Akt is frequently activated in HER2/neu-positive breast cancers and associated with poor prognosis among hormone-treated patients.
Akt/PKB is a serine/threonine kinase that plays an important role in survival when cells are exposed to different apoptotic stimuli. Aberrant activation of Akt/PKB in breast carcinoma is associated with poor prognosis and resistance to endocrine therapy and chemotherapy. The Akt signaling pathway currently attracts considerable attention as a new target for effective therapeutic strategies. We therefore investigated the relationship between activation of Akt and clinicopathologic variables including hormone receptor and HER2/neu status. Breast cancer tissues obtained from 252 patients were utilized for this study. We evaluated Akt activation by immunohistochemical assessment of the expression of phosphorylated Akt (pAkt) at Ser-473. Eighty-four cases (33.3%) were diagnosed as positive for pAkt expression. pAkt was significantly associated with HER2/neu overexpression (p < 0.0001). There was an inverse correlation between pAkt and PR expression (p = 0.0321); however, there was no association between pAkt and ER expression. Survival analysis showed that pAkt positivity was associated with poor disease-free survival in cases with postoperative hormone therapy; however, there was no association in cases without hormone therapy. Our results indicate that Akt activation induced poor prognosis in patients who received adjuvant hormone therapy. This finding suggests that inhibition of the Akt signaling pathway may increase the efficacy of hormone therapy and improve the prognosis of patients who receive adjuvant hormone therapy.


Effects of HIF-1α on Spermatogenesis of Varicocele Rats by Regulating VEGF/PI3K/Akt Signaling Pathway.
Hypoxia-inducible factor-1α (HIF-1α) participates in the regulation of spermatogenic function in rats with varicocele (VC), and the PI3K/Akt pathway plays an important role in it. In the present research, we applied the CRISPR/Cas9 gene editing technique to silence the HIF-1α gene of VC rat testis, to explore the effect of HIF-1α on apoptosis of spermatogenic cells in VC rats through the PI3K/Akt pathway. Sprague Dawley rats were randomly assigned to four groups, including the normal rat group (group N), VC model group (group V), VC + HIF-1α-lentivirus group (group H), and VC + luciferase-lentivirus group (group L). Apoptosis of spermatogenic cells in rat testis was tested by TUNEL Kit. The morphologic changes of seminiferous tubules were viewed by a light microscope. Expressions of VEGF, Akt, p-Akt, p70S6K, and p-p70S6K were detected by means of Western blot, immunofluorescence, or immunohistochemistry methods. One-way ANOVA was applied to analyze the diverseness between groups. Compared with group N, the distribution of germ cells was disordered, apoptosis of spermatogenic cells increased significantly, and the expression of VEGF, p-Akt, and p-p70S6K was also increased in group V. Compared with group V, the damage of seminiferous epithelium in group H was improved, and the arrangement of the seminiferous epithelium was almost orderly. Apoptosis of spermatogenic cells decreased significantly, and the expression of VEGF, p-Akt, and p-p70S6K protein was decreased (P < 0.05). There was no significant difference between group N and group H (P > 0.05).In conclusion, HIF-1α is regulated by hypoxia in rats with varicocele to regulate its downstream gene VEGF which regulates spermatogenesis, and the PI3K/Akt signaling pathway plays a regulatory role in this process.


Follicular arrest in polycystic ovary syndrome is associated with deficient inhibin A and B biosynthesis.
Previous studies suggest that inhibin subunit expression is decreased in granulosa cells of women with polycystic ovary syndrome (PCOS). The objective of this study was to test the hypothesis that inhibin A and inhibin B protein concentrations are also decreased in PCOS follicles. The design was a parallel study. The study was performed at an in vitro fertilization suite. We studied women with regular cycles (n = 36) and women with PCOS (n = 8). Follicular fluid was aspirated from the follicles of women with PCOS (n = 14 follicles) and from women with regular cycles at various times during the follicular phase (n = 50 follicles). Inhibin A and B concentrations from PCOS follicles were compared with those in size-matched follicles, dominant follicles (> or = 10 mm), and subordinate follicles from regularly cycling women. Inhibin A (220 +/- 38 vs. 400 +/- 72 IU/ml; P < 0.05) and inhibin B (75.4 +/- 10.4 vs. 139 +/- 26 ng/ml; P < 0.05) concentrations were lower in the follicular fluid of PCOS follicles compared with those of size-matched follicles from regularly cycling women. Inhibin A was also lower in the follicular fluid of PCOS compared with subordinate follicles from normal women (577 +/- 166 IU/ml; P < 0.05). Inhibin A concentrations increased with increasing follicle size, resulting in significantly higher follicular fluid concentrations in dominant follicles from normal women compared with PCOS follicles (2298 +/- 228 IU/ml; P < 0.05). These data demonstrate that inhibin A and inhibin B concentrations are significantly reduced in the follicular fluid of women with PCOS compared with those in the follicular fluid of size-matched follicles from normal women, consistent with the decreased inhibin subunit mRNA expression in previous studies. These findings point to the potential importance of inhibins in normal follicle development and suggest that inhibin deficiency may play a role in the follicle arrest associated with PCOS.


Bird skins in museum collections: are they suitable as indicators of environmental metal load after conservation procedures?
To find out whether modern conservation treatments alter the level of metals in feathers, we analysed the content of 10 metals in feathers before and after skins were washed with detergent and treated with Eulan U-33 (a commonly used preservative at museums). Feathers of 31 birds of Goshawk Accipiter gentilis, Eagle Owl Bubo bubo. Feral Pigeon Columba livia domest, and Common Eider Somateria mollissima were analysed. We found that in most cases metals were partly washed out of the feathers, but the effects were related to species and type of feather. The value of bird skins as indicators of environmental metal load is therefore affected by this treatment. It is recommended that the conservation techniques used at museums should be reconsidered if skins are intended for specimen banking for future reference in environmental monitoring schemes and research.


Nucleolar organizing regions in Crassostrea angulata: chromosomal location and polymorphism.
Specimens of Crassostrea angulata collected from several natural populations, with or without metal contamination, located along the Southwestern coast of Spain were cytogenetically analyzed. The diploid number was 20 and all 10 chromosome pairs were metacentric. The nucleolar organizing regions (NORs) were identified on the telomeric region of the chromosome pair 10 by several methods, including silver nitrate staining (AgNO3), chromomycin A3 staining (CMA3) and fluorescence in situ hybridization (FISH). One or two primary Ag-NORs in the metaphase cells were most frequently found. Very infrequently, one or two secondary NORs were seen. High Ag-NOR and rDNA polymorphisms in both the size and/or the number occurred intra-individually, inter-individually and inter-populationally. However some population-specific Ag-NOR polymorphisms were found to reach or be approaching to a level of significant difference. A comparison of number and frequencies between FISH-rDNA signals and Ag-NORs showed that some NORs were not transcriptionally active. Moreover, presence of pollutants on the medium could be favoring the presence of two NORs per cell more than acting modifying expression on the NORs.


Haploinsufficiency of RanBP2 is neuroprotective against light-elicited and age-dependent degeneration of photoreceptor neurons.
Prolonged light exposure is a determinant factor in inducing neurodegeneration of photoreceptors by apoptosis. Yet, the molecular bases of the pathways and components triggering this cell death event are elusive. Here, we reveal a prominent age-dependent increase in the susceptibility of photoreceptor neurons to undergo apoptosis under light in a mouse model. This is accompanied by light-induced subcellular changes of photoreceptors, such as dilation of the disks at the tip of the outer segments, prominent vesiculation of nascent disks, and autophagy of mitochondria into large multilamellar bodies. Notably, haploinsufficiency of Ran-binding protein-2 (RanBP2) suppresses apoptosis and most facets of membrane dysgenesis observed with age upon light-elicited stress. RanBP2 haploinsufficiency promotes decreased levels of free fatty acids in the retina independent of light exposure and turns the mice refractory to weight gain on a high-fat diet, whereas light promotes an increase in hydrogen peroxide regardless of the genotype. These studies demonstrate the presence of age-dependent and RanBP2-mediated pathways modulating membrane biogenesis of the outer segments and light-elicited neurodegeneration of photoreceptors. Furthermore, the findings support a mechanism whereby the RanBP2-dependent production of free fatty acids, metabolites thereof or the modulation of a cofactor dependent on any of these, promote apoptosis of photoreceptors in concert with the light-stimulated production of reactive oxygen species.


Domain II hairpin structure in ITS1 sequences as an aid in differentiating recently evolved animal and plant pathogenic fungi.
The hypothesis that ITS structural features can be used to define fungal groups, where sequence analysis is unsatisfactory, was examined in plant and animal pathogenic fungi. Structural models of ITS1 regions were predicted for presumed closely related species in Colletotrichum and Trichophyton anamorphs of Arthroderma species. Structural alignment of models and comparison with ITS sequence analysis identified a variable region in a conserved hairpin formed from a common inverted repeat. Thirteen different hairpin structure models were obtained for Colletotrichum species and five different models were obtained for Trichophyton species. The different structure types could be matched to individual species and species complexes as defined by ITS sequence analysis.


acorde unravels functionally interpretable networks of isoform co-usage from single cell data.
Alternative splicing (AS) is a highly-regulated post-transcriptional mechanism known to modulate isoform expression within genes and contribute to cell-type identity. However, the extent to which alternative isoforms establish co-expression networks that may be relevant in cellular function has not been explored yet. Here, we present acorde, a pipeline that successfully leverages bulk long reads and single-cell data to confidently detect alternative isoform co-expression relationships. To achieve this, we develop and validate percentile correlations, an innovative approach that overcomes data sparsity and yields accurate co-expression estimates from single-cell data. Next, acorde uses correlations to cluster co-expressed isoforms into a network, unraveling cell type-specific alternative isoform usage patterns. By selecting same-gene isoforms between these clusters, we subsequently detect and characterize genes with co-differential isoform usage (coDIU) across cell types. Finally, we predict functional elements from long read-defined isoforms and provide insight into biological processes, motifs, and domains potentially controlled by the coordination of post-transcriptional regulation. The code for acorde is available at https://github.com/ConesaLab/acorde .


