Comparison of surgical procedures for benign prostatic hyperplasia of medium-volume prostates: evaluation of the causes of rehospitalization from the French National Hospital Database (PMSI-MCO).
In France, transurethral resection of the prostate (TURP) is still the most commonly used surgical treatment for medium sized benign prostatic hyperplasia (BPH), but the Holmium Laser Enucleation of the Prostate (HoLEP) and laser vaporization procedures are becoming more common. For these three surgical procedures, we evaluate the initial complications, the short term (3 months) and the 4-12-month postoperative complications necessitating re-hospitalization. From the French national hospital data base (PMSI-MCO), all hospitalizations for BPH treatment in 2018 were extracted. We document the complications during the initial hospitalization and any subsequent rehospitalizations during the one-year postoperative period. In 2018, 67,220 patients were treated for BPH: 46,242 TURP, 13,509 HoLEP and 7469 laser vaporization. Age and anticoagulation medications were similar for men treated by the three procedures, but TURP patients were more often hypertensive. Infections and hemorrhagic complications were the most common complications at the initial hospitalization: 17%, 10%, 13% for infections and 15%, 8.1%, 11% for hemorrhagic complications respectively, and TURP performed worse than the other two procedures at the initial hospitalization. During the first three months and then the subsequent nine months, there were fewer complications than initially, with little difference between the three procedures, all differences being less than 1%. Laser vaporization techniques led to fewer complications. However, the PMSI-MCO only registers complications during hospitalizations. This study should be extended to non-hospitalized, more minor complications.


Tissue heterogeneity of mitochondrial activity, biogenesis and mitochondrial protein gene expression in buffalo.
Cellular metabolism is most invariant process, occurring in all living organisms, which involves mitochondrial proteins from both nuclear and mitochondrial genomes. The mitochondrial DNA (mtDNA) copy number, protein-coding genes (mtPCGs) expression, and activity vary between various tissues to fulfill specific energy demands across the tissues. In present study, we investigated the OXPHOS complexes and citrate synthase activity in isolated mitochondria from various tissues of freshly slaughtered buffaloes (n = 3). Further, the evaluation of tissue-specific diversity based on the quantification of mtDNA copy numbers was performed and also comprised an expression study of 13 mtPCGs. We found that the functional activity of individual OXPHOS complex I was significantly higher in the liver compared to muscle and brain. Additionally, OXPHOS complex III and V activities was observed significantly higher levels in liver compared to heart, ovary, and brain. Similarly, CS-specific activity differs between tissues, with the ovary, kidney, and liver having significantly greater. Furthermore, we revealed the mtDNA copy number was strictly tissue-specific, with muscle and brain tissues exhibiting the highest levels. Among 13 PCGs expression analyses, mRNA abundances in all genes were differentially expressed among the different tissue. Overall, our results indicate the existence of a tissue-specific variation in mitochondrial activity, bioenergetics, and mtPCGs expression among various types of buffalo tissues. This study serves as a critical first stage in gathering vital comparable data about the physiological function of mitochondria in energy metabolism in distinct tissues, laying the groundwork for future mitochondrial based diagnosis and research.


A thematic analysis of alcohol use and culture amongst elite (intercounty) Gaelic Athletic Association (GAA) players.
There are limited studies examining alcohol consumption in Gaelic Athletic Association (GAA) players. In a previous paper, we reported excess alcohol consumption, alcohol-related harms and binge drinking amongst elite GAA players. In that survey, the players were provided with an opportunity to provide comments on alcohol. This current study analyses these comments. The aim of this study was to provide a qualitative analysis of elite GAA players opinions on alcohol consumption, harms, behaviours and culture. An anonymous, web-based e-questionnaire was distributed to all registered adult elite (inter-county) GAA players. This analysed demographics, alcohol consumption, alcohol culture and alcohol-related harms. This paper is a thematic analysis of the players comments on alcohol in the GAA. Seven hundred seventy-three of 3592 (21%) players responded. One hundred fifty-two respondents (21%) commented in the free text section of the survey regarding alcohol. One hundred eleven comments (73%) were suitable for analysis. Relevant themes were a pattern of abstinence and bingeing (n = 44), excess alcohol consumption (n = 40) and drinking bans contributing to a binge drinking culture (n = 37). There was a mixed attitude to alcohol sponsorship. These data show players recognise intermittent binge drinking with periods of abstinence and alcohol-related harms. Further initiatives regarding alcohol harm reduction merit consideration including prohibition of alcohol sponsorship, similar to the GAA's ban on gambling.


Impedance monitoring for subcutaneous free flap transfers.
The assessment of thoracic blood flow by electrical impedance is a well-established technique. In an application of this a small electrode array has been developed in which an alternating electric current is passed through a subcutaneous free flap and the induced voltage across a small volume measured. A graphical display of this changing voltage illustrates the pulsatile flow through the flap, allowing continuous assessment of perfusion on a beat by beat basis. The electrode array is such that it can be placed in close contact with muscle without interface problems and can assess its viability. It is non-invasive and easily removed. We have found this accurate, easily interpreted by inexperienced staff, and a considerable reassurance in the postoperative period.


Transcriptome profiling and differential expression analysis of altered immune-related genes in goldfish (Carassius auratus) infected with Aeromonas hydrophila.
Goldfish (Carassius auratus) have been employed as a model organism to investigate the innate immune system and host-pathogen interactions. A Gram-negative bacterium called Aeromonas hydrophila has been found to cause mass mortality due to infection in a wide variety of fish species in the aquatic system. In this study, damages in Bowman's capsule, inflammatory tubular (proximal and distilled convoluted) structure, and glomerular necrosis were observed in A. hydrophila-infected head kidney of goldfish. To increase the better understanding of immune mechanisms of host defense against A. hydrophila, we performed a transcriptome analysis in head kidney of goldfish at 3 and 7 days of post-infection (dpi). Comparing to the control group, 4638 and 2580 differentially expressed genes (DEGs) were observed at 3 and 7 dpi, respectively. The DEGs were subsequently enriched in multiple immune-related pathways including Protein processing in endoplasmic reticulum, Insulin signaling pathway, and NOD-like receptor signaling pathway. The expression profile of immune-related genes such as TRAIL, CCL19, VDJ recombination-activating protein 1-like, Rag-1, and STING was validated by qRT-PCR. Furthermore, the levels of immune-related enzyme (LZM, AKP, SOD, and CAT) activities were examined at 3 and 7 dpi. The knowledge gained from the current study will be helpful for better understanding of early immune response in goldfish after A. hydrophila challenge, which will aid in future research on prevention strategies in teleost.


