Relationship between activity levels and circadian blood pressure variations.
In 17 healthy Japanese students (14 males and 3 females) an ambulatory activity level monitoring instrument (Actigraph) was attached to the wrist for 48-hour measurement of wrist movement (with 0.01G or higher acceleration). At the same time, an ambulatory blood pressure monitoring apparatus was attached to these subjects to monitor blood pressure (BP) and heart rate (HR) every 30 minutes. Sleeping hours were calculated from the activity levels. The sleeping hours obtained by the Actigraph correlated with those judged from the diary. The correlation was better for the go-to-sleep time than for the awakening time. Activity level, HR and BP showed a similar circadian variation. Activity level differed significantly between the active daytime (4500 counts/hour) and during sleep at night (720 counts/hour). The acrophase of activity level, obtained by the cosinor method, was 235 degrees which did not significantly differ from that of BP and HR. Hourly activity levels correlated with HR and BP at corresponding hours. These results suggest that BP is affected by activity levels even if this rhythm continues to recur in bedrest.


Molecular Mechanism and Prediction of Sorafenib Chemoresistance in Human Hepatocellular Carcinoma.
Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide, and prognosis remains unsatisfactory when the disease is diagnosed at an advanced stage. Many molecular targeted agents are being developed for the treatment of advanced HCC; however, the only promising drug to have been developed is sorafenib, which acts as a multi-kinase inhibitor. Unfortunately, a subgroup of HCC is resistant to sorafenib, and the majority of these HCC patients show disease progression even after an initial satisfactory response. To date, a number of studies have examined the underlying mechanisms involved in the response to sorafenib, and trials have been performed to overcome the acquisition of drug resistance. The anti-tumor activity of sorafenib is largely attributed to the blockade of the signals from growth factors, such as vascular endothelial growth factor receptor and platelet-derived growth factor receptor, and the downstream RAF/mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK cascade. The activation of an escape pathway from RAF/MEK/ERK possibly results in chemoresistance. In addition, there are several features of HCCs indicating sorafenib resistance, such as epithelial-mesenchymal transition and positive stem cell markers. Here, we review the recent reports and focus on the mechanism and prediction of chemoresistance to sorafenib in HCC.


What does social cognition look like in everyday social functioning in Huntington's disease? A protocol for a scoping review to explore and synthesise knowledge about social cognition alongside day-to-day social functioning of people with Huntington's disease.
Social cognition is problematic in Huntington's disease (HD). Despite the observations of clinicians and families, there is minimal empirical literature about how it presents in daily life and the impact on social functioning. This protocol forms the basis of a scoping review to synthesise both the quantitative knowledge and qualitative experiences of the HD community so that a visual and narrative map can address what is known and what is not known for the benefit of the community and clinicians and academics alike. An umbrella scoping review of previous work and a scoping review of newer studies of social cognition and social functioning will be undertaken. The electronic databases PubMed, Medline, PsycINFO, Web of Science, Scopus, Embase and CINAHL will be searched to identify eligible studies from starting from 2003 to June 2023. A grey literature search and grey data search will also be undertaken. Quality appraisal of the included documents will use the Critical Appraisal Skills Programme and Authority, Accuracy, Coverage, Objectivity, Date, Significance checklists. A data charting table will be used for data extraction, with analysis of qualitative data using the framework method. The review findings will be presented in a visual form and in a narrative summary. Ethical review is not usually required as scoping reviews are produced via secondary data analysis, however, this protocol includes the use of grey data from a charity web forum and so in line with best practice for internet mediated research ethical review was sought and approved (STEM Ethical Review Committee, University of Birmingham-ERN_21-1028A). Review findings will be shared with service users and disseminated through a peer-reviewed publications, conference presentations and hosted via the website of the patient association charity the HD Association.


Activation of prostaglandin E2-EP4 signaling reduces chemokine production in adipose tissue.
Inflammation of adipose tissue induces metabolic derangements associated with obesity. Thus, determining ways to control or inhibit inflammation in adipose tissue is of clinical interest. The present study tested the hypothesis that in mouse adipose tissue, endogenous prostaglandin E2 (PGE2) negatively regulates inflammation via activation of prostaglandin E receptor 4 (EP4). PGE2 (5-500 nM) attenuated lipopolysaccharide-induced mRNA and protein expression of chemokines, including interferon-γ-inducible protein 10 and macrophage-inflammatory protein-1α in mouse adipose tissue. A selective EP4 antagonist (L161,982) reversed, and two structurally different selective EP4 agonists [CAY10580 and CAY10598] mimicked these actions of PGE2. Adipose tissue derived from EP4-deficient mice did not display this response. These findings establish the involvement of EP4 receptors in this anti-inflammatory response. Experiments performed on adipose tissue from high-fat-fed mice demonstrated EP4-dependent attenuation of chemokine production during diet-induced obesity. The anti-inflammatory actions of EP4 became more important on a high-fat diet, in that EP4 activation suppressed a greater variety of chemokines. Furthermore, adipose tissue and systemic inflammation was enhanced in high-fat-fed EP4-deficient mice compared with wild-type littermates, and in high-fat-fed untreated C57BL/6 mice compared with mice treated with EP4 agonist. These findings provide in vivo evidence that PGE2-EP4 signaling limits inflammation. In conclusion, PGE2, via activation of EP4 receptors, functions as an endogenous anti-inflammatory mediator in mouse adipose tissue, and targeting EP4 may mitigate adipose tissue inflammation.


When procedures meet practice in community pharmacies: qualitative insights from pharmacists and pharmacy support staff.
Our aim was to explore how members of community pharmacy staff perceive and experience the role of procedures within the workplace in community pharmacies. Community pharmacies in England and Wales. 24 community pharmacy staff including pharmacists and pharmacy support staff were interviewed regarding their view of procedures in community pharmacy. Transcripts were analysed using thematic analysis. 3 main themes were identified. According to the 'dissemination and creation of standard operating procedures' theme, community pharmacy staff were required to follow a large amount of procedures as part of their work. At times, complying with all procedures was not possible. According to the 'complying with procedures' theme, there are several factors that influenced compliance with procedures, including work demands, the high workload and the social norm within the pharmacy. Lack of staff, pressure to hit targets and poor communication also affected how able staff felt to follow procedures. The third theme 'procedural compliance versus using professional judgement' highlighted tensions between the standardisation of practice and the professional autonomy of pharmacists. Pharmacists feared being unsupported by their employer for working outside of procedures, even when acting for patient benefit. Some support staff believed that strictly following procedures would keep patients and themselves safe. Dispensers described following the guidance of the pharmacist which sometimes meant working outside of procedures, but occasionally felt unable to voice concerns about not working to rule. Organisational resilience in community pharmacy was apparent and findings from this study should help to inform policymakers and practitioners regarding factors likely to influence the implementation of procedures in community pharmacy settings. Future research should focus on exploring community pharmacy employees' intentions and attitudes towards rule-breaking behaviour and the impact this may have on patient safety.


Effects of mycorrhizal colonisation on Thymus polytrichus from heavy-metal-contaminated sites in northern England.
A study was performed to establish whether colonisation with arbuscular mycorrhizal (AM) fungi is beneficial to wild thyme [ Thymus polytrichus A. Kerner ex Borbás ssp. britannicus (Ronn.) Kerguelen (Lamiaceae)] growing in the heavy-metal-contaminated soils along the River South Tyne, United Kingdom. T. polytrichus plants of the same genotype were grown under controlled conditions with and without Zn contamination, and differences between AM-colonised and -uncolonised plants in mean shoot and root growth (dry weight) and Zn concentration were assessed. When grown in the heavy-metal-contaminated, low-P soil from one of the South Tyne sites, AM-colonised plants grew significantly larger than uncolonised plants; however, there was no significant difference in growth between AM and non-AM plants grown in an artificial substrate with a larger available P concentration, with or without Zn contamination. Mycorrhizal colonisation increased tissue Zn concentrations during the experiments. It is concluded that AM fungi are beneficial, if not essential, to T. polytrichus growing in the low-nutrient soils along the River South Tyne, because of their role in enhancing plant uptake of P (and possibly other nutrients). There was no evidence from this study that the fungi reduce plant uptake of heavy metals at these sites, but rather increase Zn uptake. However, the resulting tissue metal concentrations do not appear to be large enough to be detrimental to plant growth.


Evaluations of the setup discrepancy between BrainLAB 6D ExacTrac and cone-beam computed tomography used with the imaging guidance system Novalis-Tx for intracranial stereotactic radiosurgery.
The objective of this study was to evaluate the setup discrepancy between BrainLAB 6 degree-of-freedom (6D) ExacTrac and cone-beam computed tomography (CBCT) used with the imaging guidance system Novalis Tx for intracranial stereotactic radiosurgery. We included 107 consecutive patients for whom white stereotactic head frame masks (R408; Clarity Medical Products, Newark, OH) were used to fix the head during intracranial stereotactic radiosurgery, between August 2012 and July 2016. The patients were immobilized in the same state for both the verification image using 6D ExacTrac and online 3D CBCT. In addition, after radiation treatment, registration between the computed tomography simulation images and the CBCT images was performed with offline 6D fusion in an offline review. The root-mean-square of the difference in the translational dimensions between the ExacTrac system and CBCT was <1.01 mm for online matching and <1.10 mm for offline matching. Furthermore, the root-mean-square of the difference in the rotational dimensions between the ExacTrac system and the CBCT were <0.82° for online matching and <0.95° for offline matching. It was concluded that while the discrepancies in residual setup errors between the ExacTrac 6D X-ray and the CBCT were minor, they should not be ignored.


High-performance liquid chromatographic assay for ziprasidone in plasma samples: application to pharmacokinetic studies in rats.
Ziprasidone (ZRS) is among the various antipsychotic drugs indicated for treating schizophrenia. The determination of the pharmacokinetic behavior of this drug is of utmost importance in evaluating its bioavailability. The objectives of the present study are: (1) to develop and validate a sensitive, specific, accurate and precise reverse-phase high performance liquid chromatographic method for quantification of ZRS in the plasma of rats; and (2) to apply the developed method to study the pharmacokinetic profile of ZRS in rats after oral administration. The method uses a C18 (250.0 × 4.6 mm, 5 µm) column and ultraviolet detector with wavelength set at 210.0 nm. The mobile phase is acetonitrile-phosphate buffer (pH 3.6) 28:72% v/v at a flow rate of 1.0 mL/min. The internal standard (IS) is escitalopram. The extraction procedure for ZRS and IS from the biological matrix (plasma) employs liquid-liquid extraction technique using a mixture of methyl tert-butyl ether-dichloromethane (70:30% v/v). The results show good accuracy and precision over a linearity range of 20.0-3,000.0 ng/mL with r(2) ≥ 0.9986. The mean recoveries of ZRS and IS are 79.32 ± 1.16 and 84.10 ± 3.2%, respectively. The method has been successfully utilized to study the pharmacokinetic profile of ZRS in rats after oral administration.