Niche differentiation of Mucoromycotinian and Glomeromycotinian arbuscular mycorrhizal fungi along a 2-million-year soil chronosequence.
Current literature suggests ecological niche differentiation between co-occurring Mucoromycotinian arbuscular mycorrhizal fungi (M-AMF) and Glomeromycotinian AMF (G-AMF), but experimental evidence is limited. We investigated the influence of soil age, water availability (wet and dry), and plant species (native Microlaena stipoides and exotic Trifolium subterraneum) on anatomical root colonisation and DNA profiles of M-AMF and G-AMF under glasshouse conditions. We grew seedlings of each species in soils collected from the four stages of a soil chronosequence, where pH decreases from the youngest to oldest stages, and phosphorus (P) is low in the youngest and oldest, but high in the intermediate stages. We scored the percentage of root length colonised and used DNA metabarcoding to profile fungal richness and community composition associated with treatment combinations. Soil age, water availability, and plant species were important influencers of root colonisation, although no M-AMF were visible following staining of M. stipoides roots. Soil age and host plant influenced fungal richness and community composition. However, response to soil age, potential host species, and water availability differed between M-AMF and G-AMF. Root colonisation of T. subterraneum by M-AMF and G-AMF was inversely correlated with soil P level. Community composition of M-AMF and G-AMF was structured by soil age and, to a lesser extent, plant species. Richness of M-AMF and G-AMF was negatively, and positively, correlated with available P, respectively. These findings are experimental evidence of ecological niche differentiation of M-AMF and G-AMF and invite further exploration into interactive effects of abiotic and biotic factors on their communities along successional trajectories.


[Expression of T cell factor 4 in renal cell carcinoma].
To investigate of the transduction of Wnt/Frizzled pathway in nuclei and the function of TCF4 (T Cell Factor) in renal cell carcinoma. TCF4 mRNA are tested through RT-PCR and Northern Blot in renal cancer tissue and renal cancer cell strain (GRC-I). It has been certificated that TCF4 are expressed in renal cell carcinoma, at the same time, there are some different splice of TCF4 in renal cancer. A new 300bp mutant gene are found. TCF4, an important molecular of Wnt/Frizzled pathway, takes part in the formation and progression of renal cell carcinoma, different splice of TCF4 is one of the mechanism.


Medicinal chemistry strategies targeting NLRP3 inflammasome pathway: A recent update from 2019 to mid-2023.
Nod-like receptor protein 3 (NLRP3), a therapeutic target that has a close relationship with inflammatory diseases, has drawn significant attention from researchers in the field. An increasing number of NLRP3 inhibitors have been reported since NLRP3 was identified as a biomarker and inflammatory therapeutic target. Inhibiting NLRP3 has been widely studied as therapeutics for the treatment of cryopyrin associated periodic syndrome (CAPS), inflammatory bowel disease (IBD), nonalcoholic steatohepatitis (NASH), arthrolithiasis, Alzheimer's disease (AD) and Parkinson's disease (PD). This review updates the recently reported (2019 to mid-2023) molecule inhibitors targeting the NLRP3 inflammasome pathway, summarizes their structure-activity relationships (SARs), and discusses the therapeutic effects on inflammatory diseases. I hope this review will contribute to the development of novel inhibitors targeting NLRP3 inflammasome pathway as potential drugs.


Physical activity and social support mediate the relationship between chronic diseases and positive mental health in a national sample of community-dwelling Canadians 65+: A structural equation analysis.
Mental health is a critical component of healthy aging. Aging increases the likelihood of developing chronic diseases. The negative effects of chronic diseases on mental health have been extensively documented. Physical activity and social support have been reported to influence mental health positively. Data analyzed are drawn from the national Canadian Community Health Survey - Mental Health in 2012. Structural equation modeling (SEM) techniques were used to estimate and test the mediating role of physical activities and social support in the relationship between chronic disease, positive mental health, and psychological distress in a national adult population sample aged 65+. Approximately 83% of the older adults sample reported having at least one chronic disease, and the mean score of psychological distress and positive mental health was 14.15 ± 4.73 and 55.28 ± 10.67, respectively. Initial analysis found that chronic illness was negatively related to positive mental health (β= -0.72, P < 0.001) and positively related to psychological distress (β=0.98, P < 0.001). The final structural model found that physical activity and social support partially mediated the negative consequences of chronic disease on psychological distress and strengthened seniors' positive mental health. Limiting causal attribution, potential reporting bias and limited in recognizing negative and positive social support are the major limitations. Older adults with chronic diseases should be encouraged to increase physical activity and social support levels. The study outcomes have clinical implications for the delivery of mental health services to improve mental health and resilience to coping with stress among older adults.


Using empirical data to inform the ethical evaluation of placebo controlled trials.
There has been considerable debate about the ethical acceptability of using placebo-controls in clinical research. Although this debate has been rich in rhetoric, considering that much of this research is predicated upon the assumption that data from this research is vital to clinical decision-making, it is ironic that researchers have introduced little data into these discussions. Using some published research concerning the use of placebo-controls in clinical research in hypertension and psychiatric drug trials, I suggest some ways that such data might be incorporated into the ethical analysis concerning placebo use in clinical trials. This approach promises to be important for enhancing conceptual and scientific understanding as well as public policy decision-making.


GATA3 and NeuroD distinguish auditory and vestibular neurons during development of the mammalian inner ear.
The function of the zinc finger transcription factor GATA3 was studied in a newly established, conditionally immortal cell line derived to represent auditory sensory neuroblasts migrating from the mouse otic vesicle at embryonic day E10.5. The cell line, US/VOT-33, expressed GATA3, the bHLH transcription factor NeuroD and the POU-domain transcription factor Brn3a, as do auditory neuroblasts in vivo. When GATA3 was knocked down reversibly with antisense oligonucleotides, NeuroD was reversibly down-regulated. Auditory and vestibular neurons form from neuroblasts that express NeuroD and that migrate from the antero-ventral, otic epithelium at E9.5-10.5. On the medial side, neuroblasts and epithelial cells express GATA3 but on the lateral side they do not. At E13.5 most auditory neurons express GATA3 but no longer express NeuroD, whereas vestibular neurons express NeuroD but not GATA3. Neuroblasts expressing NeuroD and GATA3 were located in the ventral, otic epithelium, the adjacent mesenchyme and the developing auditory ganglion. The results suggest that auditory and vestibular neurons arise from different, otic epithelial domains and that they gain their identity prior to migration. In auditory neuroblasts, NeuroD appears to be dependent on the expression of GATA3.


Galvanic replacement mediated 3D porous PtCu nano-frames for enhanced ethylene glycol oxidation.
Three dimensional (3D) porous PtCu nano-frames with a unique hollow structure were obtained after a galvanic replacement reaction, exhibiting a high normalized mass activity of 23.1 A m-2 μg-1 towards ethylene glycol oxidation with excellent stability. The morphological evolution and catalytic mechanism were detailed.


Pharmacokinetics and other risk factors for kanamycin-induced hearing loss in patients with multi-drug resistant tuberculosis.
Objective: The toxicity associated with the use of kanamycin includes irreversible hearing loss. There are limited data describing the relationship between hearing loss and kanamycin pharmacokinetics (PK). We explored the association of kanamycin PK with hearing loss in patients on MDR-TB treatment.Design: We prospectively recruited patients on kanamycin-based MDR-TB treatment in Cape Town. Hearing thresholds from 0.25 to 16 kHz were tested at baseline and at 4, 8 and 12 weeks. We determined kanamycin concentrations at steady-state in serial plasma samples over 10 h, and explored factors associated with hearing loss.Study sample: One hundred and two participants including 58 (56.9%) men had analysable audiometric data; median age was 34.9 years, 65 (63.7%) were HIV-positive, and 24 (23.5%) had been treated for MDR-TB previously.Results: Eighty-four participants (82.4%) developed hearing loss. We found a 3% (95% CI: 1-6%, p = 0.028) increased risk of cochleotoxicity for each 10 µg h/L increase in 0-10 h AUC.Conclusion: We describe a high incidence of hearing loss in MDR-TB patients treated with kanamycin, with higher AUC0-10 significantly associated with hearing loss.


Surgical treatment of urethral distraction defect associated with pelvic fracture: a nationwide survey in Japan.
To survey practice patterns in surgical treatment for urethral distraction defect associated with pelvic fracture (PFUDD) and to analyze outcomes of the treatment in Japan. A questionnaire on surgical treatment for PFUDD to 3307 Japanese consultant urologists was sent. Responses were collected and statistically analyzed. The number of respondents was 1290 (39%). Patients surgically treated for PFUDD in the previous 5 years totaled 0 for 919 urologists (71%), one to two for 283 (22%), and three to ten for 83 (7%) urologists. Realignment for PFUDD was carried out within 2 weeks in 205 patients (23%), after 2-6 months in 607 (69%) patients, and after more than 6 months in 72 (8%) patients. Urologists operated on 361 (61%) patients endoscopically (ES), 108 (18%) by open anastomosis (OA) and 101 (17%) by pull-through operation (PT). According to the operator's impression, success rates were 65% for ES, 79% for PT and 69% for OA. Re-operation (RO) rates were 43%, 25% and 26% for ES, PT, and OA, respectively, (ES vs PT or OA; P < 0.05). Postoperative repeated urethral dilatation (PORUD) was required in 71% of ES, 77% of PT and 38% of OA cases (OA vs ES or PT; P < 0.05). PFUDD represents a rare disorder for Japanese urologists. Deferred endoscopic realignment is the preferred treatment option. Success rates were not different among three surgical treatments. OA was superior to ES and PT in terms of PORUD and RO.


Pituitary Adenylate Cyclase-Activating Polypeptide Attenuates Brain Edema by Protecting Blood-Brain Barrier and Glymphatic System After Subarachnoid Hemorrhage in Rats.
Brain edema is a vital contributor to early brain injury after subarachnoid hemorrhage (SAH), which is responsible for prolonged hospitalization and poor outcomes. Pharmacological therapeutic targets on edema formation have been the focus of research for decades. Pituitary adenylate cyclase-activating polypeptide (PACAP) has been shown to participate in neural development and brain injury. Here, we used PACAP knockout CRISPR to demonstrate that endogenous PACAP plays an endogenous neuroprotective role against brain edema formation after SAH in rats. The exogenous PACAP treatment provided both short- and long-term neurological benefits by preserving the function of the blood-brain barrier and glymphatic system after SAH. Pretreatment of inhibitors of PACAP receptors showed that the PACAP-involved anti-edema effect and neuroprotection after SAH was facilitated by the selective PACAP receptor (PAC1). Further administration of adenylyl cyclase (AC) inhibitor and sulfonylurea receptor 1 (SUR1) CRISPR activator suggested that the AC-cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) axis participated in PACAP signaling after SAH, which inhibited the expression of edema-related proteins, SUR1 and aquaporin-4 (AQP4), through SUR1 phosphorylation. Thus, PACAP may serve as a potential clinical treatment to alleviate brain edema in patients with SAH.