Hydrocephalus prevalence and outcome in a population-based cohort of children born in 1989-1998.
To determine the prevalence, aetiology and clinical outcome in children with surgically treated hydrocephalus. A population-based study of all 208 liveborn children with hydrocephalus, 124 with infantile hydrocephalus and 84 with hydrocephalus associated with myelomeningocoele, born during 1989-1998 in western Sweden. Aetiological and clinical information was collected from records. The prevalence of hydrocephalus was 0.82 per 1000 live births, 0.49 for children with infantile hydrocephalus and 0.33 for children with myelomeningocoele. The prevalence of infantile hydrocephalus decreased during the period from 0.55 to 0.43 per 1000. In this group, the aetiology was prenatal in 55% and peri-postnatal in 44% of the children. The origin was perinatal haemorrhage in all cases born very preterm. The mortality rate was 5% for children with either infantile hydrocephalus or myelomeningocoele. Mental retardation, cerebral palsy and epilepsy were significantly more frequent in the group with infantile hydrocephalus: 46% vs 16%, 31% vs 4% and 31% vs 10%, respectively. All children with infantile hydrocephalus born very preterm had at least one of these impairments, as did 80% of those with overt hydrocephalus at birth. A slightly decreasing trend for infantile hydrocephalus was observed during the 10-y period. Children with infantile hydrocephalus had a worse outcome than those with myelomeningocoele. The need for neurosurgical revisions for two-thirds of the children indicates the need for further development of prevention and treatment strategies.


Gene editing with 'pencil' rather than 'scissors' in human pluripotent stem cells.
Owing to the advances in genome editing technologies, research on human pluripotent stem cells (hPSCs) have recently undergone breakthroughs that enable precise alteration of desired nucleotide bases in hPSCs for the creation of isogenic disease models or for autologous ex vivo cell therapy. As pathogenic variants largely consist of point mutations, precise substitution of mutated bases in hPSCs allows researchers study disease mechanisms with "disease-in-a-dish" and provide functionally repaired cells to patients for cell therapy. To this end, in addition to utilizing the conventional homologous directed repair system in the knock-in strategy based on endonuclease activity of Cas9 (i.e., 'scissors' like gene editing), diverse toolkits for editing the desirable bases (i.e., 'pencils' like gene editing) that avoid the accidental insertion and deletion (indel) mutations as well as large harmful deletions have been developed. In this review, we summarize the recent progress in genome editing methodologies and employment of hPSCs for future translational applications.


Genetic characterization of influenza A virus subtype H12N1 isolated from a watercock and lesser whistling ducks in Thailand.
Monitoring of influenza A virus (IAV) was conducted in wild bird species in central Thailand. Four IAV subtype H12N1 strains were isolated from a watercock (order Gruiformes, family Rallidae) (n = 1) and lesser whistling ducks (order Anseriformes, family Anatidae) (n = 3). All H12N1 viruses were characterized by whole-genome sequencing. Phylogenetic analysis of all eight genes of the Thai H12N1 viruses indicated that they are most closely related to the Eurasian strains. Analysis of the HA gene revealed the strains to be of low pathogenicity. This study is the first to report the circulation of IAV subtype H12N1 in Thailand and to describe the genetic characteristics of H12N1 in Eurasia. Moreover, the genetic information obtained on H12N1 has contributed a new Eurasian strain of H12N1 to the GenBank database.


Influence of metyrapone and phenobarbital on sodium dichromate nephrotoxicity in developing rats.
After the administration of equal doses of sodium dichromate, chromium concentrations in the kidney were lower in young than in adult rats. To test the age-dependent sensitivity to the nephrotoxicity of dichromate, young and adult rats were given doses to achieve identical chromium concentrations in the kidney. At equal renal concentrations, young rats had less functional and morphological damage than adult rats. As phenobarbital treatment in young rats enhanced the symptoms of nephrotoxicity and metyrapone treatment in adult rats decreased the symptoms of nephrotoxicity, age-dependent differences in chromate nephrotoxicity may be linked to an increase in the enzymatic reduction of Cr(VI) with age.


Poly(alkylcyanoacrylate) colloidal particles as vehicles for antitumour drug delivery: a comparative study.
Because of the fundamental importance of new therapeutic routes for cancer treatment, a number of systems based on colloidal particles as vehicles for the delivery of chemotherapeutic agents have been devised. The target is always to provide the proper dose of the antitumour agent only at the desired locus of action, thus reducing the unwanted side effects. The systems studied in this work are nanospheres of the biodegradable polymers poly(ethyl-2-cyanoacrylate), poly(butylcyanoacrylate), poly(hexylcyanoacrylate) and poly(octylcyanoacrylate), all suitable for parenteral administration, as vehicles for 5-fluorouracil, a well studied drug used for the treatment of solid tumours. Two loading methods have been analyzed: the first one is based on drug addition during the process of generation of the particles, by an anionic emulsion/polymerization procedure, and the subsequent drug trapping in the polymeric network. The second method is based on surface adsorption in already formed nanoparticles, after incubation in the drug solution. A detailed investigation of the capabilities of the polymer particles to load this drug is described. The main factors determining the drug incorporation to the polymer network were the type of monomer, the pH and the drug concentration. The release kinetics of 5-fluorouracil is found to be controlled by the pH of the release medium, the type of drug incorporation and the type of polymer.


Polymorphisms in the 5' upstream regulatory region of p21(WAF1/CIP1) and susceptibility to oesophageal squamous cell carcinoma.
This study aims to scan the 5'-upstream regulatory region of the p21 gene to identify all putative functional single nucleotide polymorphisms (SNPs) and to evaluate the contribution of p21 variants to oesophageal squamous cell carcinoma (ESCC) in the Chinese Han population. Common SNPs were identified, and both locus-based and haplotype-based association tests were used to evaluate the potential risk of these p21 gene polymorphisms for ESCC. Immunohistochemistry assay was further performed to detect the P21 protein expression in ESCC specimens. Twenty three SNPs were identified and seven Tagging SNPs were chosen to represent all 23 SNPs. Univariate analysis indicated that the rs3829963 C and the rs2395655 G alleles increased susceptibility to ESCC (OR = 1.606 and OR = 1.572, respectively). The rs3829963 C and rs2395655 G alleles, combined with cigarette smoking, could further increase the risk for ESCC (OR = 2.657 and OR = 2.828, respectively). Additionally, the rs2395655 G allele appeared to elevate the positive rate of P21 expression in ESCC tissues, as compared to the A allele. This report demonstrates for the first time that rs3829963 and rs2395655, in the promoter of the p21 gene are potentially functional, modulating susceptibility to ESCC among the high-risk cigarette-smoking Chinese population.