Microinfusion of the metabotropic glutamate receptor agonist 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid into the nucleus accumbens induces dopamine-dependent locomotor activation in the rat.
Although the striatum has one of the highest densities of metabotropic glutamate receptor (mGluR) binding sites in the brain, little is known about their physiological role. In this study we characterized the contribution of mGluRs located in the ventral part of the striatum (the nucleus accumbens) to the control of extrapyramidal motor function. Activation of mGluRs by local infusion of the selective agonist 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD; 25, 50 and 100 nmol/0.5 microl) into the nucleus accumbens induced a dose-dependent increase in locomotor activity in rats. Intra-accumbens infusion of a selective antagonist of mGluRs, alpha-methyl-4-carboxyphenylglycine (MCPG) did not modify spontaneous locomotion but decreased the locomotor response to 1S,3R-ACPD. This effect appeared to be mediated by dopamine, since blockade of dopamine receptors with haloperidol (0.05 and 0.1 mg/kg i.p.) dose-dependently reduced 1S,3R-ACPD-induced locomotor activation. Furthermore, D-amphetamine (0.5 mg/kg, i.p.) combined with intra-accumbens infusion of 1S,3R-ACPD (100 nmol) potentiated the locomotor hyperactivity response to a higher level than that seen with a single treatment with either drug. In contrast, D-amphetamine-induced hypermotility was abolished by infusion of MCPG (100 nmol) into the nucleus accumbens. These results demonstrate that glutamate may control extrapyramidal motor function through metabotropic receptors. Furthermore, activation of metabotropic glutamate receptors appears to act in synergy with the dopamine system at the level of the nucleus accumbens to produce a motor stimulant response.


Melanoma arising after imiquimod use.
Imiquimod belongs to the class of 1H-imidazo-[4,5-c]quinolones-drugs originally developed as nucleoside analogues with the aim of finding new potential antiviral agents (Harrison et al., 1988). Indeed, Imiquimod was first released as treatment for genital warts before its actions against skin cancer were studied. Imiquimod is a relatively small sized molecule (Mr = 240.3) and is hydrophobic, allowing it to penetrate the skin epidermal barrier and therefore making it suitable for topical formulations (Gerster et al., 2005). Imiquimod has shown itself effective against skin cancers and precancerous lesions, especially basal cell cancers and actinic keratosis (Salasche et al., 2002, Beutner et al., 1999). There have been reports of Imiquimod being used as topical treatment against cutaneous metastases of melanoma and some authors have reported its use as first-line therapy against melanoma in situ (Smyth et al., 2011, Gagnon, 2011). We report a case of an invasive malignant melanoma arising de novo at the specific site of application of Imiquimod (Aldara cream 5%) for a biopsy-proven superficial BCC. Therefore while Imiquimod has added to our topical armamentarium against skin cancer, care must be exercised in prescribing this treatment and it is especially important to follow up patients regularly.


Biodegradable conduit small gap tubulization for peripheral nerve mutilation: a substitute for traditional epineurial neurorrhaphy.
Nerve regeneration and re-innervation are usually difficult after peripheral nerve injury. Epineurium neurorrhaphy to recover the nerve continuity is the traditional choice of peripheral nerve mutilation without nerve defects, whereas the functional recovery remains quite unsatisfactory. Based on previous research in SD rats and Rhesus Monkeys, a multiple centers clinical trial about biodegradable conduit small gap tubulization for peripheral nerve mutilation to substitute traditional epineurial neurorrhaphy was carried out. Herein, the authors reviewed the literature that focused on peripheral nerve injury and possible clinical application, and confirmed the clinical possibilities of biodegradable conduit small gap tubulization to substitute traditional epineurial neurorrhaphy for peripheral nerve mutilation. The biodegradable conduit small gap tubulization to substitute traditional epineurial neurorrhaphy for peripheral nerve mutilation may be a revolutionary innovation in peripheral nerve injury and repair field.


Prevalence and clinical features of adult atopic dermatitis in tertiary hospitals of China.
The prevalence of atopic dermatitis (AD) has increased substantially. Previous studies have focused mostly on pediatric patients, while epidemiological investigation on adult AD has been very limited.The aim of this study was to determine the prevalence and clinical features of adult AD in outpatients with dermatitis and eczema in China mainland.A multicenter cross-sectional study was conducted among outpatients with eczema or dermatitis from 39 tertiary hospitals of 15 provinces in China from July 1 to September 30, 2014.Of 8758 patients, 407 were adult AD. Compared with adults with other types of dermatitis, the mean age (41.8 ± 14.3 vs 42.04 ± 15.38 years, P < 0.05) and onset age (35.2 ± 11.2 vs 39.2 ± 14.0 years, P < 0.001) of adult AD were younger, and mean disease duration was longer (5.3 ± 7.1 vs 2.8 ± 4.9 years, P < 0.001). About 53.3% adult AD involved 3 or more body locations, higher than adults with other types of dermatitis (34.4%, P < 0.001), but lower than those with pediatric and adolescent AD (73.8%, P < 0.001). History of asthma (19.2% vs 6.9%, P < 0.001) or allergic conjunctivitis (21.9% vs 14.9%, P < 0.05) was more common in adult AD than pediatric/adolescent AD. Suspected bacterial infection was more frequently in adult AD than adults with other types of dermatitis (24.3% vs 14.6%, P < 0.001) and pediatric/adolescent AD (24.3% vs 14.9%, P < 0.001). More severe itching was observed in 31.4% of adult AD, higher than that of adults with other types of dermatitis (15.4%, P < 0.001), whereas similar to that of pediatric/adolescent AD (28.7%, P > 0.05). The highest (8.7%) and lowest prevalence (3.7%) of adult AD were in 25°N to 30°N and 35°N to 40°N latitude region.A substantial part of adult outpatients with eczema or dermatitis is adult AD. Middle age, more body location involvement, more suspected bacterial infection, and severe itching are the main clinical feathers of adult AD. Geographical environment and economic situation work in synergy to adult AD.


Antihemolytic and antiproteolytic properties of substituted thiosemicarbazidophenothiazines and thiazolidonylphenothiazines.
Antihemolytic and antiproteolytic properties of several 10-(1-acetyl-4-arylthiosemicarbazido) phenothiazines and their corresponding cyclized 10-(2-arylimino-3-acetylamino-4-thiazolidonyl) phenothiazines were investigated. In vitro protection of hypoosmotic hemolysis of human red blood cells by substituted thiosemicarbazidophenothiazines and substituted thiazolidonyl-phenothiazines was concentration dependent; the degree of protection ranged from 19 to 32 and 26 to 42%, respectively, at a final concentration of 0.1 mM. All phenothiazines exhibited antiproteolytic activity. The in vitro inhibition of trypsin-induced hydrolysis of bovine serum albumin by these phenothiazines was concentration dependent and competitive in nature; the degree of inhibition ranged from 30 to 50 and 32 to 79% for substituted thiosemicarbazidophenothiazines and substituted thiazolidonlyphenothiazines, respectively, at a concentration of 1mM. Cyclization of substituted thiosemicarbazidophenothiazines into the corresponding cyclized substitited thiazolidonlyphenothiazines increased the antihemolytic and antiproteolytic effectiveness of these phenothiazines.


[Texture analysis of 3D models for the prediction of the grade of clear cell renal cell carcinoma of the kidney (pilot study)].
To evaluate the possibilities of textural analysis of 3D models in differentiating the degree of nuclear dysplasia of the clear cell renal cell carcinoma (ccRCC). The specimens after surgical treatment of 190 patients with ccRCC were analyzed. In all cases, nephron-sparing surgery (NSS) was performed through laparoscopic access. The clinical characteristics were evaluated, including age, gender, tumor localization (side, surface and segments), absolute tumor volume, Charlson comorbidity index, body mass index, nephrometry scores (RENAL, PADOVA, C-index). Patients were divided into 2 groups. In group 1, there were 119 patients with the ccRCC of Grade 1 or 2, while group 2 consisted of 71 patients with ccRCC of Grade 3 and 4. All patients underwent 3D virtual planning of procedure using the 3D modeling program "Amira". At the first stage, two experienced radiologists performed manual segmentation of 3D models of kidney parenchyma tumors. At the second stage, the tumor shape was analyzed with a mathematical calculation of three indicators and more than 300 textural features of statistics of types 1-2 were extracted. Further, an intellectual analysis was carried out. For the evaluation of tumor grade according to Furman system, the classification problem was solved using the machine learning algorithm Stochastic Gradient Descent and cross-validation k=5. The accuracy of classification for the two groups of Grade 1 or 2 and Grade 3 or 4 on the F1 metric was 72.2. To build the model, the following parameters were selected: the absolute tumor volume, the Charlson comorbidity index, "Energy", the first quartile and the second decile of the pixel intensity distribution. The texture analysis of 3D models for the prediction of Fuhrman grade in ccRCC demonstrated satisfactory quality for two groups of Grade 1 or 2 and Grade 3 or 4 nuclear dysplasia.


RPL13A as a reference gene for normalizing mRNA transcription of ovarian cancer cells with paclitaxel and 10-hydroxycamptothecin treatments.
Gene transcription analysis is important in cancer research, and reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) has been demonstrated to be an effective method to evaluate gene transcription in cancer. RT‑qPCR requires an internal reference gene with a consistent level of mRNA transcription across various experimental conditions. However, it has been suggested that different treatments, including anticancer therapy, may influence the transcriptional stability of internal reference genes. Paclitaxel (PTX) and 10‑hydroxycamptothecin (HCPT) are widely used to treat various types of cancer, and a suitable internal reference gene is required in order to analyze the transcription profiles of the cells following treatment. In the current study, the transcriptional stability of 30 candidate reference genes was investigated in cancer cells following treatment with PTX and HCPT. The two ovarian cancer cell lines, UACC‑1598 and SKOV3, were treated with PTX and HCPT for 24 and 48 h, and the transcriptional levels of the candidate reference genes were subsequently evaluated by RT‑qPCR analysis. The transcriptional stability of the selected genes was then analyzed using qbase+ and NormFinder software. A total of 9 genes were demonstrated to exhibit high transcriptional stability and one of these genes, ribosomal protein L13a (RPL13A), was identified to exhibit high transcriptional stability in every group. The current study identified various reference genes suitable under different circumstances, while RPL13A was indicated to be the most suitable reference gene for analyzing the transcription profile of ovarian cancer cells following treatment with PTX and HCPT.