Diatrizoate meglumine (Hypaque) treatment for sudden hearing loss.
During the 24 month period ending in December 1978, 31 patients with sudden idiopathic sensorineural hearing loss were treated with vasodilators and Hypaque. Fifteen patients met the treatment criteria of being treated within the first month following onset, no vertigo, and the hearing loss was not complete. Twelve patients (80%) had complete return of their hearing. Two patients (13%) had partial return of their hearing, and 1 patient (6%) had no response to treatment. Of the 16 patients treated who did not meet the criteria, 6 patients (38%) had complete return of their hearing. Eight patients (50%) had partial return of their hearing and 2 patients (12%) had no return of their hearing.


Immune-Thrombotic Thrombocytopenic Purpura is a Rare Cause of Ischemic Stroke in Young Adults: Case Reports and Literature Review.
Immune thrombotic thrombocytopenic purpura (i-TTP), related to acquired ADAMTS-13 dysfunction, can lead to various neurological symptoms including ischemic stroke. To date the clinical, radiological, and biological characteristics of patients having a stroke as the inaugural manifestation of i-TTP are largely unknown. Probable immune-TTP was defined by a low ADAMTS-13 activity associated with the presence of ADAMTS-13 inhibitors and/or favorable clinicobiological response under immunological treatments. The clinical, radiological, biological data and outcome under treatment are described in a cohort of 17 patients coming from 3 local cases and a literature review. Fourteen of the 17 patients were female and the mean age was 41 years. None of the patients had the classical pentad of TTP. Only 41% had a combination of thrombocythemia and hemolysis. Stroke was multifocal in 35% and included large artery strokes. No adverse event was observed following intravenous thrombolysis. Refractory and relapsing forms were observed in 47%. The clinical, radiological, and biological presentation of patients with stroke as the inaugural presentation of i-TTP is heterogeneous. This diagnosis should be discussed in every young adult with ischemic stroke of undetermined source.


Unfolding the relationship between mortality, economic fluctuations, and health in Italy.
Despite the long-run strong negative association between economic development and mortality, their short-run relationship remains controversial. In the present work, we study co-movement between mortality growth (overall, gender- and cause-specific) and economic fluctuations in Italy over the period 1862-2013. To this aim, we use Johansen (Econometrica 59:1551-1580, 1991) procedure to jointly estimate the short- and long-run dynamics of the two variables, avoiding omitted variable bias in the cyclical co-movement extraction or spurious association attributable to trends. We also take into account possible asymmetric responses of mortality growth to shocks in GDP. We find that an increase of 1% in real GDP per capita induces a reduction in mortality rate of 0.27% for total population. Moreover, we observe that business cycle fluctuations do not affect mortality in the pre-wars era, where only the long run decreases matters driven by reduction in infections and accidents mortality. On the contrary, in the post-wars period, expansive phases of business cycle are associated with reduction in mortality growth and periods of recession generate an ever-deeper decrease. However, in this period, mortality for cancer is procyclical and significantly increasing in expansion: this reinforces the debate for controlling environmental factors.


Observation of changes in neural activity due to the static magnetic field of an MRI scanner.
To clarify whether a strong static magnetic field affects brain activity such as arousal level. We compared the electroencephalography (EEG) inside an MRI scanner in the presence/absence of the static magnetic field in two different arousal levels of task and rest conditions. Cardiac-related pulsations of head and blood flow induce an electric voltage at each EEG electrode in a static magnetic field. This induced voltage overlaps with the intrinsic EEG signal and becomes a large confounding factor. To extract the information of the intrinsic EEG from the contaminated EEG data measured in a static magnetic field, we developed a new analysis method. No significant difference was observed in the intrinsic EEG in the absence of a magnetic field, whereas in the presence of the static magnetic field, the theta frequency band of the intrinsic EEG increased, especially during the task condition, but other frequency bands did not change. Our results demonstrate that a static magnetic field affects brain activity.


MicroRNA-dependent development revealed by RNA interference-mediated gene silencing of LmDicer1 in the migratory locust.
MicroRNAs (miRNAs) are small noncoding RNAs, which participate in many biological processes. The small RNA transcriptome in the migratory locust has been characterized and 50 conserved miRNA families and 185 potential locust-specific miRNA family candidates have been identified using high-throughput sequencing. However, it is unclear whether miRNAs influence a wide variety of locusts' biological processes, such as growth or development. In insects, Dicer1 ribonuclease transforms miRNA precursors into mature miRNAs. Thus, using systemic RNA interference (RNAi) to silence the expression of Dicer1 in the migratory locust, Locusta migratoria, we reduced miRNA contents in the locust and disrupted two types of molt (nymph-nymph, and nymph-adult). The RNAi of LmDicer1 also resulted in a high mortality in L. migratora. Our study revealed that LmDicer1 was essential for miRNA regulation and development of L. migratoria. These results further support our notion that LmDicer1 could serve as an excellent target for developing novel strategies for controlling this important insect pest.


How Connecticut primary care physicians view treatments for streptococcal and nonstreptococcal pharyngitis.
Inappropriate antibiotic treatment of respiratory infections has been reported to be common; however, the specifics of this inappropriate treatment are not completely defined. The aim of this study was to gather data to determine whether physicians consider the national guidelines of treating group A B-hemolytic streptococci (GABHS) pharyngitis with penicillin (BID or TID) and not using antibiotics to treat nonstreptococcal pharyngitis. In this pilot survey, a 1-page questionnaire was sent to a random sample of Connecticut primary care physicians (PCPs) that included emergency physicians, family physicians, internists, and pediatricians. Two short hypothetical scenarios were presented: (1) an untreated male patient aged 18 years (who is not penicillin allergic) was seen the day before with fever and pharyngitis. He returns because he is still symptomatic and his throat culture (TC) is positive for GABHS; and (2) same scenario but this second patient's TC is negative for GABHS. Physicians were asked how they would treat the patients in both scenarios. Of the 642 (representing approximately 15% of all Connecticut PCPs) questionnaires sent, 386 (60%) were returned. Seventy-five of the responding physicians had not seen patients with pharyngitis within the last year and were excluded; the following results were from 311 physicians. Scenario 1: 191 of 311 physicians (61%) indicated a willingness to treat the GABHS with penicillin. Pediatricians were significantly less likely, compared with the other PCPs, to prescribe penicillin (P = 0.01) in this scenario. Seventy-seven of the 191 physicians (40%) indicated a willingness to prescribe the penicillin QID. Seven PCPs who responded to scenario 1 did not respond to scenario 2. Scenario 2: 98 of the 304 physicians (32%) indicated a willingness to prescribe antibiotics for the patient with no: streptococcal pharyngitis. Pediatricians were significantly less likely, compared with the other PCPs, prescribe antibiotics for the patient with nonstreptococcal pharyngitis in the second scenario (P < 0.001). This pilot survey found that 61% of Connecticut PCPs might treat GABHS with penicillin according to existing guidelines although the penicillin might be prescribed QID instead of the recommended BID or TID. Thirty-two percent of these PCPs reported they would use antibiotics to treat non-GABH pharyngitis.


Reconstitution of 50 S ribosomal subunits from Bacillus stearothermophilus with 5 S RNA from spinach chloroplasts and low-Mr RNA from mitochondria of Locusta migratoria and bovine liver.
Reconstitution experiments with 50 S ribosomal subunits from Bacillus stearothermophilus demonstrate that spinach chloroplast 5 S rRNA can be incorporated into the bacterial ribosome and yield biologically active particles, thereby establishing the eubacterial nature of chloroplast 5 S rRNA. In contrast, mitochondria from Locusta migratoria or bovine liver do not appear to contain discrete, low-Mr RNAs, which can replace 5 S rRNA in the functional reconstitution of B. stearothermophilus ribosomes.


Does the amount of an antitumor agent entrapped in liposomes influence its tissue distribution and cell uptake?
The effects of the amount of a drug entrapped in liposomes and polyethyleneglycol (PEG) modification on the tissue distribution in vivo and cell uptake in vitro have been examined. An increase in the amount of doxorubicin (DOX) entrapped in liposomes induced an increase in the DOX level in the plasma and tumor and a decrease in this level in the liver. The high amount of DOX entrapped demonstrated the usefulness of DOX liposomes for tumor cell uptake in vitro. The cell uptake of the liposomes depended on additional amounts of DOX and liposomal lipid. Furthermore, PEG modification of the surface of the liposomes facilitated the initial rate of liposome uptake into the tumor cells. This facilitation was attributed to the lipohydrophilic property of PEG and the fixed aqueous layer around the liposomes. Therefore, a higher amount of DOX entrapped in liposomes and PEG modification have been confirmed to be beneficial.


Prothrombin consumption as an indicator of hemorrhagic phenotype in mild platelet function disorders.
The bleeding risk of patients with mild platelet function disorders is difficult to assess and their phenotype remains ill-explored. This study was designed to establish a comprehensive biological phenotype of patients with mild platelet function disorders. Twenty patients were included with persistent abnormal light transmission aggregometry (LTA). The ISTH bleeding assessment tool (ISTH-BAT) was assessed to identify laboratory analyses associated with an abnormal hemorrhagic score. The majority of patients had defects that might affect Gαi protein signaling pathways or minor abnormalities. No LTA nor flow cytometry parameters were associated with an above-normal hemorrhagic score. However, prothrombin consumption, which corresponds to the ratio of serum residual factor II to plasma residual factor II, was significantly higher (p = .006) in the abnormal ISTH-BAT group (mean = 14%, SD = 6) compared with the normal ISTH-BAT group (mean = 8%, SD 4). Prothrombin consumption was significantly associated with ISTH-BAT score (r = .5287, IC 95% 0.0986-0.7924, p = .0165). In this group of patients, there was an association between a pathological bleeding score and increased prothrombin consumption. This test could be used as an additional indicator of platelet function abnormality liable to be related to bleeding risk.


The influence of thymic humoral factor on systemic lupus erythematosus lymphocyte function.
The influence of thymic humoral factor, THF, on systemic lupus erythematosus, SLE, lymphocyte function was investigated. Increasing numbers of SLE T-cells, rosetted at 4 degrees C or 37 degrees C, were cultured with allogeneic normal B-cells and the change in IgM synthesis was assessed. Lymphocytes of some SLE patients showed improved suppression with THF when rosetted at 37 degrees C. Normal control lymphocytes did not show a net change in suppression with THF. The subgroup of SLE patients that showed improved suppression with THF in vitro might be a more appropriate group for in vivo therapeutic trials with thymic hormone, TH, than SLE patients in general.