Ultrasonic evaluation of benign and malignant nodules in echographically multinodular thyroids.
In 165 patients with ultrasound findings of multinodular thyroids in whom thyroid resection was performed, sonographic features and pathohistologic findings of removed nodules were analyzed. Of 426 nodules removed, 70 were carcinomas and 356 benign. Carcinomas are more often hypoechogenic (p < 0.01) and contain nodular calcifications (p < 0.01), while benign nodules are more often iso-hyperechogenic (p < 0.01), showing intranodular cystic degenerative changes (p < 0.01) and perinodular hypoechogenic rim (p < 0.01). Mean diameter of carcinomatous nodules is lower than in benign nodules (p = 0.022). The relative proportion of malignant nodules is highest in the upper halves of thyroid lobes (p < 0.01). Although certain sonographic signs increase the likelihood of a given lesion being malignant or benign, the lack of absolute specificity in the ultrasound evaluation of thyroid nodules was confirmed.


Local salvage of radiorecurrent prostate cancer.
Locally recurrent prostate cancer following primary external beam radiotherapy without distant metastasis is a challenging problem, with no current consensus on the optimal management of these patients. Traditional whole-gland salvage treatments offered up to a 50% 5-year disease-free survival rate but with troubling levels of risk for significant complications. Recent progress in advanced imaging techniques has allowed a more accurate selection of patients with local-only recurrence and a selection of patients that may be suitable for newer partial-gland salvage treatments that may reduce late complications. This article reviews advances in patient selection and provides an overview of whole- and partial-gland salvage results from selected recent meta-analyses, multi-institutional series, and studies from centers of excellence for these treatment approaches. Salvage radical prostatectomy produces 5-year relapse-free survival (RFS) rates in the 50%-60% range with severe gastrointestinal (GI) toxicity in < 2% but severe genitourinary (GU) toxicity in 15%-23% of patients. The whole-gland options of high and low dose rate brachytherapy and stereotactic body radiation therapy appear to offer similar 5-year control rates, with low severe GU and GI toxicity rates of 4%-8% and <2%, respectively. Cryotherapy and high-intensity focused ultrasound (HIFU) offer similar 5-year RFS rates but carry significant risks for severe GU and GI toxicity in the range of 10%-27% and <2%, respectively. Early results of partial-gland salvage techniques in selected patients appear promising, with 3-year RFS rates of 48%-72% and rare grade 3 toxicity. It is important to understand the relative effectiveness and risks of the various treatment options to effectively counsel patients who face this distressing clinical situation. Whole-gland salvage options offer the possibility of long-term control but with significant risks of severe toxicity. Emerging data for the partial-gland salvage options in appropriately selected patients may offer hope of reasonable control rates with reduced severe toxicity.


Guided Anti-P2Y12 Therapy in Patients Undergoing PCI: Three Systematic Reviews with Meta-analyses of Randomized Controlled Trials with Homogeneous Design.
The value of guided therapy (GT) with anti-P2Y12 drugs in percutaneous coronary intervention (PCI) is unclear. Meta-analyses lumped together randomized controlled trials (RCTs) with heterogeneous designs, comparing either genotype-GT or platelet function test (PFT)-GT with unguided therapy. Some meta-analysis also included RCTs that did not explore GT, but included the effects of switching patients with high on-treatment platelet reactivity (HTPR) to alternative therapies (HTPR-Therapy). We performed three distinct systematic reviews/meta-analyses, each exploring only RCTs with homogeneous design. MEDLINE, Embase, and Central databases were searched for RCTs testing genotype-GT, PFT-GT, or HTPR-Therapy in PCI-treated patients, through October 1, 2022. Two reviewers extracted the data. Risk ratios (RRs) (95% confidence intervals) were calculated. Primary outcomes were major bleedings (MBs) and major adverse cardiovascular events (MACE). In seven genotype-GT RCTs, RRs were: MB, 1.06 (0.73-1.54; p = 0.76); MACE, 0.65 (0.47-0.91; p = 0.01), but significant risk reduction was observed in RCTs performed in China (0.30, 0.16-0.54; p < 0.0001) and not elsewhere (0.75, 0.48-1.18; p = 0.21). In six PFT-GT RCTs, RRs were: MB, 0.91 (0.64-1.28, p = 0.58); MACE, 0.82 (0.56-1.19; p = 0.30): 0.62 (0.42-0.93; p = 0.02) in China, 1.08 (0.82-1.41; p = 0.53) elsewhere. In eight HTPR-Therapy RCTs, RRs were: MB, 0.71 (0.41-1.23; p = 0.22); MACE, 0.57 (0.44-0.75; p < 0.0001): 0.56 (0.43-0.74, p < 0.0001) in China, 0.58 (0.27-1.23, p = 0.16) elsewhere. No GT strategy affected MB. Overall, genotype-GT but not PFT-GT reduced MACE. However, genotype-GT and PFT-GT reduced MACE in China, but not elsewhere. PFT-GT performed poorly compared to HTPR-Therapy, likely due to inaccurate identification of HTPR patients by PFT.


Effectiveness of virtual reality intervention on reducing the pain, anxiety and fear of needle-related procedures in paediatric patients: A systematic review and meta-analysis.
To evaluate the effectiveness of virtual reality (VR) intervention in the management of pain, anxiety and fear in paediatric patients undergoing needle-related procedures. A systematic review and meta-analysis of randomized controlled trials (RCTs). A librarian-designed search of the Cochrane Library, PubMed, Web of Science, EMBASE, CINAHL, CBM, CNKI, and Wanfang databases was conducted to identify research articles in English or Chinese on RCTs up to February 28, 2022. Two researchers independently screened eligible articles. The Cochrane Handbook for Systematic Reviews was used to assess the risk of bias in the included studies. A fixed- or random-effects meta-analysis model was used to determine the pooled mean difference based on the results of the heterogeneity test. A total of 2269 articles were initially screened. The meta-analysis included data from 27 studies representing 2224 participants. Compared with the non-VR group, the VR intervention group significantly reduced pain, anxiety, and fear in paediatric patients who underwent puncture-related procedures. Subgroup analysis showed that VR has advantages over conventional and other distraction methods. Paediatric patients undergoing needle-related procedures would benefit from VR interventions for pain, anxiety and fear management. VR intervention has the potential to reduce pain, anxiety and fear in paediatric patients undergoing puncture-related procedures. Future clinical interventions could incorporate VR into puncture procedures as an effective method to reduce negative emotions in children eligible for VR distractions. Our paper is a systematic review and meta-analysis and such details don't apply to our work.