Prognostic features of the tumor microenvironment in high-grade serous ovarian cancer and dietary immunomodulation.
High-grade serous ovarian cancer (HGSOC) is a particularly lethal malignancy that is prognostically influenced by the immune profile of the tumor microenvironment (TME). TME immune profiles have been sub-categorized according to features associated with both survival outcomes as well as response to systemic therapies. Five suggested immune phenotypes have been described and correlated with overall survival outcomes. Phenotypes associated with shorter overall survival rates appear to have prominent immunosuppressive features within their TME. The opportunity to triage patients according to their prognostic TME profile might allow selection of individual patients with poor prognostic features who could most benefit from innovative immunomodulatory treatment strategies. Two potential strategies to indirectly manipulate the TME (and oncologic outcomes) are alteration of the gut microbiome composition and alteration of TME metabolism through dietary interventions. Experimental dietary modifications in humans designed for influencing cancer outcomes are only beginning to be studied in a prospective fashion. Herein we summarize prognostic TME features in HGSOC and potential opportunities for immunomodulation via dietary and gut microbial interventions.


Electrochemical imaging of diffusion through single nanoscale pores.
A combined scanning electrochemical-atomic force microscope (SECM-AFM) has been used to probe the diffusional transport of target electroactive solutes in isolated nanopores of a track-etched membrane. A polycarbonate membrane (100-nm-diam pore size) hydrated with an electrolyte solution, containing a redox-active probe molecule, such as IrCl6(3-) or Fe(phen)3(2+), functions as the model membrane system. The use of a mobile Pt-coated AFM probe enables individual solution-filled pores to be topographically identified. Analysis of the corresponding current images for the diffusion-limited oxidation of the redox mediator indicates that solution is largely confined to pores in the membrane. Moreover, the tip collector current response provides information on diffusion of the mediator through the pore. Force-distance tip approach and retract measurements allow the radius of contact between the electrochemical-AFM tip and solution confined within a pore at the point of pull-off to be estimated.


Enantioseparation of tiropramide by HPLC.
Tiropramide is an antispasmodic drug that has a chiral center. Resolution of tiropramide enantiomers on various kinds of chiral stationary phases was performed by HPLC. A good resolution on a leucine-derived chiral stationary phase was found. An improved chromatographic condition to resolve racemic tiropramide on the CSP was examined by changing the flow rate, composition, and kind of mobile phases.


Telemedicine Buprenorphine Initiation and Retention in Opioid Use Disorder Treatment for Medicaid Enrollees.
Early COVID-19 mitigation strategies placed an additional burden on individuals seeking care for opioid use disorder (OUD). Telemedicine provided a way to initiate and maintain transmucosal buprenorphine treatment of OUD. To examine associations between transmucosal buprenorphine OUD treatment modality (telemedicine vs traditional) during the COVID-19 public health emergency and the health outcomes of treatment retention and opioid-related nonfatal overdose. This retrospective cohort study was conducted using Medicaid claims and enrollment data from November 1, 2019, to December 31, 2020, for individuals aged 18 to 64 years from Kentucky and Ohio. Data were collected and analyzed in June 2022, with data updated during revision in August 2023. The primary exposure of interest was the modality of the transmucosal buprenorphine OUD treatment initiation. Relevant patient demographic and comorbidity characteristics were included in regression models. There were 2 main outcomes of interest: retention in treatment after initiation and opioid-related nonfatal overdose after initiation. For outcomes measured after initiation, a 90-day follow-up period was used. The main analysis used a new-user study design; transmucosal buprenorphine OUD treatment initiation was defined as initiation after more than a 60-day gap in buprenorphine treatment. In addition, uptake of telemedicine for buprenorphine was examined, overall and within patients initiating treatment, across quarters in 2020. This study included 41 266 individuals in Kentucky (21 269 women [51.5%]; mean [SD] age, 37.9 [9.0] years) and 50 648 individuals in Ohio (26 425 women [52.2%]; mean [SD] age, 37.1 [9.3] years) who received buprenorphine in 2020, with 18 250 and 24 741 people initiating buprenorphine in Kentucky and Ohio, respectively. Telemedicine buprenorphine initiations increased sharply at the beginning of 2020. Compared with nontelemedicine initiation, telemedicine initiation was associated with better odds of 90-day retention with buprenorphine in both states (Kentucky: adjusted odds ratio, 1.13 [95% CI, 1.01-1.27]; Ohio: adjusted odds ratio, 1.19 [95% CI, 1.06-1.32]) in a regression analysis adjusting for patient demographic and comorbidity characteristics. Telemedicine initiation was not associated with opioid-related nonfatal overdose (Kentucky: adjusted odds ratio, 0.89 [95% CI, 0.56-1.40]; Ohio: adjusted odds ratio, 1.08 [95% CI, 0.83-1.41]). In this cohort study of Medicaid enrollees receiving buprenorphine for OUD, telemedicine buprenorphine initiation was associated with retention in treatment early during the COVID-19 pandemic. These findings add to the literature demonstrating positive outcomes associated with the use of telemedicine for treatment of OUD.


Lessons learned from the clinical development of oral peptides.
The oral delivery of peptides and proteins has been hampered by an array of obstacles. However, several promising novel oral delivery systems have been developed. This paper reviews the most advanced oral formulation technologies, and highlights key lessons and implications from studies undertaken to date with these oral formulations. Special interest is given to oral salmon calcitonin (CT), glucagon-like peptide-1 (GLP-1), insulin, PYY-(3-36), recombinant human parathyroid hormone (rhPTH(1-31)-NH2) and PTH(1-34), by different technologies. The issues addressed include (i) interaction with water, (ii) interaction with food, (iii) diurnal variation, (iv) inter- and intra-subject variability, (v) correlation between efficacy and exposure and (vi) key deliverables of different technologies. These key lessons may aid research in the development of other oral formulations.


Analysis of domain correlations in yeast protein complexes.
A growing body of research has concentrated on the identification and definition of conserved sequence motifs. It is widely recognized that these conserved sequence and structural units often mediate protein functions and interactions. The continuing advancements in high-throughput experiments necessitate the development of computational methods to critically assess the results. In this work, we analyzed high-throughput protein complexes using the domain composition of their protein constituents. Domains that mediate similar or related functions may consistently co-occur in protein complexes. We analyzed Saccharomyces cerevisiae protein complexes from curated and high-throughput experimental datasets to identify statistically significant functional associations between domains. The resulting correlations are represented as domain networks that form the basis of comparison between the datasets, as well as to binary protein interactions. The results show that the curated datasets produce domain networks that map to known biological assemblies, such as ribosome, RNA polymerase, proteasome regulators, transcription initiation and histones. Furthermore, many of these domain correlations were also found in binary protein interactions. In contrast, the high-throughput datasets contain one large network of domain associations. High connectivity of RNA processing and binding domains in the high-throughput datasets reflects the abundance of RNA binding proteins in yeast, in agreement with a previous report that identified a nucleolar protein cluster, possibly mediated by rRNA, from these complexes. The software is available upon request from the authors and is dependent on the NCBI C++ toolkit.


Controlling cosine-Gaussian beams in linear media with quadratic external potential.
We investigate both analytically and numerically the propagation dynamic of on-axis and off-axis cosine-Gaussian (CG) beams in a linear medium with quadratic external potential. CG beam propagation evolves periodically with a period depended on the potential depth (α) and whether the beam shape is symmetrical with respect to optical axis. In each period, the CG beam first splits into two sub-beams with different accelerated direction; they then reverse the accelerated direction owing to the quadratic external potential and finally merge again to reproduce its initial shape, and the whole process repeats periodically. The intensity oscillation period of the off-axis CG beam is double times than that of the on-axis one. At the special position, the beam (or spectral) shape is strongly related to the initial spectral (beam) shape. The corresponding scaled relationship is that the spatial intensity Ix (or spatial frequency axis k) is α times the spectral intensity Ik (or space axis x). The interaction of two spatially separated CG beams still exhibit periodic evolution with complex structure in the regime of focal point. The propagation dynamics of two-dimensional CG beams are also presented. When the propagation distance is exactly an integer multiple of half period, there are four focal points in the diagonal position.


[Adverse drug effects observed at French admissions departments and emergency services (Prospective study of the National Educational Association for Teaching Therapeutics and proposals for preventive measures].
Various studies have shown that adverse drug events (ADE) are a substantial cause of hospital admissions. However, little is known about the incidence and severity of ADE resulting in hospital visits. To address this issue, we conducted a prospective survey in 10 primary care and emergency departments of French public hospitals. This study was performed over two periods of one week, one in June 1999 and one in December 1999, in primary care and emergency departments of five university hospitals and five general hospitals throughout France. Out of a total of 1,937 patients consulting, 1,562 were taking at least one drug during the previous week and were included for analysis according to the protocol. Altogether, 328 (21%; 95% confidence interval 19% to 23%) of these patients receiving at least one drug consulted because of an ADE. The sex ratio (M/F) was the same in both groups with or without ADE (1.04 vs 1.02, respectively, P = 0.83). Patients with ADE were older than those without (63.5 vs 54.8 years, P < 0.0001). Furthermore, ADR patients were more likely to have a higher severity score than no-ADE group (P = 0.019). The outcome seemed to be worse in patients with an ADE. The percentage of patients treated with 2 or more drugs and the number of drug exposures were significantly higher in patients with ADE than in those without (90.9% vs 75.0%, P < 0.0001, and 5.17 vs 3.82, P < 0.0001, respectively). The most frequent causes of visits for ADE-patients were digestive (n = 53, 16.2%), neurological (n = 52, 15.9%), cardiovascular (n = 49, 14.9%) and malaise (n = 49, 14.9%) events. In total, 410 drugs were incriminated in the occurrence of 328 ADE. The most frequently incriminated drug classes were (1) psychotropic agents, including anxiolytics and/or hypnotics, antidepressants and antipsychotics (n = 84, 20.5%), (2) diuretics (n = 48, 11.7%), (3) anticoagulants (n = 38, 9.3%), (4) other cardiovascular drugs (n = 63, 15.4%), and (5) analgesics, including non steroidal antiinflammatory agents (n = 57, 13.9%). The avoidability of ADE could be estimated by an external expert panel in 280 of the 328 cases. In 106 cases (37.9%), ADE was considered to be preventable because a contra-indication or a warning about drug use had not been respected.


