Lymph node sampling is of prognostic value in early stage epithelial ovarian carcinoma.
The importance of lymph node involvement as a prognostic factor is still under debate. In the present study, the impact of surgical staging for prognosis in early stages of epithelial ovarian cancer was evaluated in a series of 113 patients. A retrospective study was carried out at the Department of Gynecological Oncology, Orebro University Hospital, during the period 1994-1998. In a subgroup of 20 out of 113 patients, pelvic lymph node sampling or pelvic lymphadenectomy was included in the standard surgical procedure. In cases of positive lymph nodes, the tumors were upstaged to FIGO Stage III. Pearson's chi-square, the t-test, the log-rank test and Cox multivariate analysis were used in the statistical analyses. The 20 patients with lymph node sampling or lymphadenectomy were compared with the remaining 93 patients without a comprehensive surgical staging procedure. A survival analysis demonstrated a significant (p = 0.005) difference in disease-free survival rates between the two subgroups, where there was a survival benefit in the subgroup of patients who had undergone comprehensive surgical staging. In a Cox proportional hazard regression analysis with disease-free survival as the endpoint, high tumor grade (HR = 3.14) and comprehensive surgical staging with at least a node sampling (HR = 0.09) were significant and independent prognostic factors. The benefit in survival after the procedure of lymph node sampling in early stages of epithelial ovarian carcinoma could probably be explained by the fact that the surgical procedure detects otherwise unrecognized Stage III disease.


Korean patients taking α1-adrenergic receptor antagonists show lower incidence of intraoperative floppy iris syndrome than western patients.
To evaluate the incidence and clinical manifestations of intraoperative floppy iris syndrome (IFIS) according to iris alterations in Korean patients taking α1-adrenergic receptor antagonists (α1-ARAs). This is a prospective observational study. Two surgeons performed cataract surgery in 758 eyes of 596 patients over a period of 12 months. Past medical history was reviewed, especially whether patients had been taking systemic α1-ARAs. Ultrasound biomicroscopy was performed to measure the iris thickness of the dilator muscle region (DMR) at half the distance between the scleral spur and the pupillary margin. Pupil diameter was measured and the occurrence of IFIS was recorded. Measurements of the α1-ARA group were compared with those of a control group matched for age and sex. IFIS occurred only in six eyes of four patients on systemic α1-ARA medications (0.8%). Pupil diameter in the α1-ARA medication group and the control group was not significantly different. The difference in mean DMR thickness in patients taking an α1-ARA and in the control group was also not statistically significant (p=0.641). However, within the α1-ARA population, the DMR thickness of IFIS cases was significantly lower than that of non-IFIS cases (p=0.013) CONCLUSIONS: The overall incidence of IFIS was far lower in Korean patients than that reported for western patients. IFIS patients taking α1-ARAs showed significantly greater iris DMR thinning than non-IFIS patients taking α1-ARAs. Our findings indicate that the interaction between α1-ARAs and melanin, which results in iris DMR atrophy and IFIS, is less strong in Korean patients (with dark irises) than western patients.


Craniotomy for supratentorial brain tumors: risk factors for brain swelling after opening the dura mater.
Cerebral swelling often occurs during craniotomy for cerebral tumors. The primary aim in this study was to determine risk factors (intracranial pressure [ICP], patient characteristics, histopathological features, neuroimaging characteristics, anesthetic regimen, and perioperative physiological data) predictive of brain swelling through the dural opening. As a secondary aim the authors attempted to define subdural ICP thresholds associated with brain swelling. The study population consisted of 692 patients (mean age 50+/-15 years) scheduled for elective craniotomy for supratentorial brain tumors. Brain swelling through the dural opening was estimated according to a four-point scale. The patients were dichotomized as those without cerebral swelling (that is, brain below the dura mater [59 patients] or brain at the level of the dura mater [386 patients]) and those with cerebral swelling (that is, moderate brain swelling [205 patients] or pronounced brain swelling [42 patients]). Logistic regression analysis was used to identify subdural ICP (odds ratio [OR] 1.9, 95% confidence interval [CI] 1.72-2.1, p < 0.0001), midline shift (OR 1.06, 95% CI 1.02-1.11, p = 0.008), a diagnosis of glioblastoma multiforme (OR 2.1, 95% CI 1.01-4.3, p = 0.047), and metastasis (OR 2.9, 95% CI 1.3-6.9, p = 0.01) as independent risk factors of intraoperative brain swelling. Thresholds for ICP associated with brain swelling were defined as follows: at an ICP less than 5 mm Hg, brain swelling rarely occurred (5% probability); at an ICP greater than 13 mm Hg, brain swelling occurred with 95% probability; and at an ICP greater than 26 mm Hg, severe brain swelling occurred with 95% probability. Subdural ICP is the strongest predictor of intraoperative brain swelling. It is possible to define thresholds of cerebral swelling and the authors recommend subdural ICP measurement as a tool to initiate preventive measures to reduce ICP before opening the dura mater.


Nonhydrolyzable d‑phenylalanine-benzoxazole derivatives retain antitubercular activity.
The emergence of drug resistant Mycobacterium tuberculosis, the causative agent of tuberculosis, demands the development of new drugs and new drug targets. We have recently reported that the d-phenylalanine benzoxazole Q112 has potent antibacterial activity against this pathogen with a distinct mechanism of action from other antimycobacterial agents. Q112 and previously reported derivatives were unstable in plasma and no free compound could be observed. Here we expand the structure-activity relationship for antimycobacterial activity and find nonhydrolyzable derivatives with decreased plasma binding. We also show that there is no correlation between antibacterial activity and inhibition of PanG, a putative target for these compounds.


Analysis of HLA genes in families with autoimmune diabetes and thyroiditis.
Type 1 diabetes (T1D) and autoimmune thyroid disease (AITD) are the most common autoimmune endocrine disorders. The similar pathogenesis of T1D and AITD and their tendency to occur together suggest that their etiology may involve common genetic factors. We hypothesized that the human leukocyte antigen (HLA) locus may contribute in part to the joint susceptibility to T1D and AITD. We therefore analyzed a data set of 40 multiplex families in which T1D and AITD clustered ("T1D-AITD families") for linkage and association with the HLA class II locus. We found evidence for linkage of the HLA region to T1D (maximum logarithm of odds score [MLS] = 7.3), to Hashimoto thyroiditis (HT) (MLS = 1.5), and to both (MLS = 3.8). Transmission disequilibrium test analysis revealed significant association of both T1D and AITD with HLA-DR3; however, only T1D was associated with HLA-DR4. We concluded that the finding of evidence for linkage of HLA with HT is in contrast to the strong evidence against linkage found in previous studies of AITD-only families; therefore, it is possible that the AITD phenotype seen in T1D families has a different genetic etiology than the AITD phenotype in AITD-only families; that HLA-DR3 was the major HLA allele contributing to the joint genetic susceptibility to T1D and AITD, whereas other alleles (e.g., DR4) are phenotype specific; and that because the logarithm of odds score for T1D + HT was lower than for T1D alone, additional non-HLA loci must contribute to the shared genetic susceptibility to T1D and AITD.


Synergistic Enhancement of Photocatalytic H2 Evolution over NH2-MIL-125 Modified with Dual Cocatalyst.
The construction of efficient photocatalysts for water splitting to enable H2 evolution is pivotal to alleviate energy issues and environmental concerns. In this work, carbon dots (CDs) were prepared by employing "green solvent" ionic liquids as carbon sources and then combined with Pt/NH2-MIL-125, resulting in the emergence of a high-efficiency photocatalyst termed CDs-Pt/NH2-MIL-125 for the first time. This composite photocatalyst exhibited outstanding photocatalytic activity in H2 production under visible light irradiation. Notably, the H2 production rate of CDs100-Pt/NH2-MIL-125 reaches up to 951.4 μmol/g/h, which was 3.1 times that of Pt/NH2-MIL-125. The characterization results indicate that CDs and Pt uniformly dispersed on the surface of NH2-MIL-125 and fabricated a synergistic compact structure, providing a high BET surface area (985 m2 g-1) and a suitable band gap. Furthermore, the distinctive embeddable-dispersed CDs and Pt, as dual cocatalyst, can harvest light and facilitate the transfer of photogenerated electrons, thereby significantly augmenting the exploitation of visible light. The plausible mechanism of photocatalytic H2 evolution over the CDs-Pt/NH2-MIL-125 catalyst was also discussed. This work introduces a promising strategy for designing high-performance CDs-MOFs-based photocatalysts, an innovative step toward achieving efficient photocatalytic water splitting for H2 production.


CKS1B, overexpressed in aggressive disease, regulates multiple myeloma growth and survival through SKP2- and p27Kip1-dependent and -independent mechanisms.
Overexpression of CKS1B, a gene mapping within a minimally amplified region between 153 to 154 Mb of chromosome 1q21, is linked to a poor prognosis in multiple myeloma (MM). CKS1B binds to and activates cyclin-dependent kinases and also interacts with SKP2 to promote the ubiquitination and proteasomal degradation of p27(Kip1). Overexpression of CKS1B or SKP2 contributes to increased p27(Kip1) turnover, cell proliferation, and a poor prognosis in many tumor types. Using 4 MM cell lines harboring MAF-, FGFR3/MMSET-, or CCND1-activating translocations, we show that lentiviral delivery of shRNA directed against CKS1B resulted in ablation of CKS1B mRNA and protein with concomitant stabilization of p27(Kip1), cell cycle arrest, and apoptosis. Although shRNA-mediated knockdown of SKP2 and forced expression of a nondegradable form of p27(Kip1) (p27(T187A)) led to cell cycle arrest, apoptosis was modest. Of importance, while knockdown of SKP2 or overexpression of p27(T187A) induced cell cycle arrest in KMS28PE, an MM cell line with biallelic deletion of CDKN1B/p27(Kip1), CKS1B ablation induced strong apoptosis. These data suggest that CKS1B influences myeloma cell growth and survival through SKP2- and p27(Kip1)-dependent and -independent mechanisms and that therapeutic strategies aimed at abolishing CKS1B function may hold promise for the treatment of high-risk disease for which effective therapies are currently lacking.


