Predicting Patient Reported Outcomes of Cognitive Function Using Connectome-Based Predictive Modeling in Breast Cancer.
Being able to predict who will likely experience cancer related cognitive impairment (CRCI) could enhance patient care and potentially reduce economic and human costs associated with this adverse event. We aimed to determine if post-treatment patient reported CRCI could also be predicted from baseline resting state fMRI in patients with breast cancer. 76 newly diagnosed patients (n = 42 planned for chemotherapy; n = 34 not planned for chemotherapy) and 50 healthy female controls were assessed at 3 times points [T1 (prior to treatment); T2 (1 month post chemotherapy); T3 (1 year after T2)], and at yoked intervals for controls. Data collection included self-reported executive dysfunction, memory function, and psychological distress and resting state fMRI data converted to connectome matrices for each participant. Statistical analyses included linear mixed modeling, independent t tests, and connectome-based predictive modeling (CPM). Executive dysfunction increased over time in the chemotherapy group and was stable in the other two groups (p < 0.001). Memory function decreased over time in both patient groups compared to controls (p < 0.001). CPM models successfully predicted executive dysfunction and memory function scores (r > 0.31, p < 0.002). Support vector regression with a radial basis function (SVR RBF) showed the highest performance for executive dysfunction and memory function (r = 0.68; r = 0.44, p's < 0.001). Baseline neuroimaging may be useful for predicting patient reported cognitive outcomes which could assist in identifying patients in need of surveillance and/or early intervention for treatment-related cognitive effects.


Incidence of constitutive and inducible clindamycin resistance among hospital-associated Staphylococcus aureus.
Clindamycin is one of the important alternative antibiotics in the therapy of Staphylococcus aureus infections. Clinical failure of clindamycin therapy has been reported due to multiple mechanisms that confer resistance to macrolides, lincosamides and Streptogramin B (MLSB) antibiotics. In vitro routine tests for clindamycin susceptibility may fail to detect inducible clindamycin resistance due to erm genes, resulting in the treatment failure. Although data from the developed countries have shown to be enormity of the problem, data from the developing countries are lacking. The aim of the study was to distinguish different resistance phenotypes in erythromycin-resistant S. aureus by a simple double-disc diffusion test (D test). A total of 153 S. aureus isolates were subjected to routine antibiotic susceptibility testing, including cefoxitin disc (30 μg) and by oxacillin screen agar. Inducible clindamycin resistance was tested by 'D test' as per CLSI guidelines. Odds ratios (OR) and 95 % confidence intervals (95 % CI) were calculated. P values were calculated using SPSS (version 18). Among 153 S. aureus isolates, 42 (27.45 %) were resistant to methicillin, whereas 111 (72.54 %) were methicillin susceptible. Out of the 63 (41.17 %) erythromycin-resistant S. aureus isolates, 14 (9.15 %) showed inducible resistance [P = 0.0002, odds ratio (OR) 18.30; 95 % confidence interval (CI) 8.72-25.77), 20 (13.07 %)] showed constitutive resistance (P = 0.002, OR 14.38, 95 % CI 5.33-21.49), while the remaining 29 (18.95 %) showed inducible phenotype. Inducible and constitutive resistance was found to be higher in MSSA when compared with MRSA. Clinical laboratories should perform D test routinely to guide the clinicians about the inducible clindamycin resistance and to prevent misuse of antibiotics.


[Effect of replication- competent adenovirus-mediated interleukin- 12 gene to chemotherapeutic sensitivity on gastric cancer cell].
To investigate the effect of replication-competent adenovirus-mediated interleukin-12 gene to chemotherapeutic sensitivity on gastric cancer cell. Replication-competent adenovirus and replication-competent adenovirus- mediated interleukin- 12 gene was constructed and expanded separately. The mortality of gastric cancer cell caused by the CNHK200- mIL- 12, Onyx- 015 in combination with different dosages of chemotherapeutic agents were evaluated by MTT assay at the same viral titer with a series of different dosages of chemotherapeutic agent,or at a series of different viral titers with the same dosage of chemotherapeutic agent. The curative effect to the xenografts gastric tumor in nude mouse was also observed by two viruses solely or together with 5-Fu. The lytic activity of replication-competent adenovirus to gastric cancer cell line SGC-7901 was relatively poor at MOI value of 0.5, but it could be improved significantly when combined with chemotherapeutic agents of ADM, 5-Fu or CAP compared to the simple chemical therapy (P< 0.05). Chemotherapeutic agent 5- Fu could not effectively kill SGC-7901 when used at a relatively low dosage of 10microg/ml,whereas its activity could be improved when combined with a replication-competent adenovirus,and the killing rate was much higher than that with replication-competent adenovirus solely (P< 0.05). The gastric tumor xenografts was prevented and killed by replication adenovirus solely or combined with 5-Fu. The replication- competent adenovirus- mediated interleukin- 12 gene can increase the chemotherapeutic sensitivity on gastric cancer cell. There is synergetic effect between the replication adenovirus and the chemotherapeutic agents in killing gastric cancer cell.


Measurement of Nasalance Scores Without Touching the Philtrum for Better Comfort During Speech Assessment and Therapy: A Preliminary Study.
The Kay Pentax nasometer uses a separator plate that touches the philtrum of a patient to separate the nasal and oral sound energies for nasalance measurement. However, the separator plate can restrict the natural movement of the patient's upper lip and generate unpleasant pressure on the patient's philtrum. The present study was intended to measure nasalance scores without touching the philtrum for better comfort during speech assessment and therapy. Nasalance scores of 10 males and 10 females having no speech disorders were measured under 4 levels (0, 5, 10, and 15 mm) of the gap between the plate and the philtrum (denoted as plate-to-philtrum gap) using Nasometer II 6450 for nasal (Nasal Sentences) and oral (Zoo Passage) stimuli. Regression formulas were established to examine the relationships between nasalance score and plate-to-philtrum gap for the stimuli. To provide nasalance scores equivalent to those measured for the contact condition, compensation factors for the 5 mm plate-to-philtrum gap measurement condition were identified for the stimuli. The nasalance scores were significantly different between the 4 different plate-to-philtrum gaps for the stimuli. Compensation factors for the Nasal Sentences and the Zoo Passage were identified as 1.17 and 0.71, respectively. The 5 mm plate-to-philtrum gap condition after multiplying the compensation factors can provide equivalent nasalance scores to the conventional contact measurement condition which may provide better comfort in speech assessment and therapy.


Isolation and characterization of chitosan from different local insects in Egypt.
Chitin was extracted from four different local sources: the shrimp (Penaeus monodon), the desert locust (Schistocerca gregaria), the honey bee (Apis mellifera) and the beetles (Calosoma rugosa). Chitosan was then obtained by deacetylation of chitin and physicochemically characterized using the Fourier transform infrared (FTIR) and X-ray diffraction. The moisture content, water binding capacity, fats binding capacity, ash content were determined and chitosans morphology was visualized using the scanning electron microscope (SEM). The difference between the obtained chitosans from three insect sources and α-chitosan from shrimp in terms of crystallinity, fibrous structure was discussed.


Analysis of Leptospira antigens by crossed immunoelectrophoresis.
Serovars icterohaemorrhagiae, canicola, and arboreae of pathogenic Leptospira interrogans and serovar patoc of saprophytic L. biflexa were examined by crossed immunoelectrophoresis. A close antigenic relationship was found between the interrogans serovars, particularly between icterohaemorrhagiae and canicola. To a much lesser extent cross-reactions were found between interrogans serovars and patoc. Comparison of three different antigenic preparations of icterohaemorrhagiae by tandem crossed immunoelectrophoresis and by absorption experiments with the patoc reference system showed the presence of several common broadly reactive antigens. Antigen 1 of the reference system, a genus-specific heat-stable protein antigen, was found in all antigenic preparations. It is a diagnostically important antigen.


A potential copper radiopharmaceutical for imaging the heart and brain: copper-labeled pyruvaldehyde bis(N4-methylthiosemicarbazone).
An investigation of the biodistribution of lipophilic copper-64 (half-life = 12.7 h) compounds has been initiated in order to screen potential tracers that could be used to measure regional cerebral and/or myocardial blood flow when labeled with generator-produced 62Cu. The 64Cu complex of pyruvaldehyde bis(N4-methylthiosemicarbazone), [64Cu]Cu-PTSM, was prepared and found to be lipophlic (octanol/saline partition coefficient, log p = 1.97 +/- 0.03). Biodistribution studies following i.v. injection of [64Cu]Cu-PTSM into rats show tracer uptake by the brain and heart. At 1, 5, and 15 min post-injection 3.3, 3.0 and 2.7% of the injected dose was found in the brain. Corresponding brain to blood ratios (per gram) were 3.2, 3.6 and 4.0 respectively. Heart to blood ratios of 7.6, 7.6 and 7.3 were observed at these same time points.


Ambient molecular imaging by desorption electrospray ionization mass spectrometry.
Desorption electrospray ionization (DESI) allows the direct analysis of ordinary objects or pre-processed samples under ambient conditions. Among other applications, DESI is used to identify and record spatial distributions of lipids and drug molecules in biological tissue sections. This technique does not require sample preparation other than production of microtome tissue slices and does not involve the use of ionization matrices. This greatly simplifies the procedure and prevents the redistribution of analytes during matrix deposition. Images are obtained by continuously moving the sample relative to the DESI sprayer and the inlet of the mass spectrometer. The timing of the protocol depends on the size of the surface to be analyzed and on the desired resolution. Analysis of organ tissue slices at 250 microm resolution typically takes between 30 min and 2 h.


A meta-analysis on the association between SSRIs and blood pressure in patients with CVD and depression.
This meta-analysis aimed to explore the association between selective serotonine reuptake inhibitors (SSRIs) and blood pressure in patients with cardiovascular disease (CVD) and depression. This study was registered on PROSPERO (CRD42022368655) and conducted in accordance with PRISMA 2020. The databases included PubMed, Web of Science, and EMBASE. The inclusion date was from the inception date through Oct. 26, 2022.Review Manager version 5.3 and Stata version 12.0 were used for data analysis. This meta-analysis included six studies, and a total number of 149 patients with CVD and depression . In the group analysis, SSRIs treatment had no effect on the systolic blood pressure (SBP) (MD = 1.01, 95%CI:-2.88, 4.90, P = 0.61) and diastolic blood pressure (DBP) (MD = 0.64, 95%CI:-1.03, 2.31, P = 0.45). In the subgroup analysis, SSRIs treatment had no effect on SBP for patients with hypertension (MD = -8.02, 95%CI:-16.84, 0.81, P = 0.08), and patients with other CVD (MD = 3.18, 95%CI:-1.15, 7.52, P = 0.15). For patients with hypertension, SSRIs treatment significantly lowered DBP (MD = -5.75, 95%CI:-10.84, -0.67, P = 0.03). But SSRIs treatment had no impact on DBP for patients with other CVD (MD = 1.41, 95%CI:-0.36, 3.18, P = 0.12). Subgroup analysis of the treatment period and the country had no significant impact on SBP and DBP. In the sensitivity analysis, there was no significant change after omitting one study in both SBP and DBP group analysis. Egger's test showed no publication bias of SBP (P = 0.183) and DBP group analysis (P = 0.392). SSRIs help to lower DBP in hypertensive patients with depression. The potential pathophysiological mechanisms may lie in serotonin function, sympathetic activation and genetic heterogeneity. Further clinic and experimental researches need to be conducted on SSRIs and blood pressure.


