Clinical effectiveness of pneumococcal vaccine. Meta-analysis.
To determine the clinical effectiveness of pneumococcal vaccine. Computerized searches of MEDLINE, EMBASE, and SCISEARCH databases were performed, reference lists of retrieved articles were reviewed, and first authors of published studies were contacted. Studies of use of pneumococcal vaccines in adults were included if the study design was a randomized or quasi-randomized controlled trial and at least one of the following clinical outcomes was reported: vaccine-type systemic pneumococcal infection, systemic pneumococcal infection, vaccine-type pneumococcal pneumonia, pneumococcal pneumonia, non-vaccine-type pneumococcal pneumonia. Study quality was assessed and descriptive information concerning the study populations, interventions, and outcome measurements was extracted for 13 trials involving more than 65,000 patients. Estimates of vaccine efficacy, based on a meta-analysis of randomized and quasi-randomized trials, were determined for clinical outcomes. Vaccination with pneumococcal polysaccharide vaccine can be expected to reduce the risk of systemic infection due to pneumococcal types included in the vaccine by 83% and systemic infection due to all pneumococci by 73%. We found no evidence that the vaccine was less efficacious for the elderly, institutionalized people, or those with chronic disease.


Dielectric Screening and Charge-Transfer in 2D Lead-Halide Perovskites for Reduced Exciton Binding Energies.
Layered lead-halide perovskites have shown tremendous success as an active material for optoelectronics. This is attributed to the electronic structure of the inorganic sublattice and large exciton binding energies due to quantum and dielectric confinement. Expanding functionalities for applications that depend on free-carrier generation requires new material design routes to decrease the binding energy. Here we use electronic structure methods with model Bethe-Salpeter equation (BSE) to examine the contributions of the dielectric screening and charge-transfer excited-states to the exciton binding energy of phenylethylammonium (PEA2PbBr4) and naphthlethylammonium (NEA2PbBr4) lead-bromide perovskites. Our model BSE calculations show that NEA introduces hole acceptor states which impose charge-transfer character on the exciton along with larger dielectric screening. This substantially decreases the exciton binding compared to PEA. This result suggests the use of organic cations with high dielectric screening and hole acceptor states as a viable strategy for reducing exciton binding energies in two-dimensional halide perovskites.


On Identity and the Political in Psychoanalysis.
Weaving subjective musings with theoretical speculation, this paper explores various themes on the question of identity. I consider identity as identification with a social location, where that social location is a function of groups. As such, identity is inherently contingent, a relational affair, a soft assembly. Though not a particularly psychoanalytic concept, identity is currently being tasked with considerable work in psychoanalysis: functioning as a hinge between the dual registers of the personal and social unconscious. Like any symptom, the term identity both obscures and indexes, signaling the urgent need for a radical revision of theory. The more we use the contingency of identity-how we find ourselves identified (by others as much as by ourselves) in this place and time, whatever this might be-rather than its fixity, thought to transcend place and time, the more that the concept of identity can be used in a specifically psychoanalytic way to help us explore the terrain of the political, which I distinguish from the terrain of politics proper. These ideas are employed to consider the current moment in psychoanalytic organizational life, which takes place under the sign of a fundamental paradigm shift (that is to say: catastrophic change).


Food allergy and food intolerance.
Adverse reactions to foods and food additives include those that involve an immune mechanism of reaction (food allergies) and those that are non-immunological in nature (food intolerance). The signs and symptoms of food allergy usually involve the skin and gastrointestinal tract and are "classic" allergic symptoms. Food intolerance occurs more frequently at all ages. A number of food additives have been implicated in food intolerance, as none involve an immune mechanism of reaction. The role of food additives in food intolerance is not well established in many cases, has been discounted in others and continues to be the subject of current research. Although the history of events concerning an adverse reaction is important and gives clues to the specific type of problem (food allergy versus food intolerance), confirmation of the reaction is sometimes desirable. This can be done either by use of a standard elimination diet of non-allergic foods, followed by open challenge or by DBFC for more difficult situations. Food allergy skin testing and other in vitro immunologic tests may be helpful as supplemental information in those cases where food allergy is suspected. The best treatment for an adverse reaction to food is avoidance. Unproven and unapproved diagnostic (e.g., leukocytotoxic test) and therapeutic techniques (e.g., sublinqual neutralization) are not recommended in food allergy management.


Numerical method based on transfer function for eliminating water vapor noise from terahertz spectra.
Water vapor noise in the air affects the accuracy of optical parameters extracted from terahertz (THz) time-domain spectroscopy. In this paper, a numerical method was proposed to eliminate water vapor noise from the THz spectra. According to the Van Vleck-Weisskopf function and the linear absorption spectrum of water molecules in the HITRAN database, we simulated the water vapor absorption spectrum and real refractive index spectrum with a particular line width. The continuum effect of water vapor molecules was also considered. Theoretical transfer function of a different humidity was constructed through the theoretical calculation of the water vapor absorption coefficient and the real refractive index. The THz signal of the Lacidipine sample containing water vapor background noise in the continuous frequency domain of 0.5-1.8 THz was denoised by use of the method. The results show that the optical parameters extracted from the denoised signal are closer to the optical parameters in the dry nitrogen environment.


Speech Detection in Noise for Young Bilaterally Implanted Children: Is There Evidence of Binaural Benefit Over the Shadowed Ear Alone?
To measure binaural benefit over the shadowed ear alone for young bilateral cochlear implant (CI) users. It was hypothesized that children who received bilateral CIs at a young age (<4 years), and had significant bilateral experience, would demonstrate lower detection thresholds for speech sounds in background noise in the bilateral CI over the unilateral CI condition when the added CI was ipsilateral to the noise source. Children receiving bilateral CIs at the Eye and Ear Hospital Clinic in Melbourne were invited to participate in a wider research project evaluating outcomes; those participating in the wider project who were bilaterally implanted by 4 years and were approximately 2 years postoperative were included in the present study. For 20 participants, detection signal to noise ratios (SNRs) were measured for speech presented from in front and noise from 90° in at least 3 of 4 device/noise conditions, namely left CI/noise right and right CI/noise left, plus bilateral CIs/noise right and bilateral CIs/noise left. As some participants could only complete testing in 3 conditions within the 1 test block, the unilateral versus bilateral comparison was performed for 1 CI (i.e., 1 noise direction) for 15 participants and for both CIs (i.e., noise left and noise right) for 5 participants. Group analysis indicated no significant difference in detection SNR between the unilateral and bilateral CI conditions when adding the left CI or right CI (for the overall group) or when adding the first or second CI (for the 15 participants with sequential bilateral CIs). Separate analyses indicated no significant difference in detection SNR between the unilateral and bilateral CI conditions for the majority of individuals; this occurred irrespective of whether the analysis indicated that the CI added in the bilateral condition was poorer-performing, better-performing, or not significantly different compared with the other CI. Four individuals demonstrated a significant improvement in the bilateral condition when the CI added in the bilateral condition was a better-performing (n = 1), poorer-performing (n = 2), or not significantly different CI (n = 1). There was no relationship between the detection SNR difference between each CI and the detection SNR difference between the unilateral and bilateral conditions. The hypothesis of a lower detection SNR in the bilateral condition was not supported by the group results or by the results for the majority of individuals. For the 4 participants who did demonstrate benefit over the shadowed ear alone, that benefit cannot be separated from the potential benefit gained as a result of the CI added in the bilateral condition being the better-performing CI for 1 of the 4. Variation in outcomes could not be related to demographic factors for this group, which was relatively homogeneous for age at bilateral CI and experience; an older, more experienced group may demonstrate greater binaural benefit in these conditions. These results can be used during counseling for families regarding postoperative expectations for young children, especially in the first 2 years.


Turbidimetry on Human Washed Platelets: The Effect of the Pannexin1-inhibitor Brilliant Blue FCF on Collagen-induced Aggregation.
Turbidimetry is a laboratory technique that is applied to measure the aggregation of platelets suspended in either plasma (platelet-rich plasma, PRP) or in buffer (washed platelets), by the use of one or a combination of agonists. The use of washed platelets separated from their plasma environment and in the absence of anticoagulants allows for studying intrinsic platelet properties. Among the large panel of agonists, arachidonic acid (AA), adenosine di-phosphate (ADP), thrombin and collagen are the most frequently used. The aggregation response is quantified by measuring the relative optical density (OD) over time of platelet suspension under continuous stirring. Platelets in homogeneous suspension limit the passage of light after the addition of an agonist, platelet shape change occurs producing a small transitory increase in OD. Following this initial activation step, platelet clots form gradually, allowing the passage of light through the suspension as a result of decreased OD. The aggregation process is ultimately expressed as a percentage, compared to the OD of platelet-poor plasma or buffer. Rigorous calibration is thus essential at the beginning of each experiment. As a general rule: calibration to 0% is set by measuring the OD of a non-stimulated platelet suspension while measuring the OD of the suspension medium containing no platelets represents a value of 100%. Platelet aggregation is generally visualized as a real-time aggregation curve. Turbidimetry is one of the most commonly used laboratory techniques for the investigation of platelet function and is considered as the historical gold standard and used for the development of new pharmaceutical agents aimed at inhibiting platelet aggregation. Here, we describe detailed protocols for 1) preparation of human washed platelets and 2) turbidimetric analysis of collagen-induced aggregation of human washed platelets pretreated with the food dye Brilliant Blue FCF that was recently identified as an inhibitor of Pannexin1 (Panx1) channels.


Age-dependent failure of axon regeneration in organotypic culture of gerbil auditory midbrain.
Inferior colliculus (IC) slice cultures from postnatal (P) day 6-8 gerbils exhibit axonal regeneration across a lesion site, and these regrowing processes can form synapses. To determine whether regenerative capacity is lost in older tissue, as occurs in vivo, slices from P12-21-day animals were grown under similar conditions. While these cultures displayed a near complete loss of neurons over 6 days in vitro, glutamate receptor antagonists (AP5 and/or CNQX) significantly enhanced survival, particularly at P12-15. In contrast, several growth factors or high potassium did not improve neuron survival. Therefore, axonal regeneration was assessed following complete transection of the commissure in AP5/CNQX-treated IC cultures from P12 animals. Neurofilament staining revealed that transected commissural axons survived for 6 days in vitro, but only a few processes crossed the lesion site and these axons did not extend into the contralateral lobe. In contrast, there was robust axonal sprouting and growth within one lobe of the IC, remote from the lesion site. When P6 and P12 tissue was explanted onto a coated substrate, the P6 axons grew onto the substrate, but the P12 axons were seemingly prevented from reaching the substrate by a veil of nonneuronal cells. Coculture of the IC and one of its afferent populations, the lateral superior olive, provided a similar finding, indicating that failure to regenerate was a general property at the age examined. These data show that neuron survival is not sufficient to permit axon regeneration at P12, and suggest that P12 lesion sites manufacture a prohibitive substrate since process outgrowth is blocked specifically at the commissure transection.


