Glucagon modulates proliferation and differentiation of human adipose precursors.
Glucagon-like peptide 1 receptor agonists (GLP-1RAs), which are currently used for the treatment of type 2 diabetes, have recently been proposed as anti-obesity drugs, due to their relevant effects on weight loss. Furthermore, dual agonists for both GLP-1R and glucagon receptor (GCGR) are under investigation for their promising action on adiposity, although underlying mechanisms still need to be clarified. We have recently demonstrated that GLP-1 and liraglutide interfere with the proliferation and differentiation of human adipose precursors, supporting the hypothesis of a peripheral action of GLP-1RA on weight. Here, we investigated glucagon activity in an in vitro model of primary human adipose-derived stem cells (ASCs). Glucagon significantly inhibited ASC proliferation in a dose- and time-dependent manner, as evaluated by cell count and thymidine incorporation. When added during in vitro-induced adipogenesis, glucagon significantly reduced adipocyte differentiation, as demonstrated by the evaluation of intracellular fat content and quantitative expression of early and mature adipocyte markers (PPARγ and FABP4, HSL). Notably, the inhibitory effect of glucagon on cell proliferation and adipogenesis was reversed by specific GLP-1R (exendin-9) and GCGR (des-His1-Glu9-glucagon(1-29)) antagonists. The presence of both receptors was demonstrated by Western blot, immunofluorescence and cytofluorimetric analysis of ASCs. In conclusion, we demonstrated a direct inhibitory action of glucagon on the proliferation and differentiation of human adipose precursors, which seems to involve both GLP-1R and GCGR. These findings suggest that the adipose stem compartment is a novel target of glucagon, possibly contributing to the weight loss obtained in vivo with dual GLP-1R/glucagon agonists.


Scurvy is still present in developed countries.
Scurvy, while uncommon, still occurs in developed countries despite the widespread availability of vitamins and fortified foods. A vitamin C deficiency prevalence of 10 to 14% in adults was reported in the National Health and Nutrition Examination Survey (NHANES) in 1994. We report the case of a 57-year-old male who presented with a combined vitamin C deficiency (scurvy) and a Zinc deficiency. He came to the emergency department complaining of a painful swollen ecchymotic leg and dyspnea. Prescriptions for narcotics did not relieve his symptoms. When a detailed dietary history was obtained, we added scurvy to the differential diagnosis. An extensive evaluation excluded trauma, coagulopathies, neoplasia, and vasculitides. The combination of a classic skin biopsy and a low vitamin C level confirmed the diagnosis. This presentation illustrates the necessity of including scurvy in the differential diagnosis of ecchymoses and demonstrates specific populations at risk: single adults and the elderly with deficient diets.


Novel spirochetes isolated from mosquitoes and black flies in the Czech Republic.
During the years 1999-2002, a total of 4,898 individuals of 26 species of hematophagous insects (4,149 mosquitoes, 583 black flies, and 166 tabanid flies) was examined for the presence of spirochetes using dark-field microscopy. There was an overall recovery of spirochetes from the midguts of Culicidae and Simuliidae of 23.5% and 11.4%, respectively. Spirochetes were not detected in Tabanidae. Seven spirochetal strains have been successfully recovered from mosquitoes and black flies: BR149 (Culex pipiens), BR151 (Cx. pipiens), BR173 (Cx. pipiens), BR177 (Cx. pipiens), BR193 (Aedes cinereus), BR208 (Cx. pipiens), and BR231 (Simulium noelleri). The strains have been adapted to laboratory conditions (BSK-H Complete medium). Their preliminary determination based on 16S rRNA gene sequencing has shown that they differ from the Lyme disease spirochete Borrelia burgdorferi sensu lato as well as other members of the Order Spirochaetales indicating novel bacterial species in the Family Spirochaetaceae.


Prepubertal mouse testis growth and maturation and androgen production are acutely sensitive to di-n-butyl phthalate.
Phthalates are plasticizers with widespread industrial, domestic, and medical applications. Epidemiological data indicating increased incidence of testicular dysgenesis in boys exposed to phthalates in utero are reinforced by studies demonstrating that phthalates impair fetal rodent testis development. Because humans are exposed to phthalates continuously from gestation through adulthood, it is imperative to understand what threat phthalates pose at other life stages. To determine the impact during prepuberty, we assessed the consequences of oral administration of 1 to 500 mg di-n-butyl phthalate (DBP)/kg/d in corn oil to wild-type (C57BL/6J) male mice from 4 to 14 days of age. Dose-dependent effects on testis growth correlated with reduced Sertoli cell proliferation. Histological and immunohistochemical analyses identified delayed spermatogenesis and impaired Sertoli cell maturation after exposure to 10 to 500 mg DBP/kg/d. Interference with the hypothalamic-pituitary-gonadal axis was indicated in mice fed 500 mg DBP/kg/d, which had elevated circulating inhibin but no change in serum FSH. Increased immunohistochemical staining for inhibin-α was apparent at doses of 10 to 500 mg DBP/kg/d. Serum testosterone and testicular androgen activity were lower in the 500 mg DBP/kg/d group; however, reduced anogenital distance in all DBP-treated mice suggested impaired androgen action at earlier time points. Long-term effects were evident, with smaller anogenital distance and indications of disrupted spermatogenesis in adult mice exposed prepubertally to doses from 1 mg DBP/kg/d. These data demonstrate the acute sensitivity of the prepubertal mouse testis to DBP at doses 50- to 500-fold lower than those used in rat and identify the upregulation of inhibin as a potential mechanism of DBP action.


Drug administration errors in hospital inpatients: a systematic review.
Drug administration in the hospital setting is the last barrier before a possible error reaches the patient. We aimed to analyze the prevalence and nature of administration error rate detected by the observation method. Embase, MEDLINE, Cochrane Library from 1966 to December 2011 and reference lists of included studies. Observational studies, cross-sectional studies, before-and-after studies, and randomized controlled trials that measured the rate of administration errors in inpatients were included. Two reviewers (senior pharmacists) independently identified studies for inclusion. One reviewer extracted the data; the second reviewer checked the data. The main outcome was the error rate calculated as being the number of errors without wrong time errors divided by the Total Opportunity for Errors (TOE, sum of the total number of doses ordered plus the unordered doses given), and multiplied by 100. For studies that reported it, clinical impact was reclassified into four categories from fatal to minor or no impact. Due to a large heterogeneity, results were expressed as median values (interquartile range, IQR), according to their study design. Among 2088 studies, a total of 52 reported TOE. Most of the studies were cross-sectional studies (N=46). The median error rate without wrong time errors for the cross-sectional studies using TOE was 10.5% [IQR: 7.3%-21.7%]. No fatal error was observed and most errors were classified as minor in the 18 studies in which clinical impact was analyzed. We did not find any evidence of publication bias. Administration errors are frequent among inpatients. The median error rate without wrong time errors for the cross-sectional studies using TOE was about 10%. A standardization of administration error rate using the same denominator (TOE), numerator and types of errors is essential for further publications.


Miconazole induces fungistasis and increases killing of Candida albicans subjected to photodynamic therapy.
Cutaneous and mucocutaneous Candida infections are considered to be important targets for antimicrobial photodynamic therapy (PDT). Clinical application of antimicrobial PDT will require strategies that enhance microbial killing while minimizing damage to host tissue. Increasing the sensitivity of infectious agents to PDT will help achieve this goal. Our previous studies demonstrated that raising the level of oxidative stress in Candida by interfering with fungal respiration increased the efficiency of PDT. Therefore, we sought to identify compounds in clinical use that would augment the oxidative stress caused by PDT by contributing to reactive oxygen species (ROS) formation themselves. Based on the ability of the antifungal miconazole to induce ROS in Candida, we tested several azole antifungals for their ability to augment PDT in vitro. Although miconazole and ketoconazole both stimulated ROS production in Candida albicans, only miconazole enhanced the killing of C. albicans and induced prolonged fungistasis in organisms that survived PDT using the porphyrin TMP-1363 and the phenothiazine methylene blue as photosensitizers. The data suggest that miconazole could be used to increase the efficacy of PDT against C. albicans, and its mechanism of action is likely to be multifactorial.


Seasonal changes of human circadian rhythms in Antarctica.
The human circadian rhythms in sleep, activity, plasma melatonin, and rectal temperature were explored under two conflicting time cues in Antarctica: an extreme photoperiod and a strict work schedule. The nine healthy male subjects stayed at the Antarctic zone (latitude 66.5-90 degrees south) for 15 mo including a 13-mo wintering at the Dome station (latitude 77 degrees south). Neither the phases nor the amounts of sleep and daily activity underwent a seasonal change. On the other hand, the peak phase of melatonin rhythm was phase delayed by 4.1 h in winter compared with summer. When the analysis is limited to the Dome data, the seasonal difference was reduced to 1.3 h. Similarly the trough phase of rectal temperature rhythm in two of three subjects was phase delayed by approximately 2 h in winter. From these findings, the sleep or activity rhythm is concluded to be reset predominantly by the work schedule, whereas the circadian rhythm in plasma melatonin and rectal temperature is substantially influenced by the photoperiod.


PP2A-Mediated Anticancer Therapy.
PP2A is a family of mammalian serine/threonine phosphatases that is involved in the control of many cellular functions including protein synthesis, cellular signaling, cell cycle determination, apoptosis, metabolism, and stress responses through the negative regulation of signaling pathways initiated by protein kinases. Rapid progress is being made in the understanding of PP2A complex and its functions. Emerging studies have correlated changes in PP2A with human diseases, especially cancer. PP2A is comprised of 3 subunits: a catalytic subunit, a scaffolding subunit, and a regulatory subunit. The alternations of the subunits have been shown to be in association with many human malignancies. Therapeutic agents targeting PP2A inhibitors or activating PP2A directly have shed light on the therapy of cancers. This review focuses on PP2A structure, cancer-associated mutations, and the targeting of PP2A-related molecules to restore or reactivate PP2A in anticancer therapy, especially in digestive system cancer therapy.