Parameterizing neural power spectra into periodic and aperiodic components.
Electrophysiological signals exhibit both periodic and aperiodic properties. Periodic oscillations have been linked to numerous physiological, cognitive, behavioral and disease states. Emerging evidence demonstrates that the aperiodic component has putative physiological interpretations and that it dynamically changes with age, task demands and cognitive states. Electrophysiological neural activity is typically analyzed using canonically defined frequency bands, without consideration of the aperiodic (1/f-like) component. We show that standard analytic approaches can conflate periodic parameters (center frequency, power, bandwidth) with aperiodic ones (offset, exponent), compromising physiological interpretations. To overcome these limitations, we introduce an algorithm to parameterize neural power spectra as a combination of an aperiodic component and putative periodic oscillatory peaks. This algorithm requires no a priori specification of frequency bands. We validate this algorithm on simulated data, and demonstrate how it can be used in applications ranging from analyzing age-related changes in working memory to large-scale data exploration and analysis.


Automated assignment of SCOP and CATH protein structure classifications from FSSP scores.
We present an automated procedure to assign CATH and SCOP classifications to proteins whose FSSP score is available. CATH classification is assigned down to the topology level, and SCOP classification is assigned to the fold level. Because the FSSP database is updated weekly, this method makes it possible to update also CATH and SCOP with the same frequency. Our predictions have a nearly perfect success rate when ambiguous cases are discarded. These ambiguous cases are intrinsic in any protein structure classification that relies on structural information alone. Hence, we introduce the "twilight zone for structure classification." We further suggest that to resolve these ambiguous cases, other criteria of classification, based also on information about sequence and function, must be used.


Selective transcription of an insulin-regulated gene in nuclear extracts of rat hepatoma cells.
We have previously shown that when H4 hepatoma cells are pretreated with insulin, plant lectins, phorbol esters, or insulin mediator, the steady state concentration of gene 33 mRNA is markedly increased. The increase in gene 33 mRNA concentration with insulin is due to an increase in the transcription rate of this gene. In the present report we demonstrate that nuclear extracts prepared from H4 hepatoma cells pretreated with insulin exhibit enhanced transcription of gene 33 RNA from a DNA template containing the cap site and 1500 bp upstream of the 33 gene. This is a stable effect of insulin on the nuclear RNA polymerase II system since it is observed in frozen and thawed nuclear extracts as well as fresh nuclear extracts.


Audiological profile of adult Long COVID patients.
Hearing loss is one of the self-reported symptoms of Long COVID patients, however data from objective and subjective audiological tests demonstrating diminished hearing in Long COVID patients has not been published. Respondents of a large Long COVID online survey were invited to the ENT-department for an otologic exam. The participants were split into three groups based on their history of SARS-CoV-2 infection and persistence of symptoms. Respondents with a history of a SARS-CoV-2 infection were allocated to the Long COVID group, if they reported persistent symptoms and to the Ex COVID group, if they had regained their previous level of health. Participants without a history of SARS-CoV-2 infection made up the No COVID control group. In total, 295 ears were examined with otoscopy, tympanograms, pure tone audiometry and otoacoustic emissions. Ears with known preexisting hearing loss or status post ear surgery, as well as those with abnormal otoscopic findings, non-type A tympanograms or negative Rinne test were excluded. Compared to the No COVID and Ex COVID groups, we did not find a clinically significant difference in either hearing thresholds or frequency specific TEOAEs. However, at 500 Hz the data from the left ear, but not the right ear showed a significantly better threshold in the Ex COVID group, compared to Long COVID and No COVID groups. Any of the other tested frequencies between 500 Hz and 8 kHz were not significantly different between the different groups. There was a significantly lower frequency-specific signal-to-noise-ratio of the TEOAEs in the Long COVID compared to the No COVID group at 2.8 kHz. At all other frequencies, there were no significant differences between the three groups in the TEOAE signal-to-noise-ratio. This study detected no evidence of persistent cochlear damage months after SARS-CoV-2 infection in a large cohort of Long COVID patients, as well as those fully recovered.


Exosomes loaded with ultrasmall Pt nanoparticles: a novel low-toxicity alternative to cisplatin.
Platinum nanoparticles have been demonstrated to have excellent anticancer properties. However, because of the lack of specificity they must be delivered to the tumor in amounts sufficient to reach the desired therapeutic objectives. Interestingly, exosomes are considered as excellent natural selective delivery nanotools, but until know their targeting properties have not being combined with the anticancer properties of platinum nanoparticles. In this work we combine the targeting capabilities of exosomes and the antitumoral properties of ultrasmall (< 2 nm) platinum nanoparticles as a novel, low toxicity alternative to the use of cisplatin. A mild methodology based on the room temperature CO-assisted in situ reduction of Pt2+ precursor was employed to preserve the integrity of exosomes, while generating ultrasmall therapeutic PtNPs directly inside the vesicles. The resulting PtNPs-loaded exosomes constitute a novel hybrid bioartificial system that was readily internalized by the target cells inducing antiproliferative response, as shown by flow cytometry and microscopy experiments in vitro. In vivo Pt-Exos showed antitumoral properties similar to that of cisplatin but with a strongly reduced or in some cases no toxic effect, highlighting the advantages of this approach and its potential for translation to the clinic. In this study, a nanoscale vector based on ultrasmall PtNPs and exosomes has been created exhibiting antitumoral properties comparable or higher to those of the FDA approved cisplatin. The preferential uptake of PtNPs mediated by exosomal transfer between certain cell types has been exploited to create a selective antitumoral novel bioartificial system. We have demonstrated their anticancer properties both in vitro and in vivo comparing the results obtained with the administration of equivalent amounts of cisplatin, and showing a spectacular reduction of toxicity.


New developments in the genetics, pathogenesis, and therapy of IgA nephropathy.
Recent years have brought notable progress in the field of IgA nephropathy. Here, we highlight important new directions and latest developments, including successful discovery of several genetic susceptibility loci, formulation of the multihit pathogenesis model, introduction of the Oxford pathology scoring system, and formalization of the Kidney Disease Improving Global Outcomes (KDIGO) consensus treatment guidelines. We focus on the latest genetic findings that confirm a strong contribution of inherited factors and explain some of the geoethnic disparities in disease susceptibility. Most IgA nephropathy susceptibility loci discovered to date encode genes involved in the maintenance of the intestinal epithelial barrier and response to mucosal pathogens. The concerted pattern of interpopulation allelic differentiation across all genetic loci parallels the disease prevalence and correlates with variation in local pathogens, suggesting that multilocus adaptation might have shaped the present-day landscape of IgA nephropathy. Importantly, the 'Intestinal Immune Network for IgA Production' emerged as one of the new targets for potential therapeutic intervention. We place these findings in the context of the multihit pathogenesis model and existing knowledge of IgA immunobiology. Lastly, we provide our perspective on the existing treatment options, discuss areas of clinical uncertainty, and outline ongoing clinical trials and translational studies.


mRNA Delivery Using Bioreducible Lipidoid Nanoparticles Facilitates Neural Differentiation of Human Mesenchymal Stem Cells.
Mesenchymal stem cells (MSCs) are widely used in regenerative medicine and tissue engineering and delivering biological molecules into MSCs has been used to control stem cell behavior. However, the efficient delivery of large biomolecules such as DNA, RNA, and proteins into MSCs using nonviral delivery strategies remains an ongoing challenge. Herein, nanoparticles composed of cationic bioreducible lipid-like materials (lipidoids) are developed to intracellularly deliver mRNA into human mesenchymal stem cells (hMSCs). The delivery efficacy to hMSCs is improved by adding three excipients including cholesterol, 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-polyethylene glycol (DSPE-PEG) during lipidoid nanoparticle formulation. Using an optimized lipidoid formulation, Cas9 mRNA and single guide RNA (sgRNA) targeting neuron restrictive silencing factor (NRSF) are delivered to hMSCs, leading to successful neural-like differentiation as demonstrated by the expression of synaptophysin (SYP), brain-derived neurotrophic factor (BDNF), neuron-specific enolase (NSE), and neuron-specific growth-associated protein (SCG10). Overall, a synthetic lipid formulation that can efficiently deliver mRNA to hMSCs is identified, leading to CRISPR-based gene knockdown to facilitate hMSCs transdifferentiation into neural-like lineage.


Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Ribavirin.
Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release solid oral dosage forms containing ribavirin are reviewed. Ribavirin is highly soluble, but its permeability characteristics are not well defined. Therefore according to the Biopharmaceutical Classification System, and taking a "worst case" approach, ribavirin should be assigned to class III. As ribavirin is transported across the brush border membrane of the human jejunum by hCNT2, it shows saturable uptake in the intestine. However, no common excipients have been shown to compete for ribavirin absorption, nor have problems with BE of immediate release ribavirin formulations containing different excipients and produced by different manufacturing methods been reported in the open literature. So the risk of bioinequivalence caused by these factors appears to be low. Ribavirin is considered a narrow therapeutic index drug, as judged by comparing the minimum effective concentration and minimum toxic concentrations in blood. Although ribavirin would not be eligible for approval via a Biopharmaceutical Classification System-based biowaiver procedure according to today's guidances due to its narrow therapeutic index, the risks of biowaiving should be weighed against the considerable risks associated with studying BE of ribavirin products in healthy subjects.