Interface driven energy filtering of thermoelectric power in spark plasma sintered Bi(2)Te(2.7)Se(0.3) nanoplatelet composites.
Control of competing parameters such as thermoelectric (TE) power and electrical and thermal conductivities is essential for the high performance of thermoelectric materials. Bulk-nanocomposite materials have shown a promising improvement in the TE performance due to poor thermal conductivity and charge carrier filtering by interfaces and grain boundaries. Consequently, it has become pressingly important to understand the formation mechanisms, stability of interfaces and grain boundaries along with subsequent effects on the physical properties. We report here the effects of the thermodynamic environment during spark plasma sintering (SPS) on the TE performance of bulk-nanocomposites of chemically synthesized Bi(2)Te(2.7)Se(0.3) nanoplatelets. Four pellets of nanoplatelets powder synthesized in the same batch have been made by SPS at different temperatures of 230, 250, 280, and 350 °C. The X-ray diffraction, transmission electron microscopy, thermoelectric, and thermal transport measurements illustrate that the pellet sintered at 250 °C shows a minimum grain growth and an optimal number of interfaces for efficient TE figure of merit, ZT∼0.55. For the high temperature (350 °C) pelletized nanoplatelet composites, the concurrent rise in electrical and thermal conductivities with a deleterious decrease in thermoelectric power have been observed, which results because of the grain growth and rearrangements of the interfaces and grain boundaries. Cross section electron microscopy investigations indeed show significant grain growth. Our study highlights an optimized temperature range for the pelletization of the nanoplatelet composites for TE applications. The results provide a subtle understanding of the grain growth mechanism and the filtering of low energy electrons and phonons with thermoelectric interfaces.


School health in pediatric residency training: 1994.
To explore efforts of pediatric residency programs to provide future pediatricians with appropriate school health skills (given the growing recognition that school health programs have a positive effect on child health). A survey was mailed to the directors of all 214 accredited pediatric residency programs in the United States. Based on an overall response rate of 72%, a defined clinical experience in school health is required in only 34% of programs and offered by 43%. It usually consists of occasional half days during block rotations. Content included consultation on children with chronic illness, classroom observations, and participation in school-based clinics, health education classes, and multidisciplinary team meetings. Many residency programs viewed core topics in school health as appropriate for pediatric residency curriculum, and many of them included such instruction. In the programs that offered school health, dollars were generated only 16% of the time, and the funding level was seldom significant (>$50 000). Tomorrow's pediatricians will need training in comprehensive school health (including education, service provision, and the assurance of a medical home for some children in the school), but school health is a minor part of the curricular experience for today's pediatric residents. Future investigations should target barriers to comprehensive school health training (including financial impediments) and look at alternative school and community experiences and their effect on trainees, schools, and school-aged children.


Six-month efficacy of benfluorex vs. placebo or metformin in diet-failed type 2 diabetic patients.
Six-month efficacy of benfluorex (Mediator) (150-450 mg/day) was assessed in a double-blind multicenter study vs. placebo or metformin hydrochloride (850-2550 mg/day). After a 2-month run-in period of strict dieting, 722 type 2 diabetic patients were randomized (1:2:2) to receive placebo (n=144), benfluorex (n=294) or metformin (n=284). After a 5-week dose-finding phase, the efficacy of benfluorex was compared with that of placebo (test for difference, main analysis) and metformin (non-inferiority test, secondary analysis) during a 6-month fixed-dose treatment. At entry after strict dieting, there was no difference between groups for HbA(1C) (placebo, 7.4%+/-1.5%; benfluorex, 7.7%+/-1.6%; metformin, 7.8%+/-1.6%) and fasting plasma glucose (FPG; placebo, 9.7+/-2.3 mmol/l; benfluorex, 10.0+/-2.0 mmol/l; metformin, 10.2+/-2.5 mmol/l). At the end of the dose-finding phase, mean doses were 2.71 tablets/day for placebo group, 2.65 tablets/day for benfluorex (397.5 mg/day) and 2.50 tablets/day for metformin (2125 mg/day). At the end of treatment, HbA(1C) level decreased by 0.60% ( p<0.001) in benfluorex patients while it increased by 0.50% ( p<0.001) with placebo (intent-to-treat analysis). The mean endpoint difference was -0.86% (SE, 0.17%; p<0.001). Mean endpoint difference in HbA(1C) between benfluorex and metformin was 0.28% (SE, 0.12%) [90% CI, 0.07 to 0.48] (non-inferiority test, p=0.037). Treatment with benfluorex was well tolerated; 39% of these patients reported one or more emergent adverse events (compared to 38% on placebo and 43% on metformin) and only two patients suffered a treatment-related, serious adverse event. This study demonstrates that benfluorex: (1) significantly reduces HbA1C and fasting plasma glucose when compared to placebo; (2) has a good safety profile; and (3) has relatively lower potency compared to metformin, although the non-inferiority test (equivalence limit for HbA(1C) of 0.5%) was significant.


Association of an ACSL1 gene variant with polyunsaturated fatty acids in bovine skeletal muscle.
The intramuscular fat deposition and the fatty acid profiles of beef affect meat quality. High proportions of unsaturated fatty acids are related to beef flavor and are beneficial for the nutritional value of meat. Moreover, a variety of clinical and epidemiologic studies showed that particularly long-chain omega-3 fatty acids from animal sources have a positive impact on human health and disease. To screen for genetic factors affecting fatty acid profiles in beef, we initially performed a microsatellite-based genome scan in a F(2) Charolais × German Holstein resource population and identified a quantitative trait locus (QTL) for fatty acid composition in a region on bovine chromosome 27 where previously QTL affecting marbling score had been detected in beef cattle populations. The long-chain acyl-CoA synthetase 1 (ACSL1) gene was identified as the most plausible functional and positional candidate gene in the QTL interval due to its direct impact on fatty acid metabolism and its position in the QTL interval. ACSL1 is necessary for synthesis of long-chain acyl-CoA esters, fatty acid degradation and phospholipid remodeling. We validated the genomic annotation of the bovine ACSL1 gene by in silico comparative sequence analysis and experimental verification. Re-sequencing of the complete coding, exon-flanking intronic sequences, 3' untranslated region (3'UTR) and partial promoter region of the ACSL1 gene revealed three synonymous mutations in exons 6, 7, and 20, six noncoding intronic gene variants, six polymorphisms in the promoter region, and four variants in the 3' UTR region. The association analysis identified the gene variant in intron 5 of the ACSL1 gene (c.481-233A>G) to be significantly associated with the relative content of distinct fractions and ratios of fatty acids (e.g., n-3 fatty acids, polyunsaturated, n-3 long-chain polyunsaturated fatty acids, trans vaccenic acid) in skeletal muscle. A tentative association of the ACSL1 gene variant with intramuscular fat content indicated that an indirect effect on fatty acid composition via modulation of total fat content of skeletal muscle cannot be excluded. The initial QTL analysis suggested the ACSL1 gene as a positional and functional candidate gene for fatty acid composition in bovine skeletal muscle. The findings of subsequent association analyses indicate that ACSL1 or a separate gene in close proximity might play a functional role in mediating the lipid composition of beef.


Urodynamic detrusor overactivity in patients with overactive bladder symptoms.
To evaluate the relationship between urodynamic detrusor overactivity (DO) and overactive bladder (OAB) symptoms in men and women. We reviewed the records of adult males and females who attended a tertiary referral center for urodynamic evaluation of OAB syndrome symptoms with the presence or absence of DO. DO was calculated for symptoms alone or in combination. The overall incidence of DO was 76.1% and 58.7% in male and female OAB patients, respectively. Of men 63% and 61% of women with urgency (OAB dry) had DO, while 93% of men and 69.8% of women with urgency and urgency urinary incontinence (OAB wet) had DO. Of women, 58% who were OAB wet had stress urinary incontinence symptoms with 26.4% having urodynamic stress incontinence. 6% of men and 6.5% of women with OAB symptoms had urodynamic diagnosis of voiding difficulties with postvoid residual greater than 100 mL. Combination of symptoms is more accurate in predicting DO in OAB patients. The multivariate disease model for males included urge urinary incontinence (UUI) and urgency while for females it included UUI and nocturia. There was a better correlation in results between OAB symptoms and the urodynamic diagnosis of DO in men than in women, more so in OAB wet than in OAB dry. Combination of symptoms of the OAB syndrome seems to have a better correlation with objective parameters from the bladder diary, filling cystometry, and with the occurrence of DO.


Metoprolol, fentanyl and stress responses to microlaryngoscopy. Effects on arterial pressure, heart rate and plasma concentrations of catecholamines, ACTH and cortisol.
Forty patients undergoing microlaryngoscopy were anaesthetized with thiopentone and nitrous oxide. Twenty patients received metoprolol 200 mg in a slow-release tablet once daily for 4 days up to, and including, the morning of operation, and 10 mg i.v. shortly before induction of anaesthesia. The other patients received placebo tablets and physiological saline i.v., instead. Both groups of 20 patients were further subdivided, half of the patients receiving fentanyl 1.0-1.5 mg during anaesthesia, the effect of which was antagonized by naloxone at the end of the procedure. The other patients received saline i.v. instead of fentanyl or naloxone. Metoprolol decreased heart rate and the general level of arterial pressure during anaesthesia, but did not affect the fluctuations in pressure. Arterial plasma noradrenaline concentrations during microlaryngoscopy were enhanced by metoprolol, in comparison with placebo, the reverse being the case for cortisol concentrations. Fentanyl decreased arterial pressure and plasma ACTH and cortisol concentrations regardless of whether the patient had received metoprolol. Plasma adrenaline and noradrenaline concentrations were decreased by fentanyl in the patients receiving metoprolol.


