On the front lines of the opioid epidemic: Rescue by naloxone.
Naloxone is a specific, high affinity opioid antagonist that has been used to treat suspected or confirmed overdose for more than 40 years. Naloxone use was initially confined to an emergency room setting, but the dramatic rise in opioid overdose events over the past two decades has, with increasing frequency, shifted naloxone use to first responders including police, emergency medical technicians, and the friends and family of overdose victims. The opioids responsible for overdose events have also evolved, from prescription opioids to heroin and most recently, very high potency synthetic opioids such as fentanyl. In 2016, synthetic opioids were linked to more overdose fatalities than either prescription opioids or heroin. In this review, I will discuss the evolution and use of naloxone products by first responders and the development of additional rescue medications in response to the unprecedented dangers posed by synthetic opioids.


[Hemodialysis in children (author's transl)].
Long term hemodialysis and kidney transplantation has proved to be a very efficient method in the treatment of renal failure in childhood. Accordingly, the number of children treated by dialysis and transplantation in Europe is still increasing. At this time more than 1250 have been treated. As a result of recent studies, one to two children under the age of 15 years per one million population per one year reach the terminal stage of renal insufficiency. We performed our own informative study in 1975 to estimate the needs for dialysis facilities in Austria. Our results are in line with those of other projects. In view of the special childhood problems (growth, puberty, psychological problems, schooling etc.) there is a need for specialized pediatric centers which should include the facilities for nephrologic out- and in-patient treatment, a dialysis team consisting of a pediatrician, pediatric nurses, teacher, child psychologist, dietician and social worker. These enormous investments in apparature, personnel and organization are justified by the good results of survival and the reasonably normal life these children can lead.


Presentation of HIV-associated nephropathy and outcome in HAART-treated patients.
Among the numerous renal diseases observed in human immunodeficiency virus (HIV) patients, HIV-associated nephropathy (HIVAN) is a major cause of end-stage renal disease (ESRD). The purpose of our study was to describe the presentation and outcome of HIVAN in the era of highly active antiretroviral therapy (HAART). We analysed clinical features and outcome of 57 patients with histologically proven HIVAN diagnosed between 2000 and 2009 in four teaching hospitals in Paris, France. This series was characterized by median age of 41 years (18-58), frequent African origin (87%), severe renal dysfunction [estimated glomerular filtration rate (eGFR) 20 mL/min/1.73m(2) (1-68)], high-grade proteinuria [4.1 g/day (0.6-16.8)], high proportion of sclerotic glomeruli [31.5% (0-95)], high HIV load [4.5 log copies/mL (0-6.7)] and low CD4+ count [127/mm(3) (3-713)]. Nevertheless, a non-negligible proportion of patients did not present with these typical features. Follow-up data were available for 51 patients. ESRD occurred in 30 patients (58.8%). Median renal survival was 40 months. Baseline characteristics significantly associated with ESRD were as follows: severity of renal dysfunction, percentage of sclerotic glomeruli, time from HIV infection to HIVAN diagnosis longer than 1 year and prior exposure to antiretroviral drugs. There was an insignificant trend towards better renal outcome being associated with viral suppression during follow-up. Use of renin-angiotensin system (RAS) blockers was associated with higher renal survival (P < 0.05). Despite HAART, HIVAN led to ESRD in more than half of the cases. Early recognition of the disease is crucial to start HAART and RAS blockers before irreversible renal injury.


Improved beat asynchrony detection in early blind individuals.
Although early blind (EB) individuals are thought to have a better musical sense than sighted subjects, no study has investigated the musical rhythm and beat processing abilities in EB individuals. Using an adaptive 'up and down' procedure, we measured the beat asynchrony detection threshold and the duration discrimination threshold, in the auditory and vibrotactile modalities in both EB and sighted control (SC) subjects matched for age, gender, and musical experience. We observed that EB subjects were better than SC in the beat asynchrony detection task; that is, they showed lower thresholds than SC, both in the auditory and in the vibrotactile modalities. In addition, EB subjects had a lower threshold than SC for duration discrimination in the vibrotactile modality only. These improved beat asynchrony detection abilities may contribute to the known excellent musical abilities often observed in many blind subjects.


Synthesis of multi-unit protein hetero-complexes in the gas phase via ion-ion chemistry.
The synthesis of protein hetero-complex ions via ion-ion reactions in the gas phase is demonstrated in a quadrupole ion trap. Bovine cytochrome c cations and bovine ubiquitin anions are used as reactant species in the stepwise construction of complexes containing as many as six protein sub-units. For any set of reactants, a series of competitive and consecutive reactions is possible. The yield of complex ions for any given sequence of reactions is primarily limited by the presence of competitive reactions. Proton transfer represents the most important competitive reaction that adversely affects protein complex synthesis. In the present data, proton transfer takes place most extensively in the first step of complex synthesis, when single protein sub-units are subjected to reaction with one another. Proton transfer is found to be less extensive when one of the reactants is a protein complex. The generation of hexameric hetero-complexes containing two cytochrome c molecules and four ubiquitin molecules is demonstrated with two different synthesis approaches. The first involved the initial reaction of several charge states of cytochrome c and several charges states of ubiquitin. The sequence of reactions in this example illustrates the array of possible competitive and consecutive reactions associated with even a relatively simple set of multiply charged reactants. The second approach involved the initial reaction of the 9(+) charge state of cytochrome c and the 5(-) charge state of ubiquitin. The latter approach highlights the utility of the multi-stage mass spectrometric (MS(n)) capabilities of the ion trap in defining reactant ion identities (i.e. charge states and polarities) so that synthesis reactions can be directed along a particular set of pathways.


A revisitation of the Förster energy transfer near a metallic spherical nanoparticle: (1) Efficiency enhancement or reduction? (2) The control of the Förster radius of the unbounded medium. (3) The impact of the local density of states.
The central motivation of this theoretical revisitation comes from the fact that some experimental works about Förster energy transfer report improvement of the Förster efficiency when the donor-acceptor molecular pair is in the vicinity of a metallic particle, while others found efficiency deterioration. In the presence of a nanoscale metallic sphere, we calculate contour plots of the Förster energy transfer rate KF and the Förster efficiency η as a function of the acceptor position rA for a fixed donor position. These contour plots clearly highlight the influence of the sphere on KF and η as the donor position, the orientations of donor and acceptor dipoles, and the particle size are varied; also the impact on KF(rA) and η due to the excitation of surface plasmons is easily noticeable from these contour plots. Moreover, we obtain the enhancement factor KF/KF0 (KF0 refers to the case without sphere) against the donor-surface separation for particular donor-acceptor spatial distributions, several particle sizes, and distinct molecular dipole orientations. Therefore, our calculations provide a systematic analysis of the Förster energy transfer in the presence of a metallic nanosphere. Based on these results, we formulate hypotheses for explaining the aforementioned contradictory experimental results about η. To complement our study, we examine the impact of the local density of states ρ on KF. KF is practically unperturbed by sphere when the intermolecular separation R is ≲ 3 nm, since the direct donor-acceptor electromagnetic interaction is dominant. On the contrary, when R ≳ 3 nm, the nanosphere perturbs KF and this perturbation is stronger if plasmonic resonances are excited. KF/KF0 can greatly be enhanced in certain regions, but these regions coincide with low-efficiency regions, compromising applications involving the Förster process. In the presence of the nanosphere, the high Förster efficiency region (η ≥ 0.5) has the same shape as that for the case without sphere, but its extension (Förster radius Ro) is reduced; this effect is a consequence of the large increase of the donor direct decay rate and Ro depends strongly on donor position. Consequently, the sphere controls Ro that is associated with the efficiency pattern that corresponds to the unbounded medium; this effect can be exploited in the measuring technique of nanoscale displacements of proteins that is based on the fluorescence resonant energy transfer. The functional form of KF(ρ) is determined by the intermolecular separation R, the spatial configuration and the dipole orientations of the molecular pair, and the donor proximity to the nanoparticle.


Necrosis of a large hepatic tumor after hemorrhage and subsequent selective arterial embolization.
This case report describes a young female patient presenting with acute intra-abdominal hemorrhage originating from a large tumor in the liver, most likely a hepatocellular adenoma. The bleeding was stopped by selective embolization of right hepatic artery branches. Subsequently, partial hepatectomy was performed after 6 mo. Macro- and microscopic examination showed complete necrosis and absence of tumorous tissue. The patient was discharged without complications, and subsequent follow-up until 22 mo after resection did not reveal any new lesions in the liver. This case emphasizes the significance of selective arterial embolization in the management of bleeding liver tumors and questions the need for (partial) hepatectomy after this procedure in selective cases.


Infection with murine norovirus 4 does not alter Helicobacter-induced inflammatory bowel disease in Il10(-/-) mice.
Infection of laboratory mice with murine noroviruses (MNV) is widely prevalent. MNV alters various mouse models of disease, including the Helicobacter bilis-induced mouse model of inflammatory bowel disease (IBD) in Mdr1a(--) mice. To further characterize the effect of MNV on IBD, we used mice deficient in the immunoregulatory cytokine IL10 (Il10(-/-) mice). In vitro infection of Il10(-/-) bone marrow-derived macrophages (BMDM) with MNV4 cocultured with H. bilis antigens increased the gene expression of the proinflammatory cytokines IL1β, IL6, and TNFα as compared with that of BMDM cultured with H. bilis antigens only. Therefore, to test the hypothesis that MNV4 infection increases inflammation and alters disease phenotype in H. bilis-infected Il10(-/-) mice, we compared the amount and extent of inflammation in Il10(-/-) mice coinfected with H. bilis and MNV4 with those of mice singly infected with H. bilis. IBD scores, incidence of IBD, or frequency of severe IBD did not differ between mice coinfected with H. bilis and MNV4 and those singly infected with H. bilis. Mice infected with MNV4 only had no appreciable IBD, comparable to uninfected mice. Our findings suggest that, unlike in Mdr1a(-/-) mice, the presence of MNV4 in Il10(-/-) mouse colonies is unlikely to affect the IBD phenotype in a Helicobacter-induced model. However, because MNV4 altered cytokine expression in vitro, our results highlight the importance of determining the potential influence of MNV on mouse models of inflammatory disease, given that MNV has a tropism for macrophages and dendritic cells and that infection is widely prevalent.