HLA class II signals sensitize B lymphocytes to apoptosis via Fas/CD95 by increasing FADD recruitment to activated Fas and activation of caspases.
Human leukocyte antigen (HLA) class II heterodimers have a well defined role in peptide presentation to helper T lymphocytes. Moreover, engagement of HLA class II molecules leads to signal transduction in the antigen presenting cell. Signaling via HLA-DR increases CD95 mediated hypoploidy in B-cell blasts. Given the importance of CD95 for the homeostasis of lymphocyte populations, we examined the impact of the HLA-DR signal on the most proximal events in the CD95 apoptotic pathway. CD95 activation recruits the adapter molecule Fas-associated death domain protein (FADD) and thereby provides a scaffold for procaspase-8 activation. The HLA-DR signal increased both recruitment of FADD and activation of caspases-3 and -8 via CD95 activation. Sensitization was tightly controlled because neither FADD recruitment to CD95 nor caspase activation was induced via HLA-DR alone. In contrast, the HLA-DR signal and the CD95 signal both led to decreased mitochondrial membrane potential. Taken together, these data indicate that ligand interaction with HLA class II molecules preactivates the antigen presenting cell for death in the event of a subsequent interaction with the CD95 ligand. This would ensure termination of a specific immune response, particularly in cells with limited sensitivity to CD95 mediated apoptosis alone.


Analysis of cortisol in hair--state of the art and future directions.
Changes to long-term secretion of the glucocorticoid cortisol are considered to play a crucial role in mediating the link between chronic stress and the development of numerous immune system related diseases. However, obtaining valid assessments of long-term cortisol levels is difficult due to limitations of previous measurement strategies in blood, saliva or urine. This review discusses evidence on a recent methodological development assumed to provide a considerable advancement in this respect: the analysis of cortisol in hair. Being incorporated into the growing hair, hair cortisol concentrations (HCC) are assumed to provide a retrospective reflection of integrated cortisol secretion over periods of several months. Over the past years, supportive evidence has accumulated regarding several fundamental characteristics of HCC, including its validity as an index of long-term systemic cortisol levels, its reliability across repeated assessments and its relative robustness to a range of potential confounding influences. Based on this groundwork, research has now also commenced to utilise HCC for answering more specific questions regarding the role of long-term cortisol secretion in different stress and health-related conditions. The possibility of extending hair analysis to also capture long-term secretion of other steroid hormones (e.g., androgens or estrogens) provides a further intriguing prospect for future research. Given its unique characteristics, the use of hair analysis holds great promise to significantly enhance current understanding on the role of steroid hormones in psychoimmunological research.


A robust Th-azole framework for highly efficient purification of C2H4 from a C2H4/C2H2/C2H6 mixture.
Separation of C2H4 from C2H4/C2H2/C2H6 mixture with high working capacity is still a challenging task. Herein, we deliberately design a Th-metal-organic framework (MOF) for highly efficient separation of C2H4 from a binary C2H6/C2H4 and ternary C2H4/C2H2/C2H6 mixture. The synthesized MOF Azole-Th-1 shows a UiO-66-type structure with fcu topology built on a Th6 secondary building unit and a tetrazole-based linker. Such noticeable structure, is connected by a N,O-donor ligand with high chemical stability. At 100 kPa and 298 K Azole-Th-1 performs excellent separation of C2H4 (purity > 99.9%) from not only a binary C2H6/C2H4 (1:9, v/v) mixture but also a ternary mixture of C2H6/C2H2/C2H4 (9:1:90, v/v/v), and the corresponding working capacity can reach up to 1.13 and 1.34 mmol g-1, respectively. The separation mechanism, as unveiled by the density functional theory calculation, is due to a stronger van der Waals interaction between ethane and the MOF skeleton.


Structural Evolution of Anatase-Supported Platinum Nanoclusters into a Platinum-Titanium Intermetallic Containing Platinum Single Atoms for Enhanced Catalytic CO Oxidation.
Strong metal-support interactions characteristic of the encapsulation of metal particles by oxide overlayers have been widely observed on large metal nanoparticles, but scarcely occur on small nanoclusters (<2 nm) for which the metal-support interactions remain elusive. Herein, we study the structural evolution of Pt nanoclusters (1.5 nm) supported on anatase TiO2 upon high-temperature H2 reduction. The Pt nanoclusters start to partially evolve into a CsCl-type PtTi intermetallic compound when the reduction temperature reaches 400 °C. Upon 700 °C reduction, the PtTi nanoparticles are exclusively formed and grow epitaxially along the TiO2 (101) crystal faces. The thermodynamics of the formation of PtTi via migration of reduced Ti atoms into Pt cluster is unraveled by theoretical calculations. The thermally stable PtTi intermetallic compound, with single-atom Pt isolated by Ti, exhibits enhanced catalytic activity and promoted catalytic durability for CO oxidation.


Choriocarcinoma with cerebral metastases coexistent with a first pregnancy.
A case is presented of choriocarcinoma with cerebral metastases which was unsuspected until a life-threatening life-threatening situation occurred. A viable infant was born and there was dramatic response to treatment with probable cure.


Expression of genes related to antioxidation, immunity, and heat stress in Gambusia affinis exposed to the heavy metals Cu and Zn.
Water pollution is an increasingly serious problem. Here, Cu and Zn ions were used as stress factors, and G. affinis served as a test organism. Fluorescence quantitative PCR was used to detect changes in the expression of antioxidant genes (SOD, GST, CAT), heat stress genes (Hsp70, Hsp90, Hspd1, Hsc70), and immune system-related genes (IL-1β, IL-8) in G. affinis exposed to Cu and Zn ions over time. To explore the toxic effects of Cu and Zn on G. affinis. The results showed that the 48 h LC50 concentrations of the heavy metals Cu and Zn to G. affinis were 0.17 mg/L and 44.67 mg/L, respectively. Within 48 h, with prolonged Cu exposure, the relative expression levels of the Hsp70, Hsp90, Hspd1, Hsc70, SOD, GST, and CAT genes in the gill tissue first showed a significant increase and then gradually decreased. Gene expression peaked between 9 and 36 h. The relative expression levels of SOD and GST genes in liver tissue showed a gradual decline. Within 48 h, with prolonged Zn exposure, the expression levels of SOD, CAT, and GST genes in G. affinis first increased and then fell before finally rising. The expression levels of IL-1β and IL-8 mRNA showed varying degrees of upward trends, and the expression of IL-8 was the highest for all gill tissue. To sum up, Cu and Zn have strong toxic effects on G. affinis, which makes it possible to use G. affinis as indicator organisms for aquatic environmental pollution.


How Hepatologists Use Liver Biopsy in the Evaluation of Liver Disease?
This article focuses on how hepatologists view the role of liver biopsy in diagnosis, assessment, and management of chronic and acute liver disease, and its variable use among different etiologies of liver disease and in the evaluation of liver fibrosis.


[Recovery].
The historical fatalism of the impossibility of recovering from psychosis eased from the 1970s with the shaping of the idea of a possible recovery. Recovery is today the objective for the patient and caregivers. The key to achieving this lies in the encounter with Others. A collective approach, on the level of the institution, must be established. The aim is to create opportunities for the patient to express their doubts and feelings.


Structure-activity relationships of steroid hormones on muscarinic receptor binding.
A total of fifty steroidal compounds were tested for their inhibition on the binding of muscarinic receptor antagonist, [3H]quinuclidinyl benzilate ([3H](-)QNB), to the hypothalamic membranes prepared from male rats. Among the compounds tested, the active structures (with IC50 values less than or equal to 100 microM in parentheses) are: progesterone (40), 5 beta-pregnane-3,20-dione (40), deoxy-corticosterone (50), 5 beta-pregnane-17 alpha,21-diol-3,20-dione (30), 11-desoxy-17-hydroxycorticosterone (22), 17 alpha-hydroxyprogesterone (20), 5 beta-pregnan-17 alpha-ol-3,20-dione (24), 5 beta-androstane-3,17-dione (100), and 5 beta-dihydrotestosterone (100). By examining all the compounds tested, the following structure-activity relationship became apparent: (a) The ring A-reduced steroidal structures with a 5 beta-conformation were more potent than those with a 5 alpha-conformation; (b) 17 alpha-hydroxylation of the steroidal ring increased the steroid's inhibitory activity; (c) The C3 carbonyl group was essential for activity; (d) Reduction of the C3 carbonyl group or aromatization of the ring A abolished the steroid's inhibitory activity; (e) Oxidation of the C11 position of ring C resulted in a decrease or loss of inhibitory activity; and (f) Different modifications of the side chain of ring D by acetylation resulted in either an increase or a decrease in the inhibitory activity. The structure-activity relationship as revealed in this study might provide an insight for the synthesis of a steroidal molecule with a high affinity for the muscarinic receptor as well as for the search of a more potent and physiologically relevant steroidal metabolite possessing the ability to interact with the muscarinic receptor.


Aquastatin A, an inhibitor of mammalian adenosine triphosphatases from Fusarium aquaeductuum. Taxonomy, fermentation, isolation, structure determination and biological properties.
A new inhibitor of mammalian adenosine triphosphatases, designated aquastatin A, has been isolated from a fungus identified as Fusarium aquaeductuum. The structure of this compound has been determined by MS and NMR analyses. It inhibits Na+/K(+)-ATPase with an IC50 value of 7.1 microM, and H+/K(+)-ATPase with an apparent IC50 value of 6.2 microM.


Association between hematologic parameters and functional impairment among geriatric inpatients: Data of a prospective cross-sectional multicenter study ("GeriPrävalenz2013").
Objective of this study was to analyse the association between impairment of Barthel Index items and hematologic parameters in geriatric inpatients. Patient recruitment of the "GeriPrävalenz2013" study has been described before. in-patient aged>=70years; exclusion criteria: actual cancer disease or cancer associated treatment. Anemia was defined according to WHO criteria. Physical impairment was assessed by Barthel Index (BI). Association between all 10 items of the BI and hematologic parameters was statistically evaluated. Anemia prevalence was 55.1% (319/579) with BI impairment in 96.2% patients. T-test revealed significant lower BI in anemic patients (47.9 vs 54.3; p=0.004). Binary logistic regression revealed that growing age, reduced MCV, reduced iron levels and reduced Hb levels were associated with increased impairment of several items of the Barthel-Index. Interestingly, increased levels of albumin and folic acid (FA) were associated with increased impairment of BI items. Anemia and lower levels of anemia related parameters showed a negative impact on ADL and physical performance based on BI items. An impaired total BI should result in an analysis of BI subitems, particularly if anemia related laboratory parameters are deviant. Reasons for the negative impact of elevated FA and albumin levels on BI remain speculative.