Strong-field ionization of flash pyrolysis reaction products.
We report the coupling of a flash pyrolysis molecular beam source with nonresonant strong-field ionization in a time-of-flight mass spectrometer. The saturation laser intensities at which ionization occurs for the various product species are generally found to correlate closely with the ionization energies, as has been seen for closed-shell molecules. It is then possible to use this correlation to identify the product and quantify isomers from among several candidate species whose ionization energies are known. The approach is analogous to using tunable vacuum ultraviolet ionization to identify reaction products.


Expression of keratin and vimentin intermediate filaments in rabbit bladder epithelial cells at different stages of benzo[a]pyrene-induced neoplastic progression.
Rabbit bladder epithelium, grown on collagen gels and exposed to the chemical carcinogen benzo[a]pyrene, produced nontumorigenic altered foci as well as tumorigenic epithelial cell lines during 120-180 d in culture. Immunofluorescence studies revealed extensive keratin filaments in both primary epithelial cells and benzo[a]pyrene-induced altered epithelial foci but showed no detectable vimentin filaments. The absence of vimentin expression in these cells was confirmed by two-dimensional gel electrophoresis. In contrast, immunofluorescence staining of the cloned benzo[a]pyrene-transformed rabbit bladder epithelial cell line, RBC-1, revealed a reduction in filamentous keratin concomitant with the expression of vimentin filaments. The epithelial nature of this cell line was established by the observation that cells injected into nude mice formed well-differentiated adenocarcinomas. Frozen sections of such tumors showed strong staining with antikeratins antibodies, but no detectable staining with antivimentin antibodies. These results demonstrated a differential expression of intermediate filament type in cells at different stages of neoplastic progression and in cells maintained in different growth environments. It is apparent that the expression of intermediate filaments throughout neoplastic progression is best studied by use of an in vivo model system in parallel with culture studies.


Exposure to DBP and High Iodine Aggravates Autoimmune Thyroid Disease Through Increasing the Levels of IL-17 and Thyroid-Binding Globulin in Wistar Rats.
Autoimmune thyroid disease (AITD) is the most common autoimmune disease that causes hypothyroidism. High iodine is a well-known factor that can induce thyroid disorders, including Hashimoto's thyroiditis, one of the main types of AITD. Recent epidemiological studies have indicated that phthalates, especially di-n-butyl phthalate (DBP) may induce thyroid disease. In this study, we aim to determine the effects and underlying mechanisms of high iodine and/or DBP exposure on AITD. Female Wistar rats were modeled with thyroglobulin and exposed to high iodine and/or DBP. We investigated histopathological changes in the thyroid and measured thyroid hormone levels in serum to assess thyroid function. In the thyroid and liver, we detected oxidative stress, proinflammatory factors (IL-1β, IL-6, and IL-17) and the activation of activator protein 1 (AP-1), a transcription factor that is related to the synthesis of the thyroxine-binding globulin (TBG) and the activation of Th17. After blocking AP-1 with SP600125, we detected TBG and the Th17 related cytokines (IL-6 and IL-17). The data showed that thyroid damage and the alteration of thyroid hormones were greater when the rats were exposed to both high iodine and DBP. Coexposure to DBP and high iodine enhanced the activation of AP-1 in the liver and thyroid, and induced an increase in the levels of TBG in serum and IL-17 in the thyroid. Blocking AP-1 activation prevented the increase of TBG and IL-17. The results indicate that high iodine and/or DBP exposure exacerbated AITD through altering TBG levels in serum and aggravating IL-17 in the thyroid.


Comparison of oral and i.v. acetylcysteine in the treatment of acetaminophen poisoning.
The efficacy, safety, and cost issues that should be considered when deciding on the appropriate route of acetylcysteine for the treatment of patients with acetaminophen poisoning are reviewed. Oral and i.v. acetylcysteine appear to be equally effective when given within 8-10 hours of acetaminophen overdose. Anaphylactoid reactions to i.v. acetylcysteine have generally been reported in 3-6% of acetaminophen-poisoned patients. Dosing errors and hyponatremia have occurred in pediatric patients receiving i.v. acetylcysteine. Several investigators found an increased rate of anaphylactoid reactions in patients treated with i.v. acetylcysteine whose pretreatment serum acetaminophen levels were nontoxic. Compounding i.v. acetylcysteine from the oral preparation is less expensive than using premade i.v. solution. State pharmacy laws dictate whether extemporaneous compounding of acetylcysteine from the oral formulation is allowed. Oral acetylcysteine administration has resulted in minimal anaphylactoid reactions and is safer than i.v. acetylcysteine. Oral therapy should preferentially be considered in patients with asthma or atopic histories. The most important factors to consider when selecting the route of acetylcysteine administration include individual susceptibility, the severity of acetaminophen toxicity, and the time interval between acetaminophen ingestion and initiation of acetylcysteine therapy. Oral acetylcysteine administered within 8-10 hours of acetaminophen overdose prevents liver toxicity in the majority of patients who tolerate it and have no contraindications to therapy. I.V. acetylcysteine should be administered when patients are treated more than 10 hours postingestion of acetaminophen overdose or have underlying conditions preventing oral treatment. Anaphylactoid reactions are rare and occur more frequently in patients treated with the i.v. preparation.


Unusual presentation of spinal lipomatosis.
Spinal epidural lipomatosis (SEL) is a rare condition characterized by overgrowth of normal adipose tissue in the extradural space within the spinal canal that can lead to significant spinal cord compression. It is most commonly reported in patients receiving chronic glucocorticoid therapy. Other causes can include obesity and hypercortisolism. Occasionally, idiopathic SEL will occur in patients with no known risk factors, but cases are more generally reported in obesity and males. We present the case of a 35 year-old non-obese woman found to have rapidly progressive SEL that was not associated with any of the common causes of the disorder.


[Effects of immunosuppressants on cultured rat macrophages and Schwann's cells].
To explore the effects of several immunosuppressants on the cell numbers of cultured rat macrophages and Schwann's cells. The macrophages and Schwann's cells were cultured from the new-born Wistar rats. Different concentrations of methylprednisolone (10(-3), 10(-4), 10(-6) and 10(-8) mol/L), CsA (10(-5), 10(-6), 10(-7) and 10(-8) mol/L) and FK506 (10(-6), 10(-7), 10(-8) and 10(-9) mol/L) were administrated to the cells, while control group was given no drugs. Twenty-four, 48 and 72 hours after administration, the cells from different concentrations were measured with MTT methods respectively. The results were compared and analyzed statistically. Only high concentration methylprednisolone (10(-4) mol/L) and a certain range of concentrations of CsA (10(-6), 10(-7) and 10(-8) mol/L) and FK506 (10(-7), 10(-8) and 10(-9) mol/L) can provide protection to cultured rat macrophages. Under most concentrations, CsA and FK506 had no effects on the cell number of cultured rat Schwann's cell. Only with high concentration CsA (10(-5) mol/L) and methylprednisolone (10(-3) mol/L) could significantly decreased the cell number of Schwann's cell. Long time (72 hours) and low dosage (10(-8) mol/L) administration of methylprednisolone could significantly protect Schwann's cell. High concentration methylprednisolone and some certain concentration CsA and FK506 can protect cultured rat macrophages. But high concentration CsA and methylprednisolone prohibit the proliferation of Schwann's cells. Only long time and low dosage methylprednisolone can protect cultured rat Schwann's cells.


P(RNCH(2)CH(2))(3)N: efficient 1,4-addition catalysts.
The 1,4-addition of primary alcohols, higher nitroalkanes, and a Schiff's base of an alpha-amino ester to alpha,beta-unsaturated substrates produces the corresponding products in moderate to excellent yields when carried out at -63 to 70 degrees C in the presence of catalytic amounts of the nonionic strong bases P(RNCH(2)CH(2))(3)N (R = Me, i-Pr, i-Bu) in isobutyronitrile. Diastereoselectivity for the anti form of the product is high in the case of the Schiff's base in the absence of lithium ion. These catalysts are easily removed from the product by either column filtration through silica gel or via aqueous workup.


Treating peripheral arterial disease percutaneously with atherectomy.
To determine clinical outcomes of patients who underwent percutaneous revascularization (PR) with multiple devices. PR cases at a private, tertiary referral hospital were reviewed retrospectively. Limb salvage and patency rates were calculated by the Kaplan Meier method. Historical and procedural factors were analyzed by multivariate Cox proportional hazards models. We identified 66 patients and 87 limbs with 261 lesions, including 38 patients with critical limb ischemia (CLI) (51 limbs, 171 lesions). PR incorporated multiple devices (2.0 ± 1.2 devices/lesion, 2.4 ± 1.6 devices/procedure), including balloon angioplasty (57%), excisional atherectomy (54%), orbital atherectomy (44%), and stenting (13%). Last imaged patency was at 18 ± 13 months and last clinical follow-up was 22 ± 12 months. Thirty-five of 87 limbs had ≥1 repeat PR. In 51 limbs with CLI, limb salvage was 75% at 3 years. Independent predictors of amputation were higher creatinine (P=.01; hazard ratio [HR], 1.4), Rutherford category (P=.03; HR, 3.5), and history of coronary artery bypass graft (CABG) (P=.03; HR, 8.9). Overall patency remained 75% through 3 years. Loss of patency or primary patency (patency without repeat PR) was predicted by higher creatinine, Rutherford category, chronic total occlusion, history of CABG, female gender, current and past smoking. Use of excisional atherectomy maintained overall patency (P=.01; HR, 0.36). An aggressive approach to PR with frequent use of atherectomy resulted in high rates of limb salvage and patency. Smoking cessation and excisional atherectomy may improve patency rates.