Cannabis in the treatment of alcoholism.
Cannabis, alone or in conjunction with disulfiram, was not particularly effective in inducing alcoholics to enter or remain in treatment.


eccDNAdb: a database of extrachromosomal circular DNA profiles in human cancers.
Extrachromosomal circular DNA (eccDNA) elements are circular DNA molecules that are derived from but are independent of chromosomal DNA. EccDNA is emerging as a rising star because of its ubiquitous existence in cancers and its crucial role in oncogene amplification and tumor progression. In the present study, whole-genome sequencing (WGS) data of cancer samples were downloaded from public repositories. Afterwards, eccDNAs were identified from WGS data via bioinformatic analyses. To leverage database coverage, eccDNAs were also collected by manual curation of literatures. Gene expression and clinical data were downloaded from TCGA and CCLE and then used to investigate the roles of eccDNAs in cancers. Finally, the first integrated database of eccDNAs, eccDNAdb, was developed. eccDNAdb currently includes 1270 eccDNAs, which were identified in 480 samples (of 42 cancers) after analyzing a total number of 3395 tumor samples (of 57 cancers) including patient tissues, patient-derived xenografts, and cancer cell lines. A total number of 54,901 eccDNA genes were annotated and included in the database as well. With the integration of gene expression, clinical information and chromatin accessibility data, eccDNAdb enables users to easily determine the biological function and clinical relevance of eccDNAs in human cancers. In conclusion, eccDNAdb is freely accessible at http://www.eccdnadb.org . To our knowledge, eccDNAdb is the first database in the eccDNA research field. It is expected to provide insight for novel cancer therapies.


Revolutionizing Medical Education: Can ChatGPT Boost Subjective Learning and Expression?
ChatGPT is an AI tool that can be used to enhance medical education by helping students develop subjective learning and expression skills. These skills are critical in clinical practice, but the current medical education system is heavily focused on objective assessments, such as Multiple Choice Questions (MCQs). Students from non-English speaking backgrounds can particularly struggle with expressing themselves in English, which is the primary language of instruction in many medical schools worldwide. ChatGPT can provide additional language support for these students to help them develop their language skills and communicate effectively. ChatGPT can be used in small group assessments to serve as a benchmark for students to strive for in their medical education. By comparing their answers to ChatGPT's responses, students can identify gaps in their knowledge and work to fill them. ChatGPT can also provide students with feedback on their writing style and language usage, helping them to improve their subjective expression of medical knowledge. Furthermore, ChatGPT can be used to simulate patient encounters for medical students. By interacting with ChatGPT, students can practice taking medical histories and documenting symptoms accurately. In continuing medical education (CME) programs, physicians can also benefit from ChatGPT's capabilities. By using ChatGPT to search for the latest research articles, clinical trials, and treatment guidelines, physicians can stay informed and provide the best care possible to their patients. Overall, ChatGPT has the potential to be a valuable tool in medical education by helping students and physicians develop the essential skills required for clinical practice, such as communication, problem-solving, and critical thinking.


Successful treatment of Cryptococcus gattii neurocryptococcosis in a 5-year-old immunocompetent child from the French Guiana Amazon region.
Compared to the incidence in adults, cryptococcosis is rare among children. We report a case of neurocryptococcosis due to Cryptococcus gattii in a five-year-old girl without identified risk factors living in French Guiana. Neurological surgery in combination with long-term antifungal treatment with amphotericin B and 5-flucytosine successfully resolved the cryptococcal infection. Subsequent molecular characterization of the Cryptococcus isolate revealed that the infection was caused by a C. gattii genotype AFLP6B/VGIIb strain.


High-resolution real-time ultrasonography. A new tool in the diagnosis of acute appendicitis.
A prospective study was performed to assess the sensitivity and specificity of ultrasonographic evaluation in 44 patients with suspected appendicitis. We found ultrasonographic evaluation to have a sensitivity rate of 89 percent, a specificity rate of 86 percent, and an overall accuracy rate of 87 percent. These results are very similar to those in other recently reported studies. We also identified certain patients in whom nondiagnostic studies are likely. Our results suggest that ultrasonographic evaluation may be of particular use in selected patients who do not demonstrate the classical signs and symptoms of acute appendicitis.


Proposed algorithm for management of patients with thyroid nodules/focal lesions, based on ultrasound (US) and fine-needle aspiration biopsy (FNAB); our own experience.
The standard management in patients with thyroid nodules is to assess the risk of malignancy, based on cytological examination. On the other hand, there are thyroid patterns of ultrasound (US) image, associated with an increased risk of malignancy. The aim of our study was to create a diagnostic algorithm that would employ both data from US examination (expressed by a total score, according to our scoring system) and FNAB results, classified according to Bethesda system (The Bethesda System for Reporting Thyroid Cytopathology - TBSRTC categories). 100 thyroid cancer foci (94 papillary carcinomas, 4 medullary carcinomas, 2 undifferentiated carcinomas) and 100 benign focal lesions were selected during postoperative histopathological examination of thyroid glands excised during surgery from 111 patients. The corresponding US images of each lesion - performed in the course of preoperative diagnostics - were evaluated for the presence of seven (7) different features in US image, suggesting a malignant character of lesion, viz. vascularity, i.e., the increased central intranodular blood flows, microcalcifications, "taller-than-wide" orientation, solid composition, hypoechogenicity, irregular margin and either absence of peripheral halo or the presence of outer shell of uneven thickness, surrounding the lesion. The sensitivity, specificity, positive predictive values, negative predictive values and odds ratios for each US feature were calculated. IN US IMAGE OF THE ANALYZED CANCER FOCI, WE OBTAINED THE FOLLOWING VALUES OF ODDS RATIO FOR EACH OF THE ABOVE MENTIONED FEATURES SUGGESTING MALIGNANCY: "taller-than-wide" orientation - odds ratio - 301.0, microcalcifications - 24.67, increased intranodular vascularity - 20.44, hypoechogenicity - 18.61, irregular margins - 7.81, absence of halo - 5.88, and solid composition - 4.16. Taking into account our own experience and the present data, in juxtaposition with the opinions of other authors, we propose a division of US features into 3 groups of different prognostic importance, expressed by a total score calculated based on our scoring system. Accordingly, microcalcifications, "taller-than-wide" orientation, the increased intranodular vascularity, and hypoechogenicity constitute one group - each of the features in this group is awarded 1 point. In turn, the characteristics of minor prognostic importance, such as irregular margin, absence of halo, solid composition, and large size (a diameter longer than 3.0 cm) - are associated with the granting 0.5 points each. The most important prognostic features - a rapid growth (enlargement) of nodules/focal lesions and a presence of pathologically altered lymph nodes are associated with the granting 3 points for each. Our scoring system can be applied in order to better assessment of thyroid US patterns in whole. In patients with a total score ranging from 0 < 4 points there is US pattern of a low risk of malignancy, with ≥ 4 < 7 points - intermediate risk, and in patients with a score ≥ 7 points - a high risk in question. Complementary use of our scoring system and FNAB TBSRTC categories can help to make optimal clinical decisions as regards the selection of treatment strategy.


Does Adherence to Preoperative Surgical Selection Criteria Reduce the Rate of Prosthetic Joint Infection in Primary and Revision Total Knee Arthroplasties?
There has been recent increased focus on the importance of modifiable risk factors that can affect the risk of potentially avoidable complications such as prosthetic joint infection (PJI). We aimed to assess the relationship between adherence to a preoperative optimization protocol at our institution and its influence on the rate of PJI after primary and revision total knee arthroplasty (TKA). A single-institution, retrospective study was conducted on all elective primary and revision TKAs performed over a 2-year period. PJI was diagnosed using the 2011 Musculoskeletal Infection Society criteria. Surgical outcomes and PJI were assessed relative to adherence to preoperative optimization criteria. Compliance was set as a binary variable with any case that did not meet all criteria deemed noncompliant. A total of 669 TKAs met inclusion criteria, including 510 primary and 159 revision TKAs. Overall compliance was 61.3%. There were 26 PJIs (3.9%) in total. The PJI rate was 1.2% (6) among primary and 14.4% (20) among revision TKAs. The rate of PJI among cases that met the preoperative optimization criteria was 2.4% (5), and the rate among cases that did not was 6.2% (21) (P < .05). Adherence to preoperative optimization criteria may decrease the incidence of PJI after primary and revision TKA, but further study is needed to confirm the findings of this study.


Pioglitazone increases macrophage apoptosis and plaque necrosis in advanced atherosclerotic lesions of nondiabetic low-density lipoprotein receptor-null mice.
Thiazolidinediones (TZDs), which have actions that involve both peroxisome proliferator-activated receptor (PPAR)-gamma-dependent and -independent effects, improve insulin sensitivity in type II diabetes and inhibit early atherogenesis in mice. However, the effects of TZDs on advanced lesion progression are unknown. Pioglitazone and rosiglitazone enhanced macrophage apoptosis by a number of stimuli, including those thought to be important in advanced atherosclerosis. Macrophage death was not enhanced by non-TZD PPARgamma activators, and TZD-induced apoptosis was still observed in PPARgamma-deficient macrophages. In wild-type macrophages, death enhancement was associated with reduced activation of the cell-survival mediator nuclear factor-kappaB. TZDs also increased the ability of macrophages to phagocytically clear apoptotic cells, which is proposed to protect against plaque necrosis in advanced lesions. The mechanism of this effect was complex, involving both PPARgamma-dependent and -independent mechanisms. To explore the net effect on advanced atherosclerosis in vivo, Ldlr-/- mice were fed a nondiabetogenic cholesterol-enriched diet to promote midstage lesions. Then, pioglitazone was administered with the diet for an additional 10 weeks. Aortic root lesions from the pioglitazone-treated mice showed a substantial increase in apoptotic cells and plaque necrosis compared with lesions from non-drug-treated mice. The potential atheroprotective effects of TZDs conferred by insulin sensitization may be partially offset by adverse effects on advanced atherosclerosis. Because the mechanisms of the beneficial and proposed adverse effects may differ, these findings have potentially important implications for drug optimization.


Benchmark dose for cadmium-induced renal effects in humans.
Our goal in this study was to explore the use of a hybrid approach to calculate benchmark doses (BMDs) and their 95% lower confidence bounds (BMDLs) for renal effects of cadmium in a population with low environmental exposure. Morning urine and blood samples were collected from 820 Swedish women 53-64 years of age. We measured urinary cadmium (U-Cd) and tubular effect markers [N-acetyl-beta-d-glucosaminidase (NAG) and human complex-forming protein (protein HC) ] in 790 women and estimated glomerular filtration rate (GFR; based on serum cystatin C) in 700 women. Age, body mass index, use of nonsteroidal anti-inflammatory drugs, and blood lead levels were used as covariates for estimated GFR. BMDs/BMDLs corresponding to an additional risk (benchmark response) of 5 or 10% were calculated (the background risk at zero exposure was set to 5%) . The results were compared with the estimated critical concentrations obtained by applying logistic models used in previous studies on the present data. For both NAG and protein HC, the BMDs (BMDLs) of U-Cd were 0.5-1.1 (0.4-0.8) microg/L (adjusted for specific gravity of 1.015 g/mL) and 0.6-1.1 (0.5-0.8) microg/g creatinine. For estimated GFR, the BMDs (BMDLs) were 0.8-1.3 (0.5-0.9) microg/L adjusted for specific gravity and 1.1-1.8 (0.7-1.2) microg/g creatinine. The obtained benchmark doses of U-Cd were lower than the critical concentrations previously reported. The critical dose level for glomerular effects was only slightly higher than that for tubular effects. We suggest that the hybrid approach is more appropriate for estimation of the critical U-Cd concentration, because the choice of cutoff values in logistic models largely influenced the obtained critical U-Cd.