Intra-Plaque Vessels on Contrast-Enhanced Ultrasound Sonography Predict Carotid Plaque Histology.
Although the echogenicity of carotid plaques on carotid enhanced ultrasound (CEUS) was reported to correlate with the historological density of intra-plaque neovessels, it is unclear whether the intra-plaque vessel size is associated with carotid plaque vulnerability. We evaluated the relationship of size of intra-plaque vessels on CEUS with carotid plaque histology. We prospectively registered patients with carotid stenosis who were hospitalized to receive carotid endarterectomy between 2012 and 2016. CEUS was performed by ultrasound specialists using a 7-MHz linear transducer (GE LOGIQ7; GE Healthcare, Milwaukee, WN, USA). Sonazoid® was used for conducting CEUS. The sizes of microbubbles inside the plaques were scored at 0, 1, 3, and 5 min after the injection of contrast agent, and were categorized according to our defined vascular score (Vas-S; 0: the effect of contrast was not recognized; 1: the microbubbles were visible, but so blurred and vague that their shape could not be recognized; 2: dot or string-like microbubbles with movement, localized in part or the whole site of the plaque). At histological examination, we simplified the modified American Heart Association classification and defined as an atherosclerotic category (Ath-cat; 1: unruptured plaque; 2: ruptured plaque; 3: healed plaque). We then assessed the correlation of Vas-S with Ath-cat, which describes the process of rupture and restoration of carotid plaques. A total of 97 patients were included in this study. A higher Ath-cat was significantly associated with higher Vas-S at any time. Spearman signed-rank test indicated that Vas-S at 1 min was most strongly correlated with Ath-cat (ρ = 0.43, p = 0.001). Receiver operating curve analysis indicated that a Vas-S of 0 at 1 min was significantly associated with an unruptured plaque (area under curve [AUC] 0.72, p = 0.006), while a Vas-S of 2 at 1 min was significantly associated with a healed plaque (AUC 0.72, p = 0.001). Vas-S values of 0 and 2 at 1 min indicated unruptured and healed plaques respectively. Thus, a Vas-S of 1 at 1 min is an indicator of a ruptured plaque. The intra-plaque vessel size on CEUS was significantly associated with carotid plaque histology, and may predict the process of plaque rupture and restoration.


An expanding population of the giant liver fluke (Fascioloides magna) in elk (Cervus canadensis) and other ungulates in Canada.
Giant liver fluke (Fascioloides magna) populations readily expand under suitable conditions. Although extirpated from the eastern slopes of the Canadian Rocky Mountains in the early 1960s, the fluke reappeared following natural spread through mountain passes from British Columbia. Herein, we assessed epizootiology of the fluke population two decades later. Between 1984 and 1991, 534 ungulates, including 381 elk (Cervus canadensis), 68 mule deer (Odocoileus hemionus hemionus), 54 white-tailed deer (Odocoileus virginianus), and 31 moose (Alces alces) from adjacent areas of Alberta (AB) and British Columbia (BC), Canada, were examined for giant liver flukes. Prevalence in elk increased from 53% to 79% (1984-91) in Banff National Park (BNP) in AB and 77% to 100% (1985-89) in Kootenay National Park (KNP) in BC. Super-infections (>100 flukes) were more common in later years. Generally, prevalence increased over time and with increasing age of elk. Intensity was lowest in young-of-year (BNP 8±5, KNP 3), but similar in yearlings (BNP 36±11, KNP 23±8) and adults (BNP 33±5, KNP 32±6). Prevalence was similar in male and female elk. Intensity was higher in males (BNP 47±7, KNP 46±12) than in females (BNP 28±6, KNP 22±4), although the maximum number of flukes (545) occurred in a female elk. Prevalence and intensity differed among other species of ungulates but patterns were similar in each park. Prevalence was lower in mule deer (BNP 6%, KNP 4%) than in white-tailed deer (BNP 44%, KNP 28%) and moose (BNP 52%, KNP 63%). Intensity differed among these species but never exceeded 30 flukes. Gravid flukes occurred only in elk and white-tailed deer. Transmission occurred primarily in late summer-fall and in wet habitats. At least seven elk died as a direct result of fluke infection. In this region, elk and white-tailed deer maintain the F. magna population with spillover into moose and, rarely, mule deer.


A point of view: The need to identify an antigen in psyconeuroimmunological disorders.
Several lines of evidence support a mutual relationship between the nervous system and the immune system. Therefore, it is not surprising that some neuropsychiatric disorders are also characterized by immune abnormalities. In patients with phobic disorders and in patients with migraine without aura some common immune abnormalities have been detected and, in particular, natural immunity deficits, exaggerated release of proinflammatory cytokines and circulating bacterial endotoxins have been found. In other neurological disease, some etiologic factors have been detected as in the case of Guillain-Barrè syndrome in which molecular mimicry between Campylobacter jejuni endotoxin and GM1 ganglioside may cause an acute inflammatory polyneuropathy. On the other hand, attempts to identify an antigen have been made in patients with Alzheimer's disease and schizophrenia. Finally, the chronic fatigue syndrome, an old illness in search for an antigen, risk factors and precipitating agents have been described but evidence for a specific antigen is still lacking.


Antithrombin-binding octasaccharides and role of extensions of the active pentasaccharide sequence in the specificity and strength of interaction. Evidence for very high affinity induced by an unusual glucuronic acid residue.
The antithrombotic activity of low molecular weight heparins (LMWHs) is largely associated with the antithrombin (AT)-binding pentasaccharide sequence AGA(*)IA (GlcN(NAc/NS,6S)-GlcA-GlcN(NS,3,6S)-IdoUA(2S)-GlcN(NS,6S)). The location of the AGA(*)IA sequences along the LMWH chains is also expected to influence binding to AT. This study was aimed at investigating the role of the structure and molecular conformation of different disaccharide extensions on both sides of the AGA(*)IA sequence in modulating the affinity for AT. Four high purity octasaccharides isolated by size exclusion chromatography, high pressure liquid chromatography, and AT-affinity chromatography from the LMWH enoxaparin were selected for the study. All the four octasaccharides terminate at their nonreducing end with 4,5-unsaturated uronic acid residues (DeltaU). In two octasaccharides, AGA(*)IA was elongated at the reducing end by units IdoUA(2S)-GlcN(NS,6S) (OCTA-1) or IdoUA-GlcN(NAc,6S) (OCTA-2). In the other two octasaccharides (OCTA-3 and OCTA-4), AGA(*)IA was elongated at the nonreducing side by units GlcN(NS,6S)-IdoUA and GlcN(NS,6S)-GlcA, respectively. Extensions increased the affinity for AT of octasaccharides with respect to pentasaccharide AGA(*)IA, as also confirmed by fluorescence titration. Two-dimensional NMR and docking studies clearly indicated that, although elongation of the AGA(*)IA sequence does not substantially modify the bound conformation of the AGA(*)IA segment, extensions promote additional contacts with the protein. It should be noted that, as not previously reported, the unusual GlcA residue that precedes the AGA(*)IA sequence in OCTA-4 induced an unexpected 1 order of magnitude increase in the affinity to AT with respect to its IdoUA-containing homolog OCTA-3. Such a residue was found to orientate its two hydroxyl groups at close distance to residues of the protein. Besides the well established ionic interactions, nonionic interactions may thus contribute to strengthen oligosaccharide-AT complexes.


Mood Stabilizers, Oxidative Stress and Antioxidative Defense in Euthymia of Bipolar Disorder.
Hitherto literature indicates that mood stabilizers exert variable effects on oxidative and antioxidative systems, which are involved in the pathogenesis of Bipolar Disorder. Herein we primarily sought to characterize markers of peripheral oxidative stress during euthymia in adults with Bipolar Disorder under current intake of different mood stabilizers (lithium, anticonvulsants and atypical antipsychotics/AAPs). Peripheral oxidative stress parameters (TBARS/Thiobarbituric acid-reactive-substances, MDA/ malondialdehyde and carbonyl proteins) and antioxidative markers (SOD/Cu/Zn superoxide dismutase, GST/glutathione Stransferase and TAC/total antioxidative capacity) were measured in serum of 115 euthymic bipolar individuals (50 females, 65 males; HAMD<11 and YMRS<8). Differences in (anti)oxidative markers between bipolar participants treated with different mood stabilizing medication were tested with MANCOVAS and ANCOVAS with SPSS.21. Bipolar individuals taking lithium had significantly lower oxidative parameters than test persons without lithium (multivariate effect for MDA and TBARS: F(2/182)= 3.956, p= 0.021; univariate effect for MDA: F(2/182)= 7.880, p= 0.006, Partial η2= 0.041). Subjects with AAPs had significantly higher MDA and TBARS levels compared to participants without AAPs (multivariate effect F(2/182)= 3.122, p= 0.046, Partial η2= 0.033). Patients taking anticonvulsants had significantly lower GST levels than patients without antiepileptic medication (F(1/165)= 4.501, p= 0.035, Partial η2= 0.027). Lithium taking participants had the lowest MDA and TBARS levels, while AAP taking test persons had high oxidative stress markers. The observed effects on oxidative markers may provide a mechanistic basis for understanding lithium's neuroprotective effects.


High serum IgA and activated Th17 and Treg predict the efficacy of abatacept in patients with early, seropositive rheumatoid arthritis.
To identify the predictive biomarkers for achieving remission with abatacept in patients with seropositive rheumatoid arthritis (RA). We enrolled patients with RA who were treated with abatacept. We compared the baseline laboratory results and longitudinal immune-phenotyping data between patients who achieved remission and those who did not achieve remission at 6 months according to the clinical disease activity index. One hundred and twenty RA patients were enrolled. In the seropositive patients with early RA (n = 24), high serum IgA levels, anti-citrullinated peptide (CCP) titers, and neutrophil counts before treatment were predictors of remission (area under the curve [AUC], 0.659, 0.741, and 0.704, respectively). Additionally, activated Th17 (aTh17) cells and activated Treg (aTreg) cells before treatment were found to be significantly higher in patients with remission compared to those without remission (2.9% vs 1.1%, P = 0.02; 34.3% vs 17%, P = 0.03, respectively). The measurement of longitudinal cell subpopulation revealed a decrease in the effector CD4 T cell population after abatacept treatment, which correlated with anti-CCP titers and neutrophil counts, and was associated with remission achievement. In seropositive patients with established RA (n = 79), high RF titers and low IFN-γ levels were associated with the good response to abatacept. Our study has shown that serum IgA levels, anti-CCP titer, and neutrophil counts are predictive biomarkers for predicting the response to abatacept in patients with seropositive and early RA and may reflect the inhibition of effector CD4 T cell subpopulations by abatacept. Key Points • Serum IgA levels and neutrophil counts are novel biomarkers for predicting the efficacy of abatacept. • Those may reflect the inhibition of effector CD4 T cell subpopulations by abatacept.