Phase I study of a combination of s-1 and weekly paclitaxel in patients with advanced or recurrent gastric cancer.
A phase I study of weekly intravenous paclitaxel combined with a fixed dose of S-1, a dihydropyrimidine-dehydrogenase-inhibitory oral fluoropyrimidine, was conducted for patients with advanced or recurrent gastric cancer (ARGC). Endpoints of this study were to examine the toxicity profile OF this regimen and to determine the recommended dose (rd) of paclitaxel. S-1 was fixed at a dose of 80 mg/m(2) per day and was administered for 2 weeks (days 1--14) followed by a 2-week rest. Two dose levels of paclitaxel (level 1: 60 mg/m(2), level 0: 50 mg/m(2)) were studied. Paclitaxel was infused over 1 h on days 1, 8, and 15. Plasma sampling was performed to characterize the pharmacokinetics and pharmacodynamics of paclitaxel in some patients. Fifteen patients were enrolled (6 patients in level 1, and 9 patients in level 0). Dose-limiting toxicities were defined as grade 4 hematological (including grade 3 febrile neutropenia) and grade 3 non-hematological (except anorexia, nausea, vomiting and depilation) toxicities. Three of 6 patients in level 1 developed grade 4 neutropenia or grade 3 febrile neutropenia, and 1 of them also showed grade 3 diarrhea, which settled the maximum-tolerated dose at this level. At level 0, 2 of 9 patients developed grade 4 neutropenia or grade 3 febrile neutropenia, and the RD of paclitaxel for this protocol was set at this level. Pharmacologic studies demonstrated the persistence of significant serum paclitaxel levels over 24 h after drug administration at both levels. Objective responses according to Response Evaluation Criteria in Solid Tumors were observed in 3 of 6 patients who had measurable disease. A combination of S-1 and weekly paclitaxel was feasible and well tolerated, and is suggested to produce a worthwhile response in ARGC. These results warrant further investigation, and a phase II study has already been started.


Modulation of rat brain opioid receptors by cannabinoids.
The interaction of delta 9-tetrahydrocannabinol (delta 9-THC) and related cannabinoids with opioid receptors of neuronal membranes has been investigated. Treatment of membranes with delta 9-THC consistently decreased specific in vitro binding of [3H]dihydromorphine (mu opioid) in a dose-dependent fashion. Similar dose-dependent changes were elicited by cannabidiol and (+/-)-hexahydrocannabinol. Equilibrium binding studies in which brain membranes were titrated with [3H]dihydromorphine in the presence of delta 9-THC demonstrated that the decrease in [3H]dihydromorphine binding is due to a reduction in the number of binding sites, with no significant alteration in receptor affinity. This result suggests that the interaction of delta 9-THC with opioid receptors is a noncompetitive one. Delta 9-THC also inhibited the binding of the delta opioid [3H]D-Pen2, D-Pen5-enkephalin and the opioid antagonist [3H]naloxone (Ki = 16 and 19 microM, respectively) but failed to inhibit the binding of the kappa opioid [3H]ethylketocyclazocine (after suppression of mu and delta receptor binding), the phencyclidine analog [3H]N-(1-[2-theinyl]cyclohexyl)piperidine, the dopamine antagonist [3H]spiroperidol or the muscarinic antagonist [3H]quinuclidinyl benzilate. Moreover, delta 9-THC inhibited the binding of [3H]etorphine (potent opioid agonist) to solubilized, partially purified opioid receptors with a Ki value similar to that observed for the membrane-bound receptors. This finding indicates that the allosteric modulation of the opioid receptor by delta 9-THC is the result of a direct interaction with the receptor protein or with a specific protein-lipid complex and not merely the result of a perturbation of the lipid bilayer of the membrane.(ABSTRACT TRUNCATED AT 250 WORDS)


Cationic amino acid transport across the blood-brain barrier is mediated exclusively by system y+.
Cationic amino acid (CAA) transport is brought about by two families of proteins that are found in various tissues: Cat (CAA transporter), referred to as system y+, and Bat [broad-scope amino acid (AA) transporter], which comprises systems b0,+, B0,+, and y+L. CAA traverse the blood-brain barrier (BBB), but experiments done in vivo have only been able to examine the BBB from the luminal (blood-facing) side. In the present study, plasma membranes isolated from bovine brain microvessels were used to identify and characterize the CAA transporter(s) on both sides of the BBB. From these studies, it was concluded that system y+ was the only transporter present, with a prevalence of activity on the abluminal membrane. System y+ was voltage dependent and had a Km of 470 +/- 106 microM (SE) for lysine, a Ki of 34 microM for arginine, and a Ki of 290 microM for ornithine. In the presence of Na+, system y+ was inhibited by several essential neutral AAs. The Ki values were 3-10 times the plasma concentrations, suggesting that system y+ was not as important a point of access for these AAs as system L1. Several small nonessential AAs (serine, glutamine, alanine,and glycine) inhibited system y+ with Ki values similar to their plasma concentrations, suggesting that system y+ may account for the permeability of the BBB to these AAs. System y+ may be important in the provision of arginine for NO synthesis. Real-time PCR and Western blotting techniques established the presence of the three known nitric oxide synthases in cerebral endothelial cells: NOS-1 (neuronal), NOS-2 (inducible), and NOS-3 (endothelial). These results confirm that system y+ is the only CAA transporter in the BBB and suggest that NO can be produced in brain endothelial cells.


Nurses' spontaneous reporting of adverse drug reactions: expert review of routine reports.
The aims of this study were to analyse spontaneously reported adverse drug reactions according to their previous description, seriousness, causality and the reporting professional. Previous findings showed that fewer nurses than physicians and pharmacists report adverse drug reactions. This is not attributed to any lack of ability in identifying adverse drug reactions. Adverse drug reactions received by the Central Portugal Regional Pharmacovigilance Unit, between 2001 and 2011, were studied. Certain and probable adverse drug reactions were included to test differences between professional groups for serious and non-serious adverse drug reactions. The Central Portugal Regional Pharmacovigilance Unit received 1014 adverse drug reactions. Fifty-four nurses reported 66 adverse drug reactions, whereas 232 physicians and 145 pharmacists reported 589 and 357 adverse drug reactions, respectively. Considering the number of practising professionals, it was estimated that 0.55% of nurses, 3.96% of physicians and 7.08% of pharmacists have reported an adverse drug reaction. Of the 633 adverse drug reactions assessed as certain or probable, 46 (21 serious), 387 (192 serious) and 198 (77 serious) were reported from nurses, physicians and pharmacists, respectively. There were no differences in the reporting of serious adverse drug reactions among nurses, physicians and pharmacists. Nurses are able to identify serious adverse drug reactions although they report less than other professionals. Nurses need to increase their involvement in spontaneous reporting schemes by taking responsibility for routinely reporting suspected adverse drug reactions.


Cellular distribution of L-glutamate decarboxylase (GAD) and gamma-aminobutyric acidA (GABAA) receptor mRNAs in the retina.
1. Gamma-aminobutryic acid (GABA), a major inhibitory transmitter of the vertebrate retina, is synthesized from glutamate by L-glutamate decarboxylase (GAD) and mediates neuronal inhibition at GABAA receptors. GAD consists of two distinct molecular forms, GAD65 and GAD67, which have similar distribution patterns in the nervous system (Feldblum et al., 1990; Erlander and Tobin, 1991). GABAA receptors are composed of several distinct polypeptide subunits, of which the GABAA alpha 1 variant has a particularly extensive and widespread distribution in the nervous system. The aim of this study was to determine the cellular localization patterns of GAD and GABAA alpha 1 receptor mRNAs to define GABA- and GABAA receptor-synthesizing neurons in the rat retina. 2. GAD and GABAA alpha 1 mRNAs were localized in retinal neurons by in situ hybridization histochemistry with 35S-labeled antisense RNA probes complementary to GAD67 and GABAA alpha 1 mRNAs. 3. The majority of neurons expressing GAD67 mRNA is located in the proximal inner nuclear layer (INL) and ganglion cell layer (GCL). Occasional GAD67 mRNA-containing neurons are present in the inner plexiform layer. Labeled neurons are not found in the distal INL or in the outer nuclear layer (ONL). 4. GABAA alpha 1 mRNA is expressed by neurons distributed to all regions of the INL. Some discretely labeled cells are present in the GCL. Labeled cells are not observed in the ONL. 5. The distribution of GAD67 mRNA demonstrates that numerous amacrine cells (conventional, interstitial, and displaced) and perhaps interplexiform cells synthesize GABA. These cells are likely to employ GABA as a neurotransmitter. 6. The distribution of GABAA alpha 1 mRNA indicates that bipolar, amacrine, and perhaps ganglion cells express GABAA receptors having an alpha 1 polypeptide subunit, suggesting that GABA acts directly upon these cells.


Influence of mycophenolate mofetil dosage and plasma levels on the occurrence of chronic lung allograft dysfunction in lung transplants: a retrospective cohort analysis.
Development of chronic lung allograft dysfunction is a limiting factor for post-lung transplant survival. We evaluated whether the dose of the immunosuppressant mycophenolate mofetil or plasma concentrations of the active metabolite mycophenolic acid affect the development of chronic lung allograft dysfunction. In this retrospective cohort study we recruited 71 patients with a lung transplant between 2010 and 2014 which survived the first year after transplantation up to 1 July 2021. An event-time-analytical Cox proportional-hazards regression model with time-varying-covariates (18,431 measurements for MPA, mycophenolate mofetil dosage, lymphocytes) was used to predict chronic lung allograft dysfunction, with adjustment for sociodemographic factors and lung function at baseline. 37 patients did not develop chronic lung allograft dysfunction (age 41.3 ± 15.6 years, baseline FEV1 95.5 ± 19.1% predicted) and 34 patients developed chronic lung allograft dysfunction (age 50.9 ± 13.3 years, baseline FEV1 102.2 ± 25.4% predicted). Mean mycophenolic acid did not differ significantly between the groups (2.8 ± 1.7 and 3.0 ± 2.3 mg/l; p = 0.724). In the first 4 post-transplant years the death rate was 25%. A total of 50% of the patients died by the ninth post-transplant year. There was a dose-effect relationship between mycophenolate mofetil dosage, mycophenolic acid (r2 = 0.02, p <0.001), as well as lymphocyte levels (r2 = -0.007, p <0.001), but only the traditional risk factor age predicted chronic lung allograft dysfunction. Continuously measured mycophenolic acid did not predict chronic lung allograft dysfunction (hazard ratio 0.98, 95% confidence interval 0.90-1.06, p = 0.64 over a period of 382.97 patient-years). Mycophenolate mofetil dosage and mycophenolic acid were not associated with chronic lung allograft dysfunction development. Thus, the mycophenolate mofetil dose or mycophenolic acid plasma concentration are not a primary factor related to organ rejection, but chronic lung allograft dysfunction may be influenced by other components of immunosuppression or other factors.