Role of regulatory T cells in experimental autoimmune glomerulonephritis.
Anti-glomerular basement membrane (anti-GBM) disease is characterized by antibodies and T cells directed against the Goodpasture antigen, the noncollagenous domain of the α3-chain of type IV collagen [α3(IV)NC1] of the GBM. Consequences are the deposition of autoantibodies along the GBM and the development of crescentic glomerulonephritis (GN) with rapid loss of renal function. Forkhead box protein P3 (Foxp3)+ regulatory T (Treg) cells are crucial for the maintenance of peripheral tolerance to self-antigens and the prevention of immunopathology. Here, we use the mouse model of experimental autoimmune GN to characterize the role of Treg cells in anti-GBM disease. Immunization of DBA/1 mice with α3(IV)NC1 induced the formation of α3(IV)NC1-specific T cells and antibodies and, after 8-10 wk, the development of crescentic GN. Immunization resulted in increased frequencies of peripheral Treg cells and renal accumulation of these cells in the stage of acute GN. Depletion of Treg cells during immunization led to enhanced generation of α3(IV)NC1-specific antibodies and T cells and to aggravated GN. In contrast, depletion or expansion of the Treg cell population in mice with established autoimmunity had only minor consequences for renal inflammation and did not alter the severity of GN. In conclusion, our results indicate that in anti-GBM disease, Treg cells restrict the induction of autoimmunity against α3(IV)NC1. However, Treg cells are inefficient in preventing crescentic GN after autoimmunity has been established.


[Morphology and morphogenetic mechanisms of brain lesions in acute generalized peritonitis].
Pronounced alterations of brain elements (vessels, neurocytes, glial cells, neural fibers and synaptic apparatus) are observed in acute generalized peritonitis. The following morphological forms of peritoneal encephalopathy were recognized: diffuse-focal lesions, incomplete partial necroses, inflammatory changes in the form of meningitis and encephalitis. The morphological changes were provoked by some factors resultant from developing endotoxicosis and homeostatic disorders. Structural disturbances may play a leading role in polyorganic insufficiency and under certain conditions may have an independent tanatogenetic significance.


Tyrosine hydroxylase: purification from PC-12 cells, characterization and production of antibodies.
Tyrosine hydroxylase has been purified to homogeneity from cultured PC-12 cells. The protein migrates as a single band with a molecular weight of 60,000 on sodium dodecyl sulfate polyacrylamide electrophoresis. Two-dimensional electrophoresis of the pure enzyme resolves three spots (each with molecular weights of 60,000) with isoelectric points of 5.4, 5.8 and 5.9. This charge heterogeneity cannot be explained by the presence of sugar or lipid moieties on the enzyme. Amino acid analysis indicates a relatively high content of hydrophobic amino acids and a lower serine content than other preparations of tyrosine hydroxylase. The enzyme hydroxylates tryptophan at approximately 1% of its rate of tyrosine hydroxylation but will not catalyze the hydroxylation of phenylalanine. Polyclonal antibodies were produced in rabbits against pure tyrosine hydroxylase and were judged to be monospecific by Western blot analysis. The IgG fraction was isolated from serum, and when coupled to cyanogen bromide activated Sepharose, could be used to purify tyrosine hydroxylase from crude extracts in a single step. The antiserum proved to be very useful in immunoprecipitation and immunocytochemical experiments with tyrosine hydroxylase.


Differentiation of T cells in nude mice.
Cells bearing the T-cell differentiation alloantigens TL and Thy-1 were enumerated in preparations of spleen and lymph node cells of nu/nu mice. Healthy nu/nu mice had few or no demonstrable TL+ or Thy-1+ cells whereas mice with viral hepatitis, including some born of nu/nu X nu/nu matings, had many. Healthy nu/nu mice were treated daily with the thymic hormone thymopoietin or with ubiquitin, polypeptides that induce the differentiation of TL+Thy-1" cells from TL-Thy-1- precursors in vitro. After 14 days, 20 to 40 percent of their spleen cells were of the TL+Thy-1+ phenotype typical of thymocytes and 10 to 25 percent of their lymph node cells were TL-Thy-1+, typical of later T-cell differentiation. Similar frequencies of such cells were found in untreated nu/nu mice suffering from severe viral hepatitis. These data conform to the current view that prothymocytes are preprogrammed cells whose maturation to thymocytes, normally induced in the thymus by thymopoietin, can be triggered by other agents under abnormal circumstances. Tests of T-cell function were not included in this study.


Pharmacokinetic and pharmacodynamic analysis of fluorouracil during 72-hour continuous infusion with and without dipyridamole.
During a phase I trial of 3-day simultaneous continuous intravenous infusions of varying doses of fluorouracil (5FUra) and 7.7 mg/kg/d of dipyridamole, we examined the relationships between 5FUra dose and steady-state plasma concentration (Css) and the percentage reduction in WBCs, as well as the percentage frequency of stomatitis. The 5FUra was administered at doses ranging from 185 mg/m2/d times three to 3,600 mg/m2/d times three. In 42 patients, 86 cycles of 5FUra plus dipyridamole and 28 cycles of 5FUra alone were analyzed. The Css of 5FUra varied even within the same dose level. When patients receiving the same 5FUra dose were considered, the interpatient coefficient of variation of 5FUra Css in cycles of 5FUra plus dipyridamole was 23% +/- 4.2%. For courses of 5FUra alone, the coefficient of variation of 5FUra was 15.6% +/- 6.5%. When the occurrence of any degree of stomatitis was related to the Css 5FUra, with patients grouped in cohorts of 2-mumol/L increments, the following equations accurately described the frequency of stomatitis: for 5FUra plus dipyridamole, percentage frequency of stomatitis = 100(1-e-0.114Css), r2 = 0.88; for 5FUra alone, percentage frequency stomatitis = 100(1-e0.122Css), r2 = 0.80. When 5FUra dose was substituted for Css, these relationships were as follows: percentage frequency of stomatitis = 100(1-e-0.00031 [dose]), r2 = 0.85; and percentage frequency of stomatitis = 100(1-e-0.00051 [dose]), r2 = 0.80. When the relationship between the percentage reduction in WBC and Css 5FUra was examined, statistically significant relationships were also apparent: for 5FUra plus dipyridamole, percentage reduction in WBC = 100(1-e-0.085Css), r2 = 0.46; for 5FUra alone, percentage reduction in WBC = 100(1-e-0.060Css), r2 = 0.61. When 5FUra dose was substituted for Css, these relatinships were as follows: percentage reduction in WBC = 100(1-e-0.00023 [dose]), r2 = 0.40; percentage reduction in WBC = 100(1-e-0.00024 [dose]), r2 = 0.65. The relationship between either Css 5FUra or dose 5FUra and either stomatitis or myelosuppression were also well described by the modified Hill equation (J Theor Biol 20:171-201, 1968). These analyses indicate that it should be possible to develop therapeutic regimens wherein 5FUra is administered to achieve a targeted Css determined by the risk and severity of toxicity deemed acceptable.


Distinct Mechanisms Regulate Lck Spatial Organization in Activated T Cells.
Phosphorylation of the T cell receptor (TCR) by the kinase Lck is the first detectable signaling event upon antigen engagement. The distribution of Lck within the plasma membrane, its conformational state, kinase activity, and protein-protein interactions all contribute to determine how efficiently Lck phosphorylates the engaged TCR. Here, we used cross-correlation raster image correlation spectroscopy and photoactivated localization microscopy to identify two mechanisms of Lck clustering: an intrinsic mechanism of Lck clustering induced by locking Lck in its open conformation and an extrinsic mechanism of clustering controlled by the phosphorylation of tyrosine 192, which regulates the affinity of Lck SH2 domain. Both mechanisms of clustering were differently affected by the absence of the kinase Zap70 or the adaptor Lat. We further observed that the adaptor TSAd bound to and promoted the diffusion of Lck when it is phosphorylated on tyrosine 192. Our data suggest that while Lck open conformation drives aggregation and clustering, the spatial organization of Lck is further controlled by signaling events downstream of TCR phosphorylation.


Anaesthetic management of a difficult intubation.
Intubation management of a patient with polyostotic fibrous dysplasia is described. The principles in planning for a difficult intubation are discussed.


Tissue-specific thyroid hormone regulation of gene transcripts encoding iodothyronine deiodinases and thyroid hormone receptors in striped parrotfish (Scarus iseri).
In fish as in other vertebrates, the diverse functions of thyroid hormones are mediated at the peripheral tissue level through iodothyronine deiodinase (dio) enzymes and thyroid hormone receptor (tr) proteins. In this study, we examined thyroid hormone regulation of mRNAs encoding the three deiodinases dio1, dio2 and dio3 - as well as three thyroid hormone receptors trαA, trαB and trβ - in initial phase striped parrotfish (Scarus iseri). Parrotfish were treated with dissolved phase T(3) (20 nM) or methimazole (3 mM) for 3 days. Treatment with exogenous T(3) elevated circulating T(3), while the methimazole treatment depressed plasma T(4). Experimentally-induced hyperthyroidism increased the relative abundance of transcripts encoding trαA and trβ in the liver and brain, but did not affect trαB mRNA levels in either tissue. In both sexes, methimazole-treated fish exhibited elevated dio2 transcripts in the liver and brain, suggesting enhanced outer-ring deiodination activity in these tissues. Accordingly, systemic hyperthyroidism elevated relative dio3 transcript levels in these same tissues. In the gonad, however, patterns of transcript regulation were distinctly different with elevated T(3) increasing mRNAs encoding dio2 in testicular and ovarian tissues and dio3, trαA and trαB in the testes only. Thyroid hormone status did not affect dio1 transcript abundance in the liver, brain or gonads. Taken as a whole, these results demonstrate that thyroidal status influences relative transcript abundance for dio2 and dio3 in the liver, provide new evidence for similar patterns of dio2 and dio3 mRNA regulation in the brain, and make evident that fish exhibit tr subtype-specific transcript abundance changes to altered thyroid status.