A comparative study of serum proteins ability to scavenge active oxygen species: O2-. and OCl-.
The ability of serum proteins (albumin, immunoglobulin G) and protein antioxidants (ceruloplasmin, superoxide dismutase and transferrin) to react with O2-. and OCl-, was studied. The interaction between serum proteins and OCl- was shown to be non-specific. Ceruloplasmin is the most effective OCl- trapping protein, and it reacts with O2-. with a considerable efficiency. Therefore, ceruloplasmin is supposed to be the main scavenger of toxic oxygen species generated by stimulated neutrophils.


Nucleotide triphosphates are required for the transport of glycolate oxidase into peroxisomes.
All peroxisomal proteins are nuclear encoded, synthesized on free cytosolic ribosomes, and posttranslationally targeted to the organelle. We have used an in vitro assay to reconstitute protein import into pumpkin (Cucurbita pepo) glyoxysomes, a class of peroxisome found in the cotyledons of oilseed plants, to study the mechanisms involved in protein transport across peroxisome membranes. Results indicate that ATP hydrolysis is required for protein import into peroxisomes; nonhydrolyzable analogs of ATP could not substitute for this requirement. Nucleotide competition studies suggest that there may be a nucleotide binding site on a component of the translocation machinery. Peroxisomal protein import also was supported by GTP hydrolysis. Nonhydrolyzable analogs of GTP did not substitute in this process. Experiments to determine the cation specificity of the nucleotide requirement show that the Mg2+ salt was preferred over other divalent and monovalent cations. The role of a putative protonmotive force across the peroxisomal membrane was also examined. Although low concentrations of ionophores had no effect on protein import, relatively high concentrations of all ionophores tested consistently reduced the level of protein import by approximately 50%. This result suggests that a protonmotive force is not absolutely required for peroxisomal protein import.


CYP82Y1 is N-methylcanadine 1-hydroxylase, a key noscapine biosynthetic enzyme in opium poppy.
Noscapine is a phthalideisoquinoline alkaloid investigated for its potent pharmacological properties. Although structurally elucidated more than a century ago, the biosynthesis of noscapine has not been established. Radiotracer studies have shown that noscapine is derived from the protoberberine alkaloid (S)-scoulerine and has been proposed to proceed through (S)-N-methylcanadine. However, pathway intermediates involved in the conversion of N-methylcanadine to noscapine have not been identified. We report the isolation and characterization of the cytochrome P-450 CYP82Y1, which catalyzes the 1-hydroxylation of N-methylcanadine to 1-hydroxy-N-methylcanadine. Comparison of transcript and metabolite profiles of eight opium poppy chemotypes revealed four cytochrome P-450s, three from the CYP82 and one from the CYP719 families, that were tightly correlated with noscapine accumulation. Recombinant CYP82Y1 was the only enzyme that accepted (R,S)-N-methylcanadine as a substrate with strict specificity and high affinity. As expected, CYP82Y1 was abundantly expressed in opium poppy stems where noscapine accumulation is highest among plant organs. Suppression of CYP82Y1 using virus-induced gene silencing caused a significant reduction in the levels of noscapine, narcotoline, and a putative downstream secoberbine intermediate and also resulted in increased accumulation of the upstream pathway intermediates scoulerine, tetrahydrocolum-bamine, canadine, and N-methylcanadine. The combined biochemical and physiological data support the 1-hydroxylation of (S)-N-methylcanadine catalyzed by CYP82Y1 as the first committed step in the formation of noscapine in opium poppy.


Terrestrial pesticide exposure of amphibians: an underestimated cause of global decline?
Amphibians, a class of animals in global decline, are present in agricultural landscapes characterized by agrochemical inputs. Effects of pesticides on terrestrial life stages of amphibians such as juvenile and adult frogs, toads and newts are little understood and a specific risk assessment for pesticide exposure, mandatory for other vertebrate groups, is currently not conducted. We studied the effects of seven pesticide products on juvenile European common frogs (Rana temporaria) in an agricultural overspray scenario. Mortality ranged from 100% after one hour to 40% after seven days at the recommended label rate of currently registered products. The demonstrated toxicity is alarming and a large-scale negative effect of terrestrial pesticide exposure on amphibian populations seems likely. Terrestrial pesticide exposure might be underestimated as a driver of their decline calling for more attention in conservation efforts and the risk assessment procedures in place do not protect this vanishing animal group.


Myoclonus in a case of suspected progressive rubella panencephalitis.
Predominantly unilateral myoclonus induced by movement of the affected parts in a 21-year-old Japanese man with suspected progressive rubella panencephalitis appeared in the course of treatment for epilepsy with anticonvulsant drugs after five years. Antirubella antibody levels in the serum and CSF were elevated and IgM antibody against rubella was found in the serum. An EEG recorded while the patient was awake showed diffuse 3- to 4-Hz theta activity with high voltage. The neurological symptoms are progressing slowly.


[Significance of immunological investigation in pulmonary pathology].
An extensive range of investigations were used in a comparative study of immune reactivity in the tuberculous pulmonary pathology, as well as in sarcoidosis, pneumonia and cancer of the lungs. T and B lymphocyte populations were followed, indexes of leucocyte migration, induced lymphoblastogenesis to phytohaemagglutinin, and the serum levels of immunoglobulins. Also the intensity of the hypersensitivity to tuberculin was investigated, to allergens extracted from staphylococcus and streptococcus strains, as well as against organ antigens (pulmonary tissues). Differences were evidenced, of immunologic reactivity in various nosologic entities investigated. The dynamic follow-up of some of the cases has demonstrated that the immunological reactivity varies in parallelly with severity of cases, deficiences being corrected by adequate therapy. The immunologic status may be considered a criterium for a rational pathogenetic treatment, for assessing the efficiency of such a treatment, as well as for the differential diagnosis of pulmonary diseases.


The Effectiveness of Stewardship Interventions to Reduce the Prescribing of Extended-Release Opioids for Acute Pain: A Systematic Review.
To evaluate the effectiveness of stewardship interventions in reducing the prescribing of extended-release opioids for acute pain. Systematic review of randomized controlled trials, pre-post intervention studies, cohort studies and case-control studies. A search was conducted using Medline, Scopus, Cochrane Central Register of Controlled Trials, International Pharmaceutical Abstracts, and PsycINFO from inception to March 24, 2019. Search terms included opioids, interventions, extended-release, and acute pain. Included articles were original research articles outlining the impact of stewardship interventions on reducing the prescribing of extended-release opioids for acute pain. The search resulted in 1,264 articles after the removal of duplicates. Of these, 141 full texts were assessed, with three eligible for inclusion. One additional article was obtained via a manual search. Three studies explored forcing function interventions; two included prior authorization policies, which saw decreases in extended-release/long-acting scripts by 18-36%, while another evaluated order restrictions producing increased adherence to guidelines by 36%. One study explored the impact of education targeting prescribers and patients through a risk mitigation and evaluation strategy, which decreased extended-release/long-acting quarterly script volumes by 4.3%. All studies were performed at system levels. Forcing function interventions decreased extended-release/long-acting prescriptions and increased adherence to guidelines to a greater extent than less restrictive interventions such as education. Forcing function interventions implemented at system levels show promise in decreasing the prescribing of extended-release opioids for acute pain. The current lack of literature warrants future research to increase understanding of the effectiveness of such interventions.


A conserved pattern of brain scaling from sharks to primates.
Several patterns of brain allometry previously observed in mammals have been found to hold for sharks and related taxa (chondrichthyans) as well. In each clade, the relative size of brain parts, with the notable exception of the olfactory bulbs, is highly predictable from the total brain size. Compared with total brain mass, each part scales with a characteristic slope, which is highest for the telencephalon and cerebellum. In addition, cerebellar foliation reflects both absolute and relative cerebellar size, in a manner analogous to mammalian cortical gyrification. This conserved pattern of brain scaling suggests that the fundamental brain plan that evolved in early vertebrates permits appropriate scaling in response to a range of factors, including phylogeny and ecology, where neural mass may be added and subtracted without compromising basic function.


Detecting Depression-related Movement Changes in Older Adults using Smart Home Motion Sensors - A Feasibility Study.
Smart home sensor data is being increasingly used to identify health risks through passive tracking of specific behaviours and activity patterns. This study explored the feasibility of using motion sensor data to track changes in daytime movement patterns within the home, and their potential association with depression in older adults. This study analysed the motion sensor data collected during a one-year smart home trial, and explored their association with Geriatric Depression Scale (GDS) scores collected at three different time points during the trial (i.e., baseline, mid-trial, and end-trial). Our results showed that movement patterns are generally reduced when older adults are in a depressed state compared to when being in a not-depressed state. In particular, the reduced movement activity in depressed states was significant (p<.05) when the participant's GDS state changed between depressed and not-depressed for the first time during the three time points of the trial when GDS was collected.Clinical relevance- Our results establish the feasibility and potential use of motion sensor data from ambient sensors in a smart home for passive and remote assessment of older adults' depression status, that is comparable to their GDS scores, through changes in their in-home day-time movement patterns. Also since reduced movement activity may be a general indicator of potential health risks, this study provides preliminary evidence for using in-home movement activity monitoring as an general indicator of health risks.


Gastrin-releasing peptide messenger ribonucleic acid expression in the hypothalamic paraventricular nucleus is altered by melanocortin receptor stimulation and food deprivation.
Gastrin-releasing peptide (GRP) is a bombesin-like peptide widely distributed in the gastrointestinal tract and central nervous system. In the brain, GRP mRNA is located in the hypothalamic paraventricular nucleus (PVN), a region that receives neural input from the arcuate nucleus and plays a critical role in food intake and energy balance. Because GRP neurons are localized in the vicinity of projection sites in the PVN for peptides that participate in energy homeostasis, we investigated whether GRP mRNA expression in the PVN may be sensitive to challenges imposed by either 38 h food deprivation or stimulation of the melanocortin system by the melanocortin 3/4 receptor agonist, melanotan II (MTII). We found that food deprivation significantly decreased GRP mRNA expression, whereas lateral ventricular MTII administration increased GRP mRNA expression in ad libitum-fed rats 4 h after administration. Furthermore, administration of MTII at a dose that reduces 24 h food intake and body weight prevented the decrease in GRP mRNA expression observed in animals that were pair fed to the amount of food consumed by those injected with MTII. These results demonstrate that food deprivation and stimulation of the melanocortin system produce opposing changes in GRP gene expression in the PVN, suggesting that GRP-containing neurons in the PVN may be part of the hypothalamic signaling pathway controlling food intake and energy balance.