Customized one-step preparation of sgRNA transcription templates via overlapping PCR Using short primers and its application in vitro and in vivo gene editing.
Overlap extension polymerase chain reaction (PCR) is a powerful technology for DNA assembly. Based on this technology, we synthesized DNA templates, which were transcribed into sgRNA in vitro, and further detected their efficiency of purified sgRNAs with Cas9 nuclease. The sgRNAs synthesized by this approach can effectively cleave the DNA fragments of interest in vitro and in vivo. Compared with the conventional method for generating sgRNA, it does not require construction of recombinant plasmids and design of primers to amplify sgRNA core fragment. Only several short primers with overlapped sequences are needed to assemble a DNA fragment as the template of sgRNA. This modified and simplified method is highly applicable and less time-consuming.


Prevalence of Diabetes and Impaired Fasting Glycemia in Patients With Oral Cancer: A Retrospective Study in Hungary.
Diabetes mellitus (DM) is one of the most common chronic metabolic disorders. Our research aimed to demonstrate the relationship between DM and oral cancer. We pursued a retrospective research study in Hungary between January 2019 and December 2020. We investigated 597 inpatient records and compared them to the results of our previous studies (1998-2002 and 2012-2015). The frequency of patients with DM in the oral cancer group is 2.45 times higher today than 20 years ago. The prevalence rate of DM and oral malignancies increased from 14.6% to 35.8%. In the oral cancer group, 54.4% of the patients had elevated blood glucose levels and of these, 61.1% of them had type 2 diabetes, 34.2% had impaired fasting glycemia, and only 4.7% had type 1 diabetes. We observed that 45.3% of them were smokers. Of those whose blood sugar levels were under 6.1 mmol/l, the mean body mass index was 25.33 [standard deviation (SD)=±4.5; range=15.57-39.84], while among patients with DM, it was 26.92 (SD=±5.8; range=18.36-44.08). It may be necessary to continuously monitor the patient's blood sugar level to maintain euglycemic levels when managing patients with malignant oral lesions.


Effects of water temperature on pulmonary volumes in immersed human subjects.
Pulmonary volumes and capacities have been measured at three water temperatures (Tw = 25, 34, 40 degrees C) in standing subjects immersed up to the shoulders. The comparison of data obtained in air with those obtained in thermoneutral immersion (Tw = 34 degrees C) confirms the results previously published in several studies. The comparison of data obtained in immersion at different Tw shows: 1. A significant decrease in vital capacity (VC) with bath temperature (VC 40 degrees C greater than VC 34 degrees C greater than VC 25 degrees C). The same decrease is observed in the inspiratory reserve volume (IRV) while the expiratory reserve volume (ERV), the residual volume (RV) and the functional residual capacity (FRC) do not vary. 2. A significant decrease in maximum breathing capacity (MBC) with bath temperature (MBC 40 degrees C greater than MBC 25 degrees C). 3. A significant increase in tidal volume (VT) in cold or hot water compared to thermoneutral water (VT40 degrees C greater than VT34 degrees C; VT34 degrees C less than VT25 degrees C) during quiet breathing. Breathing frequency does not change, thus ventilation (V) follows the same evolution as VT. The relative abdominal (ABD) contribution to VT, estimated by a double belt inductance plethysmograph, is reduced at Tw = 25 degrees C but unchanged at Tw = 40 degrees C compared to thermoneutral bath. Beside variations in the metabolic state, the variations of the pulmonary volumes as a function of Tw are estimated to be mainly due to alterations in respiratory muscles functioning.


Systemic vibriosis due to non-cholera vibrio.
A case of extraintestinal vibriosis with septicaemia due to a non-cholera vibrio, from which the patient had recovered, is presented. Diagnostically useful clinical and laboratory data are described together with an outline of the combined medical and surgical treatment regimen which is employed. The association with excessive alcohol consumption and liver diseases is noted.


Comparison of cell viability assessment and visualization of Aspergillus niger biofilm with two fluorescent probe staining methods.
Filamentous fungi are ubiquitous and frequent components of biofilms. A means to visualize them and quantify their viability is essential for understanding their development and disruption. However, quantifying filamentous fungal biofilms poses challenges because, unlike yeasts and bacteria, they are not composed of discrete cells of similar size. This research focused on filamentous fungal biofilms that are representative of those in the built environment. The objective of this study was to develop a rapid method to examine biofilm structure and quantify live (metabolically active/ membrane undamaged) and dead (inactive/ membrane damaged) cells in Aspergillus niger biofilms utilizing a fluorescent probe staining method and confocal laser scanning microscopy (CLSM). For this, we compared two commercially available probe staining kits that have been developed for bacterial and yeast systems. One method utilized the classic cell stain FUN 1 that exhibits orange-red fluorescent intravacuolar structures in metabolically active cells, while dead cells are fluoresced green. The second method utilized a combination of SYTO9 and propidium iodide (PI), and stains cells based on their membrane morphology. SYTO9 is a green fluorescent stain with the capacity to penetrate the living cell walls, and PI is a red fluorescent stain that can only penetrate dead or dying cells with damaged cell membranes. Following staining, the biofilms were imaged using CLSM and biofilm volumes and thickness were quantified using COMSTAT, a computer program that measures biofilm accumulation from digital image stacks. The results were compared to independent measurements of live-dead cell density, as well as a classic cell viability assay-XTT. The data showed that the combination of SYTO9 and PI is optimal for staining filamentous fungal biofilms.


Conformation-sensitive modification of the type II calmodulin-dependent protein kinase by phenylglyoxal.
Chemical modification by phenylglyoxal was used to investigate relationships between the structure, function, and regulation of the type II calmodulin-dependent protein kinase. Modification of the protein kinase by phenylglyoxal resulted in specific labeling of one distinct site, most likely an important arginine residue, with concomitant inactivation of the enzyme. Labeling and inactivation of the protein kinase was prevented by Mg2+-ADP which suggests that modification occurred at, or in close proximity to, its nucleotide-binding pocket. Half-maximal protection by Mg2+-ADP was enhanced by calmodulin which decreased the K0.5 for ADP from 540 to 61 microM. This response of the enzyme to calmodulin indicates that the modulator protein increases the affinity of the protein kinase for nucleotides. Inactivation of the enzyme by phenylglyoxal was dependent on the presence of Mg2+ or Ca2+/calmodulin, and further enhanced by the simultaneous addition of these effectors to the reaction. The Mg2+ effect is indicative of binding of this divalent metal ion to the protein kinase even in the absence of calmodulin and nucleotides. The stimulation of the modification reaction by calmodulin indicates an increase in the reactivity or accessibility of the modified residue in response to calmodulin-regulated conformational changes on the enzyme. The calmodulin-induced changes observed in this study may play important roles in the molecular mechanisms of activation of the type II calmodulin-dependent protein kinase.


Roles of autophagy-related genes in conidiogenesis and blastospore formation, virulence, and stress response of Beauveria bassiana.
Autophagy is a conserved intracellular recycling mechanism, in which autophagy-related genes 12 and 16 (ATG12 and ATG16) function in a complex controlling the ubiquitin-like conjugation system. In the insect-pathogenic fungus Beauveria bassiana, ATG12 and ATG16 were functionally characterized. Disruption of BbATG12 or BbATG16 resulted in the absence of autophagic bodies under starvation stress. ΔBbATG12 and ΔBbATG16 mutant strains displayed similar defects in asexual development (conidiation and blastospore formation) and tolerance to oxidative stress. ΔBbATG16 strain exhibited the impaired growth on the media with gelatin or chitin as a single nitrogen source, and ΔBbATG12 displayed decreased growth on the media with sucrose, fructose or maltose as a single carbon source. Both BbATG12 and BbATG16 were required for fungal virulence. BbATG16 mutation had more effects on fungal virulence than BbATG12 in topical infection assay, although both genes had similar contributions to fungal virulence in intrahemocoel injection assay. This study indicates that BbATG12 and BbATG16 mediate diverse biological functions in addition to their convergent roles in autophagy.


Retinal and extra-retinal photoreceptor responses and reproductive performance of Japanese quail (Coturnix coturnix japonica) following exposure to different photoperiodic regime.
Japanese quail is a truly photoperiodic avian species. In general long days are gonado-stimulatory and short days are gonado-inhibitory for this poultry bird. To investigate the correlation of retinal and extra-retinal photoreceptors with different photoperiodic conditions quail were divided into 2 groups and kept under long day (16L: 8D) and short day (8L: 16D) condition separately to develop photosensitivity and scotosensitivity respectively. Transfer of long day quail to intermediate day-length (13.5L: 10.5D) developed photorefractoriness (relative) and prolonged exposure to short photoperiodic conditions led the birds to develop scotorefractoriness. Increased expression of mRNA and immunosignaling of photoreceptors rhodopsin, transducin in eye and hypothalamus while decreased mRNA expression of melatonin receptors (Mel1b, Mel1c) were noted in the eyes of photosensitive (PS) and scotorefractory (SR) quail compared to photorefractory (PR) and scotosensitive (SS) birds respectively. Decreased expression of hypothalamic GnIH and melatonin receptors mRNA was observed in PS and SR birds compared to PR and SS birds respectively. Modulation of retinal and extra retinal photoreceptors leads to increased spermatogenesis as well as mRNA expression of steroidogenic genes and androgen receptor in the testis of sexually active PS and SR quail. These results led us to conclude that gonadal stimulation in PS as well as SR quail is outcome of activated retinal and extra retinal photoreceptors which lowered melatonin receptors and GnIH expression. Contrarily testicular inhibition in PR and SS is the outcome of decreased photoperception. It is suggested that decreased photoperception in SS quail increases after prolong exposure of the short day (in SR) leading to increased activity of HPG axis.