Utilization of carbon and nitrogen-containing compounds for neomycin production by Streptomyces fradiae.
A number of carbon and nitrogen compounds were tested for their effect on growth of Streptomyces fradiae 3535 and neomycin production. Dextrin, starch, and maltose were excellent carbon sources for neomycin production, and sodium nitrate, aspartic acid, and glutamic acid were adequate nitrogen sources. Studies on biochemical changes during fermentation in four typical media indicated that there was no direct relation between the growth of the organism and neomycin formation. The pH of the medium might be an important factor for neomycin synthesis. The quantitative formation of neomycin components depended on the variation of carbon and nitrogen sources. On the basis of this study, a suitable synthetic medium for neomycin production has been developed.


[Variations in plasma protein components during extracorporeal circulation].
In this research we have determined the behaviour of proteic plasmatic pattern and some enzymes during extracorporeal circulation and we noted a constant increase of albumin and of the ratio Alb/Glob. We observed also variations of some enzymes. Our opinion according other AA. is that this changes are determined principally by the large dose of heparin necessary during the C.E.C.


Central control of energy balance by amylin and calcitonin receptor agonists and their potential for treatment of metabolic diseases.
The prevalence of obesity and associated comorbidities such as type 2 diabetes and cardiovascular disease is increasing globally. Body-weight loss reduces the risk of morbidity and mortality in obese individuals, and thus, pharmacotherapies that induce weight loss can be of great value in improving the health and well-being of people living with obesity. Treatment with amylin and calcitonin receptor agonists reduces food intake and induces weight loss in several animal models, and a number of companies have started clinical testing for peptide analogues in the treatment of obesity and/or type 2 diabetes. Studies predominantly performed in rodent models show that amylin and the dual amylin/calcitonin receptor agonist salmon calcitonin achieve their metabolic effects by engaging areas in the brain associated with regulating homeostatic energy balance. In particular, signalling via neuronal circuits in the caudal hindbrain and the hypothalamus is implicated in mediating effects on food intake and energy expenditure. We review the current literature investigating the interaction of amylin/calcitonin receptor agonists with neurocircuits that induce the observed metabolic effects. Moreover, the status of drug development of amylin and calcitonin receptor agonists for the treatment of metabolic diseases is summarized.


Adriamycin and cyclophosphamide versus hydroxyurea in advanced prostatic cancer. A randomized Southwest Oncology Group study.
Over a 24-month period, the Southwest Oncology Group (SWOG) conducted a randomized prospective chemotherapeutic trial in 158 patients with advanced prostatic cancer. Patients were initially randomized to receive either a combination of Adriamycin and cyclophosphamide (AC) or a single agent, hydroxyurea (H), and then crossed over to the other treatment on failure. Of the 137 evaluable patients, 43 (31%) had classically measurable metastatic disease in the lymph nodes, skin, chest, or liver. Focusing their efforts on this subset of patients with measurable disease, the authors of this report found the combination AC to have a superior response rate to the single agent, hydroxyurea. Objective response to AC was seen in 6 of 19 (32%) and in only one of 24 (4%) patients randomized to hydroxyurea (P = 0.06, Fisher's exact test). However, in the larger group of 137 evaluable patients, a survival advantage was not seen for those individuals treated with AC. Failure to demonstrate a survival advantage for an objectively superior drug combination would suggest the need for more active phase II agents in this disease.


Early stages of Golgi vesicle and tubule formation require diacylglycerol.
We have investigated the role for diacylglycerol (DAG) in membrane bud formation in the Golgi apparatus. Addition of propranolol to specifically inhibit phosphatidate phosphohydrolase (PAP), an enzyme responsible for converting phosphatidic acid into DAG, effectively prevents formation of membrane buds. The effect of PAP inhibition on Golgi membranes is rapid and occurs within 3 min. Removal of the PAP inhibitor then results in a rapid burst of buds, vesicles, and tubules that peaks within 2 min. The inability to form buds in the presence of propranolol does not appear to be correlated with a loss of ARFGAP1 from Golgi membranes, as knockdown of ARFGAP1 by RNA interference has little or no effect on actual bud formation. Rather, knockdown of ARFGAP1 results in an increase in membrane buds and a decrease of vesicles and tubules suggesting it functions in the late stages of scission. How DAG promotes bud formation is discussed.


Highly regio- and stereoselective acylboration, acylsilation, and acylstannation of allenes catalyzed by phosphine-free palladium complexes: an efficient route to a new class of 2-acylallylmetal reagents.
A new method for the synthesis of substituted 2-acylallylmetal reagents in a highly regio- and stereoselective fashion involving a three-component assembly of allenes, acyl chlorides, and bimetallic reagents (B-B, Si-Si, and Sn-Sn) catalyzed by phosphine-free palladium complexes is described. Treatment of various allenes (CR(2)R(3)=C=CH(2)) with acyl chlorides (R(1)COCl) and bispinacolatodiboron in the presence of PdCl(2)(CH(3)CN)(2) in toluene at 80 degrees C gave 2-acylallylboronates in moderate to good yields. The acylsilation of allenes with acid chlorides and hexamethyldisilane (5) proceeded successfully in the presence of Pd(dba)(2) in CH(3)CN affording the corresponding allylsilanes (CR(2)R(3)=C(COR(1))CH(2)SiMe(3)) in good to moderate yields. Several chloroformates (R(4)OCOCl) also react with 1,1-dimethylallene (2a) and 5 to afford allylsilanes (CR(2)R(3)=C(COOR(4))CH(2)SiMe(3)) in 66-70% yields. Acylstannation of allenes could also be achieved by slow addition of hexabutylditin (10) to the reaction mixture of acyl chloride (or chloroformate) and allene 2a in CH(3)CN in the presence of Pd(dba)(2) at 60 degrees C; the corresponding 2-substituted allylstannanes were isolated in moderate to good yields. The above catalytic reactions are completely regioselective and highly stereoselective. A mechanism is proposed to account for the catalytic reactions and the stereochemistry.


Molecular detection of free cancer cells in pleural lavage fluid from esophageal cancer patients.
The clinical significance of free cancer cells in pleural lavage fluid detected by molecular methods during surgery remains uncertain in esophageal squamous cell cancer (ESCC). We therefore evaluated the relationship between free cancer cells and clinicopathological findings, and compared the reverse transcriptase-polymerase chain reaction (RT-PCR) method with conventional cytological examination. Pleural lavage fluid from 38 consecutive patients was obtained at two time points; immediately after thoracotomy and before thorax closure. Papanicolaou and Giemsa staining as well as carcinoembryonic antigen (CEA)-specific RT-PCR were performed. The positivity rates obtained using cytological examination and CEA-mRNA expression were 5.3 and 15.8%, respectively. Positive results were observed in pleural lavage fluid after tumor resection. No significant differences in clinicopathologic factors were seen, irrespective of CEA-mRNA expression status. Among the 5 patients exhibiting CEA-mRNA positivity, 2 experienced hematogenous recurrence, 2 experienced mixed recurrence and 1 experienced pleural dissemination. With regard to mode of recurrence and mean period between surgery and relapse, no significant differences were seen between CEA-mRNA-positive and CEA-mRNA-negative patients. Although disease recurred in almost all patients exhibiting CEA-mRNA expression, due to the relatively small sample in the present study the clinical significance must be investigated further in a larger number of patients.


Pharmacology of endogenous neuroactive steroids.
Neuroactive steroids are potent endogenous neuromodulators with rapid actions in the central nervous system. Neuroactive steroids have been claimed to have specific physiological roles in normal or pathological brain function. This article reviews the emerging evidence that progesterone-, deoxycorticosterone-, and testosterone-derived endogenous neuroactive steroids play an important role in the modulation of neural excitability and brain function. Neuroactive steroids such as allopregnanolone and allotetrahydrodeoxycorticosterone (THDOC) are extremely potent positive allosteric modulators of GABAA receptors with sedative, anxiolytic, and anticonvulsant properties. The sulfated neuroactive steroids pregnenolone sulfate (PS) and dehydroepiandrosterone sulfate (DHEAS), which are negative GABAA receptor modulators, induce anxiogenic and proconvulsant effects. Thus, natural fluctuations in neuroactive steroid levels during the menstrual cycle and stress could affect several nervous system functions. There is strong evidence that allopregnanolone and THDOC are involved in the pathophysiology of premenstrual syndrome, catamenial epilepsy, major depression, and stress-sensitive brain disorders. Neuroactive steroids PS and DHEAS have been shown to modulate memory functions. However, the significance of the testosterone-derived neuroactive steroid 3alpha-androstanediol is not well understood. Like naturally occurring neuroactive steroids, synthetic derivatives such as ganaxolone have been proven in preclinical and clinical studies to be effective anticonvulsants with great potential for human use. Future research on inhibition or stimulation of specific neuroactive steroid synthesizing enzymes could provide an improved understanding and novel approaches for the treatment of anxiety, epilepsy, and depression.


Chicken macrophages synthesize and secrete avidin in culture.
It was previously shown that avidin, a glycoprotein secreted in vivo by chicken oviduct, is produced by cultured transformed or damaged chicken embryo fibroblasts [27]. This report demonstrates synthesis and secretion of large amounts of avidin by macrophages isolated from chicken yolk sac. Avidin was secreted to the culture medium as shown by immunoprecipitation of metabolically labeled proteins. In the culture medium of macrophages the avidin concentration (up to 47.5 +/- 0.5 microgram/mg cellular protein) exceeded, in agreement with previous findings, that of fibroblasts (up to 7.3 +/- 0.7 microgram/mg) infected with transforming retroviruses (Rous sarcoma virus, its mutants temperature sensitive for transformation and OK 10 virus). No difference between the macrophage avidin and the egg white avidin was detected by both the heat-induced [14C] biotin exchange assay and immunoblotting (subunit Mr = 15600). By immunofluorescence 10 to 20% of the cells were positive for avidin, independent of the time in culture (1-30 days). The staining pattern varied between dense or granular perinuclear and strong reticulo-granular fluorescence throughout the cytoplasm. Double staining for avidin and the Golgi region by wheat germ agglutinin showed that avidin is concentrated, and might be processed, in the Golgi complex. The production of avidin by macrophages supports a role for avidin in host defence mechanisms.


Occurrence and characterization of lectins in actinomycetes.
25 species of actinomycetes were tested for the occurrence of lectins. Using a battery of normal and desialized erythrocytes, each species was screened for 3 types of lectin activity i.e. surface bound, extracellular and intracellular. As many as 13 species showed one or more types of activity; some of them were characterized with regard to their biological action spectrum and sugar specificity.