Microvascularization on collared peccary placenta: a microvascular cast study [corrected] in late pregnancy.
The microvascularization of the collared peccary (Tayassu tajacu) placenta was studied by vascular casts and immunolocalization of α-smooth muscle actin and vimentin, to identify the three dimensional organization and vascular flow interrelation in the microvasculature between the maternal and fetal compartments of the placentae. The immunolocalization of vimentin in the vascular endothelium and in the smooth muscle cells of blood vessels showed indented capillaries along the uterine epithelium and the trophoblast at the sides of complementary maternal and fetal microfolds, or rugae. This confers the three-dimensional structure observed in vascular casts. On the maternal side, casts demonstrated uterine folds coated by with primary and secondary ridges, and by areolae dispersed between these ridges. The arteriole runs through the center/middle of ridges, branching at the top into a microvascular network wall in a basket-like fashion. At the base of these baskets venules were formed. On the fetal side, arterioles branched centrally in the fetal rugae into a capillary network in a bulbous form, complementary to the opposite maternal depressions forming the baskets. At the base of the bulbous protrusions, the fetal venules arise. The blood vessel orientation in the materno-fetal interface of the placentae of collared peccaries suggests a blood flow pattern of the type countercurrent to cross current. The same pattern has been reported in domestic swine demonstrating that, even after 38 million years, the Tayassuidae and Suidae families exhibit similar placental morphology, which is here characterized at the microvascular level.


Retina specialists treating age-related macular degeneration recommend different approaches for patients than they would choose for themselves.
To evaluate the presence of cognitive biases among retina physicians when recommending treatment options for exudative age-related macular degeneration. Two random samples of retina specialists were surveyed regarding their treatment and dosing regimen choices among three anti-vascular endothelial growth factor biologics (aflibercept, bevacizumab, and ranibizumab). One group was asked to provide recommendations for a standardized hypothetical patient with exudative age-related macular degeneration, whereas the other group was asked to provide recommendations as if they themselves were the standardized hypothetical patient with exudative age-related macular degeneration. Two hundred and twenty-six respondents (28.3%) completed the survey and were divided equally between the survey groups. For patients, most physicians recommended bevacizumab (52.2%), but when choosing for themselves, physicians were divided equally among all 3 biologics (P = 0.011). The results were influenced by geographical location of the physician but not by the gender or length of practice. Furthermore, physicians differed in dosing regimen selection with the majority (73%) choosing treat and extend for patients, whereas only 63% selected this regimen for themselves (P = 0.004). When considering cases of exudative age-related macular degeneration, physicians would recommend different treatments for themselves than they would for a patient.


RANTES correlates with inflammatory activity and synaptic excitability in multiple sclerosis.
Alterations of synaptic transmission induced by inflammatory activity have been linked to the pathogenic mechanisms of multiple sclerosis (MS). Regulated upon activation, normal T-cell expressed, and secreted (RANTES) is a pro-inflammatory chemokine involved in MS pathophysiology, potentially able to regulate glutamate release and plasticity in MS brains, with relevant consequences on the clinical manifestations of the disease. To assess the role of RANTES in the regulation of cortical excitability. We explored the association of RANTES levels in the cerebrospinal fluid (CSF) of newly diagnosed MS patients with magnetic resonance imaging (MRI) and laboratory measures of inflammatory activity, as well its role in the control of cortical excitability and plasticity explored by means of transcranial magnetic stimulation (TMS), and in hippocampal mouse slices in vitro. CSF levels of RANTES were remarkably high only in active MS patients and were correlated with the concentrations of interleukin-1β. RANTES levels were associated with TMS measures of cortical synaptic excitability, but not with long-term potentiation (LTP)-like plasticity. Similar findings were obtained in mouse hippocampal slices in vitro, where we observed that RANTES enhanced basal excitatory synaptic transmission with no effect on LTP. RANTES correlates with inflammation and synaptic excitability in MS brains.


Immunodietica: interrogating the role of diet in autoimmune disease.
Diet is an environmental factor in autoimmune disorders, where the immune system erroneously destroys one's own tissues. Yet, interactions between diet and autoimmunity remain largely unexplored, particularly the impact of immunogenetics, one's human leukocyte antigen (HLA) allele make-up, in this interplay. Here, we interrogated animals and plants for the presence of epitopes implicated in human autoimmune diseases. We mapped autoimmune epitope distribution across organisms and determined their tissue expression pattern. Interestingly, diet-derived epitopes implicated in a disease were more likely to bind to HLA alleles associated with that disease than to protective alleles, with visible differences between organisms with similar autoimmune epitope content. We then analyzed an individual's HLA haplotype, generating a personalized heatmap of potential dietary autoimmune triggers. Our work uncovered differences in autoimmunogenic potential across food sources and revealed differential binding of diet-derived epitopes to autoimmune disease-associated HLA alleles, shedding light on the impact of diet on autoimmunity.


Dietary diosgenin attenuates subacute intestinal inflammation associated with indomethacin in rats.
We investigated the effects of dietary diosgenin (Dio), a plant-derived sapogenin, on indomethacin (Indo)-induced intestinal inflammation and alterations in bile secretion in rats. In anesthetized rats, bile secretion, intestinal inflammation, and blood chemistry were assessed 3 days after two subcutaneous injections of Indo given 24 h apart. Dio (> 80 mg.kg-1.day-1) pretreatment significantly inhibited weight and food intake decreases and intestinal inflammation. This protective effect was confirmed by examination of gross and histological findings and intestinal myeloperoxidase activity. Dio significantly increased biliary cholesterol (Chol) output and prevented the decreases in bile flow, bile acid output, and biliary alpha-muricholic acid and the increases in biliary hyodeoxycholic acid, deoxycholic acid, and hydrophobicity index of bile. Significantly more biliary Chol and phospholipids were present in macromolecules separate from bile acids and Indo in Dio-treated rats. Dio significantly increased the elimination constant of Indo and reduced plasma Indo levels at 3 and 12 h but did not influence biliary secretion of Indo for 3.5 h after injection. Although Dio dose-dependently attenuated subacute intestinal inflammation and normalized bile secretion in this model, it may also compromise the anti-inflammatory action of indo.


Management of voiding dysfunction with an implantable neuroprosthesis.
We have been very encouraged by these preliminary results concerning the efficacy and safety of functional electrical neuromodulation in the management of chronic voiding complaints. There are a large number of patients within the standard practice of urology who are potential candidates for this form of management. The techniques of peripheral nerve evaluation and implantation are relatively simple to master and free of significant risks or complications. If the long-term results of the multicenter clinical trial parallel our preliminary results, this is a technique which should be embraced by urologists as a significant therapeutic advance in our field.


Jagged-1 mutation analysis in Italian Alagille syndrome patients.
Alagille syndrome (AGS) is an autosomal dominant disorder with developmental abnormalities affecting the liver, heart, eyes, vertebrae, and craniofacial region. The Jagged-1 (JAG1) gene, which encodes a ligand of Notch, has recently been found mutated in AGS. In this study, mutation analysis of the JAG1 gene performed on 20 Italian AGS patients led to the identification of 15 different JAG1 mutations, including a large deletion of the 20p12 region, six frameshift, three nonsense, three splice-site, and two missense mutations. The two novel missense mutations were clustered in the 5' region, while the remaining mutations were scattered throughout the gene. The spectrum of mutations in Italian patients was similar to that previously reported. We also studied in detail a complex splice site mutation, 3332dupl8bp, which was shown to lead to an abnormal JAG1 mRNA, resulting in a premature stop codon. With the exception of the missense mutations, the majority of the JAG1 mutations are therefore likely to produce truncated proteins. Since the phenotype of the patient with a complete deletion of the JAG1 gene is indistinguishable from that of patients with intragenic mutations, our study further supports the hypothesis that haploinsufficiency is the most common mechanism involved in AGS pathogenesis. Furthermore, our data confirmed the absence of a correlation between the genotype of the JAG1 gene and the AGS phenotype.


Hormonal changes during parturition in heifers and goats are related to the phases and severity of labour.
Parturition is a natural event that involves stress and pain for the mother. We thus hypothesized that levels of stress hormones measured during parturition could reflect levels reached in response to severe discomfort and pain of other kinds as well. The aim of this study was therefore to determine whether plasma concentrations of cortisol, adrenaline, noradrenaline, beta-endorphin, met-enkephalin, vasopressin and oxytocin vary depending on the phase and severity of labour in dairy heifers (ten) and dairy goats (six), and how these hormones interact with each other. Blood samples were taken once a day for 3 days before labour and for 3 days afterwards and at predetermined phases during labour. All heifers delivered one calf and five of them needed obstetrical assistance. Two of the goats delivered one kid, and four had twins; all kidded without help. The cortisol concentration peaked when the calf and the first kid were born. In the heifers, plasma adrenaline increased after delivery, while the noradrenaline concentration did not change significantly in heifers that needed assistance, but increased during expulsion in heifers calving without help. In the goats, adrenaline and noradrenaline concentrations increased in association with expulsion of the first kid. The beta-endorphin concentration increased during labour in goats. In heifers that needed assistance, beta-endorphin concentration increased 1 h after labour but there was no change in heifers that did not need assistance. The met-enkephalin concentration was elevated during expulsion in heifers and fluctuated in the goats. Both oxytocin and vasopressin increased during expulsion in both groups of heifers, but vasopressin increased four times more in heifers needing assistance. In the goats, oxytocin reached its highest levels just as the feet of the first kid became visible, and vasopressin peaked as the head emerged. Parturition took longer in heifers that needed assistance than in those that did not. It is concluded that, even though the pattern of change differed between hormones during labour, the changes were related to the phases of labour. A longer labour therefore meant that the hormone concentrations stayed elevated for longer. Vasopressin reached high levels in goats and was the only hormone for which plasma concentrations were higher in heifers that needed assistance than in those that did not, indicating that this hormone is released in order to deal with the pain-related stress associated with labour.