Analysis of in vivo single cell behavior by high throughput, human-in-the-loop segmentation of three-dimensional images.
Analysis of single cells in their native environment is a powerful method to address key questions in developmental systems biology. Confocal microscopy imaging of intact tissues, followed by automatic image segmentation, provides a means to conduct cytometric studies while at the same time preserving crucial information about the spatial organization of the tissue and morphological features of the cells. This technique is rapidly evolving but is still not in widespread use among research groups that do not specialize in technique development, perhaps in part for lack of tools that automate repetitive tasks while allowing experts to make the best use of their time in injecting their domain-specific knowledge. Here we focus on a well-established stem cell model system, the C. elegans gonad, as well as on two other model systems widely used to study cell fate specification and morphogenesis: the pre-implantation mouse embryo and the developing mouse olfactory epithelium. We report a pipeline that integrates machine-learning-based cell detection, fast human-in-the-loop curation of these detections, and running of active contours seeded from detections to segment cells. The procedure can be bootstrapped by a small number of manual detections, and outperforms alternative pieces of software we benchmarked on C. elegans gonad datasets. Using cell segmentations to quantify fluorescence contents, we report previously-uncharacterized cell behaviors in the model systems we used. We further show how cell morphological features can be used to identify cell cycle phase; this provides a basis for future tools that will streamline cell cycle experiments by minimizing the need for exogenous cell cycle phase labels. High-throughput 3D segmentation makes it possible to extract rich information from images that are routinely acquired by biologists, and provides insights - in particular with respect to the cell cycle - that would be difficult to derive otherwise.


CRF-evoked bradycardia in urethane-anesthetized rats is blocked by naloxone.
CRF, injected IV at a dose of 6 nmol/kg, produced a fall in blood pressure and in heart rate in urethane-anesthetized rats. The CRF-bradycardia was not obtained in hypophysectomized animals, in animals pretreated with dexamethasone, or in animals pretreated with the narcotic antagonist, naloxone (1 mg/kg, IV). By contrast, the hypotensive effects of CRF were not affected by these procedures. Vagotomy or pretreatment with a low dose of N-methylnaloxone did not affect the CRF-bradycardia, indicating that the slowing of the heart was not due to parasympathetic stimulation or due to a peripherally mediated opioid chemoreflex. The results suggested that the CRF-bradycardia was mediated by the release of opioid peptides from the pituitary.


Study on the method of enucleation of anterior uterine fibroids by transverse incision of the lower uterine segment during cesarean section.
A retrospective study was conducted to investigate the effectiveness and feasibility of fibroid enucleation in the anterior wall of the uterus by transverse uterine incision during cesarean section. The medical history, surgical data, preoperative and postoperative changes in the blood system, and complications of 90 pregnant women who underwent myomectomy of the anterior uterine wall during cesarean section at the second Department of Maternal and Child Health Hospital of Fujian Province were analyzed retrospectively. No significant differences were noted in the leiomyoma number, pathological type, preoperative and postoperative hemoglobin level, perioperative bleeding incidence, blood transfusion frequency, postoperative fever incidence, and duration of lochia between the study and control groups. The proportion of large fibroids was slightly higher in the study group than in the control group (p < 0.05), and the operation time and average hospitalization time were slightly longer in the study group than in the control group (p < 0.05). The distribution of type III-V fibroids was slightly more in the study group than in the control group (p < 0.05), and the distribution of type VI fibroids in the study group was less than that in the control group (p < 0.05). Fibroid enucleation is safe and effective in the anterior wall of the uterus through the lower uterine transverse incision in cesarean section. It has the potential to reduce the risk of pelvic and intrauterine adhesions in the future.


Improving cell survival and engraftment in vivo via layer-by-layer nanocoating of hESC-derived RPE cells.
Human embryonic stem cell-derived retinal pigment epithelial (hESC-RPE) cell transplants have served as a cell therapy for treating retinal degenerative diseases. However, how to optimize the survival and engraftment of hESC-RPE cells is a great challenge. Here, we report hESC-RPE cells that are embedded with polyelectrolytes gelatin and alginate by layer-by-layer (LbL) self-assembly technique, based on the opposite charge of alternate layers. Cells were assessed for cell survival, immunogenicity, and function in vitro and in vivo. This strategy obviously decreased the immunogenicity of hESC-RPE cells without affecting its activity. LbL-RPE cell transplants into the subretinal space of Royal College of Surgeons (RCS) rats optimized cell engraftment and decreased immunogenicity compared to untreated RPE cell transplants (immunosuppression was not used during the 21-week study). Visual-functional assay with electroretinogram recordings (ERGs) also showed higher B wave amplitudes in RCS rats with LbL-RPE cell transplants. We demonstrate that transplanted LbL-RPE cells have better viability and grafting efficiency, optimized immunogenicity, and visual function. Therefore, LbL engineering is a promising method to increase the efficacy of hESC-RPE cell transplantation.


Nodal spacing along regenerated axons following a crush lesion of the developing rat sciatic nerve.
The relation between internodal length (L) and fibre diameter (D) was examined light microscopically in teased specimens from normal developing rat sciatic nerves, and from rat sciatic nerves which had regenerated following crush lesions at various postnatal ages. In newborn rat pups virtually all sciatic nerve axons are unmyelinated and myelination is an essentially postnatal event. Between 2 weeks and 6 months maximal L increases from 500 microns to 1400 microns and maximal D increases from 6-8 microns to 16 microns. The increase in L matches the length growth of the hindlimb. Signs of myelin sheath remodelling are absent during normal development. Examination of regenerated nerves showed that the lengths of the internodes along large-medium-sized axons, are strongly dependent on crush age. In neonatally crushed nerves, the slope is close to normal. With increasing crush age the inclination of the regression line gradually decreases. Signs of myelin sheath remodelling are not seen in regenerated nerves crushed at birth or 1-2 weeks after birth. However, such signs are present in regenerated nerves crushed 3 weeks or more after birth. These observations support the view that myelin sheath remodelling in regenerated rat sciatic nerves is directly related to a deficient length growth following myelination.


Polymethine Dye-Functionalized Nanoparticles for Targeting CML Stem Cells.
In chronic myelogenous leukemia (CML), treatment with tyrosine kinase inhibitors (TKI) is unable to eradicate leukemic stem cells (LSC). Polymethine dye-functionalized nanoparticles can be internalized by specific cell types using transmembrane carrier proteins. In this study we investigated the uptake behavior of various polymethine dyes on leukemia cell lines and searched for carrier proteins that guide dye transport using RNA interference. The results show that the uptake of DY-635 is dependent on organic anion transport protein 1B3 (OATP1B3) in CML cells and immature myeloid precursor cells of CML patients. In contrast to nonspecific poly(lactide-co-glycolic acid) (PLGA) nanoparticle constructs, DY-635-functionalization of nanoparticles led to an uptake in CML cells. Investigation of these nanoparticles on bone marrow of CML patients showed a preferred uptake in LSC. The transcription of OATP1B3 is known to be induced under hypoxic conditions via the hypoxia-inducing factor 1 alpha (HIF1α), thus also in the stem cells niche. Since these cells have the potential to repopulate the bone marrow after CML treatment discontinuation, eliminating them by means of drug-loaded DY-635-functionalized PLGA nanoparticles deployed as a selective delivery system to LSC is highly relevant to the ongoing search for curative treatment options for CML patients.


[Investigations of drug-related sulfhydryl oxidation in isolated rabbit lenses].
The appearance of cataract in human lenses mainly consists in the formation of a protein network initiated by oxidative processes. Two types of covalent bondings are produced in the cristallins during cataractogenesis: The formation of C-N bonds produced from amino groups of the cristallin proteins and aldehyd or keto groups derived from the oxidation of sugars or unsaturated fatty acids. The formation of S-S bonds from SH groups specially in the gamma-cristallins. These disulfid bonds are scarcely reducible by reductants such as ascorbic acid or glutathione. Experimentally these SS bonds can be produced in rabbit lenses by incubation with riboflavin in the light. The presence of Pherajod during the incubation period prevents the oxidation of SH groups.


Determining protein concentrations of the human ventricular proteome.
Proteomics is mostly used for measurements of relative differences in protein concentrations. Although such analyses are meaningful for comparing differences between two and more conditions, they do not directly provide details on the absolute protein concentrations within a system. Now, proteomics is heading more towards absolute quantitative strategies with results being expressed in copies/cell or ng/mg tissue. In the cardiac context, such quantitative information is crucial for (1) evaluating the feasibility of selecting a certain protein as potential novel drug target, (2) the expected concentration excreted into the circulation when selecting a biomarker, and (3) to build a model of cardiac function at the molecular level. At the same time, by mass spectrometry-based proteomics, a wealth of spectral information is gathered that can be used to evaluate protein levels of a select set of novel disease-altered proteins using, for instance, single reaction monitoring. Here we describe how to build a quantitative map of the human left ventricular proteome using a simple yet effective mass spectrometry-based spectral count method.


Information on early medical abortion for women using an audiovisual animation vs face-to-face consultation: A consortium randomized and quasi-randomized trial.
There is some evidence that audiovisual formats can be an effective way of providing information about early medical abortion (EMA). A short animation (3 minutes) was developed about EMA in three languages that summarized the EMA process for use in the UK, France and Sweden. We conducted a multicenter randomized controlled trial to compare information on EMA delivered by an animated film vs a face-to-face consultation. Women requesting EMA (≤9 weeks' gestation) from abortion clinics in Edinburgh (UK), Paris (France) and Stockholm (Sweden) were recruited. The primary outcome was women's recall of prespecified key information on EMA. Secondary outcomes were acceptability of mode of information delivery, clarity and helpfulness of information rated on a Likert scale. The study was prospectively registered with clinicaltrials.gov, ID number: NCT03417362. 172 women completed the study (Edinburgh = 50, Paris = 78, Stockholm = 48). There was no statistically significant difference in recall scores between the animation and standard arms in Edinburgh and Stockholm sites. However, the difference between arms at the Paris site was statistically significant (P = .007) in favor of the animation. All participants in the animation arm rated it as an acceptable way to receive information on EMA. A "short" audiovisual animation can adequately and acceptably deliver key information about EMA. This intervention could be used routinely to provide standardized and high-quality information to women seeking EMA.