Loop Electrosurgical Excision Procedure versus Cryotherapy in the Treatment of Cervical Intraepithelial Neoplasia: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.
Invasive cervical cancer is proceeded by a phase of preinvasive disease that is slow to progress and can be detected, treated, and collectively referred to as cervical intraepithelial neoplasia (CIN). Several excisional and ablative treatments for CIN have been studied, with loop electrosurgical excision procedure (LEEP) and cryotherapy being the two most commonly utilized. The objective of this systematic review and meta-analysis of randomized controlled trials (RCTs) was to compare the compare harms and benefits of LEEP versus cryotherapy in women with CIN. Electronic databases were searched from their inception until May 2018. We included all RCTs comparing cryotherapy versus LEEP in women with CIN. We included trials evaluating both HIV-seropositive and HIV-seronegative women. The primary outcome was the persistence of the disease at 6-month follow-up. Meta-analysis was performed using the random-effects model to produce summary treatment effects in terms of relative risk (RR) with 95% confidence interval (CI). Four trials, including 1035 women with CIN, were identified as relevant and included in the meta-analysis. Women who received LEEP for CIN had a significantly lower persistence at 6-month follow-up biopsy (RR: 0.87, 95% CI: 0.76-0.99) and significantly lower recurrence at 12-month follow-up biopsy (RR: 0.91, 95% CI: 0.84-0.99) compared to those who received cryotherapy. No between-group differences were found in the complications rate, but the analyses were not powered for these outcomes. In women with CIN, treatment with LEEP was associated with a significantly lower risk of persistence disease at 6 months and recurrence disease at 12 months compared to treatment with cryotherapy.


Integrating sphere port error in diffuse reflectance measurements.
The impact of a finite thickness integrating sphere port on the measurement of diffuse reflectance is addressed in a combined numerical and experimental study. It is shown that for a finite thickness port, additional light losses occur due to scattering between the sphere port wall and the test sample, causing the sample reflectance to be underestimated. Monte Carlo ray tracing is applied to obtain quantitative estimates of the resulting measurement error for the case of a diffusely reflecting sample. The effects of sample reflectance, port geometry, and illumination beam size on the measurement error are explored. Experimental data collected with a pair of integrating sphere reflectometers with different port geometries support the validity of the numerical results. It is argued that finite port thickness may be an important source of measurement error, even for a well-designed integrating sphere port, and a strategy for minimizing this error is discussed.


Evidence of intralocus recombination at the Glu-3 loci in bread wheat (Triticum aestivum L.).
Recombination at the Glu-3 loci was identified, and strong genetic linkage was observed only between the amplicons representing i-type and s-type genes located, respectively, at the Glu-A3 and Glu-B3 loci. The low-molecular weight glutenin subunits (LMW-GSs) are one of the major components of wheat seed storage proteins and play a critical role in the determination of wheat end-use quality. The genes encoding this class of proteins are located at the orthologous Glu-3 loci (Glu-A3, Glu-B3, and Glu-D3). Due to the complexity of these chromosomal regions and the high sequence similarity between different LMW-GS genes, their organization and recombination characteristics are still incompletely understood. This study examined intralocus recombination at the Glu-3 loci in two recombinant inbred line (RIL) and one doubled haploid (DH) population, all segregating for the Glu-A3, Glu-B3, and Glu-D3 loci. The analysis was conducted using a gene marker system that consists of the amplification of the complete set of the LMW-GS genes and their visualization by capillary electrophoresis. Recombinant marker haplotypes were detected in all three populations with different recombination rates depending on the locus and the population. No recombination was observed between the amplicons representing i-type and s-type LMW-GS genes located, respectively, at the Glu-A3 and Glu-B3 loci, indicating tight linkage between these genes. Results of this study contribute to better understanding the genetic linkage and recombination between different LMW-GS genes, the structure of the Glu-3 loci, and the development of more specific molecular markers that better represent the genetic diversity of these loci. In this way, a more precise analysis of the contribution of various LMW-GSs to end-use quality of wheat may be achieved.


Iterative structure-based improvement of a fusion-glycoprotein vaccine against RSV.
Structure-based design of vaccines, particularly the iterative optimization used so successfully in the structure-based design of drugs, has been a long-sought goal. We previously developed a first-generation vaccine antigen called DS-Cav1, comprising a prefusion-stabilized form of the fusion (F) glycoprotein, which elicits high-titer protective responses against respiratory syncytial virus (RSV) in mice and macaques. Here we report the improvement of DS-Cav1 through iterative cycles of structure-based design that significantly increased the titer of RSV-protective responses. The resultant second-generation 'DS2'-stabilized immunogens have their F subunits genetically linked, their fusion peptides deleted and their interprotomer movements stabilized by an additional disulfide bond. These DS2 immunogens are promising vaccine candidates with superior attributes, such as their lack of a requirement for furin cleavage and their increased antigenic stability against heat inactivation. The iterative structure-based improvement described here may have utility in the optimization of other vaccine antigens.


Haploinsufficient TNAP Mice Display Decreased Extracellular ATP Levels and Expression of Pannexin-1 Channels.
Hypophosphatasia (HPP) is a rare heritable metabolic bone disease caused by hypomorphic mutations in the ALPL (in human) or Akp2 (in mouse) gene, encoding the tissue-nonspecific alkaline phosphatase (TNAP) enzyme. In addition to skeletal and dental malformations, severe forms of HPP are also characterized by the presence of spontaneous seizures. Initially, these seizures were attributed to an impairment of GABAergic neurotransmission caused by altered vitamin B6 metabolism. However, recent work by our group using knockout mice null for TNAP (TNAP-/-), a well-described model of infantile HPP, has revealed a deregulation of purinergic signaling contributing to the seizure phenotype. In the present study, we report that adult heterozygous (TNAP+/-) transgenic mice with decreased TNAP activity in the brain are more susceptible to adenosine 5'-triphosphate (ATP)-induced seizures. Interestingly, when we analyzed the extracellular levels of ATP in the cerebrospinal fluid, we found that TNAP+/- mice present lower levels than control mice. To elucidate the underlying mechanism, we evaluated the expression levels of other ectonucleotidases, as well as different proteins involved in ATP release, such as pannexin, connexins, and vesicular nucleotide transporter. Among these, Pannexin-1 (Panx1) was the only one showing diminished levels in the brains of TNAP+/- mice. Altogether, these findings suggest that a physiological regulation of extracellular ATP levels and Panx1 changes may compensate for the reduced TNAP activity in this model of HPP.


Familial dysalbuminemic hyperthyroxinemia: cumulative experience in 29 consecutive patients.
The syndrome of familial dysalbuminemic hyperthyroxinemia (FDH), an inherited abnormality characterized by the presence of a variant serum albumin with preferential affinity for T4, is recognized with increasing frequency as a cause of elevated total and free T4 serum values in clinically euthyroid patients with normal TSH levels. Hyperthyroxinemia caused by this syndrome is occasionally confused with hyperthyroidism or thyroid hormone resistance syndromes, which may prompt unnecessary treatment. To better define the clinical and biochemical characteristics of patients with FDH, we undertook a retrospective analysis of the experience at our institution with this condition. We reviewed our cumulative experience in 29 consecutive patients with FDH diagnosed between 1970 and 1991. FDH was diagnosed in 18 males and 11 females (mean age, 42.7 years) on the basis of clinical euthyroidism, increased total T4 and increased/normal free T4 serum values, normal T3 and TSH serum values, increased T4 binding to serum albumin, and low/normal T4 binding to T4-binding globulin and serum prealbumin. Clinical thyroid examination revealed no abnormalities except for goitre in five patients, and the results of radioiodine uptake studies were normal. Patients with subsequently documented FDH were referred for evaluation of "unusual" findings on thyroid function tests or FDH was detected on routine thyroid function tests or identified on family screening. Euthyroid hyperthyroxinemia in combination with a family history compatible with FDH correctly suggested FDH in seven patients. Clinical euthyroidism in conjunction with a normal basal sensitive TSH value in a hyperthyroxinemic patient differentiates euthyroid hyperthyroxinemia from thyrotoxicosis, obviating unnecessary therapy. Detection of excessive thyroxine binding to serum albumin establishes the diagnosis of FDH and allows it to be differentiated from thyroid hormone resistance syndromes. After a diagnosis of FDH has been established, family screening is advisable. Hyperthyroxinemia in clinically euthyroid patients ("euthyroid hyperthyroxinemia") is recognized with increasing frequency and should prompt a careful diagnostic evaluation. The differential diagnosis of this condition may be difficult because it includes various common and unusual syndromes, including quantitative or qualitative changes in thyroid hormone-binding proteins, circulating antibodies against thyroid hormones, resistance to thyroid hormones, influences from drugs, and acute somatic or psychiatric illness (1). The recently recognized syndrome of familial dysalbuminemic hyperthyroxinemia (FDH), an inherited abnormality with autosomal dominant transmission, is characterized by the presence of a variant serum albumin with preferential affinity for T4 (2-4). Typically, FDH is detected incidentally or patients are referred to endocrinologists on the basis of "unusual" results on routine thyroid function testing, revealing consistently elevated total T4 and elevated or normal free T4 values in a clinically euthyroid patient with normal TSH levels (1,5). Unfortunately, hyperthyroxinemia due to FDH may be confused with hyperthyroidism or thyroid hormone resistance syndromes, prompting repeated unnecessary laboratory testing and possibly even inappropriate treatment (1,3,6,7). Herein, we describe the clinical and biochemical characteristics of 29 consecutive patients with documented FDH.


Family studies in melanoma: identification of the atypical mole syndrome (AMS) phenotype.
Thirteen families have been studied clinically as the basis for a linkage study of susceptibility to cutaneous melanoma. Previous studies have shown that a number of families with predisposition to melanoma have abnormal naevi, now known as the atypical mole syndrome (AMS) phenotype. Many groups performing linkage studies using families selected from geographical areas with higher rates of melanoma have concentrated on the diagnosis of melanoma to identify presumptive gene carriers. In the UK, in the absence of extended families with multiple cases of melanoma, we have attempted to identify gene carriers through the presence of the AMS phenotype. Previously the AMS phenotype has been poorly defined and so we have developed a scoring system to define the AMS in an attempt to allow for variation in expression among gene carriers. In this report, we document the clinical characteristics of all 13 families and the use of our scoring system. The pattern of inheritance within these selected families of the AMS phenotype with or without melanoma is consistent with a dominant gene.