Detection of environmental and morphological adaptation despite high landscape genetic connectivity in a pest grasshopper (Phaulacridium vittatum).
Widespread species that exhibit both high gene flow and the capacity to occupy heterogeneous environments make excellent models for examining local selection processes along environmental gradients. Here we evaluate the influence of temperature and landscape variables on genetic connectivity and signatures of local adaptation in Phaulacridium vittatum, a widespread agricultural pest grasshopper, endemic to Australia. With sampling across a 900-km latitudinal gradient, we genotyped 185 P. vittatum from 19 sites at 11,408 single nucleotide polymorphisms (SNPs) using ddRAD sequencing. Despite high gene flow across sites (pairwise FST = 0.0003-0.08), landscape genetic resistance modelling identified a positive nonlinear effect of mean annual temperature on genetic connectivity. Urban areas and water bodies had a greater influence on genetic distance among sites than pasture, agricultural areas and forest. Together, FST outlier tests and environmental association analysis (EAA) detected 242 unique SNPs under putative selection, with the highest numbers associated with latitude, mean annual temperature and body size. A combination of landscape genetic connectivity analysis together with EAA identified mean annual temperature as a key driver of both neutral gene flow and environmental selection processes. Gene annotation of putatively adaptive SNPs matched with gene functions for olfaction, metabolic detoxification and ultraviolet light shielding. Our results imply that this widespread agricultural pest has the potential to spread and adapt under shifting temperature regimes and land cover change.


Bone mineral content in renal transplant patients.
Bone mineral content (BMC) in the forearm was measured in 158 renal transplant patients to elucidate the relationship between bone mass and the development of bone lesions following renal transplantation. In renal transplant patients with aseptic necrosis of bone and with spontaneous fractures the BMC was significantly reduced compared with age and sex matched renal transplant control patients. Other factors connected with low BMC were age, sex, prolonged dialysis prior to transplantation, post-transplant hypercalcemia and elevated serum alkaline phosphatase at the time of the study. No relation between BMC and duration of immunosuppressive treatment was demonstrated.


Digit ratio (2D:4D) in homosexual and heterosexual men from Austria.
Neurohormonal theories of sexual orientation emphasize the organizational effects of testosterone on the developing brain. A recent suggestion, that the ratio of the length of the 2nd and 4th digits (2D:4D) is negatively correlated with prenatal testosterone, has led to a number of studies of 2D:4D in homosexual and heterosexual men and women. The results have been mixed. In comparison to heterosexual men, mean 2D:4D in gay men has been reported to be hypermasculinized (lower 2D:4D), hypomasculinized (higher 2D:4D), or to show no significant difference. Here, we report mean 2D:4D in Austrian homosexual and heterosexual men. We found no significant difference between means for homosexual and heterosexual 2D:4D, with values for both falling between 0.96 to 0.97. There are now 6 reports of 2D:4D in heterosexual and homosexual men. Considering Caucasian men, the studies from the United States show low heterosexual mean 2D:4D, and homosexual mean 2D:4D is higher or similar to that of heterosexuals. The European studies show high heterosexual mean 2D:4D, and comparisons with homosexuals reveal the latter to have lower or similar mean 2D:4D to that of heterosexuals. We discuss these results in relation to the suggestion that mean 2D:4D in heterosexual men differs across populations but mean 2D:4D in homosexuals shows less geographical variation (the "uniform mean hypothesis"). It is concluded that more data are required to clarify whether or not there is a 2D:4D effect for sexual orientation in men.


The dose-to-mother method to measure milk intake in infants by deuterium dilution: a validation study.
A validation study of the dose-to-mother deuterium dilution method to measure breast-milk intake has been carried out on ten infants from a Nutrition Recovery Centre in Santiago, Chile. Formula milk labelled with exponentially decreasing doses of deuterium oxide represented milk from a 'pseudo mother' of these exclusively bottle-fed infants. Unlabelled formula represented milk from other sources. Deuterium levels in the infants' body water were measured on saliva samples by mass spectroscopy. The data were fitted in a two-compartment steady-state model of the mother-child system to estimate the flow of labelled water from the 'mother' to the infant and the 'mother' and infant's water elimination constants. A dose-to-child experiment was also carried out on each infant to determine the deuterium dilution space and total daily water intake. Total and labelled water flows from deuterium dilution were used to calculate total, labelled and unlabelled formula milk intakes which were compared to the same quantities measured by bottle weighing. Water elimination constants calculated from the dose-to-mother experiments underestimated by 17 per cent the initially set mother constant and overestimated by 21 per cent the infant constants calculated from the dose-to-child experiments. Rate constants, however, have little effect on the estimated water flows so that there was good agreement between values from deuterium dilution and from direct weighing. Mean (SD) total formula, labelled formula and unlabelled formula intakes were 865 (129) g/d, 417 (74) g/d and 448 (106) g/d, respectively, when measured by deuterium dilution, compared with 856 (116) g/d, 414 (71) g/d and 441 (68) g/d when measured by direct weighing. The mean per cent differences were 1.1 per cent, 0.7 per cent and 1.6 per cent and the mean absolute differences for individuals, 4.3 (1.9) per cent, 4.8 (3.1) per cent and 9.7 (6.6) per cent, respectively.


Toward emotion aware computing: an integrated approach using multichannel neurophysiological recordings and affective visual stimuli.
This paper proposes a methodology for the robust classification of neurophysiological data into four emotional states collected during passive viewing of emotional evocative pictures selected from the International Affective Picture System. The proposed classification model is formed according to the current neuroscience trends, since it adopts the independency of two emotional dimensions, namely arousal and valence, as dictated by the bidirectional emotion theory, whereas it is gender-specific. A two-step classification procedure is proposed for the discrimination of emotional states between EEG signals evoked by pleasant and unpleasant stimuli, which also vary in their arousal/intensity levels. The first classification level involves the arousal discrimination. The valence discrimination is then performed. The Mahalanobis (MD) distance-based classifier and support vector machines (SVMs) were used for the discrimination of emotions. The achieved overall classification rates were 79.5% and 81.3% for the MD and SVM, respectively, significantly higher than in previous studies. The robust classification of objective emotional measures is the first step toward numerous applications within the sphere of human-computer interaction.


Is direct oral amoxicillin challenge a viable approach for 'low-risk' patients labelled with penicillin allergy?
Spurious penicillin allergy (PenA) is a major public health problem. Up to 10% of the population and 20% of inpatients are labelled with PenA, but only <5%-10% have a proven allergy following comprehensive investigations. PenA tests are labour intensive and require specialist input, which may not be readily available due to limited allergy services. Therefore, patients with PenA receive alternative antibiotics that are associated with higher rates of iatrogenic infections, antimicrobial resistance and a longer hospital stay with consequent increased costs. Recent evidence suggests that a supervised 'direct' oral amoxicillin challenge (without performing allergy tests) is a safe option in low-risk patients (those least likely to be allergic based on history). Patient selection for this procedure is based on a careful guideline-based risk stratification process. Further research is needed to validate this intervention in routine clinical practice and explore potential facilitators and barriers to implementation in different healthcare settings.


Recent advances in the etiology and treatment of Crohn's disease.
Significant advances have been achieved in the understanding of the pathogenesis of Crohn's disease (CD). A number of susceptibility genes have been detected by large genome wide screening-approaches. We do not completely understand the function of most of these genetic variants, however, there is good evidence that most of them are associated with the recognition and detection of luminal bacteria as well as defence against this microbiota. The important role of intestinal bacteria for the onset of CD is now clear. The intestinal bacteria and other "environmental" factors certainly contribute to CD pathogenesis: the respective genetic variations now termed as "susceptibility factors" exist since ten thousands of years. However, the incidence of CD is largely dependent on factors such as childhood hygiene or socioeconomic status; factors that are determined by living conditions and environment. New therapeutic concepts emerge from these insights. The most important progress in recent years certainly is the introduction of biologics in the therapy of CD. TNF blockers have been shown to be very effective for the control of complicated disease courses. However, more time will be needed until the concepts on pathogenesis evolve into new therapeutics that are introduced into clinical routine and guidelines. The hygiene hypothesis has led to the administration of helminths to CD patients to modulate the intestinal immune system. Another new approach is to improve the mucosal barrier function, which has been shown to be impaired in CD patients.


Investigating Key Factors Related to the Decision of a Do-Not-Resuscitate Consent.
The decision to sign a do-not-resuscitate (DNR) consent is critical for patients concerned about their end-of-life medical care. Taiwan's National Health Insurance Administration (NHIA) introduced a family palliative care consultation fee to encourage family palliative care consultations; since its implementation, identifying which families require such consultations has become more important. In this study, the Taiwanese version of the Palliative Care Screening Tool (TW-PCST) was used to determine each patient's degree of need for a family palliative care consultation. This study analyzed factors associated with signing DNR consents. The results may inform family palliative care consultations for families in need, thereby achieving a higher DNR consent rate and promoting the effective use of medical resources, including time, labor, and funding. In this retrospective study, logistic regression analysis was conducted to determine which factors affected the DNR decisions of 2144 deceased patients (aged ≥ 20 years), whose records were collected from the Taipei City Hospital health information system from 1 January to 31 December 2018. Among the 1730 patients with a DNR consent, 1298 (75.03%) received family palliative care consultations. The correlation between DNR consent and family palliative care consultations was statistically significant (p < 0.001). Through logistic regression analysis, we determined that participation in family palliative care consultation, TW-PCST score, type of ward, and length of stay were significant variables associated with DNR consent. This study determined that TW-PCST scores can be used as a measurement standard for the early identification of patients requiring family palliative care consultations. Family palliative care consultations provide opportunities for patients' family members to participate in discussions about end-of-life care and DNR consent and provide patients and their families with accurate medical information regarding the end-of-life care decision-making process. The present results can serve as a reference to increase the proportion of patients willing to sign DNR consents and reduce the provision of ineffective life-prolonging medical treatment.