Synovial sarcoma. A clinicopathologic and ultrastructural study of 42 cases.
This clinicopathologic study concerns 42 cases of synovial sarcoma (13 biphasic and 29 monophasic), including electron-microscopic examination of five cases, among 753 cases of soft tissue sarcomas. The age of the patients ranged from 9 to 70 years, with a median of 35 years. Tumors occurred most commonly on the extremities with 31 on the lower extremities. Histologically the monophasic type on this occasion included tumors with focal or minimal biphasic differentiation (9 cases) in addition to totally monophasic tumor (20 cases). A comparative light microscopy revealed otherwise inappreciable differences in histologic characteristics between the monophasic synovial sarcoma and certain other spindle cell sarcomas. Ultrastructurally, the cells composing the spindle-cell area of the synovial sarcoma contained basically the same elements as did the cells forming epithelioid or gland-like structures, and as the cells in the areas of gradual transitions of the two. One exception was that the cells lining the gland-like lumina had microvillar projections. Characteristic secretory-like granules, similar to those seen in the synovial type B cell of the normal human synovium, were evident in all five cases studied electron microscopically. In contrast to the findings of others, patients with monophasic tumors had a better prognosis, 58% surviving 5 years compared to 36% for those with biphasic tumors.


Review of rodent hypertensive glaucoma models.
Glaucoma is a neurodegenerative disease characterized by the progressive loss of retinal ganglion cells (RGCs). Elevated intraocular pressure (IOP) is a primary risk factor for the development and progression of glaucoma. Rodent models of glaucoma have greatly improved our understanding of the pathophysiology of glaucoma and served as a useful tool to investigate neuroprotective agents. An ideal glaucoma animal model should be easy to induce, reproducible, biologically plausible and predictable. Of the available animal models of glaucoma, rodents are commonly studied because they have a relatively short life span and can be genetically altered. A successful hypertensive glaucoma model should induce structural glaucomatous changes: including loss of retinal nerve fibres, retinal ganglion cells and optic-disc cupping along with IOP elevation. The level and duration of IOP elevation should be titratable depending on the targeted glaucomatous damage. This review summarizes the outcomes of induced rodent hypertensive glaucoma models including intracameral injection of microbeads, laser photocoagulation, episcleral vein cauterization, injection of hypertonic saline and hyaluronic acid. We aim to provide a detailed overview of each of the models with a focus on parameters that defines a successful glaucoma model. The induced IOP elevation and duration of elevation varied among the different models and strain of rodent; nonetheless, they all achieved a sustainable raised IOP with corresponding RGC loss. The limitations of each model are discussed.


The Drug Overdose Epidemic in the U.S.-Mexico Border Region: Shifts, Progression, and Community Characteristics.
Previous studies show the reach of the current drug overdose epidemic into the U.S.-Mexico border region, albeit with a unique border-specific wave pattern compared to national waves and a delayed onset of fentanyl involvement (Wave I: 2002-2011, Wave II: 2012-2016, and Wave III: since 2017). The objective of this study is to examine the community predictors and the progression of overdose deaths across the U.S-Mexico border-specific epidemic waves. Descriptive epidemiological profile of border communities across the unfolding of the opioid epidemic, integrated data from the CDC-WONDER multiple causes of death data set, the CDC SVI, Uniform Crime Report, and the Behavioral Risk Factor Surveillance System. Using spatially adjusted Bayes rates by border-specific epidemic waves, we provide a descriptive profile of the spatial unfolding of the drug overdose epidemic. Negative binomial regression models assessed community predictors of overdose deaths across waves. Spatial analysis identified moderate to steep increases in drug overdose deaths over the three waves along the border. The impact and unfolding of the epidemic in the U.S.-Mexico border region were not uniform and affecting communities with differing severity and timing. Our study also finds support for social vulnerability and community violence as predictors of overdose deaths over the current wave of the epidemic. Findings suggest that more disadvantaged U.S.-Mexico border communities may encounter increasing rates of overdose death over the coming years. Interventions need to target not only the supply side but also the underlying social root causes for sustainable overdose prevention.


Subcellular localization of blood group A substance produced by pancreatic adenocarcinoma induced in hamsters by N-nitrosobis(2-oxopropyl)amine (BOP) and by its cell line (PC-1).
The subcellular localization and biochemical characteristics of blood group A antigen were studied by immunogold methods and by SDS-PAGE and Western blotting procedures in N-nitrosobis)2-oxopropyl)amine (BOP)-induced pancreatic cancer (PC) in Syrian hamsters, in the pancreatic cancer cell line (PC-1) derived from a primary induced pancreatic cancer, and in intrapancreatic and subcutaneous transplants of PC-1 cells. Normal hamster duodenal epithelial cells expressing A antigen were compared with the normal hamster pancreas (lacking A antigen), human PC tissues from patients with blood group A and human PC cell lines. Blood group A antigen was present on the membrane of hamster duodenal cells, but was absent in the normal pancreatic cells. A antigen was localized mainly on the cell membrane of the hamster cancer cells both in vivo and in vitro. Glycoproteins with blood group A specificity were observed by SDS-PAGE and Western blotting procedures in the membrane fraction of PC-1 cells, with a major component of molecular mass of approximately 120 kd. Similar migration patterns were observed in the primary induced PC and in subcutaneous and intrapancreatic transplants of PC-1 cells. Membrane preparations from cell lines derived from two primary pancreatic cancers from patients of blood group A and from human pancreatic cell lines, CD11 and CD18, showed a major A reactive component with a molecular mass similar to that found in the hamster PC cells. These findings suggest that: (i) both the hamster and human PC cells in vitro produce glycoproteins with blood group A specificity of similar molecular masses; (ii) differences exist in the structure of the glycoprotein immunoreactive with the anti-A antigen between the normal and cancerous cells; and (iii) differences exist in the molecular mass of the anti-A reactive substance between hamsters and human PC cells and between tissues in vivo and in vitro.


Adjuvant radiotherapy with brachytherapy boost in soft tissue sarcomas.
The standard primary treatment for soft tissue sarcoma (STS) is a wide surgical resection, preceded or followed by radiotherapy. Purpose of this retrospective study was to assess the efficacy of perioperative brachytherapy (BRT) plus postoperative external beam radiation therapy (EBRT) in patients with intermediate-high risk STS. BRT delivered dose was 20 Gy. External beam radiation therapy was delivered with 3D-technique using multiple beams. The prescribed dose was 46 Gy to the PTV. Neoadjuvant and adjuvant chemotherapy (CHT) was used in patients with potentially chemosensitive histological subtypes. The primary aim of the study was to analyze overall survival (OS) and local control (LC) in a large patient population treated with surgery, perioperative BRT, and adjuvant EBRT ± CHT. Secondary objective was to identify prognostic factors for patients outcome in terms of LC, disease-free survival (DFS), and OS. From 2000 to 2011, 107 patients presenting 2-3 grade (FNLCC) primary or recurrent STS were treated with surgery, perioperative BRT, and adjuvant EBRT ± CHT. Five-year LC and OS were 80.9% and 87.4%, respectively. At univariate analysis, a higher LC was recorded in primary vs. recurrent tumors (p = 0.015), and in lower limb tumors vs. other sites (p = 0.027). An improved DFS was recorded in patients with lower limb tumors vs. other sites (p = 0.034). The combination of BRT and EBRT was able to achieve satisfactory results even in a patients population with intermediate-high risk STS. Patients with recurrent or other than lower limb sited tumors show a worse LC.


The Treatment for Type II First Branchial Cleft Anomalies With Abnormalities Lateral to the Tympanic Membrane.
The present study aimed to introduce the surgical method for addressing type II first branchial cleft anomalies (FBCAs) in patients with visible abnormalities lateral to the tympanic membrane. Retrospective analysis. Beijing Children's Hospital of Capital Medical University from January 2016 to January 2020. We performed a retrospective analysis of data from patients with type II FBCAs with visible abnormalities lateral to the tympanic membrane. All patients underwent magnetic resonance imaging, (MRI), computed tomography (CT), and otoscopy examinations before surgery. Data regarding the patient's age, location of the opening, side affected, MRI/CT results, otoscopy findings, the relationship between the lesion and the external auditory canal (EAC), complications, and surgical procedure were recorded. 15 patients with type II FBCAs (Work's classification) were included in our study. There were 3 different types of visible abnormalities lateral to the tympanic membrane: white masses (Type A), a fibrous band between the tympanic membrane and the EAC floor (Type B), and defects in the inferior wall of the EAC (Type C). Types A and C demonstrated internal fistulas of the FBCA. The roots of the FBCA in all 3 types were deep. Endoscopy was required for complete exposure of the fistula, especially for Types A and C. Some type II FBCAs patients had visible abnormalities lateral to the tympanic membrane. Otoscope was recommended for routine examination. For these kinds of patients, combined endoscopy during surgery was helpful for reducing the recurrence rate. Level 3.


Pilomatricoma on the Sole Following Wart Treatment.
Pilomatricoma is a benign skin tumor that arises from hair follicle stem cells. It typically presents in the facial region and rarely involves the palms and soles. A 15-year-old boy presented with a solitary tender nodule on the left sole. He had a history of plantar warts on the same site and had received multiple treatments including cryotherapy and intralesional bleomycin injection for nine months. Excisional biopsy was performed, and the specimen showed a well-demarcated mass in the deep dermis with basaloid cells undergoing abrupt keratinization. Ghost cells were seen with calcification. Based on these findings, he was diagnosed with pilomatricoma on the sole. We report a case of pilomatricoma, which developed on a site without hair follicles.


Lack of cell cycle regulation of telomerase activity in human cells.
Conflicting reports have appeared concerning the cell cycle regulation of telomerase activity and its possible repression during quiescence and cell differentiation. We have reexamined these issues in an attempt to uncover the basis for the discrepancies. Variations in extracted telomerase activity during the cell cycle are not observed in cells sorted on the basis of DNA content. Variations are observed in cells synchronized using some biochemical cell cycle inhibitors, but only with those agents where cellular toxicity is evident. A progressive decline in telomerase activity is observed in cells whose growth rate is reduced from seven to eight population doublings per week to one to two doublings per week. Telomerase is largely absent in cells that truly exit the cell cycle and do not divide over the 7-day period. Although it is not necessary for all cell types to regulate telomerase in the same way, we conclude that in the immortal cultured cell lines examined, extracted telomerase activity does not change significantly during progression through the stages of the cell cycle. Telomerase activity generally correlates with growth rate and is repressed in cells that exit the cell cycle and become quiescent.