Deep learning model for distinguishing Mayo endoscopic subscore 0 and 1 in patients with ulcerative colitis.
The aim of this study was to address the issue of differentiating between Mayo endoscopic subscore (MES) 0 and MES 1 using a deep learning model. A dataset of 492 ulcerative colitis (UC) patients who demonstrated MES improvement between January 2018 and December 2019 at Samsung Medical Center was utilized. Specifically, two representative images of the colon and rectum were selected from each patient, resulting in a total of 984 images for analysis. The deep learning model utilized in this study consisted of a convolutional neural network (CNN)-based encoder, with two auxiliary classifiers for the colon and rectum, as well as a final MES classifier that combined image features from both inputs. In the internal test, the model achieved an F1-score of 0.92, surpassing the performance of seven novice classifiers by an average margin of 0.11, and outperforming their consensus by 0.02. The area under the receiver operating characteristic curve (AUROC) was calculated to be 0.97 when considering MES 1 as positive, with an area under the precision-recall curve (AUPRC) of 0.98. In the external test using the Hyperkvasir dataset, the model achieved an F1-score of 0.89, AUROC of 0.86, and AUPRC of 0.97. The results demonstrate that the proposed CNN-based model, which integrates image features from both the colon and rectum, exhibits superior performance in accurately discriminating between MES 0 and MES 1 in patients with UC.


Are heat shock proteins therapeutic target for Parkinson's disease?
Heat shock proteins (HSPs), known as molecular chaperone to assist protein folding, have recently become a research focus in Parkinson's disease (PD) because the pathogenesis of this disease is highlighted by the intracellular protein misfolding and inclusion body formation. The present review will focus on the functions of different HSPs and their protective roles in PD. It is postulated that HSPs may serve as protein folding machinery and work together with ubiquitin-proteasome system (UPS) to assist in decomposing aberrant proteins. Failure of UPS is thought to play a key role in the pathogenesis of PD. In addition, HSPs may possess anti-apoptotic effects and keep the homeostasis of dopaminergic neurons against stress conditions. The critical role of HSPs and recent discovery of some novel HSPs inducers suggest that HSPs may be potential therapeutic targets for PD and other neurodegenerative disorders.


[Chemotherapy and psychotherapies. Attempt at integration].
After a brief historic reminder, the author reviews certain difficulties in integrating psychotherapeutic practice. These difficulties are within the global frame of association of techniques and therapists. Criticizing the bifocal tendency, the author justifies an integrated practice and conceptualisation in the area of severe mental disorders. Finally the author proposes elements of a general theory of psychotherapy permitting chemotherapy to find its place as an "armed psychotherapy" or "psychotherapy in reality".


From molecular diagnostics to personalized testing.
Gene-based molecular diagnostics is changing the practice of medicine and will continue to do so for the foreseeable future. The major underlying principle of these diagnostic tests is the use of specific nucleic acid sequences as surrogates; amplification of the surrogate markers enables the detection of pathogens or disease-related gene mutations. Gene targets can be amplified by target-, probe- or signal-based methods. Combined use of nucleic acid amplification and enzyme-linked immunosorbent assay with methods such as immuno-polymerase-chain reaction allows us to detect protein at femtogram (10(15) g) levels. A variety of choices are available for the detection of amplified amplicons with the fluorophore-linked nanoparticles as the most sensitive markers. The unique advantages of using covalently-linked nanoparticles include the detection of single molecules, the ability to enrich molecules of interest with unprecedented detection sensitivity (up to zeptogram levels, 10(21) g) and the flexibility of multiple functionalization. Automation appears to be the current trend for high-volume molecular testing of infectious diseases. Molecular profiling of various diseases using genomic or proteomic approaches opens up a molecule wonderland with promise and emergence of new molecular testing that will likely impact the practice of medicine to a greater degree in the future. The future of molecular-based testing and the journey toward personalized testing will be discussed.


Short-term outcomes of laparoscopic total gastrectomy for gastric cancer: a comparative study with laparoscopic distal gastrectomy at a high-volume center.
Laparoscopic distal gastrectomy (LDG) for gastric cancer has gradually gained popularity. However, laparoscopic total gastrectomy (LTG) has been reported rarely when compared with LDG. This study was designed to evaluate the surgical outcomes as well as the morbidity and mortality of LTG compared with LDG to confirm the feasibility and safety of LTG. We reviewed the data of patients at our institution undergoing LTG (n = 448) or LDG (n = 956) for gastric cancer between January 2008 and July 2016. Then the clinical characteristics and perioperative clinical outcomes of the two groups were compared. Except for tumor size and stage, there were no statistically significant differences in the clinicopathological parameters between the groups. LTG was associated with significantly longer operation time, late time to postoperative diet, and longer hospital stay compared with the LDG group. Overall complications developed in 60 patients (13.4%) and surgical complications in 48 patients (10.7%) after LTG. Postoperative complications were less frequent in the LDG group than in the LTG group (8.4% versus 13.4%, p < .01), and fewer surgical complications were observed with LDG than with LTG (7.5% versus 10.7%, p = .05). The results of LTG were favorable even though are not inferior to those of LDG. LTG for gastric cancer is technically feasible and safe. However, because of the limits of this study, other high-quality studies are needed for further evaluation.


A survey of the safety of doctors driving home after a night 'on call'.
The 'on-call' system for doctors within the health service maintains a continuity of care. However, allowing doctors to drive home after a night on call may pose a public hazard. The aim of this survey was to assess doctors' opinions regarding the safety of driving without adequate sleep.


Chemical kinetic mechanisms and scaling of two-dimensional polymers via irreversible solution-phase reactions.
Two-dimensional (2D) polymers are extended networks of multi-functional repeating units that are covalently linked together but confined to a single plane. The past decade has witnessed a surge in interest and effort toward producing and utilizing 2D polymers. However, facile synthesis schemes suitable for mass production are yet to be realized. In addition, unifying theories to describe the 2D polymerization process, such as those for linear polymers, have not yet been established. Herein, we perform a chemical kinetic simulation to study the recent synthesis of 2D polymers in homogeneous solution with irreversible chemistry. We show that reaction sites for polymerization in 2D always scale unfavorably compared to 3D, growing as molecular weight to the 1/2 power vs 2/3 power for 3D. However, certain mechanisms can effectively suppress out-of-plane defect formation and subsequent 3D growth. We consider two such mechanisms, which we call bond-planarity and templated autocatalysis. In the first, although single bonds can easily rotate out-of-plane to render polymerization in 3D, some double-bond linkages prefer a planar configuration. In the second mechanism, stacked 2D plates may act as van der Waals templates for each other to enhance growth, which leads to an autocatalysis. When linkage reactions possess a 1000:1 selectivity (γ) for staying in plane vs rotating, solution-synthesized 2D polymers can have comparable size and yield with those synthesized from confined polymerization on a surface. Autocatalysis could achieve similar effects when self-templating accelerates 2D growth by a factor β of 106. A combined strategy relaxes the requirement of both mechanisms by over one order of magnitude. We map the dependence of molecular weight and yield for the 2D polymer on the reaction parameters, allowing experimental results to be used to estimate β and γ. Our calculations show for the first time from theory the feasibility of producing two-dimensional polymers from irreversible polymerization in solution.


Chuan Huang Fang combining reduced glutathione in treating acute kidney injury (grades 1-2) on chronic kidney disease (stages 2-4): A multicenter randomized controlled clinical trial.
Lack of effective drugs for acute kidney injury (AKI) grades 1-2 is a crucial challenge in clinic. Our previously single-center clinical studies indicated Chuan Huang Fang (CHF) might have nephroprotection in AKI on chronic kidney disease (CKD) (A on C) patients by preventing oxidant damage and inhibiting inflammation. Reduced glutathione (RG) has recently been shown to increase the clinical effectiveness of high-flux hemodialysis among patients with severe AKI. In this multicenter randomized controlled clinical study, we designed a new protocol to assess the efficacy and safety of CHF combining RG in patients with A on C. We also explored therapeutic mechanisms from renal fibrosis biomarkers. 98 participants were randomly and equally divided into the RG and RG + CHF subgroups. The RG and RG + CHF groups received general treatments with RG and a combination of RG and CHF, respectively. The therapy lasted for 2 weeks. In this study, the primary assessment result was a difference in the slope of serum creatinine (Scr) over the course of 2 weeks. The secondary evaluation outcomes were alterations in blood urea nitrogen (BUN), uric acid (UA), estimated glomerular filtration rate (eGFR), urinary AKI biomarkers, renal fibrosis biomarkers (transforming growth factor-β 1 (TGF-β 1), connective tissue growth factor (CTGF)), and traditional Chinese medicine (TCM) symptoms. Furthermore, vital signs and adverse events (AEs) were observed. Both groups had a slower renal function decline after treatment than before treatment. Compared with RG group, more reductions of Scr, BUN, UA, and better improvement of eGFR were observed in RG + CHF group (p < 0.05). Additionally, the levels of urinary AKI biomarkers, renal fibrosis biomarkers, and TCM syndromes were decreased in RG + CHF group versus RG group (p < 0.05). No significant between-group differences were observed of AEs. We thus concluded this novel therapy of CHF combining RG might be a useful method for treating A on C patients.


Diabetic retinopathy.
The focus of this article is to discuss the care given to an elderly lady, Mrs Pitt, (a pseudonym) who is suffering from Diabetic Retinopathy (DR) and attending our Out Patient Department (OPD). It will start with a brief description of diabetes and the associated complications, and then give a more in-depth description of DR and the relevant anatomy and physiology. It will then give details of Mrs Pitt's history and her current care and treatment. All information will be supported by current, relevant literature.


Sodium chloride transport across the chicken coprodeum. Basic characteristics and dependence on sodium chloride intake.
1. The transport characteristics of the chicken coprodeum have been examined in vitro using the isolated mucosa. The short-circuit current (I(sc)), the transepithelial electrical potential difference (p.d.), the unidirectional transmural fluxes (J(ms), J(sm)) of sodium and chloride measured in the short-circuited state, and the unidirectional influx of sodium and chloride across the brush border membrane measured under open-circuit conditions have been studied. The effect of the sodium chloride contents of the diet on these parameters have been investigated.2. The isolated mucosa depends functionally on the presence of glucose in the incubation media. This dependence reflects the need of glucose as a fuel. There is no indication of coupling between transport of sugars and sodium across the brush border membrane. For preparations from chickens on a low sodium diet a very high and stable I(sc) can quantitatively be accounted for by the net transport of sodium. Influx of sodium across the brush border membrane is not significantly different from the net flux of sodium. By feeding the chickens a high sodium diet the I(sc) is reduced by more than 95%, the net transport of sodium is abolished, and the transepithelial electrical conductance is reduced by more than 50%.3. Both unidirectional transepithelial fluxes of chloride, and the serosa to mucosa flux of sodium appear to proceed through a paracellular shunt.4. Under the conditions of the low sodium diet the paracellular pathway appears to be anion selective. Whereas, under the conditions of the high sodium regimen the paracellular route appears to be cation selective. After adaptation to a high sodium diet the influx of sodium across the brush border membrane is only moderately reduced. Consequently the decisive event in the adaptation must be localized elsewhere.