Clinical applications of scanning electron microscopy and energy dispersive X-ray analysis in dermatology--an up-date.
Dermatological papers comprising scanning electron microscopy (SEM) and energy dispersive X-ray (EDX) analysis data published 1983 through 1986 in international journals are reviewed, as an update to our 1984 paper on Clinical applications of scanning electron microscopy and X-ray microanalysis in dermatology. The present paper not only deals with a review of recent publications in this area but also presents the application of microincineration to hair and cryosectioned freeze-dried skin specimens. Examples of the increased contrast obtained in hair cross sections are presented and a discussion on the feasibility of microincineration at analysis of hair and skin cross sections is given. Particle probe analysis (EDX: energy dispersive X-ray analysis and PMP: proton microprobe analysis) as applied to hair and skin samples are presented with stress put on the proton probe analysis. The complementarity of EDX and PMP is demonstrated and future applications are suggested.


Effectiveness of a resin-modified glass ionomer liner in reducing hypersensitivity in posterior restorations: a study from the practitioners engaged in applied research and learning network.
The objectives of this randomized comparative effectiveness study conducted by members of the Practitioners Engaged in Applied Research and Learning (PEARL) Network were to determine whether using a resin-modified glass ionomer (RMGI) liner reduces postoperative hypersensitivity (POH) in dentin-bonded Class I and Class II resin-based composite (RBC) restorations, as well as to identify other factors (putative risk factors) associated with increased POH. PEARL Network practitioner-investigators (P-Is) (n = 28) were trained to assess sensitivity determination, enamel and dentin caries activity rankings, evaluation for sleep bruxism, and materials and techniques used. The P-Is enrolled 341 participants who had hypersensitive posterior lesions. Participants were randomly assigned to receive an RBC restoration with or without an RMGI liner before P-Is applied a one-step, self-etching bonding agent. P-Is conducted sensitivity evaluations at baseline, at one and four weeks after treatment, and at all visits according to patient-reported outcomes. P-Is collected complete data regarding 347 restorations (339 participants) at baseline, with 341 (98 percent) (333 participants) recalled at four weeks. Treatment groups were balanced across baseline characteristics and measures. RBC restorations with or without an RMGI liner had the same one-week and four-week POH outcomes, as measured clinically (by means of cold or air stimulation) and according to patient-reported outcomes. Use of an RMGI liner did not reduce clinically measured or patient-reported POH in moderate-depth Class I and Class II restorations. Cold and air clinical stimulation findings were similar between groups. Practical Implications. The time, effort and expense involved in placing an RMGI liner in these moderate-depth RBC restorations may be unnecessary, as the representative liner used did not improve hypersensitivity outcomes.


Design and Evaluation of a Patient Monitoring Dashboard for Emergency Departments.
Identification of risk patients in emergency departments is a complex interplay between clinicians, patients, working procedures, and information systems. Through a mixed methods approach, we have developed an novel patient monitoring dashboard that couples clinical data streams to convey the state and trajectory of patients admitted to the emergency d epartment. In this paper, we describe the design and implementation of the novel system by providing a description of how the project was conceived, divided into subsequent phases, and is currently being executed. Experience from this work highlights the importance of carefully assessing each on-site installation point, interdisciplinary partnerships through embedded presence, and continuous emphasis on the purpose and aim as a mean to greatly improve project momentum and buy-in.


Purification and characterization of a rat liver protein that recognizes CCAAT-homologous sequences of the metallothionein promoter and trans-activates this promoter.
C'BP-1, a protein that binds to the MRE-c' region (-135 to -110) of the mouse metallothionein-I (MT-I) gene in metal-independent manner, was purified from rat liver nuclear extract by ion exchange and affinity chromatography. Analysis by SDS-PAGE, UV cross-linking, and glycerol gradient sedimentation, taken together, showed that C'BP-1 is a dimer of the 34-kDa polypeptides. Affinity-purified C'BP-1 could significantly stimulate transcription from mouse MT-I gene promoter. DNase I footprinting with the purified protein identified two binding sites for C'BP-1 located at positions -135 to -100 and -210 to -175 with respect to the start site of MT-I gene transcription. Both C'BP-1 binding sequences were found to contain imperfect dyad of the CCAAT homology. C'BP-1 was shown to make critical contacts with the CCAAT homology by methylation interference analysis and competition electrophoretic mobility shift assay with mutants harboring alterations in the CCAAT homology. An antibody that specifically recognizes C/EBP delta partially supershifted C'BP-1/MRE-c' complex, suggesting that C'BP-1 is identical to C/EBP delta or is closely related to C/EBP delta.


Comparison of Avena sativa, vinegar, and hydroxyzine for uremic pruritus of hemodialysis patients: a crossover randomized clinical trial.
Uremic pruritus is a common complication in patients with chronic kidney disease. While its cause is not known for certain, different treatments are currently applied. This study aimed to compare the effects of Avena sativa, diluted vinegar, and hydroxyzine on the reduction of uremic pruritus. In this crossover randomized clinical trial, 23 hemodialysis patients with uremic pruritus were randomly divided into 3 groups. The first group was treated with Avena sativa lotion, twice a day, for as long as 2 weeks; the second group received diluted vinegar; and the third group took hydroxyzine tablets for the same time span. After 3-day-long washout periods, the therapeutic methods were crossed over. The data were collected by a pruritus scale and a visual analogue scale, which were completed before and after the interventions. Avena sativa lotion significantly decreased the mean scores of pruritus intensity, consequences, and the verbal descriptor, although it did not have a significant effect on the frequency of pruritus and the pruritic surface. Vinegar and hydroxyzine significantly decreased all of the scores. Conclusions. Avena sativa, vinegar, and hydroxyzine were effective in decreasing pruritus. Diluted vinegar and Avena sativa can be used as a complement to hydroxyzine, which is itself a common pharmaceutical therapy.


Regulation of retinoic acid receptor alpha by protein kinase C in B16 mouse melanoma cells.
We have previously found that retinoic acid stimulates the expression of protein kinase C alpha (PKC) in B16 mouse melanoma cells. Because it has been reported that PKC can phosphorylate retinoic acid receptor (RAR) and alter its function, we determined whether changes in the level and/or activity of PKC could affect the expression or function of the RAR in B16 melanoma. Using in vivo phosphorylation and band shift techniques, we could not demonstrate that altering PKC activity and/or protein level changed the in vivo phosphorylation of RAR alpha. However activation of PKC resulted in increased RAR alpha protein. Increased receptor protein correlated with a phorbol dibutyrate-stimulated increase in receptor activation function-2 (AF-2)-dependent transcriptional activity. Use of enzyme inhibitors and dominant-negative PKCs indicated that enzyme activity was required for elevation in the RAR alpha. The PKC-mediated increase in RAR alpha was due to a 2.5-fold increase in the half-life of this protein. In contrast, the down-regulation of PKC diminished RAR alpha protein half-life and markedly inhibited AF-2-dependent transcriptional activity. The down-regulation of PKC also inhibited the binding of RAR to a retinoic acid response element and the retinoic acid induction of RAR beta expression. These findings suggest that PKC can influence retinoic acid signaling by altering the stability of RAR protein without directly phosphorylating this receptor.


Carbohydrate metabolism evaluation of terrestrial snail Subulina octona (Gastropoda, Subulinidae) experimentally infected by the Paratanaisia bragai digenetic trematode (Digenea, Eucotylidae).
Among the effects of the larval development of digenetic trematodes on their intermediate hosts, changes in the carbohydrate metabolism in the snails stand out. The aim of this study was to analyze, every 10 days after infection (d.p.i.), the effects of Paratanaisia bragai infection on the glycogen content in the digestive gland and cephalopedal mass in Subulina octona snail, and also verify the glucose concentration and the enzyme D- and L-lactate dehydrogenase activity (EC188.8.131.52 and EC126.96.36.199) (LDH) and the concentration of some metabolites(oxalic, succinic, pyruvic and lactic acid) presents in the hemolymph. Histochemical analisys were also performed. We verified a total increase of 54.81% in glucose concentration in infected snails and an oscillating pattern in the glycogen content in the cephalopedal mass and in the digestive gland. LDH activity shows an increase of 10 d.p.i. (+ 74.32%) and 40 d.p.i. (+ 47.81%) and decrease at 20 d.p.i. and 30 d.p.i. The concentrations of oxalic, succinic and pyruvic acids showed significant and progressive reductions; however, lactic acid had a significant increase. Histological and histochemical analysis showed a tissue disorganization in the cephalopedal mass of infected snails and morphological changes in the digestive gland. These results confirm that infection causes metabolic pathway changes in the snails due to activation of an alternative anaerobic pathway for producing energy, indicated by the increased lactic acid content and LDH activity.


Synthesis and evaluation of macrocyclic transition state analogue inhibitors for alpha-chymotrypsin.
Lactams 1 and 2 are readily formed from acyclic precursors in the presence of trypsin and chymotrypsin, respectively, identifying the macrocyclic ring system as a potential motif for constrained transition state analogue inhibitors of the serine peptidases. Ketone 3 was synthesized and shown to be a modest inhibitor of chymotrypsin (Ki = 220 microM), albeit 4-fold more potent than the acyclic hydroxy acid 25 (Ki = 1.5 mM as a mixture of epimers). A precursor (31) to the amino boronic acid 4 was also prepared; although this derivative was a potent inhibitor of chymotrypsin (Ki = 130 nM) by virtue of the boronic acid moiety, it showed no advantage over the des-amino analogue 32 (Ki = 120 nM), which is not capable of cyclizing.


Multi-focus excitation coherent anti-Stokes Raman scattering (CARS) microscopy and its applications for real-time imaging.
We developed a multi-focus excitation coherent anti-Stokes Raman scattering (CARS) microscope using a microlens array scanner for real-time molecular imaging. Parallel exposure of a specimen with light from two highly controlled picosecond mode-locked lasers (jitter of 30 fs through an electronic low-pass filter with 150 Hz bandwidth, point-by-point wavelength scan within 300 ms) and parallel detection with an image sensor enabled real-time imaging. We demonstrated real-time CARS imaging of polystyrene beads (frame rate of 30 fps), a giant multi-lamellar vesicle of dipalmitoylphosphatidylcholine (frame rate of 10 fps), and living HeLa cells (frame rate of 10 fps).