In vivo transport of a dynorphin-like analgesic peptide, E-2078, through the blood-brain barrier: an application of brain microdialysis.
In vivo transport through the blood-brain barrier (BBB) has been demonstrated for a dynorphin-like analgesic peptide, CH3-[125I]Tyr-Gly-Gly-Phe-Leu-Arg-CH3Arg-D-Leu-NHC2H5 ( [125I]E-2078). A remarkable time-dependent increase in the distribution volume of [125I]E-2078 in the brain parenchyma separated from blood vessels and capillaries was observed during a brain perfusion. The distribution volume of [125I]E-2078 in the brain parenchyma after 20 min of perfusion was 2.18 +/- 0.09 microliters/g brain (mean +/- SE) and was significantly greater than the distribution volume of [3H]inulin (0.994 +/- 0.138 microliters/g brain), providing in vivo evidence for the penetration of [125I]E-2078 into the brain parenchyma. Brain microdialysis was carried out to collect directly the brain interstitial fluid (ISF) during the brain perfusion of [125I]E-2078. No metabolite of [125I]E-2078 in the brain ISF was found by high-performance liquid chromatographic analysis of the brain dialysate. The concentrations of [125I]E-2078 and [14C]sucrose in the brain ISF were estimated based on an in vitro evaluation of dialysis clearance. The concentration ratio of [125I]E-2078 between the brain ISF and the brain perfusate was determined to be 2.92 x 10(-1) +/- 0.50 x 10(-1) and was approximately 100 times higher than that of [14C]sucrose (2.71 x 10(-3) +/- 1.43 x 10(-3), demonstrating transport of [125I]E-2078 through the BBB in vivo. On the other hand, no remarkable difference in the cerebrospinal fluid (CSF)-to-perfusate concentration ratios of [125I]E-2078 and [14C]sucrose was observed, indicating little contribution of the blood-CSF barrier (BCSF barrier) transport to the penetration of [125I]E-2078 into the brain.


Blindness and poverty in India: the way forward.
A few recent studies have shown that poverty is an exacerbating and often determining factor in the incidence of disabling conditions, including visual impairment. Recent estimates from the World Health Organization indicate that 90 per cent of all those affected by visual impairment live in the poorest countries of the world. India is home to one-fifth of the world's visually impaired people and therefore, any strategies to combat avoidable blindness must take into account the socio-economic conditions within which people live. This paper looks at the relationship between poverty and blindness in India and suggests strategies to address blindness prevention in a comprehensive manner.


Basic research in homeopathy and ultra-high dilutions: what progress is being made?
This report summarises the latest research developments in the field of high dilutions and homeopathy, as presented at the GIRI symposium of the leading international organisation of scientists in this field, in Florence, Italy in September 2012. The scientific community's early scepticism concerning the possible biological and pharmacological activity of highly diluted solutions, is giving way to a more open-minded attitude that no longer obstructs critical and experimental investigations in this emerging field of biomedicine.


Serum leptin and insulin concentrations in prepubertal lean, obese and insulin-dependent diabetes mellitus children.
To evaluate the relationship between serum levels of leptin and insulin in prepubertal lean, obese and insulin-dependent diabetes mellitus (IDDM) children. Prepubertal children, 16 lean, 17 obese and 16 IDDM were included in the study. Fastang serum leptin and insulin concentrations were measured by radioimmunoassays. The serum level of leptin was significantly higher in obese children than in lean and IDDM children (P < 0.0001 and P < 0.0001, respectively), and showed a positive correlation with body mass index (BMI) for the combined group (lean, obese and IDDM; r = 0.77, P < 0.0001). In addition, the serum leptin level was higher in IDDM children than in lean controls (P < 0.01), whereas no difference was found in BMI between the two groups. The mean fasting serum levels of insulin were significantly elevated in IDDM children as compared with lean controls (P < 0.01). A significant positive correlation was found between serum insulin and leptin levels for the combined group (r = 0.37, P < 0.01). When a multiple regression analysis for all subjects was performed, the total contribution of all parameters, including gender, BMI and log insulin, accounted for 75% of the leptin variation. BMI (57.8%), log insulin (14.0%) and gender (3.2%) contributed significantly to this variation. The elevated concentration of leptin in insulin-dependent diabetic children, independent of body mass index, was probably caused by chronically increased serum insulin levels. We demonstrated that not only body mass index but also insulin was a significant independent predictor of serum leptin concentrations. It is therefore suggested that insulin might play an important role in regulating serum leptin concentrations independent of adiposity.


The Impact of Magnesium Sulfate on Pain Control After Laparoscopic Cholecystectomy: A Meta-Analysis of Randomized Controlled Studies.
Magnesium sulfate has emerged as an important drug to alleviate the pain after laparoscopic cholecystectomy. However, the use of magnesium sulfate for pain control after laparoscopic cholecystectomy has not been well established. We conduct a systematic review and meta-analysis to evaluate the impact of magnesium sulfate on pain control after laparoscopic cholecystectomy. PubMed, Embase, and the Cochrane Central Register of Controlled Trials are searched. Randomized controlled trials assessing the influence of magnesium sulfate treatment versus placebo on pain control after laparoscopic cholecystectomy are included. Two investigators have independently searched articles, extracted data, and assessed the quality of included studies. This meta-analysis is performed using the random-effect model. Four randomized controlled trials involving 263 patients are included in the meta-analysis. Compared with control intervention after laparoscopic cholecystectomy, magnesium sulfate can substantially decrease pain scores at 2 hours [standard mean differences (MD)=-0.45; 95% confidence interval (CI)=-0.88 to -0.02; P=0.04] and 8 hours (standard MD=-0.62; 95% CI=-0.95 to -0.28; P=0.0003), as well as reduce analgesic consumption (standard MD=-0.40; 95% CI=-0.73 to -0.07; P=0.02), but has no substantial influence on pain scores at 24 hour (standard MD=-0.38; 95% CI=-0.79 to 0.02; P=0.07) and operation duration (standard MD=-0.09; 95% CI=-0.34 to 0.15; P=0.45). Magnesium sulfate is effective to reduce pain intensity in early stage and anesthetic consumption after laparoscopic cholecystectomy.


The impact of epidural analgesia on delivery mode in Robson class 1 women: a retrospective cohort study.
The use of epidural analgesia represents the gold standard for pain management during labor, but the influence of the use of epidural analgesia on delivery mode is not fully understood. This study aimed to analyze the impact of epidural analgesia on the delivery mode, namely, cesarean delivery, vaginal delivery, and operative vaginal delivery rates, in Robson class 1 women. A retrospective cohort study was conducted on all Robson class 1 women who delivered from January 1, 2019, to December 31, 2019, in the University Hospital of Modena. The primary outcome was the delivery mode (cesarean delivery, vaginal delivery, and operative vaginal delivery rates), and the secondary outcomes were maternal, anesthesiologic, and neonatal effects of epidural analgesia (duration of labor, duration of the second stage of labor, Apgar score, and neonatal intensive care unit admission). A total of 744 women were included in the final analysis, of which 198 (26.6%) underwent epidural analgesia on request and 546 (73.4%) did not. In women with and without epidural analgesia, the cesarean delivery rate was 8.1% vs 7%, the vaginal delivery rate was 79.3% vs 81.1%, and the operative vaginal delivery rate was 12.6% vs 11.9%, respectively. A significant increase in both the first stage of labor (66.3±38.5 vs 43.8±38.8 minutes; P<.0001) and total duration of labor (328.0±206.7 vs 201.7±168.3 minutes; P<.0001) was found in women receiving epidural analgesia. No change was recorded in the second stage of labor. A shorter duration of labor was observed (P<.0001) when epidural analgesia was started earlier (dilation: 2-4 cm vs >4 cm). No significant difference in Apgar score and neonatal intensive care unit admission was found. The use of epidural analgesia was not associated with an increased risk of cesarean delivery or operative vaginal delivery in Robson class 1 women. Further investigations are needed to evaluate its impact on the duration of labor, namely the duration of the first stage of labor, and on the possible advantages of starting epidural analgesia at an early stage.


Utility of the temperament and character inventory (TCI) in outcome prediction of laparoscopic adjustable gastric banding: preliminary report.
Research about personality factors involved in successful outcome after bariatric surgery has led to contrasting results. The reasons for such discrepancies may include the lack of assessment of adaptive personality traits and of psychiatric co-morbidity, which may limit the reliability of personality findings. This study aimed to provide exploratory data regarding preoperative personality dimensions and weight loss prediction 1 year after laparoscopic adjustable gastric banding (LAGB). Both normal and deviant personality patterns were assessed by means of the Temperament and Character Inventory (TCI). Moreover, co-morbid psychiatric disturbances were evaluated both categorically and dimensionally. 65 morbidly obese subjects applying for LAGB were evaluated preoperatively by means of the TCI, standardized diagnostic interview, rating scales and questionnaires to assess co-morbid psychopathology. After intake screening, 35 subjects (mean age 41.2, mean BMI 45.5) were accepted for and underwent LAGB. BMI reduction 1 year following LAGB was used as an outcome measure and entered as a dependent variable in a stepwise multiple regression analysis. TCI scores, presence and severity of eating, depressive and anxiety disorders, sex, age, level of education and BMI at baseline were tested as independent variables. Preoperative TCI 'Persistence' scores explained >40% of variance of BMI reduction 1 year following LAGB, irrespective of preoperative BMI, age, gender, educational level, psychiatric co-morbidity, psychopathology severity and other temperament and character features. Some personality dimensions, as measured by the TCI, may be involved in successful weight control after LAGB.


Validity of a multidimensional comprehensive psychosocial screening instrument based on the ESC cardiovascular prevention guidelines - Evidence from the general and cardiovascular patient population.
To evaluate the psychometric properties and validity of the updated version of the Dutch multidimensional Comprehensive Psychosocial Screening Instrument in patients with coronary heart disease and the general population, based upon guideline recommendations from the European Society for Cardiology. 678 participants (Mage = 48.2, SD = 16.8; 46% male) of the Dutch general population and 312 cardiac patients (Mage = 65.9, SD = 9.9; 77% male) who recently received percutaneous coronary intervention completed the Comprehensive Psychosocial Screening Instrument and validated questionnaires for depression (PHQ-9), anxiety (GAD-7), Type D personality (DS14), hostility (CMHS), anger (STAS-T), trauma (SRIP), and chronic work and family stress (ERI, MMQ-6). Confirmatory factor analysis (CFA) confirmed that the eight screened risk factors were best measured as separate entities, rather than broader indications of distress. Inter-instrument agreement, assessed with the intraclass coefficient (ICC) and the screening accuracy indicators (receiving operator characteristic [ROC] curves, sensitivity, specificity, and the positive and negative predictive values [PPV; NPV]) were good for most screened risk factors. PPV was low in low prevalence risk factors like anxiety, trauma, and depression. Overall, the current version of the Comprehensive Psychosocial Screening Instrument has an acceptable performance in both populations, with a fair to excellent level of agreement with established full questionnaires. Besides a few suggestions for further refinement, the screener may be implemented in primary care and cardiological practice.