A 12-week, double-blind comparison of olanzapine vs haloperidol in the treatment of acute mania.
This randomized controlled trial compares the efficacy and safety of olanzapine vs haloperidol, as well as the quality of life of patients taking these drugs, in patients with bipolar mania. The design consisted of 2 successive, 6-week, double-blind periods and compared flexible dosing of olanzapine (5-20 mg/d, n = 234) with haloperidol (3-15 mg/d, n = 219). Rates of remission (Young-Mania Rating Scale score of < or =12 and 21-item Hamilton Rating Scale for Depression score of < or =8 at week 6) were similar for olanzapine- and haloperidol-treated patients (52.1% vs 46.1%, respectively; P =.15). For the subgroup of patients whose index episode did not include psychotic features, rates of remission were significantly greater for the olanzapine group compared with the haloperidol group (56.7% vs 41.6%, P =.04). Relapse into an affective episode (mania and/or depression) occurred in 13.1% and 14.8% of olanzapine- and haloperidol-treated patients, respectively (P =.56). Switch to depression occurred significantly more rapidly with haloperidol than with olanzapine when using survival analysis techniques (P =.04), and significantly more haloperidol-treated patients experienced worsening of extrapyramidal symptoms, as indicated by several measures. Weight gain was significantly greater in the olanzapine group compared with the haloperidol group (2.82 vs 0.02 kg, P<.001). The olanzapine group had significant improvement in quality of life on several dimensions compared with the haloperidol group. These data suggest that olanzapine does not differ from haloperidol in achieving overall remission of bipolar mania. However, haloperidol carries a higher rate of extrapyramidal symptoms, whereas olanzapine is associated with weight gain.


Reactive effects of diary self-assessment in chronic pain patients.
Several studies of experimental and acute clinical pain have indicated reactive effects of self-assessment on pain intensity and tolerance. A recent study of chronic pain patients (vonBaeyer 1994), however, failed to show these effects. The present investigation sought to determine whether reactive effects can be produced in chronic pain patients by an intensive self-assessment protocol. Using the methodology of ecological momentary assessment (EMA; Stone and Shiffman 1994), thirty-five chronic rheumatoid arthritis patients completed diaries of pain and mood seven times a day for 1 wk. Eighteen patients were included in the final sample because they responded to at least half of the number of hourly prompts for each of the 7 days. Using repeated measures analysis of the daily means, no significant effects of time were found for any measures. Reactive effects that result in an average change in pain levels over time, therefore, do not appear to be produced by intensive self-assessment in a naturalistic context. Results are discussed in terms of cognitive and behavioral theories of pain reactivity.


Chiral crystallization of a heterodinuclear Ni-Ln series: comprehensive analysis of the magnetic properties.
Four heterodinuclear (H(2)O)(2)NiL-Ln(NO(3))(3) complexes (Ln = Tb, Dy, Er, Yb) with a double phenoxo bridge coming from the dideprotonated Schiff-base ligand are synthesized and characterized by crystal and powder X-ray diffraction studies. This series of compounds devoid of any chiral center, crystallizes in a noncentrosymmetric space group P2(1), as the previously described (H(2)O)(2)NiL-Gd(NO(3))(3) equivalent. All four complexes are ferromagnetically coupled. If this behavior is clearly shown by the χ(M)T increase at low temperature in the case of the Ni-Tb and Ni-Dy complexes, it necessitates the preparation of the Zn-Er and Zn-Yb equivalent entities to be evidenced in the case of the Ni-Er and Ni-Yb complexes. Out-of-phase susceptibility signals are found in the four cases, but the SMM behavior is neither confirmed, nor completely studied because of the presence of fast quantum tunnelling at zero field. Thorough ab initio multiconfiguration calculations are carried out, achieving a realistic account of ligand field effects, exchange coupling and magnetic anisotropy in the discussed systems. The calculations reveal the ferromagnetic intercenter exchange coupling, the interplay with spin-orbit effects leading to a Ising-like scheme of the lowest levels. The ab initio simulation of the magnetic susceptibility is in semiquantitative agreement with experimental data, certifying the reasonableness of the theoretical treatments in obtaining valuable information for the interacting mechanisms. The anisotropy is accounted for by drawing polar diagrams of state-specific magnetization functions, obtained by handling of the data resulting from ab initio calculations including the spin-orbit effects. Supplementary, Density Functional Theory (DFT) calculations are carried out, presenting new methodological clues and assessments. The DFT is not perfectly adequate for lanthanide systems because of orbital pseudodegeneracy issues. However, we show that in particular circumstances the DFT can be partly used, succeeding here in mimicking different orbital configurations of the Ni-Tb system. The DFT seems to offer reasonable estimations of exchange coupling parameters, while it remains problematic in the complete account of Ligand Field splitting. The Paper presents unprecedented methodological advances and correlations with phenomenological and heuristic interpretation of experimental data, taking into focus relevant d-f systems constructed with a prototypical binucleating ligand.


Squamous cell carcinoma masquerading as rhinophyma.
A rhinophyma lesion can mask the existence of coexisting occult skin cancers, and many types of tumors can mimic a rhinophyma. Although several coexistent malignant tumors have been reported in patients with rhinophyma, few reports have described the coexistence of rhinophyma and cutaneous squamous cell carcinoma (SCC). Herein, we report on a case of SCC in a 45-year-old man who presented with 2-month-history of a painful, erythematous, globular plaque on the tip of his nose and this lesion mimicked a rhinophyma lesion. The histopathologic examination showed a proliferation of atypical squamous cells that extended into the dermis, which was consistent with SCC. He was treated with surgical excision, and there has been no evidence of recurrence during the follow-up period of 1 year.


Establishment of a mouse model for human rhinovirus infection.
We describe here a mouse model for rhinovirus infection using a variant of human rhinovirus type 2 (HRV2/H) which replicated 50- to 300-fold in the lungs of BALB/c mice. The variant virus differed only marginally from HRV2/H according to various biochemical parameters. Use of a photosensitive inoculum and pretreatment of the animals with actinomycin D were necessary for detection of reproducible and significant levels of virus replication. This mouse model of rhinovirus infection is the first example of human rhinovirus replication in a non-primate mammal, and provides an important link for the development of rhinovirus therapy or prophylaxis.


Respiratory axon regeneration in the chronically injured spinal cord.
Promoting the combination of robust regeneration of damaged axons and synaptic reconnection of these growing axon populations with appropriate neuronal targets represents a major therapeutic goal following spinal cord injury (SCI). A key impediment to achieving this important aim includes an intrinsic inability of neurons to extend axons in adult CNS, particularly in the context of the chronically-injured spinal cord. We tested whether an inhibitory peptide directed against phosphatase and tensin homolog (PTEN: a central inhibitor of neuron-intrinsic axon growth potential) could restore inspiratory diaphragm function by reconnecting critical respiratory neural circuitry in a rat model of chronic cervical level 2 (C2) hemisection SCI. We found that systemic delivery of PTEN antagonist peptide 4 (PAP4) starting at 8 weeks after C2 hemisection promoted substantial, long-distance regeneration of injured bulbospinal rostral Ventral Respiratory Group (rVRG) axons into and through the lesion and back toward phrenic motor neurons (PhMNs) located in intact caudal C3-C5 spinal cord. Despite this robust rVRG axon regeneration, PAP4 stimulated only minimal recovery of diaphragm function. Furthermore, re-lesion through the hemisection site completely removed PAP4-induced functional improvement, demonstrating that axon regeneration through the lesion was responsible for this partial functional recovery. Interestingly, there was minimal formation of putative excitatory monosynaptic connections between regrowing rVRG axons and PhMN targets, suggesting that (1) limited rVRG-PhMN synaptic reconnectivity was responsible at least in part for the lack of a significant functional effect, (2) chronically-injured spinal cord presents an obstacle to achieving synaptogenesis between regenerating axons and post-synaptic targets, and (3) addressing this challenge is a potentially-powerful strategy to enhance therapeutic efficacy in the chronic SCI setting. In conclusion, our study demonstrates a non-invasive and transient pharmacological approach in chronic SCI to repair the critically-important neural circuitry controlling diaphragmatic respiratory function, but also sheds light on obstacles to circuit plasticity presented by the chronically-injured spinal cord.


Preparation of Monoclonal Antibody Against EMA-1 and Development of Rapid Serological Detection Method for Theileria equi Infection, Xinjiang, China.
The erythrocytic-stage surface protein equi merozoite antigen 1 (EMA-1) of Theileria equi is a major candidate for the development of a diagnostic antigen for equine piroplasmosis. In this study, BALB/c mice were immunized with purified recombinant EMA-1 to prepare monoclonal antibody (mAb) against T. equi EMA-1, and 1 mAb 5H2 was obtained that showed good reaction with infected red blood cells (RBC) in the indirect immunofluorescence assay (IFA). To develop a rapid serological detection method for T. equi infection in Xinjiang Uygur Autonomous Region, China, recombinant EMA-1 originating from the local T. equi strain and the mAb to EMA-1 were employed to develop an immunochromatographic test (ICT) to detect antibodies to T. equi in horse sera. The ICT showed high sensitivity and specificity and no cross-reaction with Babesia caballi. Ninety-two horse serum samples collected from Ili, Xinjiang, were tested by ICT and compared with the detection results of a commercial ELISA kit. The results showed that 56 of 92 (61%) serum samples were seropositive according to the ICT assay, and 50 (54%) samples were seropositive according to the ELISA kit. The ICT had a high coincidence (91.3%) but was more sensitive than the reference ELISA kit. To confirm whether the horses were infected by T. equi, 30 blood DNA samples from 92 horses were examined by PCR. The results showed that 14 of 30 (47%) horses were confirmed to be infected with T. equi by PCR, while 16 of 30 (53%) horses were seropositive by ICT. All PCR-positive horses were ICT-positive. The findings indicate that T. equi is endemic in Ili, Xinjiang, and that the ICT is reliable as a serological diagnosis method. The ICT developed in this study could be an efficient diagnostic tool to detect T. equi infection in horses in the Xinjiang area.


The Differential Contributions of Conceptual Representation Format and Language Structure to Levels of Semantic Abstraction Capacity.
This paper reviews some controversies concerning the original and revised versions of the 'hub-and-spoke' model of conceptual representations and their implication for abstraction capacity levels. The 'hub-and-spoke' model, which is based on data gathered in patients with semantic dementia (SD), is the most authoritative model of conceptual knowledge. Patterson et al.'s (Nature Reviews Neuroscience, 8(12), 976-987, 2007) classical version of this model maintained that conceptual representations are stored in a unitary 'amodal' format in the right and left anterior temporal lobes (ATLs), because in SD the semantic disorder cuts across modalities and categories. Several authors questioned the unitary nature of these representations. They showed that the semantic impairment is 'multi-modal'only in the advanced stages of SD, when atrophy affects the ATLs bilaterally, but that impariments can be modality-specific in lateralised (early) stages of the disease. In these cases, SD mainly affects lexical-semantic knowledge when atrophy predominates on the left side and pictorial representations when atrophy prevails on the right side. Some aspects of the model (i.e. the importance of spokes, the multimodal format of representations and the graded convergence of modalities within the ATLs), which had already been outlined by Rogers et al. (Psychological Review, 111(1), 205-235, 2004) in a computational model of SD, were strengthened by these results. The relevance of these theoretical problems and of empirical data concerning the neural substrate of concrete and abstract words is discussed critically. The conclusion of the review is that the highest levels of abstraction are due more to the structuring influence of language than to the format of representations.