Long-term Site Fidelity and Individual Home Range Shifts in Lophocebus albigena.
We investigated long-term site fidelity of gray-cheeked mangabey (Lophocebus albigena) groups in Kibale National Park, Uganda. Concurrently, we monitored shifts in home range by individual females and subadult and adult males. We documented home range stability by calculating the area of overlap in successive years, and by recording the drift of each group's monthly centroid from its initial location. Home ranges remained stable for 3 of our 4 groups (overlap over 10 yr >60%). Core areas were more labile, but group centroids drifted an average of only 530 m over the entire decade. Deviations from site fidelity were associated with dispersal or group fission. During natal dispersal, subadult males expanded their home ranges over many months, settling </=4 home ranges away. Adult males, in contrast, typically dispersed within a few days to an adjacent group in an area of home range overlap. Adult males made solitary forays, but nearly always into areas used by their current group or by a group to which they had previously belonged. After secondary dispersal, they expanded their ranging in the company of their new group, apparently without prior solitary exploration of the new area. Some females also participated in home range shifts. Females shifted home ranges only within social groups, in association with temporary or permanent group splits. Our observations raise the possibility that male mangabeys use a finder-joiner mechanism when moving into new home ranges during secondary dispersal. Similarly, females might learn new resource locations from male immigrants before or during group fission.


Splanchnic glucose balance and insulin resistance in the early postoperative phase of cardiac surgery.
The splanchnic balance of glucose was studied in the basal state and at three levels of "clamped" hyperinsulinemia (260 +/- 23, 510 +/- 59, 3875 +/- 367 mU/liter) in 24 patients (43-70 years of age), who had undergone coronary surgery about 1 hr previously. The splanchnic balance of glucose in the basal state was negative in all patients (-1.6 +/- 0.3 mg/kg/min) and was changed into a zero-balance within 30 min when 0.15 or 0.3 U/kg/hr of insulin was infused. At an insulin infusion rate of 1.0 U/kg/hr the net splanchnic glucose balance was turned into a significant positive balance of an average 0.9 +/- 0.3 mg/kg/min.


[Correction of nose deviations using latero-septal grafts from irradiated bovine cartilage].
Deviated noses corrective surgery is not without problems. Authors give the result obtained by the use of processed irradiated bovine cartilage (Chondroplast) as spreader graft in eighteen rhinoplasty, associated with a classical septorhinoplasty technique. The maximum background is five years. The future of the grafts can be appreciated on direct signs obtained by palpation, or indirect ones such as stability of the functional or aesthetic result, radiological visualisation of the bovine cartilage graft. Their volumetric stability is satisfactory and their guide role is excellent. This undisputed aid in the aesthetic and functional correction of deviated noses, associated with availability, easy use and a good tolerance, made the authors use spreader grafts in processed irradiated bovine cartilage as a choice technique in this indication, associated with bone and septal surgery, when local cartilage autografts are not available in sufficient quantities.


Carbon Dioxide in a Supported Ionic Liquid Membrane: Structural and Rotational Dynamics Measured with 2D IR and Pump-Probe Experiments.
Supported ionic liquid membranes (SILMs) are porous membranes impregnated with ionic liquids (ILs) and used as advanced carbon capture materials. Here, two-dimensional infrared (2D IR) and IR polarization selective pump-probe (PSPP) spectroscopies were used to investigate CO2 reorientation and spectral diffusion dynamics in SILMs. The SILM contained 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonly)imide in the poly(ether sulfone) membrane with average pore size of ∼350 nm. Two ensembles of CO2 were observed in the SILM, one in the IL phase in the membrane pores and the other in the supporting membrane polymer. CO2 in the polymer displayed a red-shifted IR absorption spectrum and a shorter vibrational lifetime of the asymmetric stretch mode compared to the IL phase. Despite the relatively large pore sizes, the complete orientational randomization of CO2 and structural fluctuations of the IL (spectral diffusion) in the pores are slower than in the bulk IL by ∼2-fold. The implication is that the IL structural change induced by the polymer interface can propagate out from the interface more than a hundred nanometers, influencing the dynamics. The dynamics in the polymer are even slower. This study demonstrates that there are significant differences in the dynamics of ILs in SILMs on a molecular level compared to the bulk IL, and the study of dynamics in SILMs can provide important information for the design of SILMs for CO2 capture.


Evaluation of magnetic resonance imaging-detected tenosynovitis in the hand and wrist in early arthritis.
Magnetic resonance imaging (MRI) is a sensitive method to detect inflammation in rheumatoid arthritis (RA), visualizing synovitis, bone marrow edema, and tenosynovitis. The prevalence of MRI-detected tenosynovitis and its diagnostic value in early arthritis are unclear. This study was undertaken to identify the frequency of MRI-detectable tenosynovitis at the metacarpophalangeal (MCP) and wrist joints in early arthritis and the association of these with RA and the severity of RA. A total of 178 patients with early arthritis underwent unilateral 1.5T extremity MRI at baseline. The MCP and wrist joints were scored using the Rheumatoid Arthritis Magnetic Resonance Imaging Scoring system and Haavardsholm's tenosynovitis score. Sixty-nine patients fulfilled the American College of Rheumatology/European League Against Rheumatism 2010 classification criteria for RA during the first year and were compared with the non-RA patients. Among the RA patients, comparisons were made with regard to anti-citrullinated protein antibody (ACPA) positivity and radiographic progression during year 1. Of all patients, 65% had MRI-detected tenosynovitis. RA patients had tenosynovitis more often than non-RA patients (75% versus 59%; P = 0.023). The flexor tendons at MCP5 and the extensor tendons at MCP2 and MCP4 and in extensor compartment I of the wrist were more frequently affected in RA patients than in other patients (odds ratios 2.8 [95% confidence interval (95% CI) 1.2-7.0], 9.1 [95% CI 1.9-42.8], 14.2 [95% CI 1.7-115.9], and 4.0 [95% CI 1.4-11.1], respectively). These associations were independent of local MRI synovitis. Specificities were all ≥82%. Within the group of RA patients, tenosynovitis scores were not associated with ACPA positivity or radiographic progression. MRI-detected tenosynovitis is commonly seen in early arthritis. The flexor tendons at MCP5, the extensor tendons at MCP2 and MCP4, and the first extensor compartment of the wrist are more often affected in RA, independent of local synovitis.


Pulsatile venoarterial perfusion using a novel synchronized cardiac assist device augments coronary artery blood flow during ventricular fibrillation.
Patients with cardiogenic shock have a very high mortality. Here we report the first use of a percutaneous pulsatile cardiac assist device, based on a diagonal pump synchronized with the heart cycle by means of an electrocardiographic signal in adult pigs. Eight domestic pigs underwent mandatory ventilation. During sinus rhythm, there were no differences between pulsatile and nonpulsatile perfusion with regard to pulmonary artery pressure, pulmonary wedge pressure, central venous pressure, mean arterial pressure (MAP), mean pulse pressure, and mean coronary artery flow (CAF). After 2 min of complete cardiac arrest (ventricular fibrillation), circulatory support with the i-cor in venoarterial nonpulsatile extracorporeal membrane oxygenation (ECMO) mode (3 L/min) restored systemic circulation, with an increase of MAP to 78.3 mm Hg and CAF to 5.27 mL/min. After changing from ECMO settings to pulsatile mode (3 L/min, 75 bpm, pulse amplitude range 3500 rpm), MAP did not change significantly (75.6 mm Hg); however, CAF increased to 8.45 mL/min. After changing back to nonpulsatile mode, MAP remained stable (83.6 mm Hg), but CAF decreased to 4.85 mL/min. Thereafter, pulsatile cardiac assist was established with a reduced blood flow of 2.5 L/min, and the pulse amplitude range was extended to 4500 rpm. Under these conditions, MAP remained stable (71.0 mm Hg), but CAF significantly increased to 15.2 mL/min (P < 0.05). Percutaneous cardiac support using a venoarterial cardiac assist device equipped with a novel diagonal pump is able to restore and increase systemic and coronary circulation during ventricular fibrillation. Electrocardiographically triggered synchronized cardiac assist provides an additional increase of coronary artery flow. These promising results are to be confirmed in humans.


Differentiation induced increase of platelet-activating factor acetylhydrolase in HL-60 cells.
Platelet-activating factor (PAF) acetylhydrolase catalyzes the conversion of PAF to lyso-PAF and acetate. In this study we show that induced cellular differentiation of HL-60 cells grown in chemically defined media by dimethylsulfoxide (DMSO) to granulocytic cells increases the acetylhydrolase activity with a concomitant increased secretion of the enzyme into the media. This increase in acetylhydrolase activity is blocked by the presence of actinomycin D (1 microM) or cycloheximide (1-2 microM) in the culture media. Acetylhydrolase is located both in the cytosolic and particulate fractions; the relative distribution of acetylhydrolase activity in the particulate fraction and cytosol increases and decreases respectively, as the differentiation progresses. The addition of an intracellular protein transport inhibitor, monensin, causes further accumulation of acetylhydrolase activity in the particulate fraction and a decrease in the media, with no effect on the acetylhydrolase activity in the cytosol. Acetylhydrolase in differentiated HL-60 cells acquires properties similar to those of the plasma acetylhydrolase in that it becomes less sensitive to 5,5'-dithiobis-2-nitrobenzoic acid and p-bromophenacylbromide inhibition than the acetylhydrolase in undifferentiated cells. The acetylhydrolase secreted into the media by the differentiated cells was almost totally insensitive to these inhibitors, whereas the acetylhydrolase from the particulate fraction gave an intermediate response; the cytosolic acetylhydrolase was sensitive to both inhibitors. However, the acetylhydrolase secreted by differentiated HL-60 cells has a different electrophoretic mobility, temperature sensitivity, and association with lipoproteins when compared to that of human plasma acetylhydrolase. Collectively, these results indicate cellular differentiation induces intracellular acetylhydrolase activity through a mechanism involving both transcriptional and translational events. Furthermore, the acetylhydrolase synthesized during the DMSO-induced differentiation of HL-60 cells is then secreted into the media via the intracellular membrane transport system for proteins. Based on results obtained with HL-60 cells as a cell model, it is likely that more than one isoform of acetylhydrolase exists in the extracellular milieu.