miR-22 regulates cell invasion, migration and proliferation in vitro through inhibiting CD147 expression in tongue squamous cell carcinoma.
Tongue squamous cell carcinoma (TSCC) is the most common type of head and neck squamous cell carcinoma (HNSCC) in China, and its survival rate remains unsatisfactory. miR-22 has been identified as a tumor suppressor in many human cancers, and high expression of CD147 occurs in many tumors. The aim of the present study was to investigate the expression and function of miR-22 in TSCC and its relationship with the expression of CD147. TCA8113 cells were transiently transfected with a miR-22 mimic/inhibitor. Subsequently, a validation with Real-time RT-PCR was performed to analyze the miR-22 expression level, and a CCK-8 proliferation assay and transwell migration and invasion assays were carried out. Cotransfections using As-miR-22/si-CD147 mRNA or a miR-22/CD147 overexpression vector were applied, and we investigated the biological effects on cotranscribed TCA8113 cells. qRT-PCR confirmed that miR-22 or As-miR-22 were successfully transfected into TCA8113 cells. Suppressing miR-22 resulted in a promotion of cell proliferation and motility and an up-regulation of CD147 in TCA8113 cells in vitro. In contrast, increasing miR-22 inhibited cell proliferation and motility and down-regulated CD147. Furthermore, the reduction or overexpression of CD147 can reverse the promoting or suppressive effects of miR-22, respectively. The down-expression of miR-22 can regulate cell growth and motility in TSCC cells, which indicates that miR-22 acts as a tumor suppressor in TSCC. Additionally, CD147 is subsequently up-regulated when miR-22 inhibited. Taken together, the findings of this research defined a novel relationship between the down-regulation of miR-22 and the up-regulation of CD147 and demonstrated that CD147 is a downstream factor of miR-22.


Evaluation of glioblastomas and lymphomas with whole-brain CT perfusion: Comparison between a delay-invariant singular-value decomposition algorithm and a Patlak plot.
Correction of contrast leakage is recommended when enhancing lesions during perfusion analysis. The purpose of this study was to assess the diagnostic performance of computed tomography perfusion (CTP) with a delay-invariant singular-value decomposition algorithm (SVD+) and a Patlak plot in differentiating glioblastomas from lymphomas. This prospective study included 17 adult patients (12 men and 5 women) with pathologically proven glioblastomas (n=10) and lymphomas (n=7). CTP data were analyzed using SVD+ and a Patlak plot. The relative tumor blood volume and flow compared to contralateral normal-appearing gray matter (rCBV and rCBF derived from SVD+, and rBV and rFlow derived from the Patlak plot) were used to differentiate between glioblastomas and lymphomas. The Mann-Whitney U test and receiver operating characteristic (ROC) analyses were used for statistical analysis. Glioblastomas showed significantly higher rFlow (3.05±0.49, mean±standard deviation) than lymphomas (1.56±0.53; P<0.05). There were no statistically significant differences between glioblastomas and lymphomas in rBV (2.52±1.57 vs. 1.03±0.51; P>0.05), rCBF (1.38±0.41 vs. 1.29±0.47; P>0.05), or rCBV (1.78±0.47 vs. 1.87±0.66; P>0.05). ROC analysis showed the best diagnostic performance with rFlow (Az=0.871), followed by rBV (Az=0.771), rCBF (Az=0.614), and rCBV (Az=0.529). CTP analysis with a Patlak plot was helpful in differentiating between glioblastomas and lymphomas, but CTP analysis with SVD+ was not.


Clinical, laboratory and genetic markers associated with erosions and remission in patients with early inflammatory arthritis: a prospective cohort study.
We investigated the relationship between clinical, laboratory and genetic markers and outcome measures in 159 patients with recent onset of inflammatory arthritis (IA). The majority of patients were managed in community-based rheumatology practice. Median duration of arthritis at baseline was 3 months with median follow-up of 4.0 years (range 0-10). Markers of disease activity and 1987 ACR criteria for rheumatoid arthritis (RA) were estimated every 6 months for the first 2 years and annually thereafter. Presence of shared epitopes (SE) was established by PCR-based method. Main outcome variables were attainment of remission and presence of erosions on X-rays of hands and feet at 3 years. Remission was seen in 34.3% of patients and was independently related to age 60 and older (odds ratio (OR) 3.2; 95% confidence interval (CI), 1.2-8.7) and inversely to the presence of rheumatoid factor (RF) (OR 8.3; 95% CI, 3.2-21.3 for persistent arthritis). Patients with two SE were likely to have persistent arthritis (P=0.006), but this was not significant when corrected for RF. Independent predictors for erosions at 3 years were RF (OR 7.5; 95% CI, 1.9-29.5) and area under the curve for number of swollen joints (OR 1.08; 95% CI, 1.02-1.16). SE status was not predictive of erosions at 3 years (OR 1.6; 95% CI, 0.7-3.7). In univariate analysis, patients possessing DERAA motif on DRB1 were less likely to have erosive disease than without this motif at 4 years (OR 0.21; 95% CI, 0.0-0.9, P=0.037) but this finding was partly explained by adjusting for RF (adjusted OR 0.24; 95% CI 0.04-1.37). In this study of recent onset IA, active disease and RF were associated with poor outcome. Whilst SE did not predict erosive disease, patients with DERAA motif may be protected against erosions whilst the presence of two SE alleles suggests persistence of arthritis.


Synthesis of neamine-based pseudodisaccharides as potential vestibulotoxic agents to treat vertigo in Ménière's disease.
Ménière's disease (MD) is a progressive disease of the inner ear characterized by recurring attacks of disabling vertigo, hearing loss and tinnitus. Patients who do not respond to vestibular sedatives or steroids may require an intratympanic application of aminoglycoside antibiotics, which destroys the vestibular function of the affected ear in order to avoid the debilitating vertigo attacks. Although effective, this procedure causes hearing loss in almost one third of the patients due to the aminoglycosides cochlear toxicity. Here we describe the synthesis of two pseudodisaccharides structurally related to neamime aiming to mimic the aminoglycosides pharmacophore core by replacing their toxic amine by azide and hydroxyl groups. Products 1 and 2 selectively promoted 'in vivo' damage to vestibular tissues without causing hearing loss or cochlear toxicity. Therefore, these pseudodisaccharides stand as promising lead compounds for the development of a safer and more effective therapeutic procedure to manage the symptoms of MD severe dizziness.