IL-17A concentration of seminal plasma and follicular fluid in infertile men and women with various clinical diagnoses.
Seminal plasma and follicular fluid (FF) cytokine analysis are valuable tools for diagnoses and validation of therapeutic approaches for improving the chance of conception. Despite the initial discovery over a decade ago, the IL-17 family has not received much attention in the case of infertility. In this study, we analyzed the level of IL-17A in seminal plasma, follicular fluid and blood serum of infertile patients with different clinical diagnoses by Enzyme Linked Immunosorbent Assay (ELISA). The results showed that the level of IL-17A was higher in seminal plasma and blood serum of varicocele patients than the control group. The level of this cytokine was higher in follicular fluid of endometriosis, polycystic ovary syndrome (PCOS) and tubal factor patients than the control group. A similar elevation in IL-17A level was observed in blood serum of these patients. Furthermore, there was a correlation between the numbers of meiosis I (MI) oocytes and the level of blood serum and follicular fluid IL-17A in PCOS patients. Our data suggest a putative role of IL-17A in mediating these conditions and may have possible applications in the development of more effective diagnostic tools and therapeutic treatments for human reproductive disorders.


Actuating Shape Memory Polymer for Thermoresponsive Soft Robotic Gripper and Programmable Materials.
For soft robotics and programmable metamaterials, novel approaches are required enabling the design of highly integrated thermoresponsive actuating systems. In the concept presented here, the necessary functional component was obtained by polymer syntheses. First, poly(1,10-decylene adipate) diol (PDA) with a number average molecular weight M n of 3290 g·mol-1 was synthesized from 1,10-decanediol and adipic acid. Afterward, the PDA was brought to reaction with 4,4'-diphenylmethane diisocyanate and 1,4-butanediol. The resulting polyester urethane (PEU) was processed to the filament, and samples were additively manufactured by fused-filament fabrication. After thermomechanical treatment, the PEU reliably actuated under stress-free conditions by expanding on cooling and shrinking on heating with a maximum thermoreversible strain of 16.1%. Actuation stabilized at 12.2%, as verified in a measurement comprising 100 heating-cooling cycles. By adding an actuator element to a gripper system, a hen's egg could be picked up, safely transported and deposited. Finally, one actuator element each was built into two types of unit cells for programmable materials, thus enabling the design of temperature-dependent behavior. The approaches are expected to open up new opportunities, e.g., in the fields of soft robotics and shape morphing.


Can homeopaths detect homeopathic medicines by dowsing? A randomized, double-blind, placebo-controlled trial.
Dowsing is a method of problem-solving that uses a motor automatism, amplified through a pendulum or similar device. In a homeopathic context, it is used as an aid to prescribing and as a tool to identify miasm or toxin load. A randomized double-blind trial was conducted to determine whether six dowsing homeopaths were able to distinguish between Bryonia in a 12c potency and placebo by use of dowsing alone. The homeopathic medicine Bryonia was correctly identified in 48.1% of bottle pairs (n=156; 95% confidence interval 40.2%, 56.0%; P=0.689). These results, wholly negative, add to doubts whether dowsing in this context can yield objective information.


Suppression of Ycf1p function by Cka1p-dependent phosphorylation is attenuated in response to salt stress.
The yeast vacuolar membrane protein Ycf1p and its mammalian counterpart, MRP1, belong to the ABCC subfamily of ATP-binding cassette transporters. Genetic evidence suggests that the yeast casein kinase 2α, Cka1p, negatively regulates Ycf1p function via phosphorylation of Ser251 within the N-terminus. In this study, we provide strong evidence that Cka1p regulates Ycf1p function via phosphorylation of Ser251. We show that the CK2 holoenzyme interacts with Ycf1p. However, genetic analysis suggests that only Cka1p is required for Ser251 phosphorylation, as the deletion of CKA1 significantly reduces Ser251 phosphorylation in vivo. Furthermore, purified recombinant Cka1p phosphorylates a Ycf1p-derived peptide containing Ser251. We also demonstrate that Ycf1p function is induced in response to high salt stress. Induction of the Ycf1p function strongly correlates with reduced phosphorylation of Ser251. Importantly, Cka1p activity in vivo is similarly reduced in response to salt stress, consistent with our finding that Cka1p directly phosphorylates Ser251 of Ycf1p. We provide genetic and biochemical evidence that strongly suggests that the induction of Ycf1p function is the result of decreased phosphorylation of Ser251. In conclusion, our work demonstrates a novel biochemical role for Cka1p regulation of Ycf1p function in the cellular response of yeast to salt stress.


Beyond Getting Rid of Stupid Stuff in the Electronic Health Record (Beyond-GROSS): Protocol for a User-Centered, Mixed-Method Intervention to Improve the Electronic Health Record System.
Up to 60% of health care providers experience one or more symptoms of burnout. Perceived clinician burden resulting in burnout arises from factors such as electronic health record (EHR) usability or lack thereof, perceived loss of autonomy, and documentation burden leading to less clinical time with patients. Burnout can have detrimental effects on health care quality and contributes to increased medical errors, decreased patient satisfaction, substance use, workforce attrition, and suicide. This project aims to improve the user-centered design of the EHR by obtaining direct input from clinicians about deficiencies. Fixing identified deficiencies via user-centered design has the potential to improve usability, thereby increasing satisfaction by reducing EHR-induced burnout. Quantitative and qualitative data will be obtained from clinician EHR users. The input will be received through a form built in a REDCap database via a link embedded in the home page of the EHR. The REDCap data will be analyzed in 2 main dimensions, based on nature of the input, what section of the EHR is affected, and what is required to fix the issue(s). Identified issues will be escalated to relevant stakeholders responsible for rectifying the problems identified. Data analysis, project evaluation, and lessons learned from the evaluation will be incorporated in a Plan-Do-Study-Act (PDSA) manner every 4-6 weeks. The pilot phase of the study began in October 2020 in the Gastroenterology Division at Mount Sinai Hospital, New York City, NY, which includes 39 physicians and 15 nurses. The pilot is expected to run over a 4-6-month period. The results of the REDCap data analysis will be reported within 1 month of completing the pilot phase. We will analyze the nature of requests received and the impact of rectified issues on the clinician EHR user. We expect that the results will reveal which sections of the EHR have the highest deficiencies while also highlighting issues about workflow difficulties. Perceived impact of the project on provider engagement, patient safety, and workflow efficiency will also be captured by evaluation survey and other qualitative methods where possible. The project aims to improve user-centered design of the EHR by soliciting direct input from clinician EHR users. The ultimate goal is to improve efficiency, reduce EHR inefficiencies with the possibility of improving staff engagement, and lessen EHR-induced clinician burnout. Our project implementation includes using informatics expertise to achieve the desired state of a learning health system as recommended by the National Academy of Medicine as we facilitate feedback loops and rapid cycles of improvement. PRR1-10.2196/25148.


Chromosomal drift, a new phenomenon in plants.
A seasonal shift in chromosome number of reproductive cells of Claytonia virginica, which coincided with near-drought conditions, resulted in a chromosome complement new to the population. The number reappeared 2 years later, the minimum time required for plants of that generation to produce flowers. Moreover, the chromosome number of root cells commonly differed from aerial organs of the same plant.


The LL-100 panel: 100 cell lines for blood cancer studies.
For many years, immortalized cell lines have been used as model systems for cancer research. Cell line panels were established for basic research and drug development, but did not cover the full spectrum of leukemia and lymphoma. Therefore, we now developed a novel panel (LL-100), 100 cell lines covering 22 entities of human leukemia and lymphoma including T-cell, B-cell and myeloid malignancies. Importantly, all cell lines are unequivocally authenticated and assigned to the correct tissue. Cell line samples were proven to be free of mycoplasma and non-inherent virus contamination. Whole exome sequencing and RNA-sequencing of the 100 cell lines were conducted with a uniform methodology to complement existing data on these publicly available cell lines. We show that such comprehensive sequencing data can be used to find lymphoma-subtype-characteristic copy number aberrations, mRNA isoforms, transcription factor activities and expression patterns of NKL homeobox genes. These exemplary studies confirm that the novel LL-100 panel will be useful for understanding the function of oncogenes and tumor suppressor genes and to develop targeted therapies.


Nitric oxide and peroxynitrite in postischemic myocardium.
Alterations in the production of nitric oxide (NO.) are a critical factor in the injury that occurs in ischemic and reperfused myocardium; however, controversy remains regarding the alterations in NO. that occur and how these alterations cause tissue injury. As superoxide generation occurs during the early period of reperfusion, the cytotoxic oxidant peroxynitrite (ONOO-) could be formed; however, questions remain regarding ONOO- formation and its role in postischemic injury. Electron paramagnetic resonance spin trapping studies, using the NO. trap Fe(2+)-N-methyl-D-glucamine dithiocarbamate (Fe-MGD), and chemiluminescence studies, using the enhancer luminol, have been performed to measure the magnitude and time course of NO. and ONOO- formation in the normal and postischemic heart. Isolated rat hearts were subjected to control perfusion, or ischemia followed by reperfusion in the presence of Fe-MGD with electron paramagnetic resonance measurements performed on the effluent from these hearts. Whereas only trace signals were present prior to ischemia, prominent NO. adduct signals were seen during the first 2 min of reflow. The reperfusion associated increase in these NO. signals was abolished by nitric oxide synthase inhibition. In hearts perfused with luminol to detect ONOO- formation, a similar marked increase was seen during the first 2 min of reperfusion that was blocked by nitric oxide synthase inhibitors and by superoxide dismutase. Either NG-nitro-L-arginine methyl ester or superoxide dismutase treatment resulted in more than twofold higher recovery of contractile function than in untreated hearts. Immunohistology studies demonstrated that the ONOO(-)-mediated nitration product nitrotyrosine was formed in postischemic hearts, but not in normally perfused controls. Thus, NO. formation is increased during the early period of reperfusion and reacts with superoxide to form ONOO-, which results in protein nitration and myocardial injury.