Bioprinting Pattern-Dependent Electrical/Mechanical Behavior of Cardiac Alginate Implants: Characterization and Ex Vivo Phase-Contrast Microtomography Assessment.
Three-dimensional (3D)-bioprinting techniques may be used to modulate electrical/mechanical properties and porosity of hydrogel constructs for fabrication of suitable cardiac implants. Notably, characterization of these properties after implantation remains a challenge, raising the need for the development of novel quantitative imaging techniques for monitoring hydrogel implant behavior in situ. This study aims at (i) assessing the influence of hydrogel bioprinting patterns on electrical/mechanical behavior of cardiac implants based on a 3D-printing technique and (ii) investigating the potential of synchrotron X-ray phase-contrast imaging computed tomography (PCI-CT) for estimating elastic modulus/impedance/porosity and microstructural features of 3D-printed cardiac implants in situ via an ex vivo study. Alginate laden with human coronary artery endothelial cells was bioprinted layer by layer, forming cardiac constructs with varying architectures. The elastic modulus, impedance, porosity, and other structural features, along with the cell viability and degradation of printed implants were examined in vitro over 25 days. Two selected cardiac constructs were surgically implanted onto the myocardium of rats and 10 days later, the rat hearts with implants were imaged ex vivo by means of PCI-CT at varying X-ray energies and CT-scan times. The elastic modulus/impedance, porosity, and structural features of the implant were inferred from the PCI-CT images by using statistical models and compared with measured values. The printing patterns had significant effects on implant porosity, elastic modulus, and impedance. A particular 3D-printing pattern with an interstrand distance of 900 μm and strand alignment angle of 0/45/90/135° provided relatively higher stiffness and electrical conductivity with a suitable porosity, maintaining high cell viability over 7 days. The X-ray photon energy of 30-33 keV utilizing a CT-scan time of 1-1.2 h resulted in a low-dose PCI-CT, which provided a good visibility of the low-X-ray absorbent alginate implants. After 10 days postimplantation, the PCI-CT provided a reasonably accurate estimation of implant strand thickness and alignment, pore size and interconnectivity, porosity, elastic modulus, and impedance, which were consistent with our measurements. Findings from this study suggest that 3D-printing patterns can be used to modulate electrical/mechanical behavior of alginate implants, and PCI-CT can be potentially used as a 3D quantitative imaging tool for assessing structural and electrical/mechanical behavior of hydrogel cardiac implants in small animal models.


Stones, bones, groans, thrones, and psychiatric overtones: Systemic associations of sclerochoroidal calcification.
Sclerochoroidal calcification (SCC) is a frequent masquerader of choroidal melanoma with important systemic associations such as hyperparathyroidism and parathyroid adenoma. Herein, we describe a case of a 67-year-old male who presented with an amelanotic choroidal lesion in the right eye (OD) and a history of kidney stones. Ultrasonography showed the lesion to be flat and calcified OD. Incidentally, a subclinical calcified plaque was also found in the fellow eye. Optical coherence tomography showed an elevated suprachoroidal mass in a table mountain configuration OD and flat configuration left eye, consistent with type 4 and type 1 SCC. The patient was referred for metabolic testing to rule out the underlying electrolyte imbalance and was found to be normal.


The sheep erythropoietin gene: molecular cloning and effect of hemorrhage on plasma erythropoietin and renal/liver messenger RNA in adult sheep.
Erythropoietin (Epo) production was studied in adult sheep. Nine ewes, body weight (BW) 39 +/- 1.3 kg, were hemorrhaged a volume of blood equivalent to 1.6% BW, and sampled at 0, 2, 4, 6, 24 h. Oxygen content (O2 CT) decreased by 2.7 +/- 0.6 ml/dl at 2 h. Plasma immunoreactive (IR) Epo was only significantly increased at 24 h, from 18.5 +/- 3.5 to 40 +/- 10.7 mU/ml (mean +/- SEM). A further 5 ewes were bled extensively (2793 +/- 82 ml) over 54 h, and killed for Epo mRNA determination. The O2 CT decreased from 12.3 +/- 1.6 to 4.1 +/- 0.6 ml/dl, and plasma Epo increased from 15 +/- 4 to 1675 +/- 287 mU/ml. The sequence of ovine Epo cDNA was derived from the kidney RNA of a severely bled sheep using reverse transcription/polymerase chain reaction (RT/PCR), and from an ovine Epo genomic clone. The cDNA encodes a peptide of 194 amino acids, including a 27 amino acid signal peptide. The deduced amino acid sequence of sheep Epo shows 82%, 78% and 80% homology with mature Epos of human, mouse and monkey, respectively. The gene structure resembles closely those of human and mouse, with 5 exons and 4 introns. The expression of the ovine Epo gene in tissues from normal and hemorrhaged sheep was analysed by a competitive RT/PCR method. Epo mRNA was difficult to detect in liver from normal sheep, but was detectable at 0.01-0.04 amol/microgram total RNA in kidney from normal sheep. In the kidneys of severely bled sheep, the Epo mRNA levels (per micrograms total RNA) increased 400-1500-fold compared to that of normal kidneys, and were approximately 60-fold greater than those in the livers of the hemorrhaged sheep.


Gene expression during the priming phase of liver regeneration after partial hepatectomy in mice.
Understanding the gene-expression patterns during liver regeneration may help to reveal how regenerative processes are initiated and controlled as well as shed new light onto processes that lead to liver disease. Using high-density oligonucleotide arrays, we have examined the gene-expression program in the livers of mice after partial hepatectomy. A time course was constructed for gene expression between 0 and 4 h after partial hepatectomy, corresponding to the priming phase of liver regeneration. The genomic program for liver regeneration involves transcription-factor generation, stress and inflammatory responses, cytoskeletal and extracellular matrix modification, and regulation of cell-cycle entry. The genome-wide changes that are observed provide a detailed and comprehensive map of the initial priming stage of liver regeneration.


Analysis of Cellular Crosstalk and Molecular Signal between Periosteum-Derived Precursor Cells and Peripheral Cells During Bone Healing Process Using a Paper-Based Osteogenesis-On-A-Chip Platform.
Periosteum-derived progenitor cells (PDPCs) are highly promising cell sources that are indispensable in the bone healing process. Adipose-derived stem cells (ADSCs) are physiologically close to periosteum tissue and release multiple growth factors to promote the bone healing process. Co-culturing PDPCs and ADSCs can construct periosteum-bone tissue microenvironments for the study of cellular crosstalk and molecular signal in the bone healing process. In the current work, a paper-based osteogenesis-on-a-chip platform was successfully developed to provide an in vitro three-dimensional coculture model. The platform was a paper substrate sandwiched between PDPC-hydrogel and ADSC-hydrogel suspensions. Cell secretion could be transferred through the paper substrate from one side to another side. Growth factors including BMP2, TGF-β, POSTN, Wnt proteins, PDGFA, and VEGFA were directly analyzed by a paper-based immunoassay. Cellular crosstalk was studied by protein expression on the paper substrate. Moreover, osteogenesis of PDPCs was investigated by examining the mRNA expressions of PDPCs after culture. Neutralizing and competitive assays were conducted to understand the correlation between growth factors secreted from ADSCs and the osteogenesis of PDPCs. In vitro periosteum-bone tissue microenvironment was established by the paper-based osteogenesis-on-a-chip platform. The proposed approach provides a promising assay of cellular crosstalk and molecular signal in 3D coculture microenvironment that may potentially lead to the development of effective bone regeneration therapy.


Density gradient separation of hematopoietic stem cells in autologous bone marrow transplantation.
Recently, the principles of density gradient cell separation have been transferred to the marrow fractionation, and the Ficoll technique by using a COBE 2991 blood cell processor has been developed and widely employed as well. This method is particularly useful in view of a chemical antineoplastic purging intended for autologous marrow transplantation. Forty marrows, which derived from patients suffering with leukemia and lymphoma, were fractionated with Ficoll on a COBE machine and in vitro purged with Mafosfamide at a dose of 50 micrograms/ml/1 x 10e7 MN cells. The density gradient separation enables to reduce the initial volume to 10%, the contaminating RBC to less than 1%, the total nucleated cells to 25% (greater than 80% of MNC) sparing about 80% of the CFU-GM. After purging, the surviving hemopoietic progenitor cells were 2.5%. The clinical effects of the fractionated purged cells were studied in 11 autotransplanted patients and compared with 14 transplants performed with untreated buffy-coat marrow derived cells. Ficoll cells produced less adverse effects at the time of reinfusion, while, as expected, the time of hematopoietic recovery was delayed in these patients (mafosfamide treated cells). These results confirm the usefulness of the gradient density cell separation to reduce the side effects of the DMSO and to make reliable the Mafosfamide purging manoeuvre, preventing the interference of contaminating RBC aldehyde dehydrogenase.


c-Abl activates p38 MAPK independently of its tyrosine kinase activity: Implications in cisplatin-based therapy.
Activation of p38 MAPK is a critical requisite for the therapeutics activity of the antitumor agent cisplatin. In this sense, a growing body of evidences supports the role of c-Abl as a major determinant of p38 MAPK activation, especially in response to genotoxic stress when triggered by cisplatin. Here, we demonstrate that p38 MAPK activation in response to cisplatin does not require the tyrosine kinase activity of c-Abl. Indeed, c-Abl can activate the p38 MAPK signaling pathway by a mechanism that is independent of its tyrosine kinase activity, but that instead involves the ability of c-Abl to increase the stability of MKK6. Similar results were obtained in chronic myeloid leukemia-derived cell lines, in which a chimeric Bcr/Abl protein mimics the effects of c-Abl overexpression on p38 MAPK activation. These findings may explain why a clinically used c-Abl inhibitor, imatinib mesylate, fails to inhibit the p38 MAPK pathway alone or in combination with cisplatin, and provide evidence of a novel signaling mechanism in which these antitumor agents act.


[Tuberculous calcifications of the bladder wall in children].
A case of tuberculous urinary bladder calcifications in a 13 year old boy is reported. The lesion is rare in adults and no case is published in the literature as occurring in children.


Liquor-cytological investigations in multiple sclerosis.
The report deals with values of cell number and total protein in intermittent and chronic-progressive multiple sclerosis taking into account age and sex. Moreover, the average values of monocytic, lymphocytic and lymphoid cells are correlated with age and sex. Finally, monocytic, lymphocytic and lymphoid cell forms are compared with agarelectrophoretic gamma 3- and gamma 4-globulin augmentation. For these investigations we summarized the parameters of 213 patients with multiple sclerosis according to the criteria of BAuer et al. (1973) and Poser et al. (1973). In intermittent multiple sclerosis there was a preponderance of lymphocytic and lymphoid cell forms, while in chronic-progressive syndromes and late polysclerosis monocytic cell reactions dominated. Although in chronic-progressive multiple sclerosis nearly the same changes in the gamma-globulin spectrum are demonstrable there seems to exist a disturbed condition of immunity which is expressed in a progressing demyelinization process.


Case report of chondroma in a grass carp (Ctenopharyngodon idella).
The grass carp (Ctenopharyngodon idella) is a herbivorous, freshwater fish species of the family Cyprinidae, and the only species of the genus Ctenopharyngodon. Neoplasms in fishes are generally less aggressive than neoplasms in mammals and are most commonly discrete, focal and benign neoplasms. A 3-year-old grass carp with a big mass on the vertebrae was referred to the clinic. According to the owner's statements, the fish had no signs of lethargy, ataxia and abnormal behaviors. The size of the mass was 7 × 6 × 6 cm. It cut hardly with audible sounds. The consistency of the mass was as hard as a cartilage. Microscopic examination revealed numerous irregular crests of hyaline cartilage beneath the skin. According to histopathologic characteristics, chondroma on the vertebrae of grass carp was diagnosed.