Clinical predictors and institutional variation in home oxygen use in preterm infants.
To assess home oxygen use in preterm infants, identify risk factors predicting home oxygen use, and quantify the extent of institutional variation in home oxygen use across neonatal intensive care units. We conducted a retrospective cohort analysis of surviving infants of 23- to 31-week gestational age discharged home in 2009, with de-identified electronic medical record information from the Pediatrix Clinical Data Warehouse. Mixed-effects logistic regression quantified clinical risk factors and institutional variation affecting home oxygen use. A total of 8167 infants were identified. Home oxygen use varied by gestational age, from 59% of infants 23 to 24 weeks gestational age to 7% of infants 29 to 31 weeks gestational age. Other risk factors included small for gestational age, congenital anomalies, mechanical ventilation in the first 72 hours, fraction of inhaled oxygen >0.4 in the first 72 hours, and patent ductus arteriosus. After adjusting for clinical risk factors, there was still a 4- to 5-fold difference in institutions' odds of home oxygen use. Home oxygen use was common in infants of earlier gestational ages and infants with more severe respiratory illness. Institutional variation accounted for 4- to 5-fold variation in home oxygen use. Families should be counseled about the likelihood of home oxygen use, and prospective research must identify optimal treatment strategies for high-risk infants.


A small inhibitor of the interaction between Bax and Bcl-X(L) can synergize with methylprednisolone to induce apoptosis in Bcl-X(L)-overexpressing breast-cancer cells.
To identify inhibitors of the interaction between Bax and Bcl-X(L). Using an assay based on biosensor technology, we screened a chemical library of 10,000 compounds for inhibitors of the interaction between Bax and Bcl-X(L). Using cell-culture systems we tested active compounds for their ability to induce apoptosis in Bcl-X(L)-overexpressing MCF7 cells and increase the sensitivities of the cells to apoptosis-inducing drugs [vincristine sulphate, dexamethasone, cycloheximide and 6alpha-methylprednisolone (MP)]. A single compound, 2',4',5',7'-tetrabromofluorescein (A5), from the library was found to inhibit this interaction efficiently. Several structural analogues of A5 were tested and two of these [4',5'-dibromofluorescein (A9) and 3,4,5,6-tetrabromofluorescein (A11)] were found to be active, and their activities were confirmed by an independent in vitro pull-down assay. These active compounds were observed to induce apoptosis in Bcl-X(L)-overexpressing MCF7 cells. Moreover, two of the compounds (A5 and A11) appeared to increase the sensitivities of the cells to MP. A more rigorous test using the isobologram technique showed that there is a synergistic cytotoxic effect between A11 and MP. We have identified a small inhibitor of the interaction between Bax and Bcl-X(L) that can synergize with methylprednisolone to induce apoptosis in Bcl-X(L)-overexpressing breast-cancer cells.


[Body weight, cardiovascular risk factors, and self-efficacy of diabetic control among obese type II diabetic patients].
The purpose of this study was to examine the effects of problem solving nursing counseling and walking exercise on weight loss, cardiovascular risk factors, and self-efficacy of diabetic control among obese diabetic patients. The Polar heart rate monitor was used for walking exercise to utilize the Biofeedback mechanism. Fifty nine diabetic patients were conveniently placed into experimental (n=35) and control groups (n=24). The experimental group participated in weekly nursing counseling for 12 weeks and was encouraged to do walking exercise using a Polar monitor. The control group remained in the same treatment as before. The data was collected from November 2003 to August 2004 and analyzed using t-tests and ANCOVAs. After 12 weeks, the participants in the experimental group reported significantly decreased body weight (p=.004) and total scores on the Parma scale (p=.001). While the participants in the control group reported significantly increased levels of blood triglyceride (p=.046) and HDL (p=.018). Based on the findings, we concluded that problem focused nursing counseling with intensified walking exercise could reduce the risk of cardiovascular complications and body weight among obese diabetic patients. Future research to explore the long-term effects of nursing counseling on diabetic complications is warranted.


Yoga as a balance intervention for middle-age and older adults with history of lateral ankle sprain: An exploratory study.
Balance deficiencies are common among aging adults. Musculoskeletal injuries such as lateral ankle sprains (LAS) also contribute to compromised balance; potentially amplifying the postural insufficiencies in these age groups with a history of LAS. Yoga has emerged as an effective balance training intervention for aging adults; but limited application exists in these age cohorts with LAS history. This study may provide important guidance for the implementation of this intervention in these populations. In this cohort design study, middle-age and older adults with a history of LAS completed an 8-week beginner-level yoga class. Balance was measured before and after the yoga intervention statically (force plate) and dynamically (star excursion balance test [SEBT]) using single-limb balance tasks. Following the yoga intervention, older adults improved static postural control in the anterior-posterior direction, as well as dynamic postural control in selected reach directions of the SEBT relative to the middle-age adults. This is an important step in exploring how to help the aging population that likely has amplifications in balance deficiencies due to a common musculoskeletal injury, LAS. While more work is needed to determine how to optimize and document balance improvements in aging adults with LAS history, yoga appears to be a promising form of intervention, particularly for older adults.


"Real-time" immersion B-scan and C-scan techniques in ophthalmic diagnosis.
The advent of new techniques in vitreous surgery has added an impetus to improve ultrasonic examination of the vitreous cavity. Rapid B-scanning is vital in the diagnosis of vitreo-retinal pathology when opacity prevents biomicroscopical examination. Serial B- and C-scan sectioning have also proved essential in the study of tumours. The C-scan is of particular value in the study of traction retinal detachments and tumours.


The synthesis, and structure-activity relationships of some long chain acyl carnitine esters on the coronary circulation of the rat isolated heart.
The synthesis of the isopropyl ester of carnitine and a series of fatty acid derivatives with fatty acid lengths C8-C30 is described. Bolus doses of these compounds (0.03-300 nmol) showed coronary vasodilator activity in the rat isolated heart. Increasing fatty acid chain length from C8 to C16 resulted in an increased vasodilator potency. Longer lasting vasodilation was observed with the C20 compound. Increasing fatty acid chain length to C30 was associated with a small dilator response preceded by vasoconstriction.


Neonatal resuscitation after severe asphyxia--a critical evaluation of 177 Swedish cases.
To evaluate neonatal resuscitation of infants born with severe asphyxia. All case records of the 472 claims for financial compensation due to suspected medical malpractice in conjunction with childbirth in Sweden between 1990 and 2005 were scrutinized. Inclusion criteria were: gestational age > or =33 completed weeks, planned vaginal onset of delivery, a reactive CTG at onset of labour, neonatal asphyxia (defined as metabolic acidosis [pH of < 7.05 and/or a base excess of < -12]), or an Apgar score <7 at 5 min. It was assessed that 177 infants suffered from cerebral palsy or early death due to severe asphyxia presumably caused by malpractice around labour. Median Apgar score at 5 min was 3, indicating that all infants needed immediate and extensive resuscitation. There was insufficient adherence to guidelines concerning neonatal resuscitation, including delayed initiation of excessive resuscitation in 19 infants, lack of satisfactory ventilation in 79 infants, and untimely interruption of resuscitation in 38 infants. Compliance with guidelines for resuscitation of severely asphyctic newborn may be improved, especially concerning ventilation and prompt paging for skilled personnel in cases of imminent asphyxia. Documentation of neonatal resuscitation must be improved to enable reliable evaluation.


Optical properties and environmental stability of oxide coatings deposited by reactive sputtering.
Refractory metal-oxide coatings are deposited by reactive dc magnetron sputtering in an oxygen environment. The optical constants and the environmental stability of silicon oxide, aluminium oxide, hafnium oxide, zirconium oxide, tantalum oxide, titanium oxide, and a blend of hafnium oxide with silicon oxide are investigated. Properties of both single-layer and multilayer interference filters are examined.


[Development of a method to proofread and correct the 3D virtual patient in CT simulation of radiotherapy].
Plexiglass and thin copper wire are used to develop a series of devices, which can proofread and correct the CT ruler and CT interval in scanning so as to guarantee the accuracy for the image of the body in 3D digitally-reconstructed radiography (DRR) in the treatment planning system.


Topical preparations for the treatment of psoriasis: a systematic review.
There is clinical uncertainty about the appropriate use of first-line topical treatments for psoriasis. To assess the relative effectiveness and tolerability of topical treatments for psoriasis suitable for use both in primary and secondary care. All major medical databases of published literature were searched electronically; references of trial reports and recent reviews were searched; authors and companies were contacted for missing data from published reports. The study selection comprised: (1) randomized placebo-controlled trials of topical treatments for psoriasis; and (2) randomized head-to-head studies of the new vitamin D3 derivative treatments for psoriasis that reported clinical outcome using a Total Severity Score (TSS), Psoriasis Area Severity Index or Investigator Assessment of Global Improvement. Eligibility and validity were assessed and data extracted independently by two authors. Clinical outcomes were pooled using a random effect standardized weighted mean difference (SWMD) metric, including 3380 patients randomized in 41 placebo (vehicle)-controlled trials and 4898 patients randomized in 28 head-to-head studies. There was a significant benefit in favour of active treatments against vehicle, SWMD: -1.06 (95% confidence interval [CI]: -1.26 to -0.86), approximately a 2-point improvement on a 12-point TSS after 6-8 weeks of treatment. The only significantly different benefit was for very potent corticosteroids: SWMD: -1.51 (95% CI: -1.76 to -1.25), approximately a 3-point improvement on a 12-point TSS. Head-to-head studies support these findings, except that calcipotriol was estimated to be more effective than dithranol, coal tar and other vitamin D3 derivatives. Polytherapy, using a potent steroid and calcipotriol, was more effective than calcipotriol alone: SWMD 0.42 (95% CI: 0.12-0.72 ) approximately a 0.8-point improvement on a 12-point TSS. No important differences in withdrawal or reporting of adverse events were identified. Trials of short duration neither adequately inform the management of chronic disease nor describe the sequelae of treatment. The evidence base for long-term care, reflecting the disease pathway, should be improved. Combination therapy with topical vitamin D analogues and steroids, and maintenance therapy following treatment response merit further investigation.


Visual Analogue Scale and Expanded Prostate Cancer Index Composite-26 in the Evaluation of Urinary Continence Recovery After Three-Dimensional Laparoscopic Radical Prostatectomy, a Single-Center Prospective Registered Study.
To assess the correlation between the Visual Analogue Scale (VAS) and the Expanded Prostate Cancer Index Composite (EPIC)-26 in the evaluation of urinary continence (UC) recovery after 3-dimensional laparoscopic radical prostatectomy (3D-LRP). 105 men underwent 3D-LRP in Seinäjoki Central Hospital Finland between November 2018 and February 2021. VAS forms and EPIC-26 questionnaires were used to assess UC preoperatively and at 6 weeks, 3-, 6-, 9-, 12-, 15-, 18-, 21-, and 24 months postoperatively. On the VAS form, the patient put a mark on the 10 cm long horizontal line in place, which described his experienced degree of UC (0 cm; fully incontinent-10 cm; fully continent). The scores for the urinary incontinence domain of EPIC-26 (UI-EPIC-26) were calculated and transformed to a scale of 0-100. Spearman´s rank correlation coefficient was used to evaluate the correlation between the VAS and UI-EPIC-26. A total of 915 VAS forms and 909 EPIC-26 questionnaires were evaluable. UC improved significantly during the first year but not after that. The medians for UI-EPIC-26 and VAS were 50.8 (0-100) and 7.2 cm (0-10 cm) at 3 months, 76.8 (14.5-100) and 8.7 cm (1.7-10 cm) at 12 months and 79.6 (8.25-100) and 9.0 cm (2.7-10 cm) at 24 months. The correlation coefficient (95% confidence interval) between VAS and UI-EPIC-26 preoperatively, at 12 months and at 24 months was 0.639 (0.505-0.743), 0.807 (0.716-0.871), and 0.831 (0.735-0.894), respectively (P < 0.001). The VAS can be utilized as an easy-to-use alternative to the EPIC-26 when evaluating UC recovery after 3D-LRP.