Subepicardial phase 0 block and discontinuous transmural conduction underlie right precordial ST-segment elevation by a SCN5A loss-of-function mutation.
Two mechanisms are generally proposed to explain right precordial ST-segment elevation in Brugada syndrome: 1) right ventricular (RV) subepicardial action potential shortening and/or loss of dome causing transmural dispersion of repolarization; and 2) RV conduction delay. Here we report novel mechanistic insights into ST-segment elevation associated with a Na(+) current (I(Na)) loss-of-function mutation from studies in a Dutch kindred with the COOH-terminal SCN5A variant p.Phe2004Leu. The proband, a man, experienced syncope at age 22 yr and had coved-type ST-segment elevations in ECG leads V1 and V2 and negative T waves in V2. Peak and persistent mutant I(Na) were significantly decreased. I(Na) closed-state inactivation was increased, slow inactivation accelerated, and recovery from inactivation delayed. Computer-simulated I(Na)-dependent excitation was decremental from endo- to epicardium at cycle length 1,000 ms, not at cycle length 300 ms. Propagation was discontinuous across the midmyocardial to epicardial transition region, exhibiting a long local delay due to phase 0 block. Beyond this region, axial excitatory current was provided by phase 2 (dome) of the M-cell action potentials and depended on L-type Ca(2+) current ("phase 2 conduction"). These results explain right precordial ST-segment elevation on the basis of RV transmural gradients of membrane potentials during early repolarization caused by discontinuous conduction. The late slow-upstroke action potentials at the subepicardium produce T-wave inversion in the computed ECG waveform, in line with the clinical ECG.


Molybdenum metabolism in plants.
The viability of plants relies on molybdenum, which after binding to the organic moiety of molybdopterin forms the molybdenum cofactor (Moco) and acquires remarkable redox properties. Moco is in the active site of critical molybdoenzymes, which use to work as small electron transport chains and participate in N and S metabolism, hormone biosynthesis, toxic compound transformations and other important processes not only in plants but also in all the other kingdoms of life. Molybdate metabolism in plants is reviewed here, with special attention to two main aspects, the different molybdate transporters that with a very high affinity participate in molybdenum acquisition and the recently discovered Moco enzyme amidoxime-reducing component. Their functionality is starting to be understood.


The Effect of Therapist and Activity Characteristics on the Purposeful Responses of Probable Alzheimer's Disease Participants.
The purpose of this study was to examine the efficacy of individual therapist sessions on the purposeful responses of probable Alzheimer's disease (AD) participants (hereby designated as "dementia participants". Three music therapists and one occupational therapist individually presented a combined total of 29 sing-along and exercise sessions to a group of seven participants, six having a diagnosis of probable Alzheimer's disease (moderate to severe cognitive decline), and one nondementia "control" participant, at an adult day care center specializing in dementia. Informed consent procedures were given to all study participants and their families. Sixteen sing-along sessions of 25-45 minutes duration consisted of live guitar playing and singing by individual music therapists. Thirteen exercises sessions of 20 minutes in length consisted of individual therapist (music or occupational) leading of exercises to a music tape ("Everyone Can Move" by Farnan & Johnson, 1988). Independent variables and their response definitions included: activity type (Sing-along, exercise); session content (music intervals, nonmusic intervals); therapist type (music, occupational); and therapist styles (singing, guitar playing). Participant dependent measures included singing/humming to songs, and movement/exercise to a therapist model (purposeful responses). All sessions were videotaped. Results indicated that the six dementia participants as a group purposefully responded significantly more during exercise than during sing-along sessions, but one of the six participants had extremely low exercise participation scores. That one participant's scores in sing-along sessions were in the range of the majority (4 of 5) of the other dementia participants' singing scores. Further analysis to help explain the discrepancy in this participant's purposeful responding indicated no significant difference in responding to individual music or occupational therapists during exercise activities, but a significant difference in individual responding to 3 different music therapists during the sing-along activities. Addi6onal analyses of the sing-along activities revealed significant differences in the total percentage of singing and guitar playing by the individual music therapists. Implications of the results for music therapy programming with dementia clients are discussed.


AlphaFold2 Can Predict Single-Mutation Effects.
AlphaFold2 (AF) is a promising tool, but is it accurate enough to predict single mutation effects? Here, we report that the localized structural deformation between protein pairs differing by only 1-3 mutations-as measured by the effective strain-is correlated across 3901 experimental and AF-predicted structures. Furthermore, analysis of ∼11 000 proteins shows that the local structural change correlates with various phenotypic changes. These findings suggest that AF can predict the range and magnitude of single-mutation effects on average, and we propose a method to improve precision of AF predictions and to indicate when predictions are unreliable.


Human epithelial beta-defensins 2 and 3 inhibit HIV-1 replication.
Mechanisms underlying mucosal transmission of HIV-1 are incompletely understood. We describe the anti-HIV-1 activity of human beta-defensins (hBD), small cationic molecules that provide protection at mucosal surfaces. HIV-1 induced expression of hBD-2 and -3 mRNA (but not that of hBD-1) 4- to 78-fold, respectively, above baseline in normal human oral epithelial cells. HIV-1 failed to infect these cells, even after 5 days of exposure. Recombinant hBD-1 had no antiviral activity, while rhBD-2 and rhBD-3 showed concentration-dependent inhibition of HIV-1 replication without cellular toxicity. Inhibition was greater against CXCR4-tropic than against the CCR5-tropic HIV-1 isolates. hBD-2 and hBD-3 induced an irreversible effect on virion infectivity, with electron microscopy confirming binding of hBDs to viral particles. Finally, hBD-2 and -3 induced downmodulation of the HIV-1 coreceptor CXCR4 (but not CCR5) in peripheral blood mononuclear cells and T lymphocytic cells as shown by confocal microscopy and flow cytometry. This study shows for the first time that HIV-1 induces beta-defensin expression in human oral epithelial cells and that beta-defensins block HIV-1 replication via a direct interaction with virions and through modulation of the CXCR4 coreceptor. These properties may be exploited as strategies for mucosal protection against HIV-1 transmission.


Alteration of neuro-dopamine and steroid hormone homeostasis in wild Bank voles in relation to tissue concentrations of PFAS at a Nordic skiing area.
Perfluoroalkyl substances (PFAS) are contaminants that are applied in a wide range of consumer products, including ski products. The present study investigated the neuro-dopamine (DA) and cellular steroid hormone homeostasis of wild Bank voles (Myodes glareolus) from a skiing area in Norway (Trondheim), in relation to tissue concentrations of PFAS. We found a positive association between brain DA concentrations and the concentration of several PFAS, while there was a negative association between PFAS and dopamine receptor 1 (dr1) mRNA. The ratio between DA and its metabolites (3,4-dihydroxyphenylacetic acid: DOPAC and homovanillic acid: HVA) showed a negative association between DOPAC/DA and several PFAS, suggesting that PFAS altered the metabolism of DA via monoamine oxidase (Mao). This assumption is supported by an observed negative association between mao mRNA and PFAS. Previous studies have shown that DA homeostasis can indirectly regulate cellular estrogen (E2) and testosterone (T) biosynthesis. We found no association between DA and steroid hormone levels, while there was a negative association between some PFAS and T concentrations, suggesting that PFAS might affect T through other mechanisms. The results from the current study indicate that PFAS may alter neuro-DA and steroid hormone homeostasis in Bank voles, with potential consequences on reproduction and general health.


Iron porphyrinate Fe(TPPS) reduces brain cell damage in rats intrastriatally lesioned by quinolinate.
It has been recently demonstrated that the reactive nitrogen species (RNS) peroxynitrite (ONOO(-)) is involved in the neurotoxic pattern produced by quinolinic acid in the rat brain [V. Pérez-De La Cruz, C. González-Cortés, S. Galván-Arzate, O.N. Medina-Campos, F. Pérez-Severiano, S.F. Ali, J. Pedraza-Chaverrí, A. Santamaría, Excitotoxic brain damage involves early peroxynitrite formation in a model of Huntington's disease in rats: protective role of iron porphyrinate 5,10,15,20-tetrakis (4-sulfonatophenyl)porphyrinate iron (III), Neuroscience 135 (2005) 463-474.]. The aim of this work was to investigate whether ONOO(-) can also be responsible for morphological alterations and inflammatory events in the same paradigm. For this purpose, we evaluated the effect of a pre-treatment with the iron porphyrinate Fe(TPPS), a well-known ONOO(-) decomposition catalyst (10 mg/kg, i.p., 120 min before lesion), on the quinolinate-induced striatal cell damage and immunoreactivities to glial-fibrilar acidic protein (GFAP), interleukin 6 (IL-6) and inducible nitric oxide synthase (iNOS), one and seven days after the intrastriatal infusion of quinolinate (240 nmol/microl) to rats. The striatal tissue from animals lesioned by quinolinate showed a significant degree of damage and enhanced immunoreactivities to GFAP, IL-6 and iNOS, both at 1 and 7 days post-lesion. Pre-treatment of rats with Fe(TPPS) significantly attenuated or prevented all these markers at both post-lesion times tested, except for GFAP immunoreactivity at 7 days post-lesion and iNOS immunoreactivity at 1 day post-lesion. Altogether, our results suggest that ONOO(-) is actively participating in triggering inflammatory events and morphological alterations in the toxic model produced by quinolinate, since the use of agents affecting its formation, such as Fe(TPPS), are effective experimental tools to reduce the brain lesions associated to excitotoxic and oxidative damage.


Effect of oral glucose on acylated and total ghrelin secretion in acromegalic patients.
The pathophysiology of ghrelin secretion in acromegaly is unclear. Our aim was to study circulating fasting ghrelin levels and their response to oral glucose in acromegalic patients and normal control subjects. 9 acromegalic patients (4 male, 5 female; 59.4+/-3.6 years; 28.6+/-1.0 kg/m2) and 9 age and BMI matched healthy control subjects (4 male, 5 female; 59.1+/-1.4 years; 26.5+/-0.8 kg/m2) were included. We obtained blood samples for glucose, insulin, GH, total ghrelin and acylated ghrelin at times 0, 30, 60, 90 and 120 minutes after 75 g of oral glucose. Fasting GH and IGF-I were statistically different between patients and controls: GH (microg/l): 6.7+/-1.4 vs. 0.8+/-0.4, p<0.01; IGF-I (ng/ml): 414+/-75 vs. 86+/-6, p<0.01. Fasting total ghrelin (pg/ml) were similar in the patient and in the control group, 916+/-132 vs. 844+/-169, p=ns. In both groups total ghrelin levels decreased during oral glucose, and nadir total ghrelin was lower than fasting ghrelin: patients: 916+/-132 vs. 747+/-95, p<0.05; controls: 844+/-169 vs. 625+/-90, p<0.05). The AUCs of total ghrelin (pg/ml*min) were not different between the two groups: 98953+/-13052 vs. 83773+/-13096, p=ns). Fasting acylated ghrelin (pg/ml) were similar in the patient and the control group 65+/-13 pg/ml vs.74+/-14 pg/ml, p=ns. In both groups acylated ghrelin levels decreased during oral glucose, and nadir acylated ghrelin levels were lower than basal acylated ghrelin levels: patients: 65+/-13 vs. 42+/-6, p<0.05; controls: 74+/-14 pg/ml vs. 37+/-4 pg/ml, p<0.05). The AUCs of acylated ghrelin (pg/ml*min) were not different between the two groups: patients: 6173+/-992 vs. controls 8648+/-2742, p=ns). In acromegalic patients there was a negative correlation between fasting, both total and acylated, ghrelin and both fasting and post oral glucose insulin levels. These data suggest that circulating total and acylated ghrelin in acromegaly is regulated by insulin and not by GH hypersecretion.