Lymphadenopathy in patients at risk for acquired immunodeficiency syndrome. Histopathology and histochemistry.
Lymph node biopsies of 12 patients at high risk for acquired immunodeficiency syndrome (AIDS) with generalized lymphadenopathy (AIDS-related complex [ARC]) and seven controls with conventional lymph node hyperplasia were examined by light microscopy and immunohistochemical staining of frozen tissue. The immunohistochemical results were quantified by planimetric means. Our findings show that the T helper/T suppressor-cytotoxic (Th/Tsc) ratio in lymph nodes from ARC patients is significantly decreased with respect to controls and that this decrease precedes the change in the Th/Tsc ratio in peripheral blood. Our findings distinguish between lymphadenopathy from patients with ARC and other forms of hyperplasia; the relation to AIDS is discussed.


[The manifestation of the readiness for differentiation of male gonadal cells in Drosophila larvae].
Male gonads of the late 1-st instar larvae were able to develop and function normally after their transplantation into larvae that start metamorphosis. Ejaculatory duct was shown to activate germ cells maturation.


The symptoms of autism including social communication deficits and repetitive and restricted behaviors are associated with different emotional and behavioral problems.
The aim of the study was to investigate the associations between symptoms of autism and emotional and behavioral problems in children with autism spectrum disorder from both caregivers' and clinicians' perspectives. Three main findings were found in our study. First, the association patterns were similar in the preschool and school-aged children. Second, different association patterns were found from caregivers' and professionals' perspectives. From the professionals' perspective, only repetitive behaviors were associated with behavioral problems, while from the caregivers' perspective, all symptoms of autism were associated with emotional and behavioral problems. Third, different types of symptoms of autism were associated with different types of emotional and behavioral problems. For example, from the professionals' perspective, restricted and repetitive behaviors were only associated with hyperactivity and inattention. From the caregivers' perspective, social emotion was associated with emotional symptoms, and other symptoms of autism were associated with hyperactivity and inattention, as well as with peer problems. The results of our study provided deeper understanding of the relationships between symptoms of autism and emotional and behavioral problems, and the findings could serve as a reference for intervention planning when clinicians approach children with autism spectrum disorder.


Antimicrobial silver nanoparticle-photodeposited fabrics for SARS-CoV-2 destruction.
Surfaces containing antiviral nanoparticles could play a crucial role in minimizing the virus spread further, specifically for COVID-19. Here in, we have developed a facile and durable antiviral and antimicrobial fabric containing photodeposited silver nanoparticles. Scanning and transmission electron microscopy, UV-VIS spectroscopy, and XPS are used to characterize the silver nanoparticles deposited cloth. It is evident that Ag0/Ag+ redox couple is formed during fabrication, which acts as an active agent. Antiviral testing results show that silver nanoparticles deposited fabric exhibits 97% viral reduction specific to SARS-CoV-2. Besides its excellent antiviral property, the modified fabric also offers antimicrobial efficiency when tested with the airborne human pathogenic bacteria Escherichia coli and fungi Aspergillus Niger. The direct photodeposition provides Ag-O-C interaction leads to firmly grafted nanoparticles on fabric allow the modified fabric to sustain the laundry durability test. The straightforward strategy to prepare an efficient antimicrobial cloth can attract rapid large-scale industrial production.


Impact on Diet Quality and Burden of Care in Sapropterin Dihydrochloride Use in Children with Phenylketonuria: A 6 Month Follow-Up Report.
In phenylketonuria (PKU) changes in dietary patterns and behaviors in sapropterin-responsive populations have not been widely reported. We aimed to assess changes in food quality, mental health and burden of care in a paediatric PKU sapropterin-responsive cohort. In an observational, longitudinal study, patient questionnaires on food frequency, neophobia, anxiety and depression, impact on family and burden of care were applied at baseline, 3 and 6-months post successful sapropterin-responsiveness testing (defined as a 30% reduction in blood phenylalanine levels). 17 children (10.8 ± 4.2 years) completed 6-months follow-up. Patients body mass index (BMI) z-scores remained unchanged after sapropterin initiation. Blood phenylalanine was stable. Natural protein increased (p < 0.001) and protein substitute intake decreased (p = 0.002). There were increases in regular cow's milk (p = 0.001), meat/fish, eggs (p = 0.005), bread (p = 0.01) and pasta (p = 0.011) intakes but special low-protein foods intake decreased. Anxiety (p = 0.016) and depression (p = 0.022) decreased in caregivers. The impact-on-family, familial-social impact (p = 0.002) and personal strain (p = 0.001) lessened. After sapropterin, caregivers spent less time on PKU tasks, the majority ate meals outside the home more regularly and fewer caregivers had to deny food choices to their children. There were significant positive changes in food patterns, behaviors and burden of care in children with PKU and their families after 6-months on sapropterin treatment.


Safety aspects related to recombinant protein expression from Semliki Forest virus vectors.
Semliki Forest virus vectors (SFV) have been developed for efficient transgene expression to result in high receptor yields(50-200 pmol receptor/mg protein) in a variety of mammalian host cells. Transfer of the SFV technology to mammalian cells growing in suspension cultures has made it feasible to produce hundreds of milligrams of receptor proteins in a short time. Large-scale production, however, raises the questions of the safety of handling virally infected cells for down-stream processing. Analysis of cell culture medium and SFV-infected cells revealed that some infectious particles were still present. Replacement of virus-containing medium at 2 h post-infection efficiently removed the majority of infectious replication-deficient SFV particles. Washes with PBS further reduced the number of infectious particles significantly both in the medium and associated with cells to levels that allowed safe handling of SFV-infected cells outside the cell culture facility for biochemical, pharmacological, or electrophysiological assays or down-stream processes in connection to receptor purification. Furthermore, engineering of novel temperature-sensitive mutant SFV vectors resulted in temperature-controlled transgene expression, which completely eliminates the risk of contaminating laboratory personnel.