Enhanced biodegradation of crude oil in soil by a developed bacterial consortium and indigenous plant growth promoting bacteria.
This study aimed to develop an efficient, cost-effective and eco-friendly bacterial consortium to degrade petroleum sludge. Four bacterial strains belonging to genera Acinetobacter and Pseudomonas were selected to constitute three different consortia based on their initial concentration. The highest degradation rate (78%) of 1% (v/v) crude oil after 4 weeks of incubation was recorded when the concentration of biosurfactant (BS) producing isolate was high. Genes, such as alkB, almA, cyp153, pah-rhdGN, nah, phnAC and cat23 were detected using the polymerase chain reaction method and their induction levels were optimal at pH 7·0. A crude oil sludge was artificially constituted, and its bacterial composition was investigated using 16S rRNA gene amplicon sequencing. The results showed that the soil bacterial community was dominated by plant growth-promoting bacteria (PGPB) after crude oil treatment. Our findings indicate the decontamination of the crude oil contaminated soil was more effective in the presence of both the constituted consortium and PGPB compared to the presence of PGPB alone. This study showed that the PGPB (Taibaiella) present in petroleum uncontaminated soil can promote the soil decontamination. The addition of both efficient hydrocarbon-degrading and BS producing bacteria is also necessary to improve the decontamination.


Alternative splicing of HSPA12A pre-RNA by SRSF11 contributes to metastasis potential of colorectal cancer.
Dysregulation of alternative splicing (AS) induced by serine/arginine-rich proteins has recently been linked to cancer metastasis. Nonetheless, as a member of the serine/arginine-rich protein family, the involvement of SRSF11 in colorectal cancer (CRC) is unknown. The TCGA dataset and clinical samples were used to assess SRSF11 expression levels in CRC. For SRSF11, functional experiments were conducted both in vitro and in vivo. RNA-seq technology was used to analyze and screen SRSF11-triggered AS events, which were then confirmed by in vivo UV crosslinking and immunoprecipitation (CLIP) and mini-gene reporter assays. Jalview software was used to determine the preferential binding motif with relation to exon skipping (ES) events. Furthermore, coimmunoprecipitation (Co-IP) and Phospho-tag SDS-PAGE experiments were used to investigate PAK5-mediated phosphorylation regulation on SRSF11, and in vitro kinase experiments validated the interaction. In CRC, SRSF11 was discovered to be overexpressed and associated with a poor prognosis. And SRSF11 played a pro-metastatic role in vitro and in vivo. By screening SRSF11-regulated AS events, we identified the binding motif of SRSF11-triggered splicing-switching of HSPA12A AS, which specifically regulated HSPA12A AS by directly binding to a motif in exon 2. Mechanistically, the HSPA12A transcript with exon 2 retention increased N-cadherin expression by promoting RNA stability. Furthermore, the oncogenic kinase PAK5 phosphorylated SRSF11 at serine 287, protecting it from ubiquitination degradation. SRSF11 exerts pro-metastatic effects in CRC by inhibiting the AS of HSPA12A pre-RNA. Our findings point to SRSF11-regulated HSPA12A splicing as a novel relationship between SRSF11-regulated splicing and CRC metastasis and suggest a PAK5/SRSF11/HSPA12A axis as a potential therapeutic target and prognostic biomarker in CRC.


Preferential loss of collaterals from goldfish retinal axons in the optic tract is delayed by tetrodotoxin.
Following optic nerve section (ONS) in goldfish, the right eye was repeatedly injected with tetrodotoxin (TTX) and the left eye with Ringer solution. At various survival periods after ONS, horseradish peroxidase (HRP) was applied to small groups of axons in dorsal or ventral retina in both eyes. Counts of labeled regenerating retinal axons show that 43 +/- 4.6% of regenerating axons course through the inappropriate brachium of the optic tract between 20 and 65 days after ONS. The amount of misrouted axons declines to 30 +/- 6.1% between 70 and 80 days after ONS. Under TTX blockade the reduction of misrouted axons is delayed but reaches 27 +/- 3.6% at 150 days after ONS.


Ultrasonically determined kidney transplant hypertrophy.
Increased renal transplant size is a criterion of acute rejection. Statistically significant increases in ultrasonically measured kidney graft dimensions were demonstrated in 8 recipients of living related donor kidneys who never had rejection crises. After an average followup of 4.9 +/- 3.8 months (range 2 to 12 months), anteroposterior, cross-sectional and pole-to-pole measurements were increased by 0.75, 1.9 and 0.58 cm., respectively. Some increase in kidney graft size is normal and should not be confused with acute rejection.


Derived epicardial potentials differentiate ischemic ST depression from ST depression secondary to ST elevation in acute inferior myocardial infarction in humans.
It was hypothesized that in acute inferior wall myocardial infarction, an additional ischemic area in the subendocardium of the noninfarcting territory would produce a selective current dipole between the infarcting and ischemic regions. A resistance network model to calculate epicardial potentials from body surface electrocardiographic potentials was developed and used to examine the hypothesis in 219 patients with acute inferior myocardial infarction. In the learning set of 110 patients, two characteristic dipole patterns were observed, each associated with a high mortality rate in the ensuing 15 months when compared with that in the remaining patients. In the test set of 109 patients, a double-blind analysis of the patterns showed that the 34 patients with a dipole pattern had a collective mortality rate of 35% at 15 months compared with a 15 month rate of 5% in the remaining patients. In the total group of 219 patients, the magnitude of ST segment elevation and both the magnitude and integral of the area voltage of ST depression on the epicardium were significantly correlated with the mortality rate (p less than 0.0002 for all variables against death at 15 months). This study strongly suggests that ST depression due to ischemia can be differentiated from ST depression secondary to the ST elevation in acute inferior infarction by the examination of epicardial potential distributions.


Role of Otoacoustic Emissions in Hearing Assessment of Neonates: A Prospective Observational Study.
Hearing plays an important role for children in learning speech and language, socialization and cognitive development. The child learns to speak based on what is heard (Rundjan et al. in Sari Pediatr 6(4):149-154, 2005). The aim of the study was to find out the percentage of hearing loss by OAE among low risk and high risk neonates. All the neonates (Low and High risk) born in a tertiary care center were screened by OAE before their discharge from the hospital and after stabilizing high risk neonates. The referred neonates were followed after two weeks. Total 722 neonates were screened of which 130 were high risk and 592 were low risk. Neonates with Serum bilirubin > 20 mg/dl or requiring exchange transfusion were excluded as OAE will be unreliable in them and they should be subjected to BERA directly. Percentage of bilateral hearing loss came to be 4.2%, 4 participants were lost to follow up and percentage of hearing loss on subsequent OAE came to be 11.6%. Low birth weight was an important risk factor for hearing loss (p value significant on initial and follow-up). Percentage of hearing loss with low birth weight, hyperbilirubenemia, low apgar score and prematurity to be 16%. Mechanical ventilation contributed 13% of total hearing loss followed by ototoxicity. Neonates with family history of childhood SNHL, in utero infection, craniofacial anomaly and bacterial meningitis contributed 3% of total hearing loss. On subsequent follow-up, one neonate was low-risk and the other 25 were high risk, of which 3 high risks showed sustained OAE refer. However the low risk neonate had normal outer hair cell function i.e. OAE pass. This study clearly demonstrates importance of Universal Neonatal Hearing Screening Programme so that hearing loss can be detected as early as possible and possible intervention can be taken at the earliest.


Dynamic MAPK/ERK Activity Sustains Nephron Progenitors through Niche Regulation and Primes Precursors for Differentiation.
The in vivo niche and basic cellular properties of nephron progenitors are poorly described. Here we studied the cellular organization and function of the MAPK/ERK pathway in nephron progenitors. Live-imaging of ERK activity by a Förster resonance energy transfer biosensor revealed a dynamic activation pattern in progenitors, whereas differentiating precursors exhibited sustained activity. Genetic experiments demonstrate that MAPK/ERK activity controls the thickness, coherence, and integrity of the nephron progenitor niche. Molecularly, MAPK/ERK activity regulates niche organization and communication with extracellular matrix through PAX2 and ITGA8, and is needed for CITED1 expression denoting undifferentiated status. MAPK/ERK activation in nephron precursors propels differentiation by priming cells for distal and proximal fates induced by the Wnt and Notch pathways. Thus, our results demonstrate a mechanism through which MAPK/ERK activity controls both progenitor maintenance and differentiation by regulating a distinct set of targets, which maintain the biomechanical milieu of tissue-residing progenitors and prime precursors for nephrogenesis.


Hydrazone as the directing group for Ir-catalyzed arene diborylations and sequential functionalizations.
The use of hemilabile pyridine-hydrazone N,N-ligands allows the highly selective Ir-catalyzed ortho,ortho'-directed diborylation of aromatic N,N-dimethylhydrazones in near-quantitative yields. One-pot sequential Suzuki-Miyaura cross-coupling with different aryl bromides provides a short entry to unsymmetrically substituted 2,6-diarylbenzaldehyde derivatives.


β-endorphin regulates alcohol consumption induced by exercise restriction in female mice.
Animal models have long been used to study the mechanisms underlying the complex association between alcohol and stress. Female mice prevented from running on a home-cage activity wheel increase voluntary ethanol consumption. β-endorphin is an endogenous opioid involved in negatively regulating the stress response and has also been implicated in the risk for excessive drinking. The present study investigates the role of β-endorphin in moderating free-choice consumption of ethanol in response to a blocked activity wheel. Female, transgenic mice with varying levels of the opioid peptide were given daily 2-h access to 20% ethanol with rotations on a running wheel blocked on alternate days. Subjects with low β-endorphin exhibited enhanced stress sensitivity by self-administering larger quantities of ethanol on days when wheel running was prevented. β-endorphin levels did not influence voluntary activity on the running wheel. There were genotypic differences in plasma corticosterone levels as well as corticotropin-releasing hormone mRNA content in multiple brain regions associated with the stress response in these free drinking and running subjects. Susceptibility to stress is enhanced in female mice with low levels of β-endorphin, and better understanding of the role for this opioid in mitigating the response to stressors may aid in the development of interventions and treatments for excessive use of alcohol in women.