Evaluation of the effect of GABA(B) agonists on the vagal nodose C-fibers in the esophagus.
Clinical studies showed that GABA(B) receptor agonists improve symptoms in patients with gastroesophageal reflux disease. One proposed mechanism of this effect is direct inhibition of the gastroesophageal vagal tension mechanosensors by GABA(B) agonists leading to reduction of reflux. In addition to tension mechanosensors, the vagal nodose ganglion supplies the esophagus with nociceptive C-fibers that likely contribute to impairment of esophageal reflex regulation in diseases. We hypothesized that GABA(B) agonists inhibit mechanically-induced activation of vagal esophageal nodose C-fibers in baseline and/or in sensitized state induced by inflammatory mediators. Ex vivo extracellular recordings were made from the esophageal nodose C-fibers in the isolated vagally-innervated guinea pig esophagus. We found that the selective GABA(B) agonist baclofen (100-300 microM) did not inhibit activation of esophageal nodose C-fibers evoked by esophageal distention (10-60 mmHg). The mechanical response of esophageal nodose C-fibers can be sensitized by different pathways including the stimulation of the histamine H(1) receptor and the stimulation the adenosine A(2A) receptor. Baclofen failed to inhibit mechanical sensitization of esophageal nodose C-fibers induced by histamine (100 microM) or the selective adenosine A(2A) receptor agonist CGS21680 (3 nM). Our data suggest that the direct mechanical inhibition of nodose C-fibers in the esophagus is unlikely to contribute to beneficial effects of GABA(B) agonists in patients with esophageal diseases.


Light sensitivity of shoot hydraulic conductance in five temperate deciduous tree species.
The light sensitivity of the shoot hydraulic conductance in five temperate deciduous tree species was measured using two methods to clarify the role of light sensitivity and the suitability of the methods used to study it. The light sensitivity measured using a method that included an interruption of ≤10min in shoot light acclimation did not differ from that measured using a method with continuous illumination. The 'noncontinuous light' methods are suitable for measuring hydraulic conductance and its light response. Light sensitivity correlated with other leaf water traits as follows: positively with the ion-mediated increase in xylem hydraulic conductance; a relative decrease in the hydraulic conductance of the laminae in response to HgCl2; a relative change in stomatal conductance in response to changes in PAR intensity or atmospheric CO2 concentration, or to a decrease in air humidity or leaf water potential; and with instantaneous water use efficiency. The traits correlated negatively with shoot hydraulic conductance, stomatal conductance and relative increases in stomatal conductance in response to increases in leaf water potential. We suggest that high light sensitivity should be considered as one of the characteristics of conservative water use in trees. Low blue light increased shoot hydraulic conductance to a similar extent to moderate white light and twice as much as moderate red light. Blue light perception is important in the light sensitivity mechanism.


[Detection of cutaneous leishmaniasis cases in Hatay and surrounding areas].
Leishmaniasis; is a disease that is transmitted by infected sand flies when they suck the blood of mammals. Cutaneous leishmaniasis (CL), which is given such names as the Antep boil in Turkey, is mostly seen on the skin and sometimes on the mucosa and heals with a recessed scar. Between June 2003 and October 2005, 55 patients with skin lesions presented at the parasitology laboratory of the Mustafa Kemal University Medical Faculty for the detection of CL. Microscopic examination showed Leishmania amastigotes in 40 patients who were given a diagnosis of CL. Thirteen patients were men (32.5%) and 27, women (67.5%). The most frequent age range was 0-20 (57.0%). The lesions were mostly found on the face in 27 (67.5%) patients and on the hands and feet in 13 (32.5%). Fourteen patients (35.0%) had 2 or more lesions. The duration of the lesions was from a minimum of 1 month to a maximum of 3 years. The patients were mostly from Iskenderun/Kirikhan, Iskenderun/Arsus Serinyol, Altinözü, Samandağ Antakya, Harbiye and they were farmers. Cutaneous leishmaniasis was more often detected during the May-June period. Some patients came to our laboratory from regions that had not reported CL before. Therefore, we think that CL has been increasing in Hatay and its surroundings.


Coating Graphene Oxide with Lipid Bilayers Greatly Decreases Its Hemolytic Properties.
Toxicity evaluation for the proper use of graphene oxide (GO) in biomedical applications involving intravenous injections is crucial, but the GO circulation time and blood interactions are largely unknown. It is thought that GO may cause physical disruption (hemolysis) of red blood cells. The aim of this work is to characterize the interaction of GO with model and cell membranes and use this knowledge to improve GO hemocompatibility. We have found that GO interacts with both neutral and negatively charged lipid membranes; binding is decreased beyond a certain concentration of negatively charged lipids and favored in high-salt buffers. After this binding occurs, some of the vesicles remain intact, while others are disrupted and spread over the GO surface. Neutral membrane vesicles tend to break down and extend over the GO, while vesicles with negatively charged membranes are mainly bound to the GO without disruption. GO also interacts with red blood cells and causes hemolysis; hemolysis is decreased when GO is previously coated with lipid membranes, particularly with pure phosphatidylcholine vesicles.


Extended use of disposable pressure transducers. A bacteriologic evaluation.
In a prospective randomized study, contamination rates of disposable pressure transducers changed every two days (n = 81) were compared with those changed at four (n = 26) or eight days (n = 50); the mean daily incidence of contamination was 3% for each group. After four days of use, the cumulative prevalences of contamination were similar. However, after eight days, the cumulative prevalence was significantly higher in transducers used without change (6.9%) than in those changed every two days (2.9%). Gram-negative bacilli were present in 63% of contaminated transducers; over half were from the patients' own flora. The only definite transducer-related bacteremia occurred on a day of initial contamination and should have been unaffected by the interval of change. Routine use of disposable transducers can be safely extended to four days, even in a busy intensive care unit.


Lattice point sets for deterministic learning and approximate optimization problems.
In this brief, the use of lattice point sets (LPSs) is investigated in the context of general learning problems (including function estimation and dynamic optimization), in the case where the classic empirical risk minimization (ERM) principle is considered and there is freedom to choose the sampling points of the input space. Here it is proved that convergence of the ERM principle is guaranteed when LPSs are employed as training sets for the learning procedure, yielding up to a superlinear convergence rate under some regularity hypotheses on the involved functions. Preliminary simulation results are also provided.


Is X-linked Recessive Ichthyosis a High Risk for Basal Cell Carcinoma?
We report a case of X-linked recessive ichthyosis with basal cell carcinoma. An 86-year-old man was referred to our department for evaluation of a 1-year history of an ulcer on his left leg. He had suffered from dry skin with scales on his entire body since childhood. Histopathological examination of the lower leg revealed intradermal proliferation of a solid nest of basaloid cells showing unclear palisading in the periphery. Marked hyperkeratosis and hypergranulosis were also seen in the adjacent dermis. Loss of the steroid sulfatase gene was found on chromosome X. Based on these finding, we made a diagnosis of X-linked recessive ichthyosis with basal cell carcinoma. To our knowledge, there has been no report of X-linked recessive ichthyosis with cutaneous malignancy. We discuss the risk of skin cancer in relation to ichthyosis.


Axonal neuropathy-associated TRPV4 regulates neurotrophic factor-derived axonal growth.
Spinal muscular atrophy and hereditary motor and sensory neuropathies are characterized by muscle weakness and atrophy caused by the degenerations of peripheral motor and sensory nerves. Recent advances in genetics have resulted in the identification of missense mutations in TRPV4 in patients with these hereditary neuropathies. Neurodegeneration caused by Ca(2+) overload due to the gain-of-function mutation of TRPV4 was suggested as the molecular mechanism for the neuropathies. Despite the importance of TRPV4 mutations in causing neuropathies, the precise role of TRPV4 in the sensory/motor neurons is unknown. Here, we report that TRPV4 mediates neurotrophic factor-derived neuritogenesis in developing peripheral neurons. TRPV4 was found to be highly expressed in sensory and spinal motor neurons in early development as well as in the adult, and the overexpression or chemical activation of TRPV4 was found to promote neuritogenesis in sensory neurons as well as PC12 cells, whereas its knockdown and pharmacologic inhibition had the opposite effect. More importantly, nerve growth factor or cAMP treatment up-regulated the expression of phospholipase A(2) and TRPV4. Neurotrophic factor-derived neuritogenesis appears to be regulated by the phospholipase A(2)-mediated TRPV4 pathway. These findings show that TRPV4 mediates neurotrophic factor-induced neuritogenesis in developing peripheral nerves. Because neurotrophic factors are essential for the maintenance of peripheral nerves, these findings suggest that aberrant TRPV4 activity may lead to some types of pathology of sensory and motor nerves.


Diffusion tubes: a method for the mass culture of ctenophores and other pelagic marine invertebrates.
The culture of pelagic marine invertebrates, especially the ctenophore Mnemiopsis leidyi, has been demonstrated in past studies dating back to the 1960s; however, the mass culture of delicate pelagic invertebrates has remained elusive. By using a pair of acrylic tubes and enabling water diffusion between them, we have been able to reliably and cost effectively mass culture several genera of ctenophores (Pleurobrachia, Hormiphora, Bolinopsis, Mnemiopsis and Leucothea), one species of siphonophore (Nanomia) and one species of larvacean (Oikopleura). The simple, compact method is effective enough to support two permanent exhibits of ctenophores at the Monterey Bay Aquarium while minimizing live food culture requirements with the potential to support further investigation of pelagic marine invertebrate ontogeny, ecology and genomics.


