narrative synthesis. We identified and analyzed 22 studies. Study designs included laboratory- and ambulatory-based studies, mixed designs, randomized controlled trials, and focus groups, and the length the device was worn ranged from days to weeks. Although views on TASs were generally positive with high compliance, some factors were indicated as potential barriers and there are suggestions to overcome these. There is a lack of research investigating the acceptability and feasibility of TAS devices as a tool to monitor alcohol consumption in clinical and nonclinical populations. Although preliminary evidence suggests their potential in short-term laboratory-based studies with volunteers, more research is needed to establish long-term daily use with other populations, specifically, in the clinical and the criminal justice system. PROSPERO CRD42021231027; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=231027.


Development and pilot testing of a health education program to improve immigrants' access to Canadian health services.
In Canada's increasing immigrant population, a phenomenon called the "healthy immigrant effect" has arisen in which health declines after four years of settling. Access to healthcare is an important consideration. There is strong evidence that immigrants lack confidence and knowledge for navigating health services. The aim of this study was to develop and pilot test the Accessing Canadian Healthcare for Immigrants: Empowerment, Voice & Enablement (ACHIEVE) program. The study employed an exploratory sequential mixed methods design. A qualitative study was completed. Program content was developed based on a scoping review and refined in a formative evaluation. Then, a pilot test of the program measured participants' perceived efficacy in improving confidence in healthcare navigation, program satisfaction, and learning in individual sessions. Researchers found significantly higher rates of health navigation and an increase in knowledge about the Canadian health system post-program. Results provide promising evidence that ACHIEVE may improve confidence in healthcare access among immigrants, demonstrating potential for dispersion on a larger scale.


Effects of early dexamethasone therapy on pulmonary fibrogenic mediators and respiratory mechanics in preterm infants.
Corticosteroid administration may prevent chronic lung disease in premature newborns, perhaps by modulating the synthesis of various cytokines, including those involved in fibrogenic processes. This study analyses the levels of three fibrogenic cytokines, namely vascular endothelial growth factor, transforming growth factor-beta 1 and basic fibroblast growth factor in tracheobronchial aspirate fluids collected from 20 premature newborns randomly assigned to the early dexamethasone group or to the control group. Furthermore, pulmonary function tests were performed on days 0 and 2 following the start of therapy. The results show that early corticosteroid administration reduces transforming growth factor-beta 1 and basic fibroblast growth factor levels, and abolishes the spontaneous vascular endothelial growth factor increase observed in untreated patients, concomitantly with significant improvement of dynamic lung compliance and shorter duration of the intubation period in the treated group of patients. Significant correlations were observed between the levels of transforming growth factor-beta 1 and vascular endothelial growth factor, indicating that the production of both these cytokines is coordinated. Finally, transforming growth factor-beta 1 ratios (day 2/day 0), representing early variations of the cytokine levels, were significantly different between treated and untreated subjects and correlated with the dynamic lung compliance ratios and the extubation day, suggesting that the downmodulation of some fibrogenic mediators may be involved in the mode of action of dexamethasone.


Further evidence that muscarinic cholinergic receptors of 1321N1 astrocytoma cells couple to a guanine nucleotide regulatory protein that is not Ni.
Inhibitory coupling of receptors to adenylate cyclase previously has been shown to be relatively sensitive to inactivation by alkylation with N-ethylmaleimide (NEM). Modification of the inhibitory guanine nucleotide regulatory protein, Ni, has been proposed to be responsible for this effect. The effects of NEM on GTP-sensitive binding of carbachol to muscarinic cholinergic receptors has been compared in a cell line (1321N1 human astrocytoma cells) in which these receptors stimulate phosphoinositide breakdown and in a cell line (NG108-15 neuroblastoma X glioma cells) in which activation of these receptors results in inhibition of adenylate cyclase. Pretreatment of membrane preparations from 1321N1 cells with NEM resulted in a concentration-dependent decrease in the extent of pertussis toxin-catalysed [32P]ADP-ribosylation of a 41 000 Da protein previously proposed to be the alpha subunit of Ni. Under conditions where 32P-labelling of Ni in 1321N1 membranes was reduced by NEM by 90%, no effect was observed on the extent of guanine nucleotide-sensitive high-affinity binding of carbachol to muscarinic cholinergic receptors. In contrast, treatment of NG108-15 membranes with NEM under the same conditions resulted in complete loss of high-affinity guanine nucleotide sensitive binding of carbachol. These results illustrate another difference between the muscarinic receptor population of these two cell lines, and support the previous proposal that muscarinic receptors of 1321N1 cells couple to a guanine nucleotide regulatory protein that is not Ni.


Passive Wireless Sensor Utilizing an Interdigital Capacitor for Ongoing Monitoring of Glucose Concentration.
The wireless glucose sensor represents a major step forward in continuous glucose monitoring. With its innovative interdigital capacitor and inductor combination, the sensor works without active components and can measure glucose levels by detecting changes in reflection magnitude of the surrounding environment. Experimental results validated the proposed passive sensor's capability in detecting glucose concentration in aqueous solution, demonstrating a linear relationship between reflection magnitude and glucose concentration ranging from 0 to 500 mg/dL with a sensitivity of 3×10-3 dB/(mg/dL). These findings make the proposed sensor a good option for continuous glucose monitoring, offering wireless measurement of blood glucose levels. Additionally, its compact size and absence of active components make it suitable for implantable applications, providing individuals with wireless invasive method of monitoring their glucose levels.


Skull base manifestations of Camurati-Engelmann disease.
To describe presenting symptoms, evaluation findings, and surgical management of cranial base hyperostosis in patients with Camurati-Engelmann disease (CED). Retrospective study and literature review. The Mayo Clinic, Rochester, Minnesota. A total of 306 patients diagnosed as having CED, including 12 primarily evaluated at our institution between 1968 and 2008, and 294 identified in the international literature. Presenting symptoms, methods of diagnosis, treatment strategies, and patient outcomes. One hundred seventy-three of 306 patients (56.5%) had radiographically proven skull base hyperostosis, whereas less than one-fourth were symptomatic. The most common manifestations of cranial base involvement were hearing loss (19.0%), headache (10.4%), exophthalmos (8.2%), and frontal bossing (7.2%); less common were vision changes, vertigo, facial weakness, symptomatic brainstem compression, facial numbness, and hyposmia. Although corticosteroids and bisphosphates may treat torso and extremity involvement, they demonstrate no benefit for symptomatic skull base disease. In select symptomatic patients, aggressive decompression surgery may provide the only means of treatment. Decompression surgery is more challenging with thick sclerotic bone, loss or obscuration of bony landmarks, and decreased supratentorial space. Patients must be counseled on the increased risks associated with surgery and the potential for redeposition of bone and recurrence of symptoms. Physicians should include CED in the differential diagnosis for patients with radiographic evidence of skull base thickening and synchronous cranial neuropathies or symptoms of elevated intracranial pressure. In mild forms of the disease, the clinical course of patients should be followed with serial examination, audiometric testing, and radiography. In select patients with progressive cranial base symptoms, aggressive wide decompression of involved neurovascular structures may provide benefit.