A Marginalized Zero-inflated Poisson Regression Model with Random Effects.
Public health research often concerns relationships between exposures and correlated count outcomes. When counts exhibit more zeros than expected under Poisson sampling, the zero-inflated Poisson (ZIP) model with random effects may be used. However, the latent class formulation of the ZIP model can make marginal inference on the sampled population challenging. This article presents a marginalized ZIP model with random effects to directly model the mean of the mixture distribution consisting of 'susceptible' individuals and excess zeroes, providing straightforward inference for overall exposure effects. Simulations evaluate finite sample properties, and the new methods are applied to a motivational interviewing-based safer sex intervention trial, designed to reduce the number of unprotected sexual acts.


Influence of chronic hyperprolactinemia induced by sulpiride on the hypothalamo-pituitary-testicular axis in normal men.
For elucidation of the effects of hyperprolactinemia on the hypothalamic-pituitary-testicular axis, five healthy men were exposed to sulpiride (300 mg/day by mouth); four among the five maintained hyperprolactinemia (71.6 to 95.3 ng/ml) for 78 days. Clomiphene citrate (CC), luteinizing hormone (LH)-releasing hormone, and human chorionic gonadotropin tests were performed before and after sulpiride treatment. The CC test, given as a measure of hypothalamic function, was carried out in each of the five volunteers before sulpiride treatment (control) and on days 14 (2 weeks) and 60 (2 months) of sulpiride administration. Each value of plasma LH stimulated by CC was integrated and expressed as a ratio of the integrated value obtained after administering CC at 2 weeks and 2 months to that from each control experiment. The mean ratio in the four subjects at 2 months (mean +/- standard deviation, 0.769 +/- 0.121) was significantly lower than that at 2 weeks (0.942 +/- 0.073; P less than 0.05) and before sulpiride treatment (1.000; P less than 0.01). Impairment of LH responses to CC by 2-month long sulpiride-induced hyperprolactinemia suggests that chronic hyperprolactinemia in men partly suppresses LH secretion by its inhibitory action on the hypothalamus.


Quorum sensing signals stimulate biofilm formation and its electroactivity for chain elongation: System performance and underlying mechanisms.
Quorum sensing signals have been widely explored in microbial communities. However, the impact of chain elongation microorganisms by quorum sensing signals of acyl homoserine lactones (AHLs) is still unclear. Here, chain elongation consortia under conditions of AHLs addition were examined in microbial electrosynthesis (MES) through 16S rRNA microbial community and metatranscriptomic analyses. The research found that N-octanoyl-L-homoserine lactone (C8-HSL) increased the caproate concentration by 61.48 % as relative to the control and showed the best performance among all the tested AHLs in MES. AHLs enhanced the redox activity of cathodic electroactive biofilms (EABs), which could be due to increased attachment of electrode microorganisms and ratios of live/dead cells. Microbial community analysis showed that AHLs increased the relative abundance of Negativicutes obviously. Meanwhile, metatranscriptomic analysis revealed that C8-HSL significantly improved CoA - transferase activity and regulated valine, leucine, isoleucine biosynthesis, and carbon metabolism. Besides, C8-HSL was beneficial to the chain elongation metabolic pathways, especially the fatty acid biosynthesis (FAB) pathway. These results not only provide metabolic insights into AHLs regulating chain elongation consortia, but also propose potential strategies for speeding up the formation of MES cathodic biofilm.


Human RECQL5 promotes metastasis and resistance to cisplatin in non-small cell lung cancer.
Non-small cell lung cancer (NSCLC) patients have a lower 5-year survival rate, and the distant tumor metastasis and drug resistance are the main reasons for the high mortality. RECQL5, a member of RecQ helicases family, has been linked to tumorigenesis of various cancers expect NSCLC. In the current study, analysis with the Cancer Genome Atlas (TCGA) dataset showed that the level of RECQL5 was elevated in LUAD (Lung Adenocarcinoma) and LUSC (lung squamous carcinomas), two major subtypes of NSCLC, which was confirmed by immunohistochemistry staining on Tissue array slides. The level of RECQL5 was also elevated in NSCLC cell lines. Further, Kaplan-Meier analysis of TCGA dataset suggested that the up-regulated RECQL5 was associated with poor prognosis of LUAD, but not with that of LUSC. Knockdown of RECQL5 significantly inhibited the invasion and migration of NSCLC cells, and suppressed epithelial-mesenchymal transition (EMT) as indicated by the changes of EMT-related proteins, while overexpression of RECQL5 displayed reverse effects. Lung metastasis was also suppressed by RECQL5 knockdown. Additionally, the addition of Akt inhibitor LY294002 reversed the effects of RECQL5 overexpression on cell migration, invasion and EMT. Moreover, knockdown of RECQL5 increased the apoptosis of cisplatin-resistant A549 cell line (A549/DDP) caused by cisplatin treatment. In summary, RECQL5 contributed to the metastasis of NSCLC and assisted NSCLC cells incompletely response to cisplatin therapy, and could be considered as a biomarker or clinical target for NSCLC.


Surface and inner cell behaviour along skeletal muscle cell in vitro differentiation.
During muscle tissue differentiation, in particular in the formation of myotubes from the myoblasts, plasma membrane changes its morpho-functional characteristics. In this study, muscle cell membrane behaviour has been studied along the differentiation of C2C12, a mouse myoblastic adherent cell line. Flat undifferentiated cells, cultured for 3-4 days in the differentiation medium, progressively become thick, long and multinucleated myotubes covered with microvilli. They lose stress fibers and adhesion to the underlying substrate evidentiating an actin redistribution, followed by the spatial organization of thick and thin myofilaments. Sarcomeres and myofibrils occasionally appear, even if a certain percentage of "myosacs" containing randomly oriented filaments can be identified all along the differentiation. M-cadherin, a molecule involved in cell-cell adhesion, also appears in the early differentiation stage, during myoblast fusion. Occasional focal contractions can also be observed in myotubes, which prompt an electrophysiological membrane analysis. When studied by means of patch clamp technique, resting membrane potential appears to undergo a transient depolarization, while input resistance increases until day 5 after differentiation induction, then successively decreases. Capacitance declines until day 5, later appearing enhanced. Moreover, with the induction of differentiation, the pattern of functional voltage-dependent ion channels changes. Therefore, during myogenesis, cell maturation is coupled with changes in cell membrane morphological features and functional characteristics.


An acid test for g proteins.
In this issue, Isom et al. (2013) report their exciting discovery that G proteins can sense pH changes to fine-tune signaling in response to metabolic changes.


Who are we missing? Underrepresentation of data sources used for pharmacoepidemiology research in the United States.
Research using healthcare databases often includes patients frequently excluded from clinical trials; yet it is not known whether commonly used data represents the overall population or specific sub-populations of interest. We aimed to examine population representativeness from data sources in recent research studies in the United States (US). We identified data sources from abstracts accepted to the 34th International Conference on Pharmacoepidemiology & Therapeutic Risk Management. The final sample included research studies using ≥1 data source from the US. We classified data sources broadly as claims, linkage, electronic health records (EHR), survey, distributed data network, and other. Studies using claims and EHRs were further classified into more specific categories, including special populations of interest (eg, children). We identified 356 abstracts. The majority used claims data (n = 201, 56.5%), followed by data linkages (n = 46, 12.9%), and EHR data (n = 39, 11.0%). Among EHR studies, most (n = 16, 41.0%) came from network data sources (eg, Kaiser Permanente). Almost half (49.4%) of claims-based studies used commercial claims data sources, followed by Medicare (22.1%), Medicaid (11.3%), and Medicare Supplemental (6.1%). Only 15% of studies included children in the study population (n = 53), with 8% focused on a pediatric topic (n = 27). We find that certain populations in the US are under-represented in pharmacoepidemiology, particularly Medicaid enrollees and children. Researchers should strive to utilize data sources that may be more representative of the US population, particularly vulnerable populations.


Emergency care within hospitals: can it be done more efficiently?
Cardiac Arrest Teams (CATs) are frequently activated by nurses when patients experience 'false arrests' (FAs). In those cases activation of the Rapid Response Team (RRT) might be more efficient. The authors determined the level of urgency of FAs to find a scope for improvement in efficiency within emergency care. CAT-activations for FAs in a university hospital from September 2009 to 2012 were retrospectively analysed and classified as urgent or less-urgent. In 26% (107/405) the CAT was activated for FAs. Calls were classified as urgent in 43% (46/107). Less urgent calls comprised 57% (61/107) of the FAs, difference 14% (95%CI: 1% to 26%). A significant part of the CAT-activations for FAs were less urgent and an RRT-activation might be more efficient. To minimise the CAT-activations for FAs, nurses need to recognise early patients who clinically deteriorate. Therefore, nurses should use the Modified Early Warning Score correctly.


Determinants of undergraduate nursing students' care willingness towards the elderly in China: Attitudes, gratitude and knowledge.
An aging population has become a serious problem in China. Improving the nursing students' care willingness is a critical way to solve this dilemma. Few studies reveal the relationship between the knowledge, care willingness, attitude towards the elderly and gratitude. This research has found that the attitude towards the elderly, the knowledge about aging, and gratitude showed correlation with care willingness. The purpose of this study is to explore the relationships among knowledge about aging, care willingness, attitude towards the elderly and gratitude. A cross-sectional descriptive design has been used. From November to December 2015, a total of 382 undergraduate nursing students in China completed the questionnaires. The response rate was 95.5%. Four questionnaires including Care Willingness to the Elderly Scale (CW), Kogan's Attitudes towards Old People scale (KAOP), the Facts on Aging Quiz (FAQ), and the Gratitude Scale. Structural equation modeling (SEM) was used to explore the relationship among those variables in this study. For Chinese nursing students, the care willingness of elderly was in medium-high level. Their attitude towards the elderly and gratitude were at the medium degree, while the knowledge about aging was at a lower level. The attitude towards older people, knowledge about aging, and gratitude were significantly correlated with care willingness. The knowledge about aging has no relationship with the attitude. Gratitude plays a mediation role between the knowledge about aging and care willingness. The experience of caring the elderly could lead to a positive impact in care willingness. The nursing students' knowledge about aging had a direct influence on their care willingness. Gratitude plays a mediating role between the knowledge about aging and care willingness to the elderly.