Sonography and computed tomography in deep cervical lipomas and lipomatosis of the neck.
Nineteen deep cervical lipomas and five patients with cervical lipomatosis were examined with computed tomography (CT) and Sonography. By means of CT, which is the imaging method of choice for both diseases, it is possible to differentiate between circumscribed lipomas and infiltrating intramuscular lipomas. In addition, an exact localization in parenchymatous organs is possible. Cervical lipomatosis is also clearly delineated. Sonography is the first imaging method in cervical swelling or lesions; therefore, knowledge of the sonomorphology of fatty tumors is mandatory. Cervical lipomas have a fairly typical sonomorphology, but it is not as pathognomonic as the density values are by means of CT. In cervical lipomatosis, an adequate pretherapeutic assessment of the depth of infiltration is not possible sonographically. Only the cervical vessels can be clearly differentiated in this condition.


Quaternary prevention: reviewing the concept.
According to the Wonca International Dictionary for General/Family Practice Quaternary Prevention is defined as: 'Action taken to identify patient at risk of overmedicalization, to protect him from new medical invasion, and to suggest to him interventions, which are ethically acceptable.' The concept of quaternary prevention was initially proposed by Marc Jamoulle and the targets were mainly patients with illness but without a disease. The purpose of this opinion article is to open the debate around a new possible definition and a new conceptual model of quaternary prevention based on the belief that quaternary prevention should be present in physicians' minds for every intervention they suggest to a patient. The debate around quaternary prevention is vital in the context of contemporary medicine and has expanded worldwide. The human being may suffer harm from medical interventions from conception, during their childhood, during their entire healthy lifetime as well as during a self-limited disease, a chronic disease, or a terminal disease. The current definition of quaternary prevention has limitations because it excludes patients and medical interventions where a quaternary prevention perspective would be needed and useful to protect patients from harm. In this context, a new definition and conceptual model of quaternary prevention is proposed. In this new proposal, quaternary prevention is defined as an 'action taken to protect individuals (persons/patients) from medical interventions that are likely to cause more harm than good.'


L-carnosine inhibits metastasis of SK-Hep-1 cells by inhibition of matrix metaoproteinase-9 expression and induction of an antimetastatic gene, nm23-H1.
Antioxidants have been suggested to inhibit the expression of matrix metalloproteinases (MMPs), especially MMP-9, which plays a critical role in tumor metastasis. Because of its antioxidant activity and the ability to chelate divalent cations, L-carnosine (LC) was tested for inhibition of MMP-9 in a highly invasive hepatocarcinoma, SK-Hep-1 cells. We found that LC (50-1,000 microM) did not directly inhibit the activity of MMP-9 in a cell-free system. However, LC significantly inhibited the expression and activity of MMP-9 protein in SK-Hep-1 cells [inhibitory concentration of 50% (IC(50))| = 105 and 63 muM, respectively). Whereas LC did not inhibit the viability of SK-Hep-1 cells at concentrations up to 1,000 microM within 3 days of incubation, this dipeptide significantly inhibited cell migration (IC(50) = 82 microM) and invasion (IC(50) = 113 microM). LC significantly (P < 0.05) and dose dependently enhanced the expression of an antimetastatic gene, nonmetastatic cells 1, protein (nm23)-H1, at both protein and messenger ribonucleic acid (mRNA) levels. MMP-9 activity inversely correlated significantly with the expression of protein (r(2) = 0.77, P < 0.001) and mRNA (r(2) = 0.65, P < 0.001) of nm23-H1 in LC-treated cells. Thus, LC can inhibit the migration and invasion of SK-Hep-1 cells, and the effect is likely associated with upregulation of nm23-H1 and downregulation of MMP-9 expression.


Effect of Linked-color Imaging on the Detection of Adenomas in Screening Colonoscopies.
Linked-color imaging (LCI) is a new image-enhancement option that emphasizes mucosal surface contrast, facilitating the differentiation between colorectal lesions and normal mucosa. This study aimed to evaluate the potential of LCI to increase the detection of colorectal adenomas in screening colonoscopies. A prospective randomized study was conducted using white-light imaging (WLI), blue-laser imaging (BLI)-bright and LCI. The outcome measures were adenoma detection rate (ADR), mean number of adenomas per patient, and withdrawal time. Lesion characteristics such as size, morphology, location, and histology were also evaluated. A total of 205 patients were randomized, and 251 adenomas were detected. The overall ADR was 62%. The ADR was 52.9% for WLI, 62.1% for BLI-bright, and 71% for LCI, and was significantly higher in the LCI group than in the WLI group (P=0.04). No significant difference was observed between LCI and BLI-bright (P=0.28) or BLI-bright and WLI (P=0.30). The mean number of adenomas per patient was 1.01, 1.03, and 1.62 for WLI, BLI-bright, and LCI, respectively, with a significant difference (P=0.02). Withdrawal time did not differ among the groups. A total of 71 adenomas were detected by WLI, 68 by BLI-bright, and 112 by LCI. There was no difference in the size and morphology of the adenomas detected, nor in the diagnosis of sessile serrated adenomas/polyps. LCI significantly increased the detection of adenomas in screening colonoscopies.


[Factors related to adoption of a family peer-education program on mental disorders. Dissemination research of the Omotenashi-Family Experiences Learning Program].
To identify effective dissemination strategies regarding a family peer-education program, the Omotenashi-Family Experiences Learning Program, on mental disorders, we evaluated factors related to the program adoption by family groups. A cross-sectional mail survey was conducted from June to September 2013, involving 12 family group associations for mental disorders and their affiliated local family groups. For the analysis, we used the conceptual framework of diffusion and dissemination of innovations in a health-care organization. We divided the adaptation process into two steps: (1) understanding the program information, involved the level of program information sharing (with or without family group members); and (2) adaptation decision, involved the adaptation plan (planned or under consideration, or no plan). Data were analyzed regarding the differences between the two categories of the dependent variable in each step, and a logistic regression was conducted in the first step. Ten associations agreed to participate in the survey. Of the 177 family groups that had not adopted the program, 110 family groups responded to the survey (response rate 62.1%). In the first step, a municipal population where the family groups were located of over 10,000 (OR = 5.53, 95%CI; 1.93-15.89), influential individuals who strongly recommended the program (OR=5.22, 95%CI; 1.46-18.69), and information acquisition through the association (OR=3.41, 95% CI; 1.27-9.17) were related to the shared program information in the family group. In the second step, data from 39 family groups that shared the program information with family members were analyzed. The family groups with adaptation plans that were planned or under consideration had significantly more board members, labor, and motivated members compared to the family groups without adaptation plans. The former groups had significantly fewer concerns with the program's difficulties, risks, and tasks than the latter groups. The former groups expected significantly more memberships and more effective mutual member support, experienced greater correspondence between concerns of the family group or family group members and the program's content, and were not opposed to the program. Greater family-group awareness of the program could occur through the involvement of influential figures and provision of program information through family group associations. Program implementation involving other family groups and for non-group member families could lead to increased program adoption.


An integrated neuroprotective intervention for brain ischemia validated by ECoG-fPAM.
Brain ischemia is a neurological deficit caused by a reduction in the blood supply to tissue, and one of the leading causes of disability in the world. Currently, the most well-known therapeutic agent for ischemia recovery is recombinant tissue plasminogen activator (rtPA), but it is viable for only a small portion (approximately 3.6%) of ischemic patients and may cause side effects such as tissue damage. Thus, introducing a new therapeutic concept for ischemia, we proposed an integrated intervention combining global and focal stimulations in this article. To investigate the potential therapeutic effect of cathodal-transcranial direct current stimulation (C-tDCS) with peripheral sensory stimulation (PSS) during the hyperacute phase of stroke, the present study evaluated neurovascular and neuroprotective responses of the rat cortex following ischemic insult. A hybrid, dual-modality system, including electrocorticography (ECoG) and functional photoacoustic microscopy (fPAM), termed ECoG-fPAM, was used to image cortical functional responses pre- and post-ischemia. Using ECoG-fPAM, results showed that cerebral blood volume (CBV) was able to be recovered during the intervention. In addition, neural activity including somatosensory evoked potentials (SSEPs) and alpha-to-delta ratio (ADR) were restored and greater than the baseline value when the integrated intervention was administered. The results of NeuN/ED-1 immunohistochemical staining and TTC staining also supported the neuroprotective effect of this intervention, protecting more neurons and decreasing the infarct size. Overall, the results acquired from the ECoG-fPAM system demonstrated that C-tDCS + PSS administered immediately following ischemia induction can significantly promote neuroprotection via inhibition of ischemia expansion and reversed cortical neurovascular functions, suggesting effective recovery.


Electroacupuncture-induced cholinergic nerve activation enhances the hypoglycemic effect of exogenous insulin in a rat model of streptozotocin-induced diabetes.
The aim of this study is to explore the mechanisms by which electroacupuncture (EA) enhances the hypoglycemic effect of exogenous insulin in a streptozotocin- (STZ-) diabetic rats. Animals in the EA group were anesthetized and subjected to the insulin challenge test (ICT) and EA for 60 minutes. In the control group, rats were subjected to the same treatment with the exception of EA stimulation. Blood samples were drawn to measure changes in plasma glucose, free fatty acids (FFA), and insulin levels. Western blot was used to assay proteins involved in insulin signaling. Furthermore, atropine, hemicholinium-3 (HC-3), and Eserine were used to explore the relationship between EA and cholinergic nerve activation during ICT. EA augmented the blood glucose-lowering effects of EA by activating the cholinergic nerves in STZ rats that had been exposed to exogenous insulin. This phenomenon may be related to enhancement of insulin signaling rather than to changes in FFA concentration.