Receding dynamics of contact lines and size-dependent adhesion on microstructured hydrophobic surfaces.
The microstructure size on textured surfaces of a given solid fraction exhibits an important effect on their properties. To understand the size effect on surface adhesion, we study the receding dynamics of the microscopic three-phase contact lines, the adhesive properties, and the relation between them on microstructured surfaces. Two types of surfaces are used, which are micropillar and micropore, respectively. First, the receding process of the contact line is directly observed by laser scanning confocal microscopy (LSCM), which shows distinct characteristics on the two types of surfaces. The micro contact line experiences pinnning, sliding, and rupture on micropillar-patterned surfaces while no rupture occurs on micropore-patterned surfaces. The three-dimensional morphology of the micromeniscus on the micropillared surfaces and the two-dimensional scanning of the cross-sections of the micromeniscus along the diagonal direction are imaged. Based on the images, the local contact angles around the micropillar at the receding front, and the curvatures of the micro-meniscus are obtained. Then, the adhesive force on these surfaces is measured, which surprisingly shows an increasing trend with the size of the microstructure for micropillared surfaces but no obvious size dependence for micropored surfaces. Wetting hysteresis is also measured to testify the similar trend with the size for the two types of surfaces. Further investigation shows that the monotonic increase of the adhesive force with the increasing size of micropillars is due to the growing difficulty of the detachment of the contact lines. The underlying mechanism responsible for the size dependence of the adhesive force is the enhancement of the local reduced pressure exerted on the top of the micropillar with increasing size, resulting from the concave profile of the outer micromeniscus.


Kidney toxicity of the BRAF-kinase inhibitor vemurafenib is driven by off-target ferrochelatase inhibition.
A multitude of disease and therapy related factors drive the frequent development of kidney disorders in cancer patients. Along with chemotherapy, the newer targeted therapeutics can also cause kidney dysfunction through on and off-target mechanisms. Interestingly, among the small molecule inhibitors approved for the treatment of cancers that harbor BRAF-kinase activating mutations, vemurafenib can trigger tubular damage and acute kidney injury. BRAF is a proto-oncogene involved in cell growth. To investigate the underlying mechanisms, we developed cell culture and mouse models of vemurafenib kidney toxicity. At clinically relevant concentrations vemurafenib induces cell-death in transformed and primary mouse and human kidney tubular epithelial cells. In mice, two weeks of daily vemurafenib treatment causes moderate acute kidney injury with histopathological characteristics of kidney tubular epithelial cells injury. Importantly, kidney tubular epithelial cell-specific BRAF gene deletion did not influence kidney function under normal conditions or alter the severity of vemurafenib-associated kidney impairment. Instead, we found that inhibition of ferrochelatase, an enzyme involved in heme biosynthesis contributes to vemurafenib kidney toxicity. Ferrochelatase overexpression protected kidney tubular epithelial cells and conversely ferrochelatase knockdown increased the sensitivity to vemurafenib-induced kidney toxicity. Thus, our studies suggest that vemurafenib-associated kidney tubular epithelial cell dysfunction and kidney toxicity is BRAF-independent and caused, in part, by off-target ferrochelatase inhibition.


Natriuretic peptides and troponins in pulmonary embolism: a meta-analysis.
The role of biomarkers such as B-type natriuretic peptides (BNP and NT-proBNP) and troponins in risk stratification of acute pulmonary embolism (APE) is still debated. A meta-analysis was performed to assess the association between raised natriuretic peptide levels, alone or in conjunction with troponins, and all-cause and APE-related mortality, serious adverse events and echographic right ventricular dysfunction. MEDLINE and EMBASE databases were searched and conference abstracts were hand searched up to February 2008. Studies were included if a 2x2 table could be constructed based on natriuretic peptide results and at least one of the outcomes. Twenty-three studies were included (1127 patients). Raised natriuretic peptide levels were significantly associated with all-cause mortality (odds ratio (OR) 6.2; 95% confidence interval (CI) 3.0 to 12.7), APE-related mortality (OR 5.0; 95% CI 2.2 to 11.5) and serious adverse events (OR 6.7; 95% CI 3.9 to 11.6), with homogeneity across studies. Among patients with raised natriuretic peptide levels, increased serum troponins were associated with a further increase in the risk of adverse outcomes. Analysis of the accuracy of natriuretic peptides in detecting right ventricular dysfunction was limited by heterogeneity across studies. BNP appeared to have better sensitivity and specificity than NT-proBNP in detecting right ventricular dysfunction. Raised levels of B-type natriuretic peptides identified a subset of patients with APE at higher risk of adverse outcomes. Among patients with raised natriuretic peptide levels, increased troponins were found to be an independent prognostic marker. The results of this meta-analysis may have important clinical implications in the management of APE.


Clinical-Scale Cell-Surface-Marker Independent Acoustic Microfluidic Enrichment of Tumor Cells from Blood.
Enumeration of circulating tumor cells (CTCs) predicts overall survival and treatment response in metastatic cancer, but as many commercialized assays isolate CTCs positive for epithelial cell markers alone, CTCs with little or no epithelial cell adhesion molecule (EpCAM) expression stay undetected. Therefore, CTC enrichment and isolation by label-free methods based on biophysical rather than biochemical properties could provide a more representative spectrum of CTCs. Here, we report on a clinical-scale automated acoustic microfluidic platform processing 5 mL of erythrocyte-depleted paraformaldehyde (PFA)-fixed blood (diluted 1:2) at a flow rate of 75 μL/min, recovering 43/50 (86 ± 2.3%) breast cancer cell line cells (MCF7), with 0.11% cancer cell purity and 162-fold enrichment in close to 2 h based on intrinsic biophysical cell properties. Adjustments of the voltage settings aimed at higher cancer cell purity in the central outlet provided 0.72% cancer cell purity and 1445-fold enrichment that resulted in 62 ± 8.7% cancer cell recovery. Similar rates of cancer-cell recovery, cancer-cell purity, and fold-enrichment were seen with both prostate cancer (DU145, PC3) and breast cancer (MCF7) cell line cells. We identified eosinophil granulocytes as the predominant white blood cell (WBC) contaminant (85%) in the enriched cancer-cell fraction. Processing of viable cancer cells in erythrocyte-depleted blood provided slightly reduced results as to fixed cells (77% cancer cells in the enriched cancer cell fraction, with 0.2% WBC contamination). We demonstrate feasibility of enriching either PFA-fixed or viable cancer cells with a clinical-scale acoustic microfluidic platform that can be adjusted to meet requirements for either high cancer-cell recovery or higher purity and can process 5 mL blood samples in close to 2 h.


Homogeneous insulin and C-Peptide sensors for rapid assessment of insulin and C-peptide secretion by the islets.
Glucose-stimulated islet insulin or C-peptide secretion experiments are a fundamental tool for studying and assessing islet function. The goal of this work was to develop Ab-based fluorescent homogenous sensors that would allow rapid, inexpensive, near-instantaneous determinations of insulin and C-peptide levels in biological samples. Our approach was to use molecular pincer design (Heyduk et al., Anal Chem 2008;80:5152-5159) in which a pair of antibodies recognizing nonoverlapping epitopes of the target are modified with short fluorochrome-labeled complementary oligonucleotides and are used to generate a fluorescence energy transfer (FRET) signal in the presence of insulin or C-peptide. The sensors were capable of detecting insulin and C-peptide with high specificity and with picomolar concentration detection limits in times as short as 20 min. Insulin and C-peptide levels determined with the FRET sensors showed outstanding correlation with determinations performed under the same conditions with enzyme-linked immunosorbent assay. Most importantly, the sensors were capable of rapid and accurate determinations of insulin and C-peptide secreted from human or rodent islets, verifying their applicability for rapid assessment of islet function. The homogeneous, rapid, and uncomplicated nature of insulin and C-peptide FRET sensors allows rapid assessment of β-cell function and could enable point-of-care determinations of insulin and C-peptide.


The Key Role of Molecular Packing in Luminescence Property: from Adjacent Molecules to Molecular Aggregates.
The luminescence materials act as the key components in many functional devices, as well as the detection and imaging systems, which can be permeated in each aspect of modern life, and attract more and more attention for the creative technology and applications. In addition to the diverse properties of organic luminogens, the multiple molecular packing at aggregated states frequently offer new and/or exciting performance. However, there still lacks comprehensive analysis of molecular packing in these organic materials, resulting in an increased gap between molecular design and practical applications. In this review, from the basic knowledge of organic compounds as single molecules, to the discernable property of excimer, charge transfer (CT) complex or self-assembly systems by adjacent molecules, and finally to the opto-electronic performance of molecular aggregates, the relevant factors to the molecular packing and practical applications are discussed. This article is protected by copyright. All rights reserved.


Single-Step BLUP with Varying Genotyping Effort in Open-Pollinated Picea glauca.
Maximization of genetic gain in forest tree breeding programs is contingent on the accuracy of the predicted breeding values and precision of the estimated genetic parameters. We investigated the effect of the combined use of contemporary pedigree information and genomic relatedness estimates on the accuracy of predicted breeding values and precision of estimated genetic parameters, as well as rankings of selection candidates, using single-step genomic evaluation (HBLUP). In this study, two traits with diverse heritabilities [tree height (HT) and wood density (WD)] were assessed at various levels of family genotyping efforts (0, 25, 50, 75, and 100%) from a population of white spruce (Picea glauca) consisting of 1694 trees from 214 open-pollinated families, representing 43 provenances in Québec, Canada. The results revealed that HBLUP bivariate analysis is effective in reducing the known bias in heritability estimates of open-pollinated populations, as it exposes hidden relatedness, potential pedigree errors, and inbreeding. The addition of genomic information in the analysis considerably improved the accuracy in breeding value estimates by accounting for both Mendelian sampling and historical coancestry that were not captured by the contemporary pedigree alone. Increasing family genotyping efforts were associated with continuous improvement in model fit, precision of genetic parameters, and breeding value accuracy. Yet, improvements were observed even at minimal genotyping effort, indicating that even modest genotyping effort is effective in improving genetic evaluation. The combined utilization of both pedigree and genomic information may be a cost-effective approach to increase the accuracy of breeding values in forest tree breeding programs where shallow pedigrees and large testing populations are the norm.


Transapical aortic valve prosthetic endocarditis.
An 83-year-old patient underwent a transapical aortic valve implantation at our institution. Four months later, she was readmitted to our institution because of fever and heart failure. A prosthetic aortic valve endocarditis was diagnosed. Because of the high surgical risk, surgery was refused and the patient died shortly after the diagnosis. We briefly discuss the implications of this finding in the prevention of infective endocarditis after transcatheter aortic valve implantation.