Comparative subgenomic mRNA profiles of SARS-CoV-2 Alpha, Delta and Omicron BA.1, BA.2 and BA.5 sub-lineages using Danish COVID-19 genomic surveillance data.
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has rapidly spread worldwide in the population since it was first detected in late 2019. The transcription and replication of coronaviruses, although not fully understood, is characterised by the production of genomic length RNA and shorter subgenomic RNAs to make viral proteins and ultimately progeny virions. Observed levels of subgenomic RNAs differ between sub-lineages and open reading frames but their biological significance is presently unclear. Using a large and diverse panel of virus sequencing data produced as part of the Danish COVID-19 routine surveillance together with information in electronic health registries, we assessed the association of subgenomic RNA levels with demographic and clinical variables of the infected individuals. Our findings suggest no significant statistical relationship between levels of subgenomic RNAs and host-related factors. Differences between lineages and subgenomic ORFs may be related to differences in target cell tropism, early virus replication/transcription kinetics or sequence features. The author(s) received no specific funding for this work.


Vitamin D intake and risk of incident hypertension: results from three large prospective cohort studies.
Emerging evidence suggests an inverse relation between vitamin D and blood pressure. We examined the independent association between intake of vitamin D and the risk of incident hypertension among participants of 3 large and independent prospective cohorts: Nurses Health Study I (NHS I; n=77,436), NHS II (n=93,803), and Health Professionals' Follow-up Study (HPFS; n=38,074). Relative risks and 95% confidence intervals for incident hypertension were computed according to quintiles of vitamin D intake using Cox proportional hazards regression and adjusted for relevant covariates. Each cohort was followed for > or =8 years. Vitamin D intake was not associated with the risk of developing hypertension. The multivariable relative risk estimates for the highest compared with lowest quintile of intake were 0.98 (0.93 to 1.04) in NHS I, 1.13 (0.99 to 1.29) in NHS II, and 1.03 (0.93 to 1.15) in HPFS. When we compared participants who consumed > or =1600 to <400 IU per day and those who consumed > or =1000 to <200 IU per day, no association was found. We conclude that higher intake of vitamin D is not associated with a lower risk of incident hypertension.


Identification of an N-terminal domain of eukaryotic DNA topoisomerase I dispensable for catalytic activity but essential for in vivo function.
We have found that deletion of a 70-amino acid domain, spanning from position 141 to 210 in the N-terminal part of human topoisomerase I, has no effect on the catalytic activity of the enzyme in vitro but suppresses the lethal consequence of overexpressing human topoisomerase I in a rad52 top1 Saccharomyces cerevisiae strain. By immunostaining, the 70-amino acid domain is shown to be necessary for nuclear location of topoisomerase I. We demonstrate that the nuclear localization signal from the SV40 large T antigen can substitute for the 70-amino acid domain, restoring both the lethal effect of overexpression and the correct subcellular localization of topoisomerase I. Thus, we have identified a domain in the N-terminal part of human topoisomerase I, nonessential for catalytic activity in vitro but serving an in vivo function by directing the enzyme to the nucleus. Based on sequence comparisons, we suggest that this domain is a conserved element in the apparently non-homologous N-terminal parts of yeast and human topoisomerase I.


Digital Health Integration With Neuromodulation Therapies: The Future of Patient-Centric Innovation in Neuromodulation.
Digital health can drive patient-centric innovation in neuromodulation by leveraging current tools to identify response predictors and digital biomarkers. Iterative technological evolution has led us to an ideal point to integrate digital health with neuromodulation. Here, we provide an overview of the digital health building-blocks, the status of advanced neuromodulation technologies, and future applications for neuromodulation with digital health integration.


[When to introduce hormone therapy after total prostatectomy with positive lymph nodes? Study of the factors influencing the time of introduction of hormone therapy].
Adjuvant hormone therapy is the standard treatment after total prostatectomy with positive lymph node. However, this treatment has side effects and at the time of the PSA era and extensive lymph node dissection, this principle is questioned. The aim of this study is to describe the oncological characteristics of patients that may explain the delay in introducing hormone therapy in patients with positive lymph node. Monocentric, retrospective study of 161 patients from November 1988 to February 2018 in a single French University Hospital, having undergone radical prostatectomy with positive lymph nodes on pathology. For each patient, preoperative data (age, clinical stage, biopsy results, d'Amico classification) and postoperative data (pathological results, number of lymph nodes removed, number of positive lympnodes, recurrence free survival, specific survival and overall survival) were collected. The date of introduction of hormone therapy was noted and survival without hormonal therapy was established according to the Kaplan Meier curve. The pre- and post-operative oncological factors that could influence hormone therapy introduction were investigated with Chi2 and Student tests (statistically significant when P<0.05). The mean number of lymph nodes removed was 12 [1-40]. The mean number of positive lymph nodes was 2.5 [1-24], the mean percentage of positive lymph nodes was 25% (2.5-100). After a mean follow-up of 95 months (3-354), 88 patients (54.6%) had no hormonal treatment. The average time to hormonal treatment was 40 months [0-310]. At 3 years, survival without hormone therapy was 52% and 51% at 5 years. Only the percentage of positive lymphnodes appeared to be a significant predictor of the introduction of hormone therapy. (29.32% vs. 21.99%, P=0.047). Hormone-free survival was significantly higher in patients with lymph node involvement less than 25% (P<0.0001) or with less than 2 positive lymph nodes (P=0.0294). Lymph node invasion is a factor of poor prognosis after total prostatectomy and leads to introduce hormone therapy. Our study identified the percentage and number of positive lymph nodes as factors that identify patients who may be delayed in introducing this hormone therapy. 3.


Plasma membranes from rat intestinal epithelial cells at different stages of maturation. I. Preparation and characterization of plasma membrane subfractions originating from crypt cells and from villous cells.
To determine the mechanism of the maturation of the brush border membrane in intestinal epithelial cells, purification of the plasma membrane from undifferentiated rat crypt cells and of the basal-lateral membrane from villous cells has been performed. The method is based on density perturbation of the mitochondria to selectively disrupt their association with the membrane. With both cell populations, two membrane subfractions displaying the same respective density on sucrose gradient have been obtained with an overall yield of 15--20% and a 10-fold enrichment of the plasma membrane markers 5'-nucleotidase and (Na+ + K+)-dependent, ouabain-sensitive ATPase chosen to follow their purification. The four fractions were constituted by sheets and apparently closed vesicles of various sizes. Each fraction was characterized by a distinct protein composition and different levels of enzyme activities. The cells, used for the preparation of the membranes, were isolated as a villus to crypt gradient. This separation and that of the membranes, led to the conclusion that the (Na+ + K+)-dependent ATPase is localized principally in the plasma membrane of all cells whatever their state of maturation, while 5'-nucleotidase is predominantly located in the basal-lateral membrane of the villous cells and may serve as a specific marker for the purification of this membrane. Finally it has been shown that aminopeptidase, dissacharidases and alkaline phosphatase do not appear simultaneously in the maturation process of the cells, alkaline phosphatase being absent from the crypt cells and aminopeptidase being the first to be synthesized. This enzyme seems to appear in the crypt cells membrane before being integrated into the mature brush border membrane.


Physico-chemical characterization-based safety evaluation of nanocalcium.
Nano- and microcalcium provided from the KFDA were compared in terms of physico-chemical properties. Calcium samples were tested using EF-TEM and X-ray diffractometry to check for size/morphology and crystal formation, respectively. Two samples of nano- and microcalcium were selected for further evaluation by FE-SEM, DLS (nano-size, 200-500nm; agglomerate, >5 μm; micro-size, 1.5-30 μm), and electron spin resonance. Both samples were heterogeneous in size, existed as single crystal and aggregated form, and did not generate reactive oxygen species. The specific surface area of nano- and microcalcium measured by N2 Brunauere Emmette Teller method was 12.90±0.27 m(2)/g and 1.12±0.19 m(2)/g, respectively. Inductively coupled plasma optical emission spectrometry analysis revealed the release of 2-3 times more calcium ion from nano- compared to microcalcium at pH 5 and 7. Genotoxicity and acute single-dose and repeated-dose 14-day oral toxicity testing in SD rats performed to evaluate the safety of nanocalcium did not reveal toxicity. However, long-term monitoring will be required for an unequivocal conclusion. A nanocalcium dose of 1 g/kg is recommended as the maximum dose for repeated dose 13-week oral toxicity. Further studies could provide details of toxicity of nanocalcium on the repeated dose 13-week oral toxicity test.


Effect of oxidative stress on dynamics of mitochondrial reticulum.
Fission of the mitochondrial reticulum (the thread-grain transition) and following gathering of mitochondria in the perinuclear area are induced by oxidative stress. It is shown that inhibitors of the respiratory chain (piericidin and myxothiazol) cause fission of mitochondria in HeLa cells and fibroblasts, whereas a mitochondria-targeted antioxidant (MitoQ) inhibits this effect. Hydrogen peroxide also induced the fission, which was stimulated by the inhibitors of respiration and suppressed by MitoQ. In untreated cells, the mitochondrial reticulum consisted of numerous electrically-independent fragments. Prolonged treatment with MitoQ resulted in drastic increase in size and decrease in number of these fragments. Local photodamage of mitochondria caused immediate depolarization of a large fraction of the mitochondrial network in MitoQ-treated cells. Our data indicate that the thread-grain transition of mitochondria depends on production of reactive oxygen species (ROS) in initial segments of the respiratory chain and is a necessary step in the process of elimination of mitochondria (mitoptosis).