EMG characteristics of low back and lower limb muscles during forward bending posture.
The study observed forward bending posture and evaluated its effect on muscular activity. The Muscular activity was monitored through the Electromyography (EMG). The objective was to extend the evaluation method of EMG due to muscular load in maintaining the posture and to investigate the existence of muscular coordination between low back and lower limb muscles during the posture. Twelve male subjects were asked to maintain the postures of six stages in bending angles from 0 to 180 degrees. The EMG of erector spinae (ES) at L1 and L5 levels, hamstrings, and gastrocnemius were recorded and analyzed by power spectral density. The characteristics of muscular activities were observed through the EMG power spectrum and the frequency. The activity changes were normalized by the relative presentation and the standardization. The relative presentation showed the level of activity changes in each posture by taking the activity during upright standing as a reference posture, and the standardization was applied to overcome the dependence of the power spectrum and the frequency upon the high standard deviation. A t test with the paired data was also applied to compare the values of EMG of the respective stages of the posture. The results showed that the activity of ES significantly increased during bending posture with an angle up to 45 degrees, and reached silent activity at 90 degrees of flexion. On the other hand, the activity of the hamstrings and gastrocnemius were recognized even when ES activity started and reached the silent activity. The lower limb muscles were considered to be always active during all stages of the posture, and they provided a greater contribution when the ES was in the silent activity.


Millisecond Coherence in a Superconducting Qubit.
Improving control over physical qubits is a crucial component of quantum computing research. Here we report a superconducting fluxonium qubit with uncorrected coherence time T_{2}^{*}=1.48±0.13 ms, exceeding the state of the art for transmons by an order of magnitude. The average gate fidelity was benchmarked at 0.99991(1). Notably, even in the millisecond range, the coherence time is limited by material absorption and could be further improved with a more rigorous fabrication. Our demonstration may be useful for suppressing errors in the next generation quantum processors.


Endarterectomy and graft replacement of severely calcified (porcelain) ascending aorta with coronary ostial involvement in a patient requiring aortic valve replacement.
We report a successful aortic valve replacement within an extensively calcified (porcelain) aorta, involving the left coronary artery ostium. Clamping such an aorta can result in embolization, dissection, and mural laceration. A 72-year-old female presented with a severely calcified and stenotic aortic valve with a peak pressure gradient of 101 mmHg. Computed tomography demonstrated extensive calcification of the ascending aorta. Coronary angiogram showed a 50% ostial left coronary artery stenosis. Under deep hypothermic circulatory arrest, the aorta was transected at the proximal arch and distal graft anastomosis was performed. This was followed by endarterectomy of the porcelain ascending aorta and the left coronary ostium. Aortic valve replacement, proximal aortic graft anastomosis, and a coronary artery bypass grafting (CABG) with the left internal thoracic artery (LITA) anastomosed to the left anterior descending artery (LAD) were then performed in a sequential manner.


[New molecular approaches to the diagnosis and prevention of toxoplasmosis].
Toxoplasmosis, a world wide distributed parasitic disease, is known to cause severe complications in foetuses or newborns from mothers acutely infected during pregnancy. More recently, an increased interest for Toxoplasma infection has come from the high incidence of Toxoplasma encephalitis in patients suffering from AIDS. For many years, research aiming at the development of a vaccine strategy has been concentrating on the identification and molecular characterization of surface antigens of the proliferative stage of the parasite, the tachyzoite. On the basis of our previous experience in other parasitic diseases we have based our research strategy with a particular emphasis given to excretory-secretory antigens (ES), to common epitopes expressed both on tachyzoites and bradyzoites, and to isotype selection. The development of a novel experimental model based on the use of athymic (nude) rats has, on the other hand, allowed by selective reconstitutions with antibodies or cells a detailed analysis of the effector mechanisms involved in resistance. Passive transfer experiments of antibodies or T cells from animals immunized with ES antigens have shown their remarkable immunogenicity whereas direct immunization with ES has led to a highly significant degree of protection in mice. Four major immunogens of 43 kD, 39 kD, 28.5 kD and 23 kD have been identified in E.S. products and shown by various techniques including colloidal gold labelling using monoclonal antibodies, to be common to the tachyzoite and bradyzoite stages and localized in their dense granules. Molecular cloning of proteins has been undertaken.(ABSTRACT TRUNCATED AT 250 WORDS)


Left External Iliac Vein Injury During Laparoscopic Pelvic Lymphadenectomy for Early-Stage Ovarian Cancer: Our Experience and Review of Literature.
Laparoscopic surgical staging is the standard treatment of early-stage ovarian tumors with similar survival outcomes if compared with laparotomic procedures. In this article, we report a case regarding an incidental external iliac vein injury during a pelvic lymphadenectomy for fertility sparing treatment of early-stage ovarian cancer with a video showing the laparoscopic repair without any consequence or side effect. A 36 year-old obese woman with Body Mass Index 30 kg/m2 referred at our hospital with an histological diagnosis of high grade ovarian serous carcinoma after a left laparoscopic salpingo-oophorectomy performed in another hospital. After an hysteroscopy with endometrial biopsy, a laparoscopic surgical staging with a pelvic and aortic lymphadenectomy with lymph-node dissection until the left renal vein, omentectomy, and appendectomy were performed. A thermal injury to the left external iliac vein occurred using the bipolar forceps during lymphadenectomy and was repaired after an immediate clamping of the site using endoclinch and the suction irrigator probe. The laceration on the iliac vein was successfully repaired using 10 mm laparoscopic titanium clips; after a follow-up of 42 months no recurrence was detected. In conclusion, laparoscopy is a safe and effective therapeutic option for fertility sparing treatment patients with early stage ovarian carcinoma with a significantly low morbidity and postoperative hospitalization, but it should be reserved for oncologic surgeons trained in advanced laparoscopic procedures and repair of vascular injuries potentially associated with high mortality rate.


Dermatofibrosarcoma Protuberans: A Rare Malignancy of the Breast.
Dermatofibrosarcoma protuberans (DFSP) of the breast is a rare skin cancer with only a few cases reported in the literature. It corresponds to approximately 1% of all soft tissue sarcomas and to less than 0.1% of all malignancies with annual incidence of 0.8-4.5 cases per million. DFSP usually affects young and middle-aged adults and it can affect any site, but most commonly the trunk and extremities. This tumor arises from the deep dermis and subcutaneous tissues and is usually locally aggressive, but rarely metastasizes. Surgery including wide local excision with free margins remains the main modality of treatment. We report a case in a 28-year-old Omani woman who presented with a right breast lump to a local secondary hospital. She was offered excision biopsy of the lump and the histology came as DFSP with involved margins. The patient was then referred to the Breast Unit at the Royal Hospital where she was reviewed by multidisciplinary team including breast surgeons, oncologists, radiation oncologists, pathologists, and breast radiologists. Her laboratory and radiological investigations did not show any signs of distal metastasis and breast ultrasound did not reveal any residual breast lesions. We performed a wide re-excision of the previous surgical scar with the underlying breast tissues down to the level of the pectoral fascia followed by treatment with radiotherapy. The final histology report showed the presence of a 4×5mm residual tumor, and all resection margins were tumor-free. At six months follow-up, she had no signs of local recurrence. We publish this case report because of its rarity.


Abiraterone Rechallenge Based on Sequential Testing of Androgen Receptor Splice Variant 7 Expression in Circulating Tumor Cells: A Case Report.
Serial analysis of circulating tumor cells (CTCs) such as androgen receptor splice variant 7 is useful in selecting treatments for castration-resistant prostate cancer (CRPC). We report a case who had been positive for androgen receptor splice variant 7 in CTCs before docetaxel, and was subsequently treated with abiraterone rechallenge because of the negative conversion of androgen receptor splice variant 7 following docetaxel. Although, the rechallenge of anti-androgen agent based on CTCs analysis is expected to be an effective approach, it is yet to be reported. Thus, we chose the candidate for abiraterone rechallenge based on serial CTCs analyses by the AdnaTest. As a result, the patient responded to abiraterone that he once had developed resistance to. Our findings reinforce the utility of AR-V7 as a biomarker in the setting of post-chemo androgen-targeted-therapy rechallenge.


Intraoperative diagnosis of facial schwannomas: a multicenter summation of clinical experience, preoperative avoidance, and intraoperative management protocol.
Preoperative differentiation of facial nerve schwannoma (FNS) from vestibular schwannoma (VS) can be challenging, and failure to differentiate between these two pathologies can result in potentially avoidable facial nerve injury. This study presents the combined experience of two high-volume centers in the management of intraoperatively diagnosed FNSs. The authors highlight clinical and imaging features that can distinguish FNS from VS and provide an algorithm to help manage intraoperatively diagnosed FNS. Operative records of 1484 presumed sporadic VS resections between January 2012 and December 2021 were reviewed, and patients with intraoperatively diagnosed FNSs were identified. Clinical data and preoperative imaging were retrospectively reviewed for features suggestive of FNS, and factors associated with good postoperative facial nerve function (House-Brackmann [HB] grade ≤ 2) were identified. A preoperative imaging protocol for suspected VS and recommendations for surgical decision-making following an intraoperative FNS diagnosis were created. Nineteen patients (1.3%) with FNSs were identified. All patients had normal facial motor function preoperatively. In 12 patients (63%), preoperative imaging demonstrated no features suggestive of FNS, with the remainder showing subtle enhancement of the geniculate/labyrinthine facial segment, widening/erosion of the fallopian canal, or multiple tumor nodules in retrospect. Eleven (57.9%) of the 19 patients underwent a retrosigmoid craniotomy, and in the remaining patients, a translabyrinthine (n = 6) or transotic (n = 2) approach was used. Following FNS diagnosis, 6 (32%) of the tumors underwent gross-total resection (GTR) and cable nerve grafting, 6 (32%) underwent subtotal resection (STR) and bony decompression of the meatal facial nerve segment, and 7 (36%) underwent bony decompression only. All patients undergoing subtotal debulking or bony decompression exhibited normal postoperative facial function (HB grade I). At the last clinical follow-up, patients who underwent GTR with a facial nerve graft had HB grade III (3 of 6 patients) or IV facial function. Tumor recurrence/regrowth occurred in 3 patients (16%), all of whom had been treated with either bony decompression or STR. Intraoperative diagnosis of an FNS during a presumed VS resection is rare, but its incidence can be reduced further by maintaining a high index of suspicion and undertaking further imaging in patients with atypical clinical or imaging features. If an intraoperative diagnosis does occur, conservative surgical management with bony decompression of the facial nerve only is recommended, unless there is significant mass effect on surrounding structures.


Toxoplasmosis: maternal and pediatric findings in 23,000 pregnancies.
An analysis of the antibody titers to toxoplasmosis for 22,845 pregnant women in the Collaborative Perinatal Project was conducted in relation to clinical and laboratory findings in the mothers and children through 7 years of age. More than 900 observations were considered for each mother and child. The major findings were in the children and included a predicted doubling in the frequency of deafness among children born to women with antibody to toxoplasmosis, a predicted 60% increase in microcephaly, and a 30% increase in low IQ (less than 70) in association with the presence of high maternal antibody titer (256 to 512) to toxoplasma. A serologically defined high-risk group of mothers was identified on the basis of high indirect hemagglutination antibody levels or seroconversions and increased IgM toxoplasma antibody levels (indirect fluorescent antibody greater than or equal to 32, enzyme-linked immunosorbent assay greater than or equal to 0.7). Of the 15 pregnancies in this group, two children had congenital toxoplasmosis and three were stillborn.