Rho signaling regulates pannexin 1-mediated ATP release from airway epithelia.
ATP released from airway epithelial cells promotes purinergic receptor-regulated mucociliary clearance activities necessary for innate lung defense. Cell swelling-induced membrane stretch/strain is a common stimulus that promotes airway epithelial ATP release, but the mechanisms transducing cell swelling into ATP release are incompletely understood. Using knockdown and knockout approaches, we tested the hypothesis that pannexin 1 mediates ATP release from hypotonically swollen airway epithelia and investigated mechanisms regulating this activity. Well differentiated primary cultures of human bronchial epithelial cells subjected to hypotonic challenge exhibited enhanced ATP release, which was paralleled by the uptake of the pannexin probe propidium iodide. Both responses were reduced by pannexin 1 inhibitors and by knocking down pannexin 1. Importantly, hypotonicity-evoked ATP release from freshly excised tracheas and dye uptake in primary tracheal epithelial cells were impaired in pannexin 1 knockout mice. Hypotonicity-promoted ATP release and dye uptake in primary well differentiated human bronchial epithelial cells was accompanied by RhoA activation and myosin light chain phosphorylation and was reduced by the RhoA dominant negative mutant RhoA(T19N) and Rho and myosin light chain kinase inhibitors. ATP release and Rho activation were reduced by highly selective inhibitors of transient receptor potential vanilloid 4 (TRPV4). Lastly, knocking down TRPV4 impaired hypotonicity-evoked airway epithelial ATP release. Our data suggest that TRPV4 and Rho transduce cell membrane stretch/strain into pannexin 1-mediated ATP release in airway epithelia.


In vivo [3H]flunitrazepam binding: imaging of receptor regulation.
The use of [3H]flunitrazepam as a ligand to measure alterations in benzodiazepine receptors in vivo in rats was investigated. Animals were injected with [3H]flunitrazepam i.v., arterial samples of [3H]flunitrazepam were obtained and, later, the animals were sacrificed to assay brain binding. [3H]flunitrazepam enters the brain rapidly and binds to benzodiazepine receptors. About two-thirds of this binding is blocked by predosing the animals with 5 mg/kg of clonazepam. The amount of remaining (nonspecific) binding correlates very well (r = 0.88) with the amount of radioactivity found in plasma at the time of death. A series of rats were lesioned unilaterally with kainic acid in the caudate-putamen several months before the infusion of [3H]flunitrazepam. In vivo autoradiography in lesioned rats showed that benzodiazepine binding in globus pallidus and substantia nigra on the side of the lesion was increased significantly as compared to the intact side. The observed changes in benzodiazepine binding were similar to those observed previously in lesioned rats using in vitro techniques. Thus, benzodiazepine receptor regulation can be imaged quantitatively using in vivo binding techniques.


Pathophysiology of acute exercise-induced muscular injury: clinical implications.
Acute muscular injury is the most common injury affecting athletes and those participating in exercise. Nearly everyone has experienced soreness after unaccustomed or intense exercise. Clinically, acute strains and delayed-onset muscle soreness are very similar. The purpose of this paper is to review the predisposing factors, mechanisms of injury, structural changes, and biochemical changes associated with these injuries. Laboratory and clinical findings are discussed to help athletic trainers differentiate between the two conditions and to provide a background knowledge for evaluation, prevention, and treatment of exercise-induced muscular injury.


Drinking and parenting practices as predictors of impaired driving behaviors among U.S. adolescents.
The purpose of this study was to identify the extent to which 10th-grade substance use and parenting practices predicted 11th-grade teenage driving while alcohol-/other drug-impaired (DWI) and riding with alcohol-/other drug-impaired drivers (RWI). The data were from Waves 1 and 2 of the NEXT Generation study, with longitudinal assessment of a nationally representative sample of 10th graders starting in 2009-2010. Multivariate logistic regression analysis was used to examine the prospective associations between proposed predictors (heavy episodic drinking, illicit drug use, parental monitoring knowledge and control) in Wave 1 and DWI/RWI. Heavy episodic drinking at Wave 1 predicted Wave 2 DWI (odds ratio [OR] = 3.73, p < .001) and RWI (OR = 3.92, p < .001) after controlling for parenting practices and selected covariates. Father's monitoring knowledge predicted lower DWI prevalence at Wave 2 when controlling for covariates and teenage substance use (OR = 0.66, p < .001). In contrast, mother's monitoring knowledge predicted lower RWI prevalence at Wave 2 when controlling for covariates only (OR = 0.67, p < .05), but the effect was reduced to nonsignificance when controlling for teen substance use. Heavy episodic drinking predicted DWI and RWI. In addition, parental monitoring knowledge, particularly by fathers, was protective against DWI, independent of the effect of substance use. This suggests that the enhancement of parenting practices could potentially discourage adolescent DWI. The findings suggest that the parenting practices of fathers and mothers may have differential effects on adolescent impaired-driving behaviors.


Safety Profile of Liver FibroScan in Patients with Cardiac Pacemakers or Implantable Cardioverter-Defibrillators.
Background. Emerging evidence suggests that nonalcoholic fatty liver disease (NAFLD) is associated with coronary artery diseases and arrhythmias. The FibroScan (Echosens, France), a widely available, noninvasive device, is able to detect liver fibrosis and steatosis within this patient population. However, the FibroScan is currently contraindicated in patients with cardiac pacemakers (PM) or implantable cardioverter-defibrillators (ICD). Objective. To determine the safety profile of FibroScan testing in patients with PM or ICD. Methods. Consecutive outpatients undergoing routine device interrogations at a tertiary level teaching hospital underwent simultaneous liver stiffness measurements. PM or ICD performance data, device types, patient demographics, medical history, and previous laboratory and conventional liver imaging results were collected. Results. Analysis of 107 subjects with 33 different types of implanted cardiac devices, from 5 different companies (Medtronic, Sorin, ELA Medical, Boston Scientific, and St. Jude), did not demonstrate any adverse events as defined by abnormal device sensing/pacing or ICD firing. This population included high risk subjects undergoing active pacing (n = 53) and with right pectoral PM placement (n = 1). None of the subjects had any clinical signs of decompensated congestive heart failure or cirrhosis during the exam. Conclusion. TE with FibroScan can be safely performed in patients with PM or ICD.


Age-dependent sensitization to the 7S-vicilin-like protein Cor a 11 from hazelnut (Corylus avellana) in a birch-endemic region.
Hazelnut (Corylus avellana) allergy exhibits age and geographically distinct sensitization patterns that have not yet been fully resolved. To study sensitization to Cor a 11 in different age groups of hazelnut-allergic patients and infants with atopic dermatitis (AD) sensitized to hazelnut in a birch-endemic region. Sera from 80 hazelnut-allergic patients, 33 infants under 1 year of age with AD (24 sensitized and 9 not sensitized to hazelnut), 32 healthy control individuals, and 29 birch pollen-allergic but hazelnut-tolerant individuals were tested for immunoglobulin (Ig) E reactivity to Cor a 11 by ImmunoCAP. IgE reactivity to Cor a 1.01, Cor a 1.04, Cor a 8, and Cor a 9 was studied by ISAC microarray. Forty patients (22 preschool children, 10 schoolchildren, and 8 adults) with systemic reactions on consumption of hazelnut were sensitized to Cor a 11 (respective rates of 36%, 40%, and 12.5%). Forty patients (6 preschool children, 10 schoolchildren, and 24 adults) reported oral allergy syndrome but only 2 of them (of preschool age) were sensitized to Cor a 11. Two (8%) of the AD infants sensitized to hazelnut showed IgE reactivity to Cor a 11. This reactivity was not observed in any of the AD infants without sensitization to hazelnut, in any of the birch-pollen allergic patients without hazelnut allergy, or in any of the healthy control individuals. Sensitization to Cor a 11 in a birch-endemic region is predominantly found in children with severe hazelnut allergy, a finding that is consistent with observations concerning sensitization to Cor a 9.


Nested clade analyses of phylogeographic data: testing hypotheses about gene flow and population history.
Since the 1920s, population geneticists have had measures that describe how genetic variation is distributed spatially within a species' geographical range. Modern genetic survey techniques frequently yield information on the evolutionary relationships among the alleles or haplotypes as well as information on allele frequencies and their spatial distributions. This evolutionary information is often expressed in the form of an estimated haplotype or allele tree. Traditional statistics of population structure, such as F statistics, do not make use of evolutionary genealogical information, so it is necessary to develop new statistical estimators and tests that explicitly incorporate information from the haplotype tree. One such technique is to use the haplotype tree to define a nested series of branches (clades), thereby allowing an evolutionary nested analysis of the spatial distribution of genetic variation. Such a nested analysis can be performed regarding the geographical sampling locations either as categorical or continuous variables (i.e. some measure of spatial distance). It is shown that such nested phylogeographical analyses have more power to detect geographical associations than traditional, nonhistorical analyses and, as a consequence, allow a broader range of gene-flow parameters to be estimated in a precise fashion. More importantly, such nested analyses can discriminate between phylogeographical associations due to recurrent but restricted gene flow vs. historical events operating at the population level (e.g. past fragmentation, colonization, or range expansion events). Restricted gene flow and historical events can be intertwined, and the cladistic analyses can reconstruct their temporal juxtapositions, thereby yielding great insight into both the evolutionary history and population structure of the species. Examples are given that illustrate these properties, concentrating on the detection of range expansion events.


Hepatitis C virus core antigen testing in liver and kidney transplant recipients.
HCV RNA levels correlate with the long-term outcome of hepatitis C in liver transplant recipients. Nucleic acid testing (NAT) is usually used to confirm HCV reinfection and to examine viral loads after liver transplantation. HCV core antigen (HCVcoreAg) testing could be an alternative to NAT with some potential advantages including very low intra- and interassay variabilities and lower costs. The performance of HCVcoreAg testing in organ transplant recipients is unknown. We prospectively studied 1011 sera for HCV RNA and HCVcoreAg in a routine real-world setting including 222 samples obtained from patients after liver or kidney transplantation. HCV RNA and HCVcoreAg test results showed a consistency of 98% with a very good correlation in transplanted patients (r > 0.85). The correlation between HCV RNA and HCVcoreAg was higher in sera with high viral loads and in samples from patients with low biochemical disease. Patients treated with tacrolimus showed a better correlation between both parameters than individuals receiving cyclosporine A. HCV RNA/HCVcoreAg ratios did not differ between transplanted and nontransplanted patients, and HCV RNA and HCVcoreAg kinetics were almost identical during the first days after liver transplantation. HCVcoreAg testing can be used to monitor HCV viral loads in patients after organ transplantation. However, the assay is not recommended to monitor antiviral therapies.