Transgene-driven protein expression specific to the intermediate pituitary melanotrope cells of Xenopus laevis.
In the present study, we examined the amphibian Xenopus laevis as a model for stable transgenesis and in particular targeted transgene protein expression to the melanotrope cells in the intermediate pituitary. For this purpose, we have fused a Xenopus proopiomelanocortin (POMC) gene promoter fragment to the gene encoding the reporter green fluorescent protein (GFP). The transgene was integrated into the Xenopus genome as short concatemers at one to six different integration sites and at a total of one to approximately 20 copies. During early development the POMC gene promoter fragment gave rise to GFP expression in the total prosencephalon, whereas during further development expression became more restricted. In free-swimming stage 40 embryos, GFP was found to be primarily expressed in the melanotrope cells of the intermediate pituitary. Immunohistochemical analysis of cryosections of brains/pituitaries from juvenile transgenic frogs revealed the nearly exclusive expression of GFP in the intermediate pituitary. Metabolic labelling of intermediate and anterior pituitaries showed newly synthesized GFP protein to be indeed primarily expressed in the intermediate pituitary cells. Hence, stable Xenopus transgenesis with the POMC gene promoter is a powerful tool to study the physiological role of proteins in a well-defined neuroendocrine system and close to the in vivo situation.


Anti-streptopolysaccharide antibody in children with rheumatic fever and scarlet fever.
As the serological test of streptococcal infection, the measurement of anti-exotoxin antibodies such as ASO is widely practiced. M protein of the cell wall of group A streptococcus has type specificity. To detect the anti M protein antibody is very significant, but it is not easy to apply this to clinical practice because there are many types and because of the difficulty of purifying M protein. C polypeptide has group specificity, so the measurement of the antibody to C polypeptide is very important as the serological test of group A streptococcus.


Secondary researchers' duties to return incidental findings and individual research results: a partial-entrustment account.
Existing attempts to explain why secondary researchers might have any obligation to return findings to the contributors of genetic samples falter because of the lack of any direct interaction between the secondary researchers and the contributors. The partial-entrustment account of these obligations defended here circumvents this problem by explaining how a chain of special responsibilities can be forged even in the absence of any direct interaction.Genet Med 2012:14(4):467-472.


Concerns About the Methodology and Data Collection in a Systematic Review.
Letter to the Editor-in-Chief in response to JOSPT article "Diagnostic Accuracy of Clusters of Pain Provocation Tests for Detecting Sacroiliac Joint Pain: Systematic Review With Meta-analysis" by Saueressig et al. J Orthop Sports Phys Ther 2022;52(1):49-50. doi:10.2519/jospt.2022.0201.


Methyl 9-(4-meth-oxy-phen-yl)-19-methyl-3,12-di-aza-penta-cyclo-[10.7.0.0(2,10).0(3,8).0(13,18)]nona-deca-1(19),13(18),14,16-tetra-ene-10-carboxyl-ate.
The title ester, C27H30N2O3, crystallizes with two independent mol-ecules in the asymmetric unit whose geometrical features are similar. In each mol-ecule, the pyrrolidine ring adopts an envelope conformation, with the fused C atom shared with the piperidine ring as the flap, and the piperidine ring adopts a chair conformation. In the crystal, C-H⋯π inter-actions link the inversion-related molecules and form a dimeric arrangement in the unit cell.


Oral arsenic trioxide for relapsed acute promyelocytic leukemia in pediatric patients.
Four patients (age 3-11 years at diagnosis) with relapsed acute promyelocytic leukemia (APL), 12-38 months from diagnosis, were treated with oral arsenic trioxide (As(2) O(3) ). One patient was treated with oral As(2) O(3) monotherapy and chemotherapy. Three patients failed initial oral or intravenous As(2) O(3) monotherapy were treated with oral As(2) O(3) plus ATRA followed by long-term oral maintenance (cumulative As(2) O(3) dose 280-2,100 mg). All patients achieved molecular remission, at a median follow up of 122 (10-132) months with no adverse effects. Oral As(2) O(3) , particularly in prolonged maintenance with oral ATRA may obviate the need of stem cell transplantation in relapsed pediatric APL.


In vitro neuraminidase inhibitory activities of four neuraminidase inhibitors against influenza viruses isolated in the 2010-2011 season in Japan.
The half maximal inhibitory concentration (IC(50)) of four neuraminidase inhibitors (NAIs), oseltamivir, zanamivir, laninamivir, and peramivir; was measured using influenza viruses isolated in the 2010-2011 influenza season in Japan. Clinical samples for viral isolation were obtained from nasal aspiration, nasopharyngeal swab, or self-blown nasal discharge and cultured with Madin-Darby canine kidney cells. The type and subtype of H3N2 or B were determined by reverse transcriptase polymerase chain reaction (RT-PCR). For the A(H1N1)pdm09 virus, the subtype was determined by real-time RT-PCR. IC(50)s to oseltamivir carboxylate, zanamivir, laninamivir, and peramivir were determined by a fluorescence-based neuraminidase inhibition assay. Influenza viruses were isolated from 269 patients. A(H1N1)pdm09, H3N2, and B were isolated from 185, 54, and 30 patients, respectively. The geometric means of IC(50) for oseltamivir were 0.86 and 0.73 nM to A (H1N1) pdm09, except for the two outlier viruses described below and H3N2, respectively, and 33.12 nM for B. The geometric means of IC(50) for the other three NAIs were lowest to A(H1N1)pdm09 and highest to B. Two A(H1N1)pdm09 isolates showed very high IC(50) values for oseltamivir (840 and 600 nM) and peramivir (19 and 24 nM). No isolate showed significantly high IC(50) values for zanamivir or laninamivir. Continuous surveillance against the emergence or spread of influenza virus with high IC(50) values for anti-influenza drugs is important.


Surgery decreases the long-term incident stroke risk in patients with primary aldosteronism.
Hypertension with hyperaldosteronism could be associated with stroke attributable to endothelial injury. Whether the detrimental effect of aldosterone on stroke among primary aldosteronism patients could be mitigated by administration of mineralocorticoid receptor antagonist or by reduction of aldosterone level via adrenalectomy is still inconclusive. Primary aldosteronism and essential hypertensive patients were enrolled in the Taiwan National Health Insurance from 1997 to 2009. We used a validated algorithm to enroll primary aldosteronism patients. We conducted a competing risk analysis, using a time-varying Cox proportional hazard model. We enrolled 3,167 primary aldosteronism patients with a subgroup of 1,047 aldosterone-producing adenoma patients, and matched these with essential hypertensive controls in a 1:4 ratio. The risk of incident stroke, both ischemic and hemorrhagic, was statistically higher in primary aldosteronism patients than in their essential hypertensive control. The differences in stroke incidences between primary aldosteronism and essential hypertensive patients significantly increased as the hypertensive period lengthened. Primary aldosteronism patients who received mineralocorticoid receptor antagonist treatment had higher risk of all stroke (competing hazard ratio = 1.83, P < .001) compared with their essential hypertensive controls. In light of this, aldosterone-producing adenoma patients had a lower risk of incident stroke after adrenalectomy (competing for hazard ratio = 0.75), but a higher cumulative risk of incident stroke after mineralocorticoid receptor antagonist only (competing for hazard ratio = 1.76) than their matched essential hypertensive patients. We observed an increased stroke risk among primary aldosteronism patients than among their matched essential hypertensive controls. A prolonged duration of hypertension was proportionate to the raised risk of stroke. Our findings emphasize the importance of aldosterone-producing adenoma benefitting from adrenalectomy in attenuating the cerebrovascular event.