Prenatal diagnosis of cystic adenomatoid malformation of the lung.
Cystic adenomatoid malformation of the lung (CAM) is an uncommon malformation in which normal tissue is replaced by cysts of various sizes. This malformation may be diagnosed prenatally with ultrasound by visualization of cystic masses in the fetal chest, which may occur in association with fetal hydrops. Three cases of fetal hydrops secondary to cystic adenomatoid malformation of the lung are described; in one case cystic lesions in the chest were clearly demonstrated.


Camera perspective bias in videotaped confessions: evidence that visual attention is a mediator.
Several experiments have demonstrated a camera perspective bias in evaluations of videotaped confessions: videotapes with the camera focused on the suspect lead to judgments of greater voluntariness than alternative presentation formats. The present research investigated potential mediators of this bias. Using eye tracking to measure visual attention, Experiment 1 replicated the bias and revealed that changes in camera perspective are accompanied by corresponding changes in duration of fixation on the suspect and interrogator. A path analysis indicated that visual attention partially mediated the bias, with at least one additional factor independently contributing to it. A proposed second factor was changes in available visual content that naturally coincide with alterations in camera perspective. Experiment 2 directly manipulated observers' focus and thus more conclusively established visual attention as one mediator of the camera perspective bias. Together the two experiments provide plausible evidence that differences in visual content may also mediate the bias.


Optical imaging of metastatic tumors using a folate-targeted fluorescent probe.
We describe the use of a tumor targeting ligand, the vitamin folic acid, to deliver an attached fluorescent probe to both primary and metastatic tumors overexpressing the folate receptor. Upon laser excitation, derived images of normal tissues generally show little or no fluorescence, whereas images of folate receptor-expressing tumors display bright fluorescence that can be easily distinguished from adjacent normal tissue. Furthermore, metastatic tumor loci of submillimeter size can also be visualized without the aid of image processing or enhancement. The sharp distinction between tumor and normal tissues provided by this technique could find application in the localization and resection of tumor tissue during surgery or in the enhanced endoscopic detection and staging of cancers.


Correction: From FOX-7 to H-FOX to insensitive energetic materials with hypergolic properties.
Correction for 'From FOX-7 to H-FOX to insensitive energetic materials with hypergolic properties' by Dharavath Srinivas et al., Chem. Commun., 2016, 52, 7668-7671.


The development of an educational checklist for individuals with CHARGE syndrome.
CHARGE syndrome is a rare genetic disorder which can impact every sensory system and is often associated with significant medical, communicative, developmental, and behavioral difficulties. Due to the rarity and complexity of CHARGE syndrome, educators often lack the expertise required to effectively understand and accommodate the needs of these students. Therefore, an educational checklist (i.e. "Checklist") was developed to provide a comprehensive tool that educators and related professionals can utilize to aid in the education of individuals with CHARGE syndrome. The Checklist was developed through collaboration with an international panel of experts; CHARGE Syndrome Research Lab at Central Michigan University (CMU); and a select group consisting of parents, professionals, and state deafblind project employees. The Checklist outlines major CHARGE characteristics, resulting educational needs, team members, consulting professionals, and suggested methods of accommodation. The Checklist may be utilized to develop and inform services for individuals with CHARGE syndrome in the schools.


Limiting artifact in CT stereotaxic periventricular procedures. Technical note.
One potential source of computerized tomography image artifact during stereotaxic data acquisition is scatter from standard steel-tipped fixation pins as supplied for use with the Brown-Roberts-Wells stereotaxic headframe. In some cases, this can hinder selection of periventricular targets. Replacement of the steel-tipped pins with aluminum-tipped pins, which produce less artifact, helps to facilitate stereotaxic intervention.


[A case report of sarcomatoid carcinoma of the bladder with metastasis to small intestine].
A 67-year-old male presented to our clinic with gross hematuria. Cystoscopic examination revealed a broad-based tumor of 2.5 cm in diameter on the lateral side of the right ureteral orifice. Under the clinical diagnosis of TCC G2 > G3, T3bNOM0, radical cystectomy with orthotopic bladder substitution was performed. Pathological diagnosis was TCC G3 with sarcomatoid carcinoma, pT2pR0pL1 pVlpN0. Adjuvant chemotherapy was not performed because of his transient poor conditions. Lung metastasis was observed 6 months postoperatively. Despite of M-VAC therapy and radiation therapy, additional metastases to brain and liver were observed. One month later, partial ileectomy specimen for occlusive ileum revealed the same histologic findings, TCC G3 with sarcomatoid carcinoma. He died 9 months postoperatively. To our knowledge, this is the first case of sarcomatoid carcinoma of the bladder with metastasis to small intestine, although 6 cases of transitional cell carcinoma of the bladder with metastasis to small intestine has been reported in Japan.


[Effect of arachidonic acid cytochrome P450ω hydroxylase Cyp4a14 gene knockout on skeletal muscle regeneration after injury].
The objective of this study was to explore the roles of arachidonic acid cytochrome P450ω hydroxylase CYP4A14 in skeletal muscle regeneration after injury. Wild-type (WT) control mice and Cyp4a14 knockout (A14-/-) mice were used to establish the muscle injury and regeneration model by intramuscular injection with cardiotoxin (CTX) on the tibial anterior (TA) muscle. The TA muscles were harvested at the time points of 0, 3, 5 and 15 days after injury. The changes in skeletal muscle regeneration and fibrosis were assessed by wheat germ agglutinin (WGA) staining and Sirius Red staining. Immunohistochemical staining was used to observe the expression of proliferation-related protein Ki-67 and macrophage marker protein Mac-2. The mRNA levels of regeneration and inflammation associated genes were analyzed by real-time PCR. The results showed that the cross-section area (CSA) of regenerated myofibers in A14-/- mice was significantly smaller (P < 0.05), while the percentage of fibrosis area was significantly higher than those in WT mice at 15 days after injury (P < 0.05). In A14-/- muscles, both the ratio of Ki-67 positive proliferating cells and the mRNA levels of differentiation associated genes Myod1 and Myog were significantly lower than those in WT muscles (P < 0.05). At 3 days after injury, the mRNA expression of inflammatory cells marker genes CD45 and CD11b and Mac-2 positive macrophages in A14-/- muscles were significantly lower than those in WT skeletal muscle (P < 0.05). Macrophages derived pro-regeneration cytokines IL-1β, IGF-1 and SDF-1 were also significantly decreased in A14-/- muscles (P < 0.05). These results suggest that arachidonic acid cytochrome P450ω hydroxylase CYP4A14 plays a critical role in skeletal muscle regeneration after injury.


If it's not there, where is it? Locating illusory conjunctions.
There is evidence that complex objects are decomposed by the visual system into features, such as shape and color. Consistent with this theory is the phenomenon of illusory conjunctions, which occur when features are incorrectly combined to form an illusory object. We analyzed the perceived location of illusory conjunctions to study the roles of color and shape in the location of visual objects. In Experiments 1 and 2, participants located illusory conjunctions about halfway between the veridical locations of the component features. Experiment 3 showed that the distribution of perceived locations was not the mixture of two distributions centered at the 2 feature locations. Experiment 4 replicated these results with an identification task rather than a detection task. We concluded that the locations of illusory conjunctions were not arbitrary but were determined by both constituent shape and color.


[Dishen Qufeng Decoction for treating allergic rhinitis: a randomized controlled trial].
To observe the clinical therapeutic effects of Dishen Qufeng Decoction (DSQFD), a compound traditional Chinese herbal medicine, in treatment of allergic rhinitis. Sixty cases of allergic rhinitis were selected and randomized into DSQFD group (30 cases) and cetirizine group (30 cases), and the patients were orally administered DSQFD and cetirizine respectively. The integrals of patients' symptoms, such as sneezing, nose running, nasal occlusion and nasal itching, signs in the nasal conchae and peripheral blood eosinophil (EOS) count were abserved count before and after treatment. DSQFD obviously improved the symptoms and signs of allergic rhinitis. The total response rate of DSQFD treatment was 83.3%, while that of the cetirizine treatment was 86.7%; the EOS counts in both groups were significantly decreased. These results showed statistical difference between the two groups. DSQFD is an effective preparation of traditional Chinese medicine for treating allergic rhinitis.


S-peptide epitope tagging for protein purification, expression monitoring, and localization in mammalian cells.
Epitope tags are widely used in cell biology and biochemistry research. The S-peptide/S-protein interaction has previously been utilized to purify polypeptides expressed in bacteria. We have now re-engineered the S-peptide/S-protein system to allow isolation of S-peptide-tagged polypeptides and their binding partners from eukaryotic cells with S-protein-agarose. In addition, two anti-S-peptide monoclonal antibodies have been generated for analysis of expression and subcellular localization of S-peptide-tagged polypeptides. These reagents make the S-peptide/S-protein system an attractive alternative to currently available epitope tagging methods.


Health and autonomy.
Individual autonomy is a prominent value in Western medicine and medical ethics, and there it is often accepted that the only way to pay proper respect to autonomy is to let the patients themselves determine what is good for them. Adopting this approach has, however, given rise to some unwanted results, thus motivating a quest for an objective conception of health. Unfortunately, the purportedly objective conceptions of health have failed in objectivity, and if a conception of health is not acceptable for all agents, the threat of offending the patients' autonomy arises. This article sketches an objective conception of health that is able to respect individual autonomy.


Understanding patch departure rules for large carnivores: lion movements support a patch-disturbance hypothesis.
We test two hypotheses that could account for patch departure by large mammalian carnivores. One hypothesis is the unsuccessful-hunt hypothesis, where carnivores leave an area after an unsuccessful hunt but continue hunting in the same area after a successful hunt. The second hypothesis is the patch-disturbance hypothesis, where carnivores depart the area after a successful hunt because of behavioral responses of prey to predator presence. We used global positioning system collars to monitor the movements of African lions (Panthera leo) and identified their kill sites to distinguish between these two hypotheses. Lions moved to a different area (≥ 5 km away) after 87% of the kills, which supports the patch-disturbance hypothesis for patch-departure behavior of large mammalian carnivores.