Revisiting basal cell carcinoma clinical margins: Leveraging natural language processing and multivariate analysis with updated Royal College of Pathologists histological reporting standards.
Data supporting the current British Association of Dermatologists guidelines for the management of basal cell carcinoma (BCC) are based on historic studies and do not consider the updated Royal College of Pathologists (RCPath) histological reporting standards. The aim of this study was to use natural language processing (NLP)-derived data and undertake a multivariate analysis with updated RCPath standards, providing a contemporary update on the excision margins required to achieve histological clearance in BCC. A validated NLP information extraction model was used to perform a rapid multi-centre, pan-specialty, consecutive retrospective analysis of BCCs, managed with surgical excision using a pre-determined clinical margin, over a 17-year period (2004-2021) at Swansea Bay University Health Board. Logistic regression assessed the relationship between the peripheral and deep margins and histological clearance. We ran our NLP algorithm on 34,955 BCCs. Out of the 1447 BCCs that met the inclusion criteria, the peripheral margin clearance was not influenced by the BCC risk level (p = 0.670). A clinical peripheral margin of 6 mm achieved a 95% histological clearance rate (95% confidence interval [CI], 0.93-0.98). Tumour thickness inversely affected deep-margin histological clearance (OR 0.720, 95% CI, 0.525-0.991, p < 0.05). Depth level 2 had a 97% probability of achieving deep-margin histological clearance across all tumour thicknesses. Updated RCPath reporting standards minimally impact the peripheral margin histological clearance in BCC. Larger clinical peripheral margins than those indicated by current guidelines may be necessary to achieve excision rates of ≥95%. These findings emphasise the need for continuous reassessment of clinical standards to enhance patient care.


The enemy as animal: Symmetric dehumanization during asymmetric warfare.
Historically, dehumanization has enabled members of advantaged groups to 'morally disengage' from disadvantaged group suffering, thereby facilitating acts of intergroup aggression such as colonization, slavery and genocide. But is blatant dehumanization exclusive to those at the top 'looking down', or might disadvantaged groups similarly dehumanize those who dominate them? We examined this question in the context of intergroup warfare in which the disadvantaged group shoulders a disproportionate share of casualties and may be especially likely to question the humanity of the advantaged group. Specifically, we assessed blatant dehumanization in the context of stark asymmetric conflict between Israelis (Study 1; N = 521) and Palestinians (Study 2; N = 354) during the 2014 Gaza war. We observed that (a) community samples of Israelis and Palestinians expressed extreme (and comparable) levels of blatant dehumanization, (b) blatant dehumanization was uniquely associated with outcomes related to outgroup hostility for both groups, even after accounting for political ideologies known to strongly predict outgroup aggression, and (c) the strength of association between blatant dehumanization and outcomes was similar across both groups. This study illuminates the striking potency and symmetry of blatant dehumanization among those on both sides of an active asymmetric conflict.


Multi-Pathway Microenvironment Regulation for Atherosclerosis Therapy Based on Beta-Cyclodextrin/L-Arginine/Au Nanomotors with Dual-Mode Propulsion.
Most of the current non-pharmacological treatment strategies for atherosclerosis (AS) suffer from poor penetration into the plaque and only aim at a certain factor in its formation process, resulting in limited therapeutic effect. Herein, a kind of nanomotor with dual-mode propulsion is constructed, which is sensitive to higher reactive oxygen species (ROS) at the AS site and near-infrared (NIR) laser by the covalent binding and self-assembly of β-cyclodextrin (β-CD) and L-arginine (LA) with immobilization of Au nanoparticles. NIR laser irradiation can be used as a driving force and to ablate inflammatory macrophages through the photothermal effect. The nitric oxide (NO) released by the nanomotors can be used as another driving force and a therapeutic agent to promote endothelial repair in the plaque site. LA can eliminate ROS in the inflammatory site, and β-CD can promote the removal of cholesterol from foam cells. In particular, the two driving modes of nanomotors synergistically promote their aggregation and penetration in the plaque. This kind of nanomotor can regulate the microenvironment of AS in multiple ways, including combination therapy for endothelial repair, lipid clearance, and reducing ROS, which is expected to become a potential non-pharmacological strategy in the treatment of AS.


Two PMS2 mutations in a Turcot syndrome family with small bowel cancers.
We report the clinicopathological, genetic, and immunohistochemical characterization of an atypical Turcot syndrome (TS) family with small bowel cancer. The tumor family history of a patient with cafè-au-lait spots (CALS) and early onset adenomas, duodenal cancer, and glioblastoma was positive for colonic adenoma (mother), jejunal (maternal grandfather), lung (father), and colorectal (paternal uncle) cancers. PMS2 genetic testing identified the nonsense 1951C>T (Q643X) and the missense 161C>T (S46I) mutations. PMS2 expression was absent in the proband's duodenal cancer with high microsatellite instability. The normal cells also displayed no PMS2 expression and some degree of instability. Our findings point out the association between PMS2 and TS, and support the hypothesis that patients with a few polyps, small bowel tumors with a very early onset, glioblastoma, and CALS should be considered as a variant of hereditary nonpolyposis colorectal cancer. A recessive model of inheritance caused by compound heterozygous mutations was consistent with the observed severe clinical phenotype and has important implications for predicting cancer risk in both the proband and his relatives.


Virulence of clinical and environmental isolates of Burkholderia oklahomensis and Burkholderia thailandensis in hamsters and mice.
Burkholderia pseudomallei is the etiologic agent of the tropical disease melioidosis and is considered to be a potential biological weapon. Two B. pseudomallei-like species, Burkholderia oklahomensis and Burkholderia thailandensis, have been described in the literature. Infections with both of these microorganisms have occurred in the United States, but little is known about the relative virulence of these isolates in animal models of infection. In this study, B. oklahomensis and B. thailandensis CDC2721121 were determined to be avirulent in hamsters and mice at all challenge doses examined. The virulence of B. thailandensis CDC3015869, on the other hand, was more similar to the virulence of isolates of B. thailandensis from Southeast Asia.


Improving decision making in forensic child sexual abuse evaluations.
Mental health professionals can assist legal decision makers in cases of allegations of child sexual abuse by collecting data using forensic interviews, psychological testing, and record reviews, and by summarizing relevant findings from social science research. Significant controversy surrounds another key task performed by mental health professionals in most child sexual abuse evaluations, i.e., deciding whether or not to substantiate unconfirmed abuse allegations. The available evidence indicates that, on the whole, these substantiation decisions currently lack adequate psychometric reliability and validity: an analysis of empirical research findings leads to the conclusion that at least 24% of all of these decisions are either false positive or false negative errors. Surprisingly, a reanalysis of existing research also indicates that it may be possible to develop reliable, objective procedures to improve the consistency and quality of decision making in this domain. A preliminary, empirically-grounded procedure for making substantiation decisions is proposed.


Global mapping of gene/protein interactions in PubMed abstracts: a framework and an experiment with P53 interactions.
Gene/protein interactions provide critical information for a thorough understanding of cellular processes. Recently, considerable interest and effort has been focused on the construction and analysis of genome-wide gene networks. The large body of biomedical literature is an important source of gene/protein interaction information. Recent advances in text mining tools have made it possible to automatically extract such documented interactions from free-text literature. In this paper, we propose a comprehensive framework for constructing and analyzing large-scale gene functional networks based on the gene/protein interactions extracted from biomedical literature repositories using text mining tools. Our proposed framework consists of analyses of the network topology, network topology-gene function relationship, and temporal network evolution to distill valuable information embedded in the gene functional interactions in the literature. We demonstrate the application of the proposed framework using a testbed of P53-related PubMed abstracts, which shows that the literature-based P53 networks exhibit small-world and scale-free properties. We also found that high degree genes in the literature-based networks have a high probability of appearing in the manually curated database and genes in the same pathway tend to form local clusters in our literature-based networks. Temporal analysis showed that genes interacting with many other genes tend to be involved in a large number of newly discovered interactions.


Challenge of Drosophila melanogaster with Cryptococcus neoformans and role of the innate immune response.
We found that the ingestion of Cryptococcus neoformans by Drosophila melanogaster resulted in the death of the fly but that the ingestion of Saccharomyces cerevisiae or the nonpathogenic Cryptococcus kuetzingii or Cryptococcus laurentii did not. The C. neoformans protein kinase A and RAS signal transduction pathways, previously shown to be involved in virulence in mammals, also played a role in killing Drosophila. Mutation of the Toll immune response pathway, the predominant antifungal pathway of the fly, did not play a role in Drosophila defense following ingestion of the yeast. However, the Toll pathway was necessary for the clearance of C. neoformans introduced directly into the hemolymph of D. melanogaster and for the survival of systemically infected flies.


Chemical constituent and antimicrobial effect of essential oil from Myrtus communis leaves on microorganisms involved in persistent endodontic infection compared to two common endodontic irrigants: An in vitro study.
Persistent infections of human root canals play a fundamental role in the failure of endodontic treatment. The purpose of this study is to determine the chemical composition of Myrtus communis (M. communis) essential oil and to assess its antimicrobial activity against Enterococcus faecalis, Staphylococcus aureus and Candida albicans compared to that of sodium hypochlorite (NaOCl) and chlorhexidine (CHX). Gas chromatography-mass spectrometry (GC-MS) was used to determine the chemical composition of essential oil from M. communis leaves. A micro-dilution susceptibility assay and disk diffusion methods were utilized to evaluate the antimicrobial activity [minimum inhibitory concentration (MIC) and minimum lethal dose concentration] of the tested solutions against selected microorganisms. GC-MS analyses revealed that M. communis contained 1, 8-Cineole (28.62%), α-Pinene (17.8%), Linalool (17.55%), and Geranylacetate (6.3%) as the major compounds and Geraniol (1.6%), α-Humulene (1.5%), eugenol (1.3%), isobutyl-isobutyrate (0.8%), and methyl chavicol (0.5%) as minor components. Chlorhexidine had the lowest MIC value among all medicaments tested. M. communis oil had less MIC values than NaOCl against both bacteria, but it had more MIC value against C. albicans. M. communis essential oil with the minimum inhibitory concentration in the range of 0.032-32 μg/mL was an effective antimicrobial agent against persistent endodontic microorganisms.


Malignant lymphoma originating in the jejunum of a long-term follow-up case of protein-losing enteropathy.
A 50-year-old female patient, who had been followed for 15 years for protein-losing enteropathy, was hospitalized due to epigastric pain. Examination on admission revealed that the patient was in the sub-ileus state. On the 26th day after admission, she complained of severe abdominal pain and shortly after she went into shock. The emergency laparotomy documented intestinal perforation and a tumor. The perforated site was right at the middle of tumor. The histological and histochemical studies identified the tumor as malignant lymphoma of B lymphocyte lineage. As far as we know, this is the third case of malignant lymphoma occurring in the jejunum in a patient with protein-losing enteropathy in Japan. The possible relationship between lymphomas and protein-losing enteropathy is discussed.