Source and sequestration of sediment organic carbon from different elevation zones in estuarine wetland, North China.
Estuarine wetland plays an important role in regulating global carbon cycle due to high terrestrial carbon input and burial. However, it is unclear how the source and sequestration of sediment organic carbon (SOC) in estuarine wetlands changes under the anthropogenic impact in the past century. In this study, combining parameters of TOC/TN ratios, δ13C, δ15N and 210Pb-chronology, temporal trends of SOC source and sequestration flux in Liaohe estuarine wetland were studied. The results showed that the source of organic carbon in Liaohe estuarine wetland was dominated by terrestrial input (contribution >60 %). Due to vegetation, TOC in shallow reed marsh was significantly higher than that of bare beach and subtidal flat. Affected by elevation, the sediment mass accumulation rate (MAR, kg·m-2·yr-1) showed differences in reed marsh (C1), bare beach (C2) and subtidal flat (C3), which were 6.57, 13.56 and 13.25 respectively in the past century. MAR fluctuated over time, it showed an overall increasing trend, especially since the 1980s. Correspondingly, the sequestration flux of SOC (SF-SOC, g·m-2·yr-1) showed an overall increasing trend with average of 82.84 (reed marsh), 151.93 (bare beach) and 123.71 (subtidal flat). Comparing to TOC, the higher MAR had a more distinct effect on carbon sequestration in Liaohe estuarine wetland. The difference in sedimentation rate and carbon sequestration are linked to the changes in sediment flux of riverine input and land utilization in the catchment area due to human activities in recent decades, including the construction of reservoirs, dams and local ditch wharf.


Preparation and characterization of biphasic calcium phosphate ceramics of desired composition.
A modified processing route for fabricating dense and porous biphasic calcium phosphate (BCP) ceramics of desired and reproducible phase composition (hydroxyapatite (HA)/beta-tricalcium phosphate (beta-TCP) ratio) has been developed. The principal idea of the route was combining a precipitation and a solid phase methods. First, a nonstoichiometric (slightly carbonated calcium-deficient) HA (CdHA) precipitate was synthesized by mixing a calcium carbonate (CaCO(3)) water suspension with an orthophosphoric acid (H(3)PO(4)) solution in abundance (related to the amount resulting in a stoichiometric HA) under definite conditions, and a powder of the precipitate was prepared and calcinated in air (860 degrees C, 1.5 h). In the second stage, a BCP ceramics of the composition determined by the calcium-deficiency in a calcinated powder (the acid abundance in a mixture) was processed by sintering powder compacts with or without a porosizer under appropriate conditions (1,200 degrees C, 2h). A calibrating dependence of the HA/beta-TCP ratio in the ceramics on the acid abundance has been plotted which enabled a controlled preparation of BCP ceramics. A correlation based on unresolved bands in nu(4)-PO (4) (3-) domain in IR-spectra of nanostructured BCP materials was found. Using the correlation, the process of CdHA --> beta-TCP transformation could be easily monitored. The density and microhardness of the BCP ceramics neglectly depended on the composition, however, the compressive strength did: the lower the HA/beta-TCP ratio, the higher the strength in the dense materials.


Synthesis, checkpoint kinase 1 inhibitory properties and in vitro antiproliferative activities of new pyrrolocarbazoles.
In the course of structure-activity relationship studies on granulatimide analogues, new pyrrolo[3,4-c]carbazoles have been synthesized in which the imidazole heterocycle was replaced by a five-membered ring lactam system or a dimethylcyclopentanedione. Moreover, the synthesis of an original structure in which a sugar moiety is attached to the indole nitrogen and to a six-membered D ring via an oxygen is reported. The inhibitory activities of the newly synthesized compounds toward checkpoint kinase 1 and their in vitro antiproliferative activities toward three tumor cell lines: murine leukemia L1210, and human colon carcinoma HT29 and HCT116 are described.


Heterologous expression of glycerol 3-phosphate dehydrogenase gene [DhGPD1] from the osmotolerant yeast Debaryomyces hansenii in Saccharomyces cerevisiae.
The role for the gene encoding glycerol 3-phosphate dehydrogenase (DhGPD1) from the osmotolerant yeast Debaryomyces hansenii, in glycerol production and halotolerance, was studied through its heterologous expression in a Saccharomyces cerevisiae strain deficient in glycerol synthesis (gpd1Delta). The expression of the DhGPD1 gene in the gpd1Delta background restored glycerol production and halotolerance to wild type levels, corroborating its role in the salt-induced production of glycerol. Although the gene was functional in S. cerevisiae, its heterologous expression was not efficient, suggesting that the regulatory mechanism may not be shared by these two yeasts.


Pasos Saludables: A Pilot Randomized Intervention Study to Reduce Obesity in an Immigrant Farmworker Population.
To evaluate a workplace-based diet and physical activity intervention to reduce obesity in a Latino farmworker population. 254 Latino farmworkers were allocated in a 1:2 control:intervention ratio to parallel groups in this randomized controlled study, [Clinical Trial ID# NCT01855282]. Intervention participants attended 10 weekly educational sessions led by promotoras. All participants had anthropometry and lifestyle habits recorded before randomization and at follow-up after 12-14 weeks. Seventy percent (n = 112 intervention and 66 control) completed the study. Intervention females (not controls) decreased the primary outcome measures of weight, BMI, and waist circumference (mean [95% CI]) of -0.7 [-1.3 to -0.1] kg, -0.3 [-0.4 to -0.2] and -0.9 [-1.7 to -0.1] cm, respectively. Intervention participants increased water consumption, fruit and vegetable servings, and moderate physical activity in a dose-dependent fashion. The successful pilot workplace intervention offers a model to reach otherwise difficult-to-access Latino farmworkers.