Pleiotropic effects of ARB on dyslipidemia.
Angiotensin II type 1 (AT1) receptor blockers (ARBs), widely used in the treatment of hypertension, have cardiovascular, cerebral, and renal protective effects beyond blood pressure control. In addition to direct end-organ protection, some ARBs have been suggested to improve abnormalities of glucose and lipid metabolisms, resulting in an anti-atherosclerotic effect in patients with hypertension. In several clinical trials, the effects of ARBs on lipid metabolism have been emerged, although the effects are heterogeneous. Certain subgroups of ARBs such as telmisartan have been identified as partial agonists for the peroxisome proliferators activated receptor (PPAR)-γ, and thus, this class of ARBs has been mostly focused on their effects on lipid metabolism. Based on the pleiotropic effects on lipid metabolism, we can envision that ARBs would provide the promising outcome for hypertensive patients aggregating metabolic risk factors, including dyslipidemia.


[Behavioral effects of thyroliberin on animals of various species].
It has been shown that there are some significant differences in behavioural effects of exogenous thyroliberin for different mammals (mice, rats, dogs, monkeys). The necessity of a careful preclinical trial of peptide drugs is discussed.


Survey findings on dental fees. A comparison from 1982-93.
The cost of health care services, including dental services, continues to rise at a rate higher than the prices of all goods and services included in the CPI for urban consumers. Increases for physician services, medical care and hospital room rates exceed those for dental care. Dentists generally do not raise their fees across-the-board, but vary increases from procedure to procedure. Increases for certain common dental procedures and services were close to the CPI for consumer goods and services. Fees for such basic preventive and diagnostic procedures--including oral exams, prophylaxes and X-rays--increased at rates well below the overall CPI for dental services.


Effects of sugars and vitamin B-6 deficiency on oxalate synthesis in rats.
Rats fed diets containing galactose as the source of carbohydrate excreted greater amounts of endogenously formed oxalic acid in their urine, compared to rats fed glucose, fructose or sucrose. Rats fed lactose showed similar but less marked effects. The greatest amounts of urinary and fecal oxalate excretions were observed among rats fed galactose and no vitamin B-6. This group had the lowest body weights after 3 weeks of feeding. Control rats fed galactose or lactose diets weighed less than those fed sucrose, glucose or fructose diets. All rats fed galactose developed cataracts. More [14C]oxalic acid was recovered in the urine and kidneys of control rats injected with D-[U-14C]galactose compared to those injected with D-[U-14C]glucose or D-[U-14C]fructose. Similar results were observed in kidneys of vitamin B-6-deficient rats. The possible mechanisms by which galactose and other sugars may be converted to oxalate are discussed.


Study of Lethal Congenital Malformations at a Tertiary-Care Referral Centre in North India.
Lethal congenital malformations (LCMs) are fatal birth defects that are an important cause of fetal/neonatal death. There is a lack of informative data about these malformations in India, a country that shares the maximum burden of neonatal mortality due to congenital birth defects. Therefore, we conducted a retrospective analysis to know the prevalence of LCMs in late pregnancy, to find out associated factor/variables and to evaluate fetal/neonatal outcome of such anomalies; at a tertiary-care referral centre in North India. All deliveries with LCMs after 24 weeks of gestation were included in the study. Data about antepartum history (maternal age, parity, education, socioeconomic status, consanguineous marriage, folic acid intake, any chronic medical disorder, availability of anomaly scan, unplanned pregnancy); intrapartum events (gestational age at delivery, mode of delivery); postpartum events (weight of the baby, gender of the baby); newborn evaluation; and details of hospital stay were recorded from medical record sheet over the duration of one year. We found that anencephaly, severe meningomyelocele, multicystic dysplastic kidneys and non-immune hydrops with major cardiac defects were more prevalent among all LCMs. On the evaluation of the various studied variables, maximum babies with LCMs were born to mothers who were between 20 and 35 years of age, those who were illiterate, belonged to middle/lower socio-economic class, multigravida, and those who had no detailed anomaly scan. We feel that there is an urgent need to formulate a universally accepted definition of LCMs, to identify preventable risk factors and to formulate management strategy for both mother and liveborn baby with LCMs, in order to minimize the hidden burden of these defects in stillbirth/ perinatal/ neonatal mortality statistics.


Ubiquitous coexisting electron-mode couplings in high-temperature cuprate superconductors.
In conventional superconductors, electron-phonon coupling plays a dominant role in generating superconductivity. In high-temperature cuprate superconductors, the existence of electron coupling with phonons and other boson modes and its role in producing high-temperature superconductivity remain unclear. The evidence of electron-boson coupling mainly comes from angle-resolved photoemission (ARPES) observations of [Formula: see text]70-meV nodal dispersion kink and [Formula: see text]40-meV antinodal kink. However, the reported results are sporadic and the nature of the involved bosons is still under debate. Here we report findings of ubiquitous two coexisting electron-mode couplings in cuprate superconductors. By taking ultrahigh-resolution laser-based ARPES measurements, we found that the electrons are coupled simultaneously with two sharp modes at [Formula: see text]70meV and [Formula: see text]40meV in different superconductors with different dopings, over the entire momentum space and at different temperatures above and below the superconducting transition temperature. These observations favor phonons as the origin of the modes coupled with electrons and the observed electron-mode couplings are unusual because the associated energy scales do not exhibit an obvious energy shift across the superconducting transition. We further find that the well-known "peak-dip-hump" structure, which has long been considered a hallmark of superconductivity, is also omnipresent and consists of "peak-double dip-double hump" finer structures that originate from electron coupling with two sharp modes. These results provide a unified picture for the [Formula: see text]70-meV and [Formula: see text]40-meV energy scales and their evolutions with momentum, doping and temperature. They provide key information to understand the origin of these energy scales and their role in generating anomalous normal state and high-temperature superconductivity.


The osteoprotegerin/RANK/RANKL system: a bone key to vascular disease.
Owing to the common coincidence of osteoporosis and vascular disease, pathophysiological links between both disorders have long been sought. The osteoprotegerin (OPG)/receptor activator of NF-kappaB (RANK)/receptor activator of NF-kappaB ligand (RANKL) cytokine network, a key regulatory system in bone homeostasis, has been implicated recently in vascular calcification, changes in matrix composition and diabetic macroangiopathy, aortic aneurysm development, heart failure and, most importantly, advanced atherosclerosis, plaque destabilization and manifestation of cardiovascular diseases. The concept of an active role of RANKL and OPG in vascular pathophysiology is intriguing and is gaining increasing support from both epidemiological and basic research. OPG serum level is considered to be a stable and reliable indicator of the overall activity of the OPG/RANK/RANKL axis and may find application as a biomarker of vascular risk and prognosis. RANKL in turn may be a suitable target for novel therapies. Pharmacological strategies for specific interference with the OPG/RANK/RANKL axis are currently being developed and evaluated in osteoporosis therapy.


Liver Safety of Statins in Prediabetes or T2DM and Nonalcoholic Steatohepatitis: Post Hoc Analysis of a Randomized Trial.
Patients with nonalcoholic fatty liver disease have a high cardiovascular risk, but statins are rarely prescribed because of fear of hepatotoxicity. To prospectively assess the long-term safety of statins in patients with prediabetes/type 2 diabetes mellitus (T2DM) and nonalcoholic steatohepatitis (NASH). Post hoc analysis of statin use during a randomized, controlled trial assessing pioglitazone vs placebo for NASH. A total of 101 patients (86 receiving statins) with biopsy-proven NASH and prediabetes/T2DM were followed for up to 36 months. Oral glucose tolerance test and percutaneous liver biopsy (baseline, month 18, and month 36); liver magnetic resonance spectroscopy and euglycemic insulin clamp (baseline and month 18). Histologic and biochemical safety of statin use among patients with NASH. Only 37% of patients were receiving statins at enrollment despite their high cardiovascular risk. Statin nonusers had higher plasma alanine aminotransferase levels but similar histologic severity of liver disease at baseline. In both statin users and nonusers, the same number of patients (n = 4) had a twofold or greater increase in plasma aminotransferases during follow-up. One statin nonuser was discontinued from the study because of this elevation. Values returned to normal without any active measure in all other cases. No changes on liver histology or hepatic insulin resistance were observed in patients with NASH newly started on a statin and receiving placebo during the main study. Statin therapy is safe in patients with prediabetes/T2DM and NASH. Given their high cardiovascular risk, statin therapy should be encouraged in this population.


Pathophysiology of coronary vascular remodeling: relationship with traditional risk factors for coronary artery disease.
The relationship between cardiovascular risk factors and vascular remodeling is a relatively new area of investigation. We discuss the various mechanisms by which cardiovascular risk factors cause vascular remodeling. Endothelial dysfunction, lipoprotein alterations, inflammation, and platelet activation are the mechanisms by which remodeling occurs. Plaque composition also plays an important role in directing remodeling. Plaque with extensive calcification is more likely to undergo constrictive remodeling. Positive and negative remodeling is based on how these factors coordinate and determine the direction of remodeling. Matrix metalloproteinases perform a crucial role in vascular remodeling. Advanced glycation end-products are key substances involved in the negative remodeling associated with diabetes. Remodeling in hypertension can be either eutrophic or hypertrophic. Endothelial dysfunction and low-grade inflammation lead to negative remodeling in hypertension. Dyslipidemia can be associated with either positive or negative remodeling. High high-density lipoprotein is associated with positive remodeling and high low-density lipoprotein with negative remodeling. Smoking causes endothelial dysfunction, increased oxidative stress, and decreased nitric oxide synthesis leading to inward remodeling. Aging also causes endothelial dysfunction and predisposes to negative remodeling. Knowledge of these associations can elucidate various clinical presentations and guide therapeutic choices in the future.


Coupling interactions in electromagnetic scattering from finite array of cavities with stratified dielectric coating.
The coupling interactions in electromagnetic scattering from a finite array of two-dimensional identical cavities engraved in a perfectly electric conducting screen covered with stratified dielectric coating are presented using an algorithm based on the hybrid finite element-boundary integral method. The solution to the scattering from a finite array of cavities is approximated using the array factor method, which does not take into account the coupling between the cavities, and is compared to the recently developed finite element-boundary element method to demonstrate the importance of the inclusion of the coupling effect. Dependence of the coupling interactions between the cavities on various parameters such as separation periods, incident angle of the plane-wave excitation, and permittivity and thickness of the dielectric coating is demonstrated quantitatively through several numerical examples.