Endothelial IKK beta signaling is required for monocyte adhesion under laminar flow conditions.
Endothelial activation induces expression of pro-inflammatory molecules that are thought to play an important role in atherogenesis through enhanced vascular monocyte recruitment. Many pro-inflammatory endothelial signals are transcriptionally regulated by members of the NF- kappa B family. The serine-threonine kinase, IKK beta, can mediate NF- kappa B activation although several alternative pathways exist. To test whether IKK beta is necessary for cytokine activation of human vascular endothelium and endothelial recruitment of human monocytes under laminar flow, we constructed a recombinant adenoviral vector carrying a dominant negative mutant of IKK beta (Ad.dnIKK beta) to transduce human umbilical vein endothelial cells (HUVEC) in vitro. We found that dnIKK beta expression effectively blocked NF-kappa B activation as assessed by nuclear translocation of NF-kappa B, I kappa B degradation, and NF-kappa B dependent reporter expression, without affecting activation of the other relevant signaling pathways, SAPK/JNK and p38. Furthermore, overexpression of dnIKK beta in TNF-alpha-stimulated HUVEC blocked induction of the surface adhesion molecules E-selectin, ICAM-1, and VCAM-1. Under simulated physiologic flow conditions, both firm adhesion and rolling of human peripheral monocytes on dnIKK beta-transduced endothelial monolayers were markedly inhibited. We conclude that IKK beta is necessary for the cytokine-induced inflammatory phenotype of human endothelium and endothelial recruitment of human monocytes under flow.


Fatal airsacculitis and pneumonia, with abortion, in an orangutan.
A 14-year-old, 76-kg female orangutan (Pongo pygmaeus) aborted a premature fetus and within hours experienced severe respiratory distress and died. Necropsy revealed evidence of chronic airsacculitis, acute bronchopneumonia, and terminal sepsis. Escherichia coli was isolated from cultures of heart blood, tracheal fluid, air-sac tissue and fluid, lung, and bile. Retrospectively, it was established that the animal had had a periodic nasal discharge for many months. The aborted infant had no evidence of infection.


S2F, a leaf-specific trans-acting factor, binds to a novel cis-acting element and differentially activates the RPL21 gene.
Tissue-specific factors control the differential expression of nuclear genes encoding plastid proteins. To identify some of these factors, the light-independent spinach RPL21 gene encoding the plastid ribosomal protein L21 was chosen as a model. The RPL21 promoter organization was defined by transient and stable transfections of RPL21 promoter deletion mutants fused to a reporter gene. The following results were obtained. (1) We identified a strong core promoter, spanning the transcription start site region, sufficient to drive high levels of gene expression. (2) We identified two non-overlapping positive and negative domains, located upstream from the core promoter region, that modulate core promoter activity independently of light. (3) We found that the positive domain contains a new cis-acting element, the S2 site, related to but different from the light-responsive GT-1 binding site. We show that the S2 site binds a leaf-specific nuclear factor (named S2F). The S2 site is conserved in the promoter region of many nuclear genes encoding plastid proteins. Experiments with transgenic tobacco plants confirmed that the S2 site is critical for positive domain activity in leaf tissues. The S2 site is thus identified as a new tissue-specific, light-independent regulatory element.


Neurobehavioral outcomes in spina bifida: Processes versus outcomes.
We review neurobehavioral outcomes and interventions for children with spina bifida. Focusing on children with spina bifida myelomeningocele, we contrast historical views of outcomes based on comparisons across content domains (e.g., language versus visual perceptual skills) with a view based on overarching processes that underlie strengths and weakness within content domains. Thus, we suggest that children with SBM have strengths when the skill involves the capacity to retrieve information from semantic memory and generate material that has been associatively linked or learned (associative processing) and general difficulties on tasks that require the construction or integration of a response (assembled processing). We use a hypothetical case to illustrate the differences in content domains versus general processes and also identify interventions that may be effective in addressing some of the cognitive and behavioral difficulties experienced variably by people with SBM. We extend these general principles to a discussion of variability in outcomes and use data from a large sample of children with spina bifida to illustrate the basis for this variability.


Provider perceptions of lack of supportive care during childbirth: A mixed methods study in Kenya.
Supportive care is a key component of person-centered maternity care (PCMC), and includes aspects such as timely and attentive care, pain control, and the health facility environment. Yet, few researchers have explored the degree of supportive care delivered or providers' perceptions on supportive care practices during childbirth. The researchers' aim is to evaluate the extent of supportive care provided to women during childbirth and to identify the drivers behind the lack of supportive care from the perspective of maternity providers in a rural county in Western Kenya. Data are from a mixed-methods study in Migori County in Western Kenya with 49 maternity providers (32 clinical and 17 non-clinical). Providers were asked structured questions on various aspects of supportive care followed by open ended questions on why certain practices were performed or not. We conducted descriptive analysis of the quantitative data and thematic analysis of the qualitative data. We analyzed data and found inconsistent and suboptimal practices with regards to supportive care. Some providers reported long patient wait times in their facilities as well as the inability to provide the best care due to staff shortages in their facilities. Others also reported low interest and inquiry about women's experience of pain during childbirth, which was driven by perceptions of pain during childbirth as normal, facility culture and norms, and lack of pain medicine. For the facility environment, providers reported relatively clean facilities. They, however, noted inconsistent water and electricity as well as inadequate safety. We conclude that many drivers of the lack of supportive care are caused by structural health systems issues, therefore a health system strengthening approach can be useful for improving the supportive care dimension of PCMC, and thus quality of care overall.


High temperatures during early development reduce adult cognitive performance and reproductive success in a wild animal population.
Global warming is rapidly changing the phenology, distribution, behaviour and demography of wild animal populations. Recent studies in wild animals have shown that high temperatures can induce short-term cognitive impairment, and captive studies have demonstrated that heat exposure during early development can lead to long-term cognitive impairment. Given that cognition underpins behavioural flexibility and can be directly linked to fitness, understanding how high temperatures during early life might impact adult cognitive performance in wild animals is a critical next step to predict wildlife responses to climate change. Here, we investigated the relationship between temperatures experienced during development, adult cognitive performance, and reproductive success in wild southern pied babblers (Turdoides bicolor). We found that higher mean daily maximum temperatures during nestling development led to long-term cognitive impairment in associative learning performance, but not reversal learning performance. Additionally, a higher number of hot days (exceeding 35.5 °C, temperature threshold at which foraging efficiency and offspring provisioning decline) during post-fledging care led to reduced reproductive success in adulthood. We did not find evidence that low reproductive success was linked to impaired associative learning performance: associative learning performance was not related to reproductive success. In contrast, reversal learning performance was negatively related to reproductive success in breeding adults. This suggests that reproduction can carry a cost in terms of reduced performance in cognitively demanding tasks, confirming previous evidence in this species. Taken together, these findings indicate that naturally occurring high temperatures during early development have long-term negative effects on cognition and reproductive success in wild animals. Compounding effects of high temperatures on current nestling mortality and on the long-term cognitive and reproductive performance of survivors are highly concerning given ongoing global warming.


Treatment of severe and moderate hypertension with minoxidil: experience in twenty-eight patients.
1. Twenty patients with severe or moderate hypertension were treated with minoxidil for 284 patient-months. 2. The blood pressure was controlled in all patients, including those refractory to maximal doses of conventional anti-hypertensive agents. 3. In patients with moderate hypertension control with minoxidil was achieved earlier and more easily than with hydrallazine. 4. Three patients developed secondary resistance and required addition of guanethidine or increased doses of diuretics. 5. Fluid retention and hypertrichosis were the main side effects with minoxidil.


[Vitamin PP and C allowances and their correction in the treatment of bronchial asthma patients].
Providing with vitamins PP and C was studied in 124 patients with bronchial asthma (59 males and 65 females). Deficiency of the vitamins was recorded in the majority of the patients during the disease exacerbation, especially in the winter-spring period of the year. Decreased providing with nicotinic acid was noted in 83%, with ascorbic acid in 96.8% of the patients. The treatment without vitamins did not lead to normalization of providing with vitamins. Applying vitamin loadings lasting many days, rational doses of vitamins PP and C were determined for the correction of providing patients with these vitamins in the period of bronchial asthma exacerbation. Depending on the severity of their state the patients should be given 90-110 mg of nicotinic acid and 275-300 mg of ascorbic acid/day, during the course of the treatment. Inclusion of rational doses of vitamins PP and C intensifies the therapy effectiveness and reduces the terms of the inpatient treatment.


Humoral immunity to phlebovirus infection.
Phleboviruses are zoonotic pathogens found in parts of Africa, Asia, Europe, and North America and cause disease symptoms ranging from self-limiting febrile illness to severe disease, including hemorrhagic diathesis, encephalitis, and ocular pathologies. There are currently no approved preventative vaccines against phlebovirus infection or antivirals for the treatment of the disease. Here, we discuss the roles of neutralizing antibodies in phlebovirus infection, the antigenic targets present on the mature polyproteins Gn and Gc, progress in vaccine development, and the prospects of identifying conserved neutralizing epitopes across multiple phleboviruses. Further research in this area will pave the way for the rational design of pan-phlebovirus vaccines that will protect against both known phleboviruses but also newly emerging phleboviruses that may have pandemic potential.


Gene conversion in the evolution of both the H-2 and Qa class I genes of the murine major histocompatibility complex.
In order to better understand the role of gene conversion in the evolution of the class I gene family of the major histocompatibility complex (MHC), we have used a computer algorithm to detect clustered sequence similarities among 24 class I DNA sequences from the H-2, Qa, and Tla regions of the murine MHC. Thirty-four statistically significant clusters were detected; individual analysis of the clusters suggested at least 25 past gene conversion or recombination events. These clusters are comparable in size to the conversions observed in the spontaneously occurring H-2Kbm and H-2Kkm2 mutations, and are distributed throughout all exons of the class I gene. Thus, gene conversion does not appear to be restricted to the regions of the class I gene encoding their antigen-presentation function. Moreover, both the highly polymorphic H-2 loci and the relatively monomorphic Qa and Tla loci appear to have participated as donors and recipients in conversion events. If gene conversion is not limited to the highly polymorphic loci of the MHC, then another factor, presumably natural selection, must be responsible for maintaining the observed differences in level of variation.