Ceftaroline: a new broad-spectrum cephalosporin.
The pharmacokinetics, pharmacodynamics, clinical efficacy, and safety of ceftaroline are reviewed. Ceftaroline, a new broad- spectrum antibiotic, is approved for the treatment of complicated skin and skin structure infections (cSSSIs) and community- acquired pneumonia (CAP). This β-lactam antibiotic has extended activity against gram-positive organisms and has activity against common gram-negative organisms. The drug's spectrum of activity includes both methicillin-resistant Staphylococcus aureus and multidrug-resistant Streptococcus pneumoniae. However, its activity against extended-spectrum β-lactamase-producing bacteria is limited. These bacteria, particularly those that express AmpC β-lactamase, greatly reduce the activity of ceftaroline. The prodrug of ceftaroline (ceftaroline fosamil) is rapidly converted to its active form (ceftaroline) in plasma. This dose-linear drug has been found to be pharmacodynamically best correlated with the percentage of time that free drug concentrations remain above the minimum inhibitory concentration. Ceftaroline's safety profile is similar to that of the other cephalosporins, with minimal adverse drug reactions, most of which are considered mild. Currently available pharmacokinetic, animal, and clinical studies have found that ceftaroline has reasonable efficacy and tolerability but have also revealed that dosing regimen modifications may be needed in patients with moderate-to-severe renal impairment. The recommended dosage of ceftaroline for the treatment of cSSSIs and CAP is 600 mg infused intravenously over 60 minutes every 12 hours. The recommended duration of therapy is 5-14 and 5-7 days for cSSSIs and CAP, respectively. Additional Phase III studies are currently underway. Ceftaroline is a new broad-spectrum cephalosporin indicated for the treatment of cSSSIs and CAP caused by susceptible gram-positive and gram-negative organisms.


DAVID: An open-source platform for real-time transformation of infra-segmental emotional cues in running speech.
We present an open-source software platform that transforms emotional cues expressed by speech signals using audio effects like pitch shifting, inflection, vibrato, and filtering. The emotional transformations can be applied to any audio file, but can also run in real time, using live input from a microphone, with less than 20-ms latency. We anticipate that this tool will be useful for the study of emotions in psychology and neuroscience, because it enables a high level of control over the acoustical and emotional content of experimental stimuli in a variety of laboratory situations, including real-time social situations. We present here results of a series of validation experiments aiming to position the tool against several methodological requirements: that transformed emotions be recognized at above-chance levels, valid in several languages (French, English, Swedish, and Japanese) and with a naturalness comparable to natural speech.


Phenolic Acids and Flavonoids Play Important Roles in Flower Bud Differentiation in Mikania micrantha: Transcriptomics and Metabolomics.
Mikania micrantha is a highly invasive vine, and its ability to sexually reproduce is a major obstacle to its eradication. The long-distance dissemination of M. micrantha depends on the distribution of seeds; therefore, inhibiting M. micrantha flowering and seed production is an effective control strategy. The number of blooms of M. micrantha differs at different altitudes (200, 900, and 1300 m). In this study, we used a combination of metabolomics and transcriptomics methods to study the patterns of metabolite accumulation in the flower buds of M. micrantha. Using LC-MS/MS, 658 metabolites were found in the flower buds of M. micrantha at three different altitudes (200, 900, and 1300 m). Flavonoids and phenolic acids were found to be the main differential metabolites, and their concentrations were lower at 900 m than at 200 m and 1300 m, with the concentrations of benzoic acid, ferulic acid, and caffeic acid being the lowest. The biosynthesis pathways for flavonoids and phenolic compounds were significantly enriched for differentially expressed genes (DEGs), according to the results of transcriptome analysis. The production of flavonoid and phenolic acids was strongly linked with the expressions of phenylalanine ammonia-lyase (PAL), caffeoyl-CoA O-methyltransferase (COMT), and 4-coumarate-CoA ligase (4CL), according to the results of the combined transcriptome and metabolome analysis. These genes' roles in the regulation of distinct phenolic acids and flavonoids during M. micrantha bud differentiation are still unknown. This study adds to our understanding of how phenolic acids and flavonoids are regulated in M. micrantha flower buds at various altitudes and identifies regulatory networks that may be involved in this phenomenon, offering a new approach for the prevention and management of M. micrantha.


SILAC proteomics based on 3D cell spheroids unveils the role of RAC2 in regulating the crosstalk between triple-negative breast cancer cells and tumor-associated macrophages.
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, and is characterized by a high infiltration of tumor-associated macrophages (TAMs). TAMs contribute significantly to tumor progression by intricately interacting with tumor cells. Deeply investigating the interaction between TNBC cells and TAMs is of great importance for finding potential biomarkers and developing novel therapeutic strategies to further improve the clinical outcomes of TNBC patients. In this study, we confirmed the interplay using both 3D and 2D co-culture models. The stable-isotype labeling by amino acids in cell culture (SILAC)-based quantitative proteomics was conducted on 3D cell spheroids containing TNBC cells and macrophages to identify the potential candidate in regulating the crosstalk between TNBC and TAMs. Ras-related C3 botulinum toxin substrate 2 (RAC2) was identified as a potential molecule for further exploration, given its high expression in TNBC and positive correlation with M2 macrophage infiltration. The suppression of RAC2 inhibited TNBC cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) in vitro. Meanwhile, knocking down RAC2 in TNBC cells impaired macrophage recruitment and M2 polarization. Mechanistically, RAC2 exerted its roles in TNBC cells and TAMs by regulating the activation of P65 NF-κB and P38 MAPK, while TAMs further elevated RAC2 expression and P65 NF-κB activation by secreting soluble mediators including IL-10. These findings highlight the significance of RAC2 as a crucial molecule in the crosstalk between TNBC and TAMs, suggesting it could be a promising therapeutic target in TNBC.


What are the physical and psychological health effects of suicide bereavement on family members? Protocol for an observational and interview mixed-methods study in Ireland.
Research indicates that experiencing the suicide of a relative can have a significant impact on family members' emotional health. However, research incorporating the impact of suicide bereavement on family members' physical health is sparse. This paper details the protocol for a mixed-methods study of suicide-bereaved family members. The study will primarily examine the physical and mental health needs of those bereaved by suicide. A secondary objective of the study is to describe the support service needs of family members bereaved by suicide. A mixed-methods approach, using semistructured interviews and self-report questionnaires, will be used. Interviews will be conducted with a group of 15-20 relatives who experienced suicide bereavement. This protocol will follow the COREQ checklist criteria for the reporting of qualitative research interviews. Thematic analysis will be used to examine experiences and impact of bereavement on psychological and physical health. Self-report quantitative data on well-being will be analysed using descriptive statistics. Ethical approval to conduct this study has been granted from the Clinical Research Ethics Committee of the Cork Teaching Hospitals. Pseudonyms will be given to participants to protect anonymity. It will be explained to participants that participation in the study is voluntary and they have to right to withdraw at any time. The findings of this research will be disseminated to regional, national and international audiences through publication in peer-reviewed international journals and presentations at scientific conferences. This research also forms part of a PhD thesis.


A comparison of arm-based and contrast-based models for network meta-analysis.
Differences between arm-based (AB) and contrast-based (CB) models for network meta-analysis (NMA) are controversial. We compare the CB model of Lu and Ades (2006), the AB model of Hong et al(2016), and two intermediate models, using hypothetical data and a selected real data set. Differences between models arise primarily from study intercepts being fixed effects in the Lu-Ades model but random effects in the Hong model, and we identify four key difference. (1) If study intercepts are fixed effects then only within-study information is used, but if they are random effects then between-study information is also used and can cause important bias. (2) Models with random study intercepts are suitable for deriving a wider range of estimands, eg, the marginal risk difference, when underlying risk is derived from the NMA data; but underlying risk is usually best derived from external data, and then models with fixed intercepts are equally good. (3) The Hong model allows treatment effects to be related to study intercepts, but the Lu-Ades model does not. (4) The Hong model is valid under a more relaxed missing data assumption, that arms (rather than contrasts) are missing at random, but this does not appear to reduce bias. We also describe an AB model with fixed study intercepts and a CB model with random study intercepts. We conclude that both AB and CB models are suitable for the analysis of NMA data, but using random study intercepts requires a strong rationale such as relating treatment effects to study intercepts.


Attenuation of an electromagnetic wave by charged dust particles in a sandstorm.
We calculate the light scattering properties of the partially charged dust particles with the Mie theory for electromagnetic waves with different frequencies, and the attenuation coefficients of an electromagnetic wave propagating in a sandstorm are also calculated. The results show that the electric charges distributed on the sand surface have a significant effect on the attenuation of the electromagnetic wave, especially for a frequency lower than 40 GHz, and attenuation coefficients increase with the magnitude of charges carried by the dust particles (expressed by the charge-to-mass ratio in this paper). For the higher frequency electromagnetic wave, such as visible light, the effect of charges carried by sand particles on its attenuation is very little, which can be ignored.


End of life care in nursing homes in Spain: Exploratory analysis and evidences of validity of a new scale.
Quality end-of-life care is a central issue in nursing homes, requiring the assessment of individual and family needs by health professionals. Although previous instruments have been developed, they usually rely on family reports and have been adapted from other clinical contexts (hospital or primary care). It is important to consider how health care professionals working in nursing homes perceive what is necessary to achieve quality end-of-life care. In this study, the objective was to develop an instrument to assess quality of end-of-life care in the context of Spanish care homes. A 24 item scale Nursing Home End of Life Care Scale (NHEOLC) was developed through a systematic evaluation of existing tools combined with an iterative process of consultation with group experts in end of life care in long term care settings. A total of 307 health care professionals agreed to participate in the study and completed the scale. The scale was grouped in six dimensions: physical, psychological aspects and spiritual aspects of care, family care, bereavement, and patient/family preferences management. The results suggest an adequate factorial structure of the scale and good internal consistency for the total score and the subscales. In addition, the results showed significant differences depending on the size of the nursing home, the category of health professionals, and their own perceptions of his work regarding end-of-life care.