Evaluation of mutagenic and genotoxic activities of new derivatives of anthracyclines.
The phenomenon of multidrug resistance is connected with an increased efflux of cytotoxic agents from the cells and is a serious problem in the treatment with anthracycline antibiotics. Search for new antitumor drugs from the anthracycline group are focused on the syntheris of derivatives with changes in saccharide and anthracycline parts. The genotoxic activity of selected nine new derivatives of anthracycline was evaluate basing on reference tests: micronucleus test in vitro and the Ames test. A correlation was observed between the results obtained in the Ames test and those received in the micronucleus test. In both tests, derivative WP903 demonstrated a strong genotoxic action.


A Systematic Review of the Implementation Challenges of Telemedicine Systems in Ambulances.
Telemedicine systems are gaining attention nationwide as a means for providing care in remote areas and allowing a small number of providers to impact a large geographic region. We systematically reviewed the literature to identify the efficacy and implementation challenges of telemedicine systems in ambulances. A search for published studies on Web of Science and PubMed was completed. Studies were selected if they included at least a pilot study and they focused on feasibility or implementation of telemedicine systems in ambulances. A total of 864 articles were used for title and abstract screening. Full text screening was completed for 102 articles, with 23 being selected for final review. Sixty-one percent of the studies included in the review focused on general emergency care, while 26% focused on stroke care and 13% focused on myocardial infarction care. The reviewed studies found that telemedicine is feasible and effective in decreasing treatment times, report a high diagnosis accuracy rate, show higher rates of positive task completion than in regular ambulances, and demonstrate that stroke evaluation is completed with comparable accuracy to the standard way of delivering care. Although this review identified life-saving benefits of telemedicine, it also showed the paucity of the scientifically sound research in its implementation, prompting further studies. Further research is needed to analyze the capabilities and challenges involved in implementing telemedicine in ambulances, especially studies focusing on human-system integration and human factors' considerations in the implementation of telemedicine systems in ambulances, the development of advanced Internet connectivity paradigms, additional applications for triaging, and the implications of ambulance location.


Evidence-based management of optic neuritis.
Optic neuritis can result from several distinct causes, including multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), and myelin oligodendrocyte glycoprotein antibody disease (MOGAD), when not idiopathic. This review discusses evidence-based treatment approaches contingent upon each specific cause of optic neuritis. Current evidence highlights the need for prompt plasmapheresis as adjunct to intravenous methylprednisolone (IVMP) in patients with NMOSD-associated optic neuritis. Recent advances have included a proliferation of novel disease modifying therapies (DMTs) for long-term management of NMOSD and an understanding of how existing therapeutic options can be leveraged to optimally treat MOGAD. In acute idiopathic or MS-associated optic neuritis, IVMP hastens visual recovery, though it does not substantially affect final visual outcomes. IVMP and adjunctive plasmapheresis are beneficial in the treatment of NMOSD-associated optic neuritis, with a shorter time-to-treatment associated with a higher likelihood of recovery. The natural history of untreated MOGAD-associated optic neuritis is unclear but treatment with IVMP is near-universal given phenotypic similarities with NMOSD. Long-term immunosuppressive therapy is warranted in patients with NMOSD as well as in patients with MOGAD with poor visual recovery or recurrent attacks.


Metal pollutants and bioelements: retrospective of interactions between magnesium and toxic metals.
Protection from heavy metals is a problem that has not been solved in a satisfactory manner so far. Usage of complexing agents in therapy of exposed workers results in both favorable outcome and recognized adverse effects. In the field of environmental protection, they cannot be used in practice, meaning that the risk of escape of metal pollutant from factory premises and their attack on the environnement remains present. The age of chemistry ('Chemistry, key to better living') has led to potent development of industry producing, at the same time, major problems induced by diffusion of metal pollutants, the nightmare of our times, like Camus' 'Plague'. According to the available results, it remains to be answered whether magnesium may influence this important problem, i.e. is this approaches the issue justifiable?


Protective effects of taurine on doxorubicin-induced acute hepatotoxicity through suppression of oxidative stress and apoptotic responses.
The organ toxicity of doxorubicin (DOX), an anthracycline antineoplastic agent, narrows the therapeutic window despite its clinical usefulness. In the present study, we determined whether taurine protected against DOX-induced hepatic injury, and explored the molecular mechanisms underlying the suppressive effects of taurine in terms of alterations in oxidative stress and apoptotic responses. DOX-induced body weight loss was completely suppressed by taurine treatment. Elevations in the serum activity levels of lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase by DOX were also dose-dependently attenuated by a concurrent treatment with taurine. Superoxide dismutase activity and reduced glutathione content in the liver were decreased following the administration of DOX, whereas these changes were suppressed when 10 mg/kg taurine was given in combination with DOX. Taurine attenuated the increased expression of mRNAs for Fas and Bax after DOX exposure. Furthermore, the formation of cleaved caspase-3 protein in the group given DOX with taurine was lower than that in the group treated with DOX alone. Our results suggest that taurine can protect against DOX-induced acute hepatic damage, the underlying mechanism of which is attributable to the suppression of oxidative stress and apoptotic responses.


Storytelling. An approach to client-centered care.
Storytelling as a communication technique influences listeners in a powerful way. The rebirth of storytelling, an old art form, is evident in nursing education programs. This approach enhances the learner's sensitivity to the illness experience. Stories relating to clinical situations use examples that address chronic illnesses, humanity, death, dying, and advance directives. Well-chosen stories have the ability to motivate, inspire, teach, or enhance the human sensitivity skills needed by interdisciplinary healthcare providers.


Differences in microbiological composition of saliva and dental plaque in subjects with different drinking habits.
Several foods have been shown to contain natural components (especially polyphenols) which display anti-adhesive properties against Streptococcus mutans, the aetiological agent responsible for dental crown caries, as well as inhibition of glucosyltransferases, which are the S. mutans enzymes involved in the synthesis of an adherent, water-insoluble glucan from sucrose. Other studies have demonstrated an in vitro action on oral plaque biofilm formation and desorption. This study evaluated whether the activity displayed in vitro by food compounds could affect the microbiological composition of saliva and dental plaque of subjects with a diet rich in these foods, comparing the results with those obtained from subjects with a different diet. The foods considered were: coffee, barley coffee, tea and wine. A total of 93 subjects were recruited into the study. Six samples of both plaque and saliva were collected from each subject at roughly one-monthly intervals. Total bacteria, total streptococci, S. mutans and lactobacilli counts were determined by culture in both saliva and dental plaque. The highest bacterial titres were recorded for the control population, while each drinking habit subgroup showed counts roughly one log lower than the controls. These differences in bacterial counts proved statistically significant (P<0.05). As far as dental plaque was concerned, while total counts did not significantly vary per mg of plaque in the subjects belonging to the different drinking habit subgroups, a significant decrease (P<0.05) was observed in those subjects drinking coffee, tea, barley coffee and wine when mutans streptococci and lactobacilli were evaluated. In several cases a more than one log decrease was observed. Plaque indices were also determined, and a significant (P<0.05) reduction in values was recorded in the subjects belonging the specific drinking habit subgroups compared to the control group. This study indicates that there is a correlation between consumption of specific foods and oral health in terms of reduced plaque deposition and lower counts of odontopathogens.


Protein-fatty acid complexes: biochemistry, biophysics and function.
Thirteen years ago, α-lactalbumin (α-LA) was first reported to form a complex with oleic acid (OA). This complex, called HAMLET (human α-lactalbumin made lethal to tumour cells), was found to be cytotoxic to cancer cells. In HAMLET, α-LA assumes a partially unfolded conformation and can bind OA in various stoichiometries. Subsequently, different groups have been able to prepare HAMLET-like cytotoxic complexes in different ways, which all involve the destabilization of α-LA, and a number of different proteins have been able to form similar complexes. This suggests that the ability to form stable complexes with lipids may be a generic feature of the polypeptide chain, although the precise structural and functional details may vary from protein to protein. We review the biophysical and biochemical properties of this class of complexes, focusing on different methods of preparation, complex structure and the role of the protein and the lipid within these complexes. The cellular effects of these complexes are multifaceted and depend on the cell types. There are strong indications that OA has an essential role, whereas the protein component, rather than having a toxic effect on its own, functions as a vehicle for transporting the toxic OA to the cells and keeping the OA in solution. Fatty acids alone can affect numerous cellular signalling and metabolic pathways, in addition to playing important roles in immune responses and inflammatory processes. Further studies will aim to determine how the molecular properties of the different protein-lipid complexes correlate with their biological efficacy.


A Single Outer-Sphere Mutation Stabilizes apo-Mn Superoxide Dismutase by 35 °C and Disfavors Mn Binding.
The catalytic active site of Mn-specific superoxide dismutase (MnSOD) is organized around a redox-active Mn ion. The most highly conserved difference between MnSODs and the homologous FeSODs is the origin of a Gln in the second coordination sphere. In MnSODs it derives from the C-terminal domain whereas in FeSODs it derives from the N-terminal domain, yet its side chain occupies almost superimposable positions in the active sites of these two types of SODs. Mutation of this Gln69 to Glu in Escherichia coli FeSOD increased the Fe3+/2+ reduction midpoint potential by >0.6 V without disrupting the structure or Fe binding [ Yikilmaz, E., Rodgers, D. W., and Miller, A.-F. ( 2006 ) Biochemistry 45 ( 4 ), 1151 - 1161 ]. We now describe the analogous Q146E mutant of MnSOD, explaining its low Mn content in terms increased stability of the apo-Mn protein. In 0.8 M guanidinium HCl, Q146E-apoMnSOD displays an apparent melting midpoint temperature (Tm) 35 °C higher that of wild-type (WT) apoMnSOD, whereas the Tm of WT-holoMnSOD is only 20 °C higher than that of WT-apoMnSOD. In contrast, the Tm attributed to Q146E-holoMnSOD is 40 °C lower than that of Q146E-apoMnSOD. Thus, our data refute the notion that the WT residues optimize the structural stability of the protein and instead are consistent with conservation on the basis of enzyme function and therefore ability to bind metal ion. We propose that the WT-MnSOD protein conserves a destabilizing amino acid at position 146 as part of a strategy to favor metal ion binding.