Elutriated lymphocytes for manufacturing chimeric antigen receptor T cells.
Clinical trials of Chimeric Antigen Receptor (CAR) T cells manufactured from autologous peripheral blood mononuclear cell (PBMC) concentrates for the treatment of hematologic malignancies have been promising, but CAR T cell yields have been variable. This variability is due in part to the contamination of the PBMC concentrates with monocytes and granulocytes. Counter-flow elutriation allows for the closed system separation of lymphocytes from monocytes and granulocytes. We investigated the use of PBMC concentrates enriched for lymphocytes using elutriation for manufacturing 8 CD19- and 5 GD2-CAR T cell products. When compared to PBMC concentrates, lymphocyte-enriched elutriation fractions contained greater proportions of CD3+ and CD56+ cells and reduced proportions of CD14+ and CD15+ cells. All 13 CAR T cell products manufactured using the elutriated lymphocytes yielded sufficient quantities of transduced CAR T cells to meet clinical dose criteria. The GD2-CAR T cell products contained significantly more T cells and transduced T cells than the CD19-CAR T cell products. A comparison of the yields of CAR T cells produced from elutriated lymphocytes with the yields of CAR T cells previous produced from cells isolated from PBMC concentrates by anti-CD3/CD28 bead selection or by anti-CD3/CD28 bead selection plus plastic adherence found that greater quantities of GD2-CAR T cells were produced from elutriated lymphocytes, but not CD19-CAR T cells. Enrichment of PBMC concentrates for lymphocytes using elutriation increased the quantity of GD2-CAR T cells produced. These results provide further evidence that CAR T cell expansion is inhibited by monocytes and granulocytes.


Relationships among maternal diet, serotonin metabolism at weaning, and protein selection of progeny.
Brain serotonin (5HT) metabolism in rats at weaning was examined in relation to their maternal dietary protein (PC) and tryptophan (TRP) concentration and to their protein feeding behavior. Pup brain TRP, 5HT, and 5-hydroxyindoleaceticacid (5HIAA) concentration was unaffected by maternal diet PC (10, 20, or 40%) but was increased by TRP additions (0.66 or 1.86%) to 40% casein diets. Turnover of brain 5HT, measured at weaning after probenecid injection, was inversely related to maternal diet PC (r = .54, P less than 0.05) but was not affected by TRP supplementation. Pups allowed to select from 10 and 60% casein diets selected during the first 3 days post-weaning, dietary PC which reflected the PC (r = 0.65, P less than 0.01), but not RRP content of their maternal diet, and also reflected brain 5HT turnover (r = .50, P less than 0.05), but not concentration, of their littermates. Thus, the relationship dietary PC to protein selection by the offspring is associated with maternal diet-maternal diet-induced changes in their brain 5HT turnover, at least as measured after probenecid administration.


Cardiac Remodeling in Hypertension: Clinical Impact on Brain, Heart, and Kidney Function.
Hypertension is the most common causative factor of cardiac remodeling, which, in turn, has been associated with changes in brain and kidney function. Currently, the role of blood biomarkers as indices of cardiac remodeling remains unclear. In contrast, cardiac imaging, including echocardiography and cardiovascular magnetic resonance (CMR), has been a valuable noninvasive tool to assess cardiac remodeling. Cardiac remodeling during the course of systemic hypertension is not the sole effect of the latter. "Remodeling" of other vital organs, such as brain and kidney, also takes place. Therefore, it will be more accurate if we discuss about "hypertensive remodeling" involving the heart, the brain, and the kidneys, rather than isolated cardiac remodeling. This supports the idea of their simultaneous assessment to identify the early, silent lesions of total "hypertensive remodeling". In this context, magnetic resonance imaging is the ideal modality to provide useful information about these organs in a noninvasive fashion and without radiation. For this purpose, we propose a combined protocol to employ MRI in the simultaneous assessment of the heart, brain and kidneys. This protocol should include all necessary indices for the evaluation of "hypertensive remodeling" in these 3 organs, and could be performed within a reasonable time, not exceeding one hour, so that it remains patient-friendly. Furthermore, a combined protocol may offer "all in one examination" and save time. Finally, the amount of contrast agent used will be limited granted that post-contrast evaluations of the three organs will be performed after 1 injection.


Atomoxetine Induced Hypomania in a Patient with Bipolar Disorder and Adult Attention Deficit Hyperactivity Disorder.
Comorbidity of bipolar disorder (BD) with attention deficit hyperactivity disorder (ADHD) is frequent. The management of comorbid ADHD and BD is complicated by the risk of induction of (hypo) mania by the medications used for ADHD treatment. Earlier reports in children and adolescents with ADHD-BD suggest that the possibility of (hypo) mania induction is low when atomoxetine is used along mood stabilizers or antipsychotics. Here, we report induction of hypomania by atomoxetine when used for the treatment of comorbid ADHD in a BD patient while on prophylactic treatment with mood stabilizers. This report indicates that atomoxetine carries the risk of induction of (hypo) mania even in stabilized BD patients. Clinicians should closely monitor such patients for (hypo) mania symptoms.


Syndrome of congenital cutis laxa with ligamentous laxity and delayed development: report of a brother and sister from Turkey.
Congenital cutis laxa with ligamentous laxity and delayed development has recently been defined as a distinct entity of autosomal recessive inheritance. Here we report on 2 new cases of this syndrome. With severe manifestations in the male, X-linked dominant inheritance is discussed. Results of ultrastructural studies of skin and biochemical studies are reported.


The integration and interpretation of pharmacogenomics - a comparative study between the United States of America and Europe: towards better health care.
The study of pharmacogenomics has, by harnessing sequence information from human genomes, the potential to lead to novel approaches in drug discovery, an individualized application of drug therapy, and new insights into disease prevention. For this potential to be realized results need to be interpreted to the prescriber into a format which dictates an action. This mini review briefly describes the history, the regulatory environment, opinions towards, and implementation, integration and interpretation of pharmacogenomics in the United States of America and Europe. The article discusses also how interpretation of pharmacogenomics could move forward to better implementation in health care.


[Differentiated contact allergy lists serve in quality improvement].
Through cooperation between the German Contact Dermatitis Research Group (DKG) and the Information Network of Departments of Dermatology (IVDK), results of standardized patch tests performed by the participating centres are centrally recorded in Germany. For this study, data from 24 departments of dermatology (19678 patients) were evaluated retrospectively and separately for 1995 and 1996. With decreasing frequency, nickel, fragrance mix, balsam of peru, and thimerosal yielded positive reactions most often; surprisingly high numbers of positive reactions were also seen with amerchol L-101 and palladium. Differentiated lists of allergens were compiled for 1995, referring to subgroups of patients (defined by gender, age, localization of eczema, geographical region, occupation, sensitization) and particular problems. In men, percentages of positive reactions were markedly lower for nickel, fragrance mix and balsam of peru than in women. Younger patients reacted more often to thimerosal and older ones to topical medical preparations. Medical allergens were also often positive in patients with leg eczema, whereas occupational allergens were found more frequently in patients with hand eczema. A comparison of positive reactions obtained in distinct geographical regions was problematic because of differences between test populations. The spectrum of allergens found in office workers was similar to that of the whole test population. Patients with positive reactions to nickel and fragrance mix had more positive reactions to unrelated allergens than the total test population. Sex- and age-adjusted frequencies of sensitization revealed a decrease in reactions to nickel and an increase in reactions to mercury allergens from 1995 to 1996. The clinical relevance of mercury reactions was often not apparent. Differentiated lists of allergens can be used to improve the quality of diagnostic and prophylactic procedures in allergic contact dermatitis.


Trends in Prescriptions of Cardioprotective Diabetic Agents After Coronary Artery Bypass Grafting Among U.S. Veterans.
Patients with type 2 diabetes undergoing coronary artery bypass grafting (CABG) are at risk for cardiovascular events. Sodium-glucose cotransporter 2 receptor inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1RA) are effective cardioprotective agents; however, their prescription among CABG patients is uncertain. The aims of this study were 1) to evaluate the overall use of SGLT2i/GLP-1RA after CABG and explore longitudinal trends and 2) to examine patient-related factors associated with the use of SGLT2i or GLP-1RA. We analyzed the nationwide Veterans Affairs (VA) database (2016-2019) to report trends and factors associated with SGLT2i or GLP-1RA prescription after CABG. Among 5,109 patients operated on at 40 different VA medical centers, 525 of 5,109 (10.4%), 352 of 5,109 (6.8%), and 91 of 5,109 (1.8%) were prescribed SGLT2i, GLP-1RA, and both, respectively. A substantial increase in the quarterly SGLT2i prescription rates (1.6% [first quarter of 2016 (2016Q1)], 33% [2019Q4]) was present but was lower for GLP-1RA (0.8% [2016Q1], 11.2% [2019Q4]). SGLT2i use was less likely with preexisting vascular disease (odd ratio [OR] 0.75, 95% CI 0.75, 0.94) or kidney disease (OR 0.72, 95% CI 0.58, 0.88), while GLP-1RA use was associated with obesity (OR 1.91, 95% CI 1.50, 2.46). The overall utilization of SGLT2i or GLP-1RA drugs in U.S. veterans with type 2 diabetes undergoing CABG is low, with SGLT2i preferred over GLP-1RA.


Betaine supplementation causes increase in carnitine metabolites in the muscle and liver of mice fed a high-fat diet as studied by nontargeted LC-MS metabolomics approach.
Betaine (BET) reduces diet-induced liver lipid accumulation, and may relieve obesity-related metabolic disturbances. The aim of our study was to analyze metabolite alterations after supplementation of BET, polydextrose (PDX, a soluble dietary fiber), or their combination (BET PDX) via drinking water to C57BL/6J mice fed a high-fat (HF) diet. BET supplementation increased BET levels in plasma, muscle, and liver (p < 0.05), and the nontargeted LC-MS metabolite profiling revealed an increase in several metabolites in the carnitine biosynthesis pathway after BET supplementation both in liver and muscle. These included carnitine and acetylcarnitine (1.4-fold, p < 0.05), propionylcarnitine and γ-butyrobetaine (1.5-fold, p < 0.05), and several other short-chain acylcarnitines (p < 0.05) in muscle. These changes were slightly higher in the BET PDX group. Furthermore, BET reduced the HF diet induced accumulation of triglycerides in liver (p < 0.05). The supplementations did not attenuate the HF diet induced increase in body weight gain or the increase in adipose tissue mass. Instead, the combination of BET and PDX tended to increase adiposity. Our results suggest that increased availability of BET in different tissues, especially in muscle, after BET supplementation has an impact on carnitine metabolism, and this could further explain the link between BET and lipid metabolism.