Carriage of Staphylococcus aureus among injection drug users: lower prevalence in an injection heroin maintenance program than in an oral methadone program.
To compare the prevalence of Staphylococcus aureus and methicillin-resistant S. aureus (MRSA) carriage among injection drug users (IDUs) treated in an injection heroin maintenance program with that among IDUs treated in an oral methadone program, and to determine predictors of S. aureus carriage. Survey. Two opiate maintenance programs at a psychiatric university clinic. A volunteer sample consisting of 94 (74%) of 127 IDUs treated in an injection opiate maintenance program with at least twice daily injections of heroin, and 70 (56%) of 125 IDUs treated in an oral methadone program. Addicts treated in the intravenous heroin substitution program had a significantly lower overall rate of S. aureus carriage (37 of 94 [39.4%] vs 42 of 70 [60%]; P = .009) and a significantly lower rate of nasal carriage (21 of 94 [22.3%] vs 30 of 70 [42.9%]; P = .005) than did addicts treated in the oral methadone program. Being treated in the oral methadone program was the only independent predictor of S. aureus carriage (odds ratio, 2.27; 95% confidence interval, 1.19-4.31; P = .012). All S. aureus isolates were susceptible to oxacillin. The regular use of needles under aseptic conditions did not increase the rate of S. aureus carriage among IDUs. Further studies are necessary to investigate whether the lower rate of S. aureus carriage among IDUs treated with intravenous heroin leads to a lower incidence of S. aureus infections in these patients.


A web-based survey of UK pharmacists to assess the effectiveness of Viagra Connect® additional risk minimisation measures.
Background To support reclassification in the UK of sildenafil citrate (50 mg) from prescription-only medicine to a pharmacy medicine (P status) under the brand name "Viagra Connect®", additional risk minimisation measures were implemented that included training materials and an optional checklist to assist community pharmacists in the safe supply of Viagra Connect® to suitable patients. Objective To evaluate the effectiveness of Viagra Connect® additional risk minimisation measures by assessing community pharmacists' participation in training, their knowledge of key risk messages, and utilisation of the checklist. Setting A post-authorisation safety study implemented as a web-based survey, conducted in a representative population of UK community pharmacists. Method A random sample of community pharmacists who received at least 1 request to supply Viagra Connect® within the past 6 months completed an online questionnaire of 33 closed-ended questions/statements with multiple-choice responses. Data were summarised using descriptive statistics. Main outcome measure Knowledge of key risk messages and dispensing practices communicated in the additional risk minimisation measures. Results The survey was completed by 345 community pharmacists. Respondents displayed a high level of knowledge of key risk messages, with ≥80 % selecting correct answers for 43/51 items. Nearly all respondents (90.1 %) reported that the training materials were useful/very useful, and reported using the checklist at the point of supply (91.9 %). Counselling of patients who requested Viagra Connect® was generally considered a positive exercise. Conclusions The Viagra Connect® additional risk minimisation measures were effective for education of community pharmacists and to ensure safe supply of Viagra Connect® behind-the-counter to patients.


Targeted next-generation sequencing assay for detection of mutations in primary myopathies.
Mutations in more than 100 different genes are known to cause hereditary primary myopathies. In patients with less distinct phenotypes several genes may have to be sequenced in order to make the correct diagnosis. The large number of possible candidate genes and overlapping phenotypes, as well as an enormous size of some of the genes such as DMD, TTN and NEB, constitute difficult challenges for molecular genetic diagnostics using conventional sequencing. Molecular characterization is nevertheless important for the final diagnosis and accurate management of the diseases. Targeted next-generation sequencing is a rapid and cost-effective method to sequence large numbers of genes simultaneously. We developed a targeted next-generation sequencing assay, MyoCap, for the coding exons and UTRs of 180 myopathy related genes including 42 novel genes that have not yet been associated with myopathies. DNA samples of four controls with known mutations and 61 patients negative for previous candidate gene approaches were sequenced. The genetic defect was totally or partly clarified in 21 patients with nine of them having potential disease-causing mutations in TTN. MyoCap provides higher read depth and coverage with lower price in the myopathy related genes compared to the whole exome sequencing and is thus very suitable for diagnostic use.


The "unexpected" growth of the private health sector in Greece.
The article analyses the situation which exists in the private health sector in Greece, it presents data on the growth of the private sector and discusses the reasons for this phenomenon in relation to privatisation trends in other European countries. The growth of private health care in Greece in the last 10 years is evident despite governmental attempts to minimise its role through the development of the National Health System in 1983 and the legislative restrictions on the private sector. Private health expenditure has increased, reaching 3.9% of the country's GNP (43% of the total expenditure in health) in 2000. The number of private hospitals and hospital beds has decreased (hospitals decreased from 468 in 1990 to 218 in 2000 and private beds decreased from 25,075 in 1980 to 15,806 in 2000) mainly because of the reduction in the number of small private hospitals. On the other hand, private doctors and private diagnostic centres have significantly increased. This situation is believed to be attributed mainly to the provision of inadequate and low quality public health services which have caused widespread dissatisfaction among the general public, and factors associated to improved standards of living, as well as the rapid growth of private insurance.


Associated neurologic abnormalities in congenital third nerve palsies.
A study of ten patients (six girls and four boys ranging in age from 17 months to 9 1/2 years) with congenital third nerve palsies showed that not all cases are benign without other signs of focal neurologic damage. Six of the ten children showed some degree of pupillary involvement, five had signs of oculomotor synkinesis, four had associated focal neurologic abnormalities, and two had generalized developmental delay. Only three children showed no signs of neurologic change except the third nerve palsy. Although congenital third nerve palsies are incompletely understood, these lesions probably occur as a result of the damage both to the peripheral nerve and to the brain stem itself. Signs of oculomotor synkinesis do not occur in all cases and the pupil is frequently spared.


Data of synthesis, characterization and luminescence measurements in 1D lanthanide coordination polymers based on lanthanides.
In this work are presented all the conditions of synthesis explored to obtain a new family of compound with formula [Ln(4-OHBBA)3(H2O)2] (Ln = La, Pr). Powder X ray diffraction was used to identify the different phases obtained in the synthetic study. FT-IR spectroscopy and TG analysis for La and Pr pure phases are also reported. Optical properties of optically active CPs materials, solid state photoluminescence properties of La, Pr, La-(5%Eu) and La-(5%Tb) compounds were explored. We report the absorption, excitation and emission spectrum of the 4'-hydroxi-4-biphenylcarboxylic acid and a comparative description of the radiative (and no-radiative) processes in solid state in Ln-(4-OHBBA) and Ln-BPDC compounds. Finally, a principal component analysis was conducted in order to take in account both signal contributions from the sensor (LCE at 384 nm and the europium emission at 610 nm) and for classifying the type of analytes used to test the sensing response of the materials.


Comparative genomics for understanding the structure, function and sub-cellular localization of hypothetical proteins in Thermanerovibrio acidaminovorans DSM 6589 (tai).
The Thermanerovibrio acidaminovorans DSM 6589 (tai) is a unique bacterium isolated from anaerobic sludge bed reactor from sugar refinery in Netherland. The comparative genomic studies for understanding the hypothetical proteins in T. acidaminovorans DSM 6589 (tai) were carried out using different bioinformatic tools and web servers. In all 320 hypothetical proteins were screened from the total available genome. The Insilico function prediction for 320 hypothetical proteins was achieved by using different online servers like CDD-Blast, Interproscan and pfam whereas, the structure prediction for 202 hypothetical proteins were deciphered by using protein structure prediction server (PS2 server). The sub-cellular localization for the identified proteins was predicted by the use of cello v2.5 for 320. The study carried out has helped us to understand the structures and functions of unknown proteins available in T. acidaminovorans DSM 6589 (tai) through comparative genomic approach.


The molecular basis of allergenicity.
Allergens are mostly innocuous antigens that elicit powerful T helper cell type 2 (Th2) responses leading to hyper-immunoglobulin E (IgE) production and allergy. Research carried out over several years has highlighted the possible role of the inherent protease activity, surface features and glycosylation patterns of allergens in the engagement of a Th2 signalling pathway. It is thought that allergens possess common features and patterns that enable them to be recognized by innate immune defences as Th2-inducing antigens. These events are further amplified by proteolytically active allergens through digestion of cell surface molecules involved in regulating innate and adaptive immune functions, favouring Th2 responses. A greater understanding of the molecular features that make proteins allergenic will help define new therapeutic targets aimed at blocking allergen recognition and protease activity.


Cell lines that express stably env gene products from three strains of HIV-1.
The products of the env gene of HIV-1 play critical roles in determining the host range of the virus and it cytopathicity, as well as forming an important focus of an infected individual's immune response to the virus. We describe the isolation and characterization of separate HeLa cell lines expressing the env gene products of three highly divergent strains of HIV-1.


Alcohol detoxification and withdrawal seizures: clinical support for a kindling hypothesis.
There has been speculation that a kindling model may have applicability to alcohol withdrawal syndromes and seizures, suggesting that repeated alcohol withdrawals may lead to increased severity of subsequent withdrawals. We evaluated historical and clinical variables of a group of male alcoholics with (n = 25) and without (n = 25) alcohol withdrawal seizures. We found that the number of detoxifications appeared to be an important variable in the predisposition to withdrawal seizures. The withdrawal seizure group had 12 of 25 (48%) patients with 5 or more previous detoxifications, compared to only 3 of 25 (12%) of the control group. A relationship between alcohol use history and withdrawal seizures was not supported by the data. These findings support the concept that previous alcohol withdrawals may "kindle" more serious subsequent withdrawal symptomatology, ultimately culminating in withdrawal seizures.


Regional morphometric abnormalities and clinical relevance in Wilson's disease.
Morphology builds Wilson's disease's clincal basis. To detect and quantify regional morphometric abnormalities, in terms of both volume and shape, in patients with Wilson's disease. Twenty-seven Wilson's disease patients and 24 healthy controls were enrolled. Specific brain structures, including the bilateral caudate, putamen, globus pallidus, thalamus, amygdala, hippocampus, red nucleus, and substantia nigra (SN), were automatically extracted from each participant's T1 -weighted image. Volume abnormalities and correlations with the modified Young scale were investigated. Furthermore, vertex-based shape analysis was performed to explore region-specific morphometric abnormalities. Significant global volume atrophy and local shape abnormalities were detected and quantified in the bilateral caudate, putamen, globus pallidus, thalamus, amygdala, red nucleus, and SN. Morphometric abnormalities of the caudate, putamen, and thalamus were strong, whereas those of the globus pallidus, amygdala, red nucleus, and SN were weaker. No hippocampal abnormalities were observed. The modified Young scale was found to correlate significantly with the volumes of the bilateral putamen and the right globus pallidus. Shape analysis revealed subregion-specific atrophy of the bilateral caudate and putamen. They were concentrated in the subregions that project to the limbic and executive cortices. Significant region-specific atrophy was also detected in the bilateral thalamic subregions that project to the primary motor, sensory, and premotor cortices. We found significant morphometric abnormalities of specific structures of interest in patients with Wilson's disease, both globally and locally. These morphometric abnormalities may serve as useful imaging biomarkers for Wilson's disease. © 2019 International Parkinson and Movement Disorder Society.