Skill Learning Through Early Clinical Exposure: An Experience of Indian Medical School.
Indian Medical curriculum being discipline based, there is a line of demarcation between preclinical and clinical subjects. The challenges in medical education include the methods that would enhance the clinical education quality; one such method been Early Clinical Exposure (ECE). ECE can help to instill the skill component of medical education in the first year students helping to minimize the line of demarcation. Hence this study was undertaken to assess the skill learning of students through early clinical exposure and to collate the perception of them. In the present study, students of 1(st) MBBS were exposed to ECE as an adjunct teaching method with preset modules. They were evaluated by Objectively Structured Clinical Examination (OSCE). Feedback was obtained from 1(st) MBBS and also from the same students after passing the 1(st) MBBS in 4(th) semester. Significant differences in pre and post OSCE scores were noted (p<0.0001). Seventy six percent students rated ECE as an excellent tool. Second year students also perceived ECE held in 1(st) year was helpful to correlate topics and increasing confidence. ECE had an effective influence on learning as manifested in skills gained by the students and their perceptions of ECE being helpful prospectively in their routine clinical posting.


Intracavernous aneurysms: treatment by proximal balloon occlusion of the internal carotid artery.
Seven patients with intracavernous aneurysms were treated by proximal balloon occlusion of the carotid artery, with no attempt to preserve carotid blood flow. After a 15-minute occlusion trial, two balloons were detached proximal to the neck of these aneurysms. Major clinical improvement occurred in six patients and no procedure-related complications were encountered (the follow-up period was 4-14 months). Because these aneurysms arise proximal to major collateral pathways, proximal carotid occlusions via endovascular techniques are simple and safe and carry with them little risk of thromboembolism.


Proteins Breaking Bad: A Free Energy Perspective.
Protein aging may manifest as a mechanical disease that compromises tissue elasticity. As proved recently, while proteins respond to changes in force with an instantaneous elastic recoil followed by a folding contraction, aged proteins break bad, becoming unstructured polymers. Here, we explain this phenomenon in the context of a free energy model, predicting the changes in the folding landscape of proteins upon oxidative aging. Our findings validate that protein folding under force is constituted by two separable components, polymer properties and hydrophobic collapse, and demonstrate that the latter becomes irreversibly blocked by oxidative damage. We run Brownian dynamics simulations on the landscape of protein L octamer, reproducing all experimental observables, for a naive and damaged polyprotein. This work provides a unique tool to understand the evolving free energy landscape of elastic proteins upon physiological changes, opening new perspectives to predict age-related diseases in tissues.


Qualitative study exploring the phenomenon of multiple electronic prescribing systems within single hospital organisations.
A previous census of electronic prescribing (EP) systems in England showed that more than half of hospitals with EP reported more than one EP system within the same hospital. Our objectives were to describe the rationale for having multiple EP systems within a single hospital, and to explore perceptions of stakeholders about the advantages and disadvantages of multiple systems including any impact on patient safety. Hospitals were selected from previous census respondents. A decision matrix was developed to achieve a maximum variation sample, and snowball sampling used to recruit stakeholders of different professional backgrounds. We then used an a priori framework to guide and analyse semi-structured interviews. Ten participants, comprising pharmacists and doctors and a nurse, were interviewed from four hospitals. The findings suggest that use of multiple EP systems was not strategically planned. Three co-existing models of EP systems adoption in hospitals were identified: organisation-led, clinician-led and clinical network-led, which may have contributed to multiple systems use. Although there were some perceived benefits of multiple EP systems, particularly in niche specialities, many disadvantages were described. These included issues related to access, staff training, workflow, work duplication, and system interfacing. Fragmentation of documentation of the patient's journey was a major safety concern. The complexity of EP systems' adoption and deficiencies in IT strategic planning may have contributed to multiple EP systems use in the NHS. In the near to mid-term, multiple EP systems may remain in place in many English hospitals, which may create challenges to quality and patient safety.


Fetal gene transfer using lentiviral vectors and the potential for germ cell transduction in rhesus monkeys (Macaca mulatta).
Genetic modification of germ cells in somatic gene therapy protocols is a concern, particularly with fetal approaches. This study focused on the potential for germ cell gene transfer post-fetal gene delivery using a human immunodeficiency virus type 1 (HIV-1)-derived lentiviral vector pseudotyped with the vesicular stomatitis virus-glycoprotein (VSV-G). Rhesus monkey fetuses (n = 47) were administered vector supernatant (10(7) infectious particles per fetus) via the intraperitoneal (IP), intrapulmonary (Ipu), or intracardiac routes (Ica) under ultrasound guidance. Tissue harvests were performed near term or 3 months postnatal age, and genomic DNA obtained to analyze for vector sequences from collected sections of gonads and gonadal cells obtained by laser capture microdissection (germ cells, stroma, epithelium). Results indicated no evidence of germ cell gene transfer in fetuses or infants with Ipu or Ica routes of administration. However, evidence of the transgene (1.33 +/- 0.78 enhanced green fluorescent protein [EGFP] copies per copy epsilon-globin) was found in females, but not males, when using the IP administration approach (p < 0.05). The highest EGFP copies were detected on the surface epithelium (p < 0.05). The results of these studies suggest that the HIV-1-derived lentiviral vector pseudotyped with VSV-G may transduce a subpopulation of gonadal cells in female fetuses with IP administration, whereas no evidence of gene transfer was shown to occur in males or with organ-targeting approaches.


A cross-sectional study to investigate motivation for physical activity in a sample of Iranian community-dwelling older adults.
Background: On the basis of the Social-Ecological Model, there are assumed to be three sources of motivation - intrapersonal, interpersonal, and community motivation - that prompt older adults to participate in physical activity (PA). These three motivational sources can lead to PA behavior adherence. Little empirical research exists that investigates which motivational source is more influential in older adults' adherence to PA, thus creating an area of interest for this research. Methods: A cross-sectional study was used to investigate the relationship between levels of PA and different sources of motivation. The convenience sample of 140 community-dwelling older adults, aged 60 and greater, living in Shiraz, Iran agreed to complete self-reported questionnaires,to measure motivation and PA. Five statistical tests were used: Independent-samples t test, one way ANOVA, Pearson correlation coefficient, chi-square, and ordinal regression. Results: Ordinal regression indicated that gender (P = 0.001, CI: 0.523-2.115) and intrapersonal motivation (P < 0.001, CI: 0.038-0.126) were useful predictors of variations in the levels of PA. Compared to males, females engaged in PA with less frequency (P = 0.006). Community motivation decreased with age (r = - 0.213, P < 0.05). There were no significant relationships between age, educational level, health status, and PA (P > 0.05). Conclusion: Interpersonal and community motivation were insignificant factors for PA participation, perhaps due to non-facilitating environment. Future research should be conducted to investigate the environmental issues that hinder PA participation in older adults.


The purification and properties of the C 1 component of Trichoderma koningii cellulase.
1. The C(1) component that was isolated from a Trichoderma koningii cellulase preparation (Wood, 1968) by chromatography on DEAE-Sephadex with a salt gradient was still associated with a trace of CM-cellulase activity (determined by reducing-sugar and viscometric methods). 2. Further chromatography on DEAE-Sephadex, with a pH gradient instead of a salt gradient, provided a C(1) component that could still produce reducing sugars from a solution of CM-cellulose (to a very limited extent), but which could no longer decrease the viscosity (i.e. under the assay conditions employed). 3. No evidence for the non-identity of C(1) component and the trace of CM-cellulase activity could be found when electrofocusing was done in a stabilized pH gradient covering three pH units (pH3-6) or, alternatively, only 0.5 pH unit (pH3.72-4.25). 4. The two protein peaks that were separated by electrofocusing in carrier ampholytes covering only 0.5 pH unit (isoelectric pH values of 3.80 and 3.95) were shown to be isoenzymes of the C(1) component: they differed in the extent to which they were associated with carbohydrate (9% and 33%). 5. The purified C(1) component had little ability to attack CM-cellulose or highly ordered forms of cellulose, but degraded phosphoric acid-swollen cellulose readily: cellobiose was the principal product of the hydrolysis (97%). 6. Dewaxed cotton fibre was degraded to the extent of 15% when exposed to high concentrations of C(1) component over a prolonged period: cellobiose was again the principal sugar present in the supernatant (96%). 7. Cellotetraose and cellohexaose were hydrolysed almost exclusively to cellobiose. 8. Evidence indicates that the C(1) component is a beta-1,4-glucan cellobiosylhydrolase.


α6-Containing GABAA Receptors: Functional Roles and Therapeutic Potentials.
GABAA receptors containing the α6 subunit are highly expressed in cerebellar granule cells and less abundantly in many other neuronal and peripheral tissues. Here, we for the first time summarize their importance for the functions of the cerebellum and the nervous system. The cerebellum is not only involved in motor control but also in cognitive, emotional, and social behaviors. α6βγ2 GABAA receptors located at cerebellar Golgi cell/granule cell synapses enhance the precision of inputs required for cerebellar timing of motor activity and are thus involved in cognitive processing and adequate responses to our environment. Extrasynaptic α6βδ GABAA receptors regulate the amount of information entering the cerebellum by their tonic inhibition of granule cells, and their optimal functioning enhances input filtering or contrast. The complex roles of the cerebellum in multiple brain functions can be compromised by genetic or neurodevelopmental causes that lead to a hypofunction of cerebellar α6-containing GABAA receptors. Animal models mimicking neuropsychiatric phenotypes suggest that compounds selectively activating or positively modulating cerebellar α6-containing GABAA receptors can alleviate essential tremor and motor disturbances in Angelman and Down syndrome as well as impaired prepulse inhibition in neuropsychiatric disorders and reduce migraine and trigeminal-related pain via α6-containing GABAA receptors in trigeminal ganglia. Genetic studies in humans suggest an association of the human GABAA receptor α6 subunit gene with stress-associated disorders. Animal studies support this conclusion. Neuroimaging and post-mortem studies in humans further support an involvement of α6-containing GABAA receptors in various neuropsychiatric disorders, pointing to a broad therapeutic potential of drugs modulating α6-containing GABAA receptors. SIGNIFICANCE STATEMENT: α6-Containing GABAA receptors are abundantly expressed in cerebellar granule cells, but their pathophysiological roles are widely unknown, and they are thus out of the mainstream of GABAA receptor research. Anatomical and electrophysiological evidence indicates that these receptors have a crucial function in neuronal circuits of the cerebellum and the nervous system, and experimental, genetic, post-mortem, and pharmacological studies indicate that selective modulation of these receptors offers therapeutic prospects for a variety of neuropsychiatric disorders and for stress and its consequences.