Feature-based phase retrieval wavefront sensing approach using machine learning.
A feature-based phase retrieval wavefront sensing approach using machine learning is proposed in contrast to the conventional intensity-based approaches. Specifically, the Tchebichef moments which are orthogonal in the discrete domain of the image coordinate space are introduced to represent the features of the point spread functions (PSFs) at the in-focus and defocus image planes. The back-propagation artificial neural network, which is one of most wide applied machine learning tool, is utilized to establish the nonlinear mapping between the Tchebichef moment features and the corresponding aberration coefficients of the optical system. The Tchebichef moments can effectively characterize the intensity distribution of the PSFs. Once well trained, the neural network can directly output the aberration coefficients of the optical system to a good precision with these image features serving as the input. Adequate experiments are implemented to demonstrate the effectiveness and accuracy of proposed approach. This work presents a feasible and easy-implemented way to improve the efficiency and robustness of the phase retrieval wavefront sensing.


Management of cancer-associated thromboembolism in vulnerable population.
Although all patients with cancer-associated thrombosis (CAT) have a high morbidity and mortality risk, certain groups of patients are particularly vulnerable. This may expose the patient to an increased risk of thrombotic recurrence or bleeding (or both), as the benefit-risk ratio of anticoagulant treatment may be modified. Treatment thus needs to be chosen with care. Such vulnerable groups include older patients, patients with renal impairment or thrombocytopenia, and underweight and obese patients. However, these patient groups are poorly represented in clinical trials, limiting the available data, on which treatment decisions can be based. Meta-analysis of data from randomised clinical trials suggests that the relative treatment effect of direct oral factor Xa inhibitors (DXIs) and low molecular weight heparin (LMWH) with respect to major bleeding could be affected by advanced age. No evidence was obtained for a change in the relative risk-benefit profile of DXIs compared to LMWH in patients with renal impairment or of low body weight. The available, albeit limited, data do not support restricting the use of DXIs in patients with CAT on the basis of renal impairment or low body weight. In older patients, age is not itself a critical factor for choice of treatment, but frailty is such a factor. Patients over 70 years of age with CAT should undergo a systematic frailty evaluation before choosing treatment and modifiable bleeding risk factors should be addressed. In patients with renal impairment, creatine clearance should be assessed and monitored regularly thereafter. In patients with an eGFR<30mL/min/1.72m2, the anticoagulant treatment may need to be adapted. Similarly, platelet count should be assessed prior to treatment and monitored regularly. In patients with grade 3-4, thrombocytopenia (<50,000 platelets/μL) treatment with a LMWH at a reduced dose should be considered. For patients with CAT and low body weight, standard anticoagulant treatment recommendations are appropriate, whereas in obese patients, apixaban may be preferred.


Dispositional optimism and physical wellbeing: the relevance of culture, gender, and socioeconomic status.
The present study examined the relationship between dispositional optimism and physical wellbeing (as reflected in physical symptom reporting) in two groups of American and Jordanian college students. It also assessed moderation effects of culture, gender, and socioeconomic status (SES). Participants were administered a questionnaire consisting of items pertaining to dispositional optimism (as measured by the Revised Life Orientation Test, LOT-R) along with items assessing physical symptom reporting and sociodemographic factors (e.g., gender, socioeconomic status). The results revealed significant negative correlations between dispositional optimism and physical symptom reporting for both American and Jordanian participants, although the magnitude of the correlation for the American group was noticeably larger than that for the Jordanian group. The results also showed that women, especially Jordanians, were more likely than men to report physical symptoms. Among Jordanians, physical symptom reporting was more common among those of lower SES. No statistically significant differences in physical symptom reporting were found between American men and women or between the two cultural groups. Multiple regression analyses revealed no statistically significant interactions between optimism and cultural background, optimism and gender, or optimism and SES. Overall, the results suggest that optimism is the factor most predictive of physical symptom reporting, followed by SES and gender. These results corroborate previous findings on the relationship between dispositional optimism and physical wellbeing, and point to crosscultural differences in relationship patterns. These differences suggest that although personality characteristics such as optimism may play an important role in the physical wellbeing of both Western and non-Western groups, the influence of sociodemographic factors such as gender and SES and their interaction with cultural variables must not be overlooked.


Intraoperative electrocorticography-guided microsurgical management for patients with onset of supratentorial neoplasms manifesting as epilepsy: a review of 65 cases.
We reviewed the surgical procedures guided by intraoperative electrocorticography and outcome of 65 patients with onset of supratentorial neoplasms manifesting as epilepsy. Clinical data were obtained for 65 patients with supratentorial neoplasms who received surgery, with the aid of intraoperative electrocorticography to screen epileptogenic foci before and after removal of neoplasms, and depth electrodes when needed. According to electrocorticography findings, appropriate surgical procedures were performed to treat the epileptogenic foci. In the control group, 72 patients received simple lesionectomy. Postoperative seizure outcomes were documented and analysed retrospectively. In the case group, 33 patients received lesionectomy only, while the other 32 patients underwent intraoperative electrocorticography-guided tailored epilepsy surgery. In total, 57 patients (87.7%) in the case group and 38 patients (52.8%) in the control group were seizure-free (Engel Class I). Comparing outcomes of patients with temporal lesions between the two groups, 80.0% patients (12/15) in the case group and 20.0% (3/15) in the control group were seizure-free. Furthermore, comparing the seizure outcomes of patients who finally underwent tailored epilepsy surgery and simple lesionectomy (33 after electrocorticography and 72 without electrocorticography), intraoperative electrocorticography-guided tailored epilepsy surgery demonstrated superiority over lesionectomy (Engel Class I; 87.5% vs. 63.8%, respectively). Electrocorticography plays an important role in the localisation of epileptogenic foci and evaluation of the effects of microsurgical procedures intraoperatively. Isolated lesionectomy is not usually sufficient for better postoperative seizure outcome. In addition, for patients with temporal tumours, especially in the non-dominant hemisphere, a more aggressive strategy, such as an anterior temporal lobectomy, is recommended.


Molecular pathways: the immunogenic effects of platinum-based chemotherapeutics.
The platinum-based drugs cisplatin, carboplatin, and oxaliplatin belong to the most widely used chemotherapeutics in oncology, showing clinical efficacy against many solid tumors. Their main mechanism of action is believed to be the induction of cancer cell apoptosis as a response to their covalent binding to DNA. In recent years, this picture has increased in complexity, based on studies indicating that cellular molecules other than DNA may potentially act as targets, and that part of the antitumor effects of platinum drugs occurs through modulation of the immune system. These immunogenic effects include modulation of STAT signaling; induction of an immunogenic type of cancer cell death through exposure of calreticulin and release of ATP and high-mobility group protein box-1 (HMGB-1); and enhancement of the effector immune response through modulation of programmed death receptor 1-ligand and mannose-6-phosphate receptor expression. Both basic and clinical studies indicate that at least part of the antitumor efficacy of platinum chemotherapeutics may be due to immune potentiating mechanisms. Clinical studies exploiting this novel mechanism of action of these old cancer drugs have been initiated. Here, we review the literature on the immunogenic effects of platinum, summarize the clinical advances using platinum as a cytotoxic compound with immune adjuvant properties, and discuss the limitations to these studies and the gaps in our understanding of the immunologic effects of these drugs. Clin Cancer Res; 20(11); 2831-7. ©2014 AACR.


Engineering aldo-keto reductase 1B10 to mimic the distinct 1B15 topology and specificity towards inhibitors and substrates, including retinoids and steroids.
The aldo-keto reductase (AKR) superfamily comprises NAD(P)H-dependent enzymes that catalyze the reduction of a variety of carbonyl compounds. AKRs are classified in families and subfamilies. Humans exhibit three members of the AKR1B subfamily: AKR1B1 (aldose reductase, participates in diabetes complications), AKR1B10 (overexpressed in several cancer types), and the recently described AKR1B15. AKR1B10 and AKR1B15 share 92% sequence identity, as well as the capability of being active towards retinaldehyde. However, AKR1B10 and AKR1B15 exhibit strong differences in substrate specificity and inhibitor selectivity. Remarkably, their substrate-binding sites are the most divergent parts between them. Out of 27 residue substitutions, six are changes to Phe residues in AKR1B15. To investigate the participation of these structural changes, especially the Phe substitutions, in the functional features of each enzyme, we prepared two AKR1B10 mutants. The AKR1B10 m mutant carries a segment of six AKR1B15 residues (299-304, including three Phe residues) in the respective AKR1B10 region. An additional substitution (Val48Phe) was incorporated in the second mutant, AKR1B10mF48. This resulted in structures with smaller and more hydrophobic binding pockets, more similar to that of AKR1B15. In general, the AKR1B10 mutants mirrored well the specific functional features of AKR1B15, i.e., the different preferences towards the retinaldehyde isomers, the much higher activity with steroids and ketones, and the unique behavior with inhibitors. It can be concluded that the Phe residues of loop C (299-304) contouring the substrate-binding site, in addition to Phe at position 48, strongly contribute to a narrower and more hydrophobic site in AKR1B15, which would account for its functional uniqueness. In addition, we have investigated the AKR1B10 and AKR1B15 activity toward steroids. While AKR1B10 only exhibits residual activity, AKR1B15 is an efficient 17-ketosteroid reductase. Finally, the functional role of AKR1B15 in steroid and retinaldehyde metabolism is discussed.


Genetic polymorphisms in CTLA4 and SLC4A2 are differentially associated with the pathogenesis of primary biliary cirrhosis in Japanese patients.
Anti-gp210 and anti-centromere antibodies are different risk factors for the progression of primary biliary cirrhosis (PBC). In order to dissect the genetic basis for the production of these autoantibodies, as well as the development and progression of PBC in Japanese patients, we examined single nucleotide polymorphisms (SNPs) in cytotoxic T-lymphocyte antigen 4 (CTLA4) and solute carrier family 4 anion exchanger, member 2 (SLC4A2), which have been associated with the pathogenesis of PBC in Caucasian patients. Four SNPs for both CTLA4 and SLC4A2 were genotyped, using the polymerase chain reaction-restriction fragment length polymorphism method and TaqMan assay, in 450 Japanese PBC patients and 371 sex-matched healthy controls. The CTLA4 rs231775, rs3087243, and rs231725 SNPs were significantly associated with PBC susceptibility. The CTLA4 rs231725 SNP was significantly associated with progression to late-stage disease. The CTLA-4 haplotype 1 (rs231775 G, rs231777 C, rs3087243 G, rs231725 A; GCGA) was a risk factor for PBC susceptibility but a protective factor for PBC progression. Conversely, the CTLA-4 haplotype 2 (ACAG) was a protective and risk factor, respectively, for PBC susceptibility and progression. In addition, the CTLA4 rs231777 SNP and haplotype 3 (ATGG) was significantly associated with anti-gp210 antibody production, while SLC4A2 haplotype 4 (rs2069443 A, rs2303933 G, rs2303937 A, rs2303941 T; AGAT) and haplotype 3 (AAGC) were significantly associated with PBC susceptibility and anti-centromere antibody production, respectively. CTLA4 and SLC4A2 genetic polymorphisms are differentially associated with PBC development and progression, as well as anti-gp210 or anti-centromere antibody production, in Japanese PBC patients.