A ten-year, single institution experience with percutaneous nephrostomy during pregnancy.
To evaluate the safety and efficacy of percutaneous nephrostomy (PCN) in pregnancy. PCN tubes were placed during 52 pregnancies in 49 patients from 2008 to 2018. The medical records during pregnancies were retrospectively reviewed for imaging findings, procedural parameters, outcomes of delivery, and complications. The mean gestational age on percutaneous nephrostomy placement was 27 weeks (range, 8-36 weeks). PCN catheters were placed for the following indications: 1) flank or lower abdominal pain (42%), 2) obstructing calculi (37%), 3) pyelonephritis (20%), and 4) obstructing endometrioma (2%). Prior to PCN, retrograde ureteric stenting was performed in 17 of 49 patients (34%) and attempted but failed in 4 patients (8%). Nephrostomy drainage relieved pain completely or significantly in all 12 patients without prior ureteral stenting, but in only 4 of 10 with retrograde ureteric stents. In one patient in whom the ureteral stent had been removed, PCN relieved her flank pain. The mean number of PCN catheter exchanges was 1.6, ranging from 0 to 9, with a mean time interval of 21.3 days between exchanges. There were 29 difficult exchanges due to encrustation in 15 patients with a mean of 20.5 days between exchanges. PCN drainage is a safe and effective treatment for managing symptomatic hydronephrosis in pregnant patients but is less effective in treating pain when retrograde ureteral stents are in place. Rapid encrustation, seen more commonly in pregnancy, tends to recur in the same patients and requires more frequent exchanges than the general population.


The effects of dihydropyridine calcium channel modulators on pentylenetetrazole convulsions.
The effects of low doses of dihydropyridine (DHP) calcium channel antagonists nimodipine, nifedipine, (-)-R-202-791, and amlodipine, the DHP calcium channel agonist BAY K 8644 were investigated on clonic convulsions to pentylenetetrazole (PTZ) in mice. Nimodipine (2-20 mg/kg) produced a dose-dependent increase in the onset time for convulsions, but did not decrease the number of mice convulsing. Nifedipine, amlodipine (10 mg/kg) and BAY K 8644 (2 mg/kg) also produced an increase in the onset time for convulsions. (-)-R-202-791 (10 mg/kg) was without effect on clonic convulsions to PTZ. BAY K 8644 increased the number of mice dying from tonic-extension convulsions to PTZ. Nimodipine did not affect convulsions elicited by strychnine. Thus, low doses of DHP calcium antagonists possess anticonvulsant properties which are structurally dependent, while DHP calcium channel activators may act to promote convulsions. These observations suggest and support previous evidence that DHP receptors are important modulatory sites for the convulsive state.


A 72-Year-Old Woman With Dyspnea, Multiple Pulmonary Nodules, and Mediastinal Lymphadenopathy.
A 72-year-old woman presented to our institution with gradually worsening shortness of breath and bilateral lower extremity edema of 3 weeks' duration. She had associated complaints of cough and intermittent hemoptysis. Her medical history was significant for hypertension and hypothyroidism. She was a former cigarette smoker with a 35 pack-year smoking history. She had no recent travel history and had a pet dog at home. Six months before the current hospitalization, evaluation for cough had revealed mediastinal lymphadenopathy at an outside institution. She underwent evaluation with an endobrachial ultrasound procedure at an outside facility 8 weeks before the current admission. The procedure demonstrated both acute and chronic inflammation, with one specimen showing few atypical cells on cytopathology and no growth on bacterial, fungal, and mycobacterial cultures. She was treated empirically with oral steroids for presumed sarcoidosis. However, this did not result in clinical benefit, and because of progressive symptoms, she presented to our institution.


PSMA-targeted small-molecule docetaxel conjugate: Synthesis and preclinical evaluation.
Prostate cancer is one of the most commonly diagnosed men's cancers and remains one of the leading causes of cancer death. The development of approaches to the treatment of this oncological disease is an ongoing process. In this work, we have carried out the selection of ligands for the creation of conjugates based on the drug docetaxel and synthesized a series of three docetaxel conjugates. In vitro cytotoxicity of these molecules was evaluated using the MTT assay. Based on the assay results, we selected the conjugate which showed cytotoxic potential close to unmodified docetaxel. At the same time, the molar solubility of the resulting compound increased up to 20 times in comparison with the drug itself. In vivo evaluation on 22Rv1 (PSMA+) xenograft model demonstrated a good potency of the synthesized conjugate to inhibit tumor growth: the inhibition turned out to be more than 80% at a dose of 30 mg/kg. Pharmacokinetic parameters of conjugate distribution were analyzed. Also, it was found that PSMA-targeted docetaxel conjugate is less toxic than docetaxel itself, the decrease of molar acute toxicity in comparison with free docetaxel was up to 20%. Obtained conjugate PSMA-DOC is a good candidate for further expanded preclinical trials because of high antitumor activity, fewer side toxic effects and better solubility.


Neurotransmitter receptors and cognitive dysfunction in Alzheimer's disease and Parkinson's disease.
Cognitive dysfunction is one of the most typical characteristics in various neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease (advanced stage). Although several mechanisms like neuronal apoptosis and inflammatory responses have been recognized to be involved in the pathogenesis of cognitive dysfunction in these diseases, recent studies on neurodegeneration and cognitive dysfunction have demonstrated a significant impact of receptor modulation on cognitive changes. The pathological alterations in various receptors appear to contribute to cognitive impairment and/or deterioration with correlation to diversified mechanisms. This article recapitulates the present understandings and concepts underlying the modulation of different receptors in human beings and various experimental models of Alzheimer's disease and Parkinson's disease as well as a conceptual update on the underlying mechanisms. Specific roles of serotonin, adrenaline, acetylcholine, dopamine receptors, and N-methyl-D-aspartate receptors in Alzheimer's disease and Parkinson's disease will be interactively discussed. Complex mechanisms involved in their signaling pathways in the cognitive dysfunction associated with the neurodegenerative diseases will also be addressed. Substantial evidence has suggested that those receptors are crucial neuroregulators contributing to cognitive pathology and complicated correlations exist between those receptors and the expression of cognitive capacities. The pathological alterations in the receptors would, therefore, contribute to cognitive impairments and/or deterioration in Alzheimer's disease and Parkinson's disease. Future research may shed light on new clues for the treatment of cognitive dysfunction in neurodegenerative diseases by targeting specific alterations in these receptors and their signal transduction pathways in the frontal-striatal, fronto-striato-thalamic, and mesolimbic circuitries.


Soluble HLA-G pre-transplant levels to identify the risk for development of infection in heart transplant recipients.
Infection is still a leading cause of death during the first year after heart transplantation. We evaluated the pre-transplant levels of HLA (Human Leukocyte antigen) - G molecules as a means of identifying heart recipients at risk of serious infections. We prospectively analyzed 122 adult heart transplant (HT) recipients. Serum samples were collected beforetransplantation and analyzed for sHLA-G levels by ELISA assay. The clinical follow-up period lasted 5 years. Clinical outcomes were bacterial infections requiring intravenous anti-microbial agents, cytomegalovirus (CMV) disease, and fungal infections requiring therapy. We found that 39 patients (32%) developed at least 1 serious bacterial infection. Higher pre-transplant sHLA-G levels were a risk factor for serious infection (above median value 5.4 ng/ml; relative risk 3.70; 95% confidence interval 1.03-12.64; p = 0.043). Patients with high levels of pre-transplant sHLA-G are also characterized by a lower overall survival at 5 years (p = 0.017), with microbial infections as major causes of death. No association was observed with the development rejection episode. Early monitoring of sHLA-G molecules proved useful for the identification of heart recipients who are at risk of serious infections.


Urinary kallikrein excretion in chronic renal failure: relationship to blood pressure and the acute effect of captopril.
Previous studies of the renal kallikrein-kinin system in chronic renal failure (CRF) have given conflicting results. We have assessed activity of this vasoactive hormone system in CRF and investigated a possible relationship to hypertension in patients with CRF: 24-hour urinary kallikrein excretion (UKa) was measured in 22 patients with CRF (9 normotensive and 13 hypertensive) and 11 healthy controls. Age, sex, urine volume, and urinary sodium excretion were similar in each group. Compared with controls, UKa was reduced in both normotensive and hypertensive patients with CRF, with no difference between CRF groups. The reduction in UKa in CRF was less than the reduction in glomerular filtration rate (GFR), as assessed by endogenous creatinine clearance (CCr). When UKa was divided by CCr, UKa/mL CCr was therefore increased, to a similar extent, in both normotensive and hypertensive patients with CRF. This suggests that release of renal kallikrein from functioning nephrons is increased in CRF. The results do not support a role for deficient kallikrein release in the genesis of hypertension in CRF, as previously suggested; however, these abnormalities could be relevant to other aspects of renal function in CRF. The converting-enzyme inhibitor, captopril, was given to 5 patients with CRF, hypertension, and low UKa. Introduction of captopril was followed by a further reduction in UKa in all subjects. Captopril is known to inhibit kininase II, the principal enzyme involved in degradation of kinins; this potentiating effect may be counteracted by a reduction in renal kallikrein release and hence in kinin generation.


Transcultural skills content in a dental curriculum: a comparative study.
Australia has the highest proportion of immigrants in the world (24% of the population is overseas-born, compared to 22% in New Zealand, 19% in Canada and 12% in the USA). In this context, dental students have become increasingly diverse in a milieu where patients are derived from increasingly diverse backgrounds. The study aims to analyse the degree to which transcultural and communication skills content is currently embedded in the medical, physiotherapy and dental curricula at a major Australian university. Undergraduate dental, medical and physiotherapy curricula were compared and critically assessed. Researchers considered the amount of transcultural and communication skills content, the number of formal contact hours for each course and the number of teaching staff involved. In addition, 21 interviews were conducted with staff at the three schools, who were involved in the curriculum development process. The medical and physiotherapy curricula had an explicit focus on transcultural and communication skills as a major and continuing element, delivered by teaching staff from a wide variety of academic and professional backgrounds. In contrast, the dental course showed an under-representation of transcultural and communication skills content which was taught by a limited number of staff from the School of Dental Science. In marked contrast to medical and physiotherapy curricula, transcultural and communication skills content had a low formal profile in the dental curriculum. A curriculum review process may be a positive step towards the development of a new training curriculum giving higher priority to transcultural and communication skills to support more effective workforce development.