Sources of maternal odors and the development of odor preferences in baby pigs.
Seven experiments utilizing 77 litters of piglets were conducted to determine the relative preferences or aversion of piglets for maternal olfactory cues. A Y-maze was used to test piglet preferences for two substances at any one time. A preference index was calculated from Y-maze data to identify whether piglets expressed a preference or aversion to the two substances tested in each session. The first two experiments examined piglet preferences for maternal fecal odors, colostrum, milk, urine and skin washings at 12 h and 7 d of age. Piglets preferred the odor of nipple washings and sow feces at 12 h of age. Piglets preferred sow fecal odors at 7 d of age in one study. The third study showed that piglets could discriminate between their mother's fecal odor and fecal odors from other sows. The fourth study examined piglet preferences for maternal fecal odors at birth, 12 h and 1, 3 and 7 d of age. At all ages tested except birth, piglets preferred sow fecal odors over water. The final three studies showed that piglets did not prefer to be near novel odors (orange and banana odors), nor did they prefer to be near the putative rat maternal pheromone, deoxycholic acid. In conclusion, piglets learn their mother's odor within the first 12 h of life. Piglets are most attracted to the odors associated with maternal feces and skin secretions. Piglet odor discriminatory ability is specific for maternal odors (not just odorous substances) and very acute (they can discriminate between mother and non-mother odors). When modifying piglet behavior to improve survival, the piglet's well-developed olfactory ability should be considered.


Lipogastrins as potent inhibitors of viral fusion.
The rate and extent of membrane fusion is markedly sensitive to membrane interfacial properties. Lipopeptides with hydrophilic peptide moieties will insert into membranes, leaving the peptide portion at the membrane-water interface. In this work, we have used a lipopeptide composed of the peptide [Nle15]-gastrin-(2-17)-amide covalently linked to 1,2-diacyl-3-mercaptoglycerol-N(alpha)-maleoyl-beta-alanine to give DM-gastrin or DP-gastrin having 14 or 16 carbon atom acyl chains, respectively. The fluorescence emission from the two Trp residues of these lipopeptides exhibited little or no blue shift upon addition of liposomes of egg-phosphatidylethanolamine containing 5 mol% G(D1a). Iodide quenching of DP-gastrin fluorescence was also independent of lipid. These results indicate that the peptide moiety is exposed to the aqueous environment even though the lipopeptide is firmly anchored to the membrane. Both DM and DP-gastrin markedly raise the bilayer to hexagonal phase transition temperature of dipalmitoleoyl phosphatidylethanolamine. However, DM-E5 lowers this phase transition temperature. These lipopeptides have effects on the overall fusion of Sendai virus to liposomes in accord with their opposite effects on lipid curvature. The lipogastrins are potent inhibitors of viral fusion, while DM-E5 slightly promotes this process. Truncated forms of DM-gastrin are also inhibitory to viral fusion, but are less inhibitory than the full lipopeptide. Analysis of the fusion kinetics shows that DP-gastrin causes a reduction in the final extent of fusion and a marked lowering of the fusion rate constant. Binding of Sendai virus to the ganglioside receptor-containing liposomes was not affected. Consideration of the various contributions to the mechanism of inhibition of viral fusion suggests that effects of lipogastrin on membrane intrinsic monolayer curvature is of primary importance.


American Society of Clinical Oncology clinical practice guideline: update on adjuvant endocrine therapy for women with hormone receptor-positive breast cancer.
To develop evidence-based guidelines, based on a systematic review, for endocrine therapy for postmenopausal women with hormone receptor-positive breast cancer. A literature search identified relevant randomized trials. Databases searched included MEDLINE, PREMEDLINE, the Cochrane Collaboration Library, and those for the Annual Meetings of the American Society of Clinical Oncology (ASCO) and the San Antonio Breast Cancer Symposium (SABCS). The primary outcomes of interest were disease-free survival, overall survival, and time to contralateral breast cancer. Secondary outcomes included adverse events and quality of life. An expert panel reviewed the literature, especially 12 major trials, and developed updated recommendations. An adjuvant treatment strategy incorporating an aromatase inhibitor (AI) as primary (initial endocrine therapy), sequential (using both tamoxifen and an AI in either order), or extended (AI after 5 years of tamoxifen) therapy reduces the risk of breast cancer recurrence compared with 5 years of tamoxifen alone. Data suggest that including an AI as primary monotherapy or as sequential treatment after 2 to 3 years of tamoxifen yields similar outcomes. Tamoxifen and AIs differ in their adverse effect profiles, and these differences may inform treatment preferences. The Update Committee recommends that postmenopausal women with hormone receptor-positive breast cancer consider incorporating AI therapy at some point during adjuvant treatment, either as up-front therapy or as sequential treatment after tamoxifen. The optimal timing and duration of endocrine treatment remain unresolved. The Update Committee supports careful consideration of adverse effect profiles and patient preferences in deciding whether and when to incorporate AI therapy.


Effects of a mental health carve-out on use, costs, and payers: a four-year study.
This study examines the effects of a mental health carve-out on a sample of continuously enrolled employees (N = 1,943) over a four-year time frame (1990-1994). The article presents a health care services utilization model of the effect of the carve-out on outpatient mental health use, cost, and source of payment in the three years post implementation relative to the year prior to the carve-out model. In the first three years of the carve-out, the likelihood of employees seeking mental health care increased in significant part because of the carve-out. For the outpatient mental health services user, the carve-out was not associated with the level of mental health services received. The carve-out was significantly associated over time with a reduction in the patient's and employer's mental health costs. This effect was more pronounced in the second and third years of the carve-out. The article explores the policy implications of these and other findings.


Medication-assisted treatment with buprenorphine: assessing the evidence.
Buprenorphine maintenance treatment (BMT) and methadone maintenance treatment (MMT) are pharmacological treatment programs for individuals with opioid use disorders. MMT is discussed in a companion article. This article describes BMT and reviews available research on its efficacy. Authors reviewed meta-analyses, systematic reviews, and individual studies of BMT from 1995 through 2012. Databases surveyed were PubMed, PsycINFO, Applied Social Sciences Index and Abstracts, Sociological Abstracts, Social Services Abstracts, and Published International Literature on Traumatic Stress. They chose from three levels of evidence (high, moderate, and low) based on benchmarks for the number of studies and quality of their methodology. They also described the evidence of service effectiveness. Sixteen adequately designed randomized controlled trials of BMT indicated a high level of evidence for its positive impact on treatment retention and illicit opioid use. Seven reviews or meta-analyses were also included. When the medication was dosed adequately, BMT and MMT showed similar reduction in illicit opioid use, but BMT was associated with less risk of adverse events. Results suggested better treatment retention with MMT. BMT was associated with improved maternal and fetal outcomes in pregnancy, compared with no medication-assisted treatment. Rates of neonatal abstinence syndrome were similar for mothers treated with BMT and MMT during pregnancy, but symptoms were less severe for infants whose mothers were treated with BMT. BMT is associated with improved outcomes compared with placebo for individuals and pregnant women with opioid use disorders. BMT should be considered for inclusion as a covered benefit.


Resolving drug selection and migration in an inbred South American Plasmodium falciparum population with identity-by-descent analysis.
The human malaria parasite Plasmodium falciparum is globally widespread, but its prevalence varies significantly between and even within countries. Most population genetic studies in P. falciparum focus on regions of high transmission where parasite populations are large and genetically diverse, such as sub-Saharan Africa. Understanding population dynamics in low transmission settings, however, is of particular importance as these are often where drug resistance first evolves. Here, we use the Pacific Coast of Colombia and Ecuador as a model for understanding the population structure and evolution of Plasmodium parasites in small populations harboring less genetic diversity. The combination of low transmission and a high proportion of monoclonal infections means there are few outcrossing events and clonal lineages persist for long periods of time. Yet despite this, the population is evolutionarily labile and has successfully adapted to changes in drug regime. Using newly sequenced whole genomes, we measure relatedness between 166 parasites, calculated as identity by descent (IBD), and find 17 distinct but highly related clonal lineages, six of which have persisted in the region for at least a decade. This inbred population structure is captured in more detail with IBD than with other common population structure analyses like PCA, ADMIXTURE, and distance-based trees. We additionally use patterns of intra-chromosomal IBD and an analysis of haplotypic variation to explore past selection events in the region. Two genes associated with chloroquine resistance, crt and aat1, show evidence of hard selective sweeps, while selection appears soft and/or incomplete at three other key resistance loci (dhps, mdr1, and dhfr). Overall, this work highlights the strength of IBD analyses for studying parasite population structure and resistance evolution in regions of low transmission, and emphasizes that drug resistance can evolve and spread in small populations, as will occur in any region nearing malaria elimination.


Dimensional-crossover-driven metal-insulator transition in SrVO3 ultrathin films.
We have investigated the changes occurring in the electronic structure of digitally controlled SrVO(3) ultrathin films across the metal-insulator transition (MIT) by the film thickness using in situ photoemission spectroscopy. With decreasing film thickness, a pseudogap is formed at E(F) through spectral weight transfer from the coherent part to the incoherent part. The pseudogap finally evolves into an energy gap that is indicative of the MIT in a SrVO(3) ultrathin film. The observed spectral behavior is reproduced by layer dynamical-mean-field-theory calculations, and it indicates that the observed MIT is caused by the reduction in the bandwidth due to the dimensional crossover.


[Hypoacusis during childhood. Diagnosis and treatment].
The evaluation of hearing is an important activity in paediatric practice, making it possible to confirm by different techniques whether the child hears well or not, a fact that might be suggested from other sources (the family, school). It is thus fundamental that this should be suitably evaluated since it will have an important incidence on the development of the child. Thus hypoacusis can be the cause of lack of adaptation or school failure, depending on age, or of language alterations. Different types of hypoacusis are described as well as techniques for its diagnosis and corresponding treatment. A reflection is offered on the problem of otitis media serous in primary care and its referral to the child ENT unit.