The Epigenetic Pacemaker: modeling epigenetic states under an evolutionary framework.
Epigenetic rates of change, much as evolutionary mutation rate along a lineage, vary during lifetime. Accurate estimation of the epigenetic state has vast medical and biological implications. To account for these non-linear epigenetic changes with age, we recently developed a formalism inspired by the Pacemaker model of evolution that accounts for varying rates of mutations with time. Here, we present a python implementation of the Epigenetic Pacemaker (EPM), a conditional expectation maximization algorithm that estimates epigenetic landscapes and the state of individuals and may be used to study non-linear epigenetic aging. The EPM is available at https://pypi.org/project/EpigeneticPacemaker/ under the MIT license. The EPM is compatible with python version 3.6 and above.


Neurotransmitter hypotheses of depression. Research update.
Recent research on the amine neurotransmitter hypotheses of depression has moved toward comparative analysis of presynaptic neurotransmitter release and postsynaptic receptor function. Although no single pathognomonic defect has been identified in major depression, alterations in these systems have been identified in subgroups of depressed patients. Therapeutic effects of antidepressant drugs may be linked to adaptive changes in brain neurotransmitter release and receptor function.


High levels of misconceptions and stigma in a community highly endemic for podoconiosis in southern Ethiopia.
The impact of public health interventions for tropical diseases is limited by lack of understanding of the sociocultural context into which these interventions are delivered. Podoconiosis (endemic non-filarial elephantiasis) is a considerable public health problem in Ethiopia, yet little is known about community understanding of it. This study aimed to assess the knowledge, attitudes and practices of community members towards podoconiosis in a highly endemic area in southern Ethiopia. A cross-sectional study was conducted in January 2007 among 438 study participants selected by multistage probability sampling. Most respondents (93.5%) had seen a patient with podoconiosis and 91.6% had heard of the local terms for podoconiosis. The proportion of respondents holding at least one misconception about causation was 93.4% (95% CI 91.1-95.7%). More than one-half (55.8%) showed stigmatising attitudes towards social interactions with podoconiosis patients and 63.8% had unfavourable attitudes towards the condition. Just over one-half (55.2%) of respondents were wearing shoes during the interview, but shoe wearing was inconsistent and inadequate to prevent podoconiosis. In this highly endemic area, the community held significant misconceptions about causation, care, treatment and prevention of podoconiosis. Community interventions for podoconiosis must include education components aimed at dispelling misconceptions and stigma.


Enhancement of photodynamic antitumor effect with pro-oxidant ascorbate.
Photodynamic therapy (PDT) is a treatment modality that utilizes photosensitizers activated by light to induce cell death via the formation of singlet oxygen and other free radicals. Although this method has its advantages for tumor treatment, it cannot be well performed for involving so many therapeutic parameters during use. Tumor recurrence is common due to insufficient treatment. Therefore, a supplemental or complemental treatment is necessary for PDT. L-ascorbate, commonly known as vitamin C, is an essential nutrient for humans. It is also a well-established pro-oxidant in the presence of certain transition metal ions. In our experiments, ascorbate was administered to tumor-bearing mice by intraperitoneal injection (i.p.) for 10 days after they were treated with PDT. We hypothesize that this supplement may improve the therapeutic outcome by as a result of the reactions between ascrobate and the metal ions induced by PDT. The results demonstrate that PDT can cause Fe and Cu ions to be released from their protein complexes. The reactions between the ions and ascorbate resulted in a post-PDT surge in reactive oxygen species (ROS) as demonstrated in vitro with chemiluminescence detection. This ultimately leads to enhanced tumor cell death and, thus, an improved treatment outcome. Based on the results that PDT induces metal ion release and ascorbate reacts with the metal ions producing subsequent ROS, an internal related, complementary and strengthened tumor treatment is established by combination of both PDT and ascorbate, as a low-toxicity and effective method.


Synthesis, characterization and in vitro antibacterial mechanism study of two Keggin-type polyoxometalates.
In this article, two Keggin-type polyoxometalates [Co(L)2]3[PMo12O40] (1) and [Co(L)2]3[PW12O40] (2) (HL = 2-acetylpyrazine thiosemicarbazone) were prepared and fully characterized. The compounds are stable in aqueous solution with different pH values and show superior antibacterial activity against Escherichia coli (E. coli: minimal inhibitory concentration (MIC) = 0.00375, 0.12 μg/mL), Agrobacterium tumefaciens (A. tumefaciens: MIC = 0.06, 0.12 μg/mL), Bacillus subtilis (B. subtilis: MIC = 0.015, 0.06 μg/mL) and especially for Staphylococcus aureus (S. aureus: MIC = 0.00048, 0.015 μg/mL) for 1 and 2, respectively. The time kill studies showed the entire killing of specific bacteria during 4 to 8 h. In addition, the possible antibacterial mechanism of compound 1 was explored systematically. The experimental results proved that cell wall/membrane damage, leakage of protein, inhibition of respiratory chain dehydrogenases activity, enhancement of intracellular reactive oxygen species (ROS) and depletion of glutathione (GSH) were the potential causes of bacteria death.


Annulated pyrazole derivatives as a novel class of urokinase (uPA) inhibitors: Green synthesis, anticancer activity, DNA-damage evaluation, and molecular modelling study.
Different series of annulated pyrazole derivatives were designed, synthesized via both green and traditional methods, and structurally characterized. In vitro uPA evaluation, antiproliferative activities and DNA binding damage was studied in this work. Thus, all the synthesized compounds were evaluated against three types of cancer cell lines; HepG-2, HCT-116, and MCF-7 cancer cell lines in addition to normal cell line WI38. Compounds 11, 20, 21, 23 and 24 displayed the most significant antiproliferative activity with IC50 ranging between 4.42 ± 0.59 μM to 11.05 ± 0.95 μM against HepG-2, HCT-116, and MCF-7 cancer cell lines compared to the reference drug, doxorubicin. Thus compound 11 exhibited cytotoxic activity with IC50 8.58 μM, 9.22 μM and 7.53 μM, compound 20 showed IC50 9.99 μM, 6.72 μM and 6.87 μM, analogue 21 displayed IC50 10.80 μM, 7.90 μM and 9.16 μM, compound 23 showed IC50 4.82 μM, 11.05 μM and 4.42 μM and derivative 24 exhibited potent cytotoxic activity with IC50 7.44 μM, 5.18 μM and 8.22 μM against HepG-2, HCT-116, and MCF-7 cancer cell lines, respectively. Additionally, compounds 11, 21, 23 and 24 showed significant uPA inhibitory activity with IC50 27.28 μM, 29.36 μM, 11.73 μM, and 7.96 μM respectively. Moreover, HCT-116 cell lines were treated with both compounds 23 and 24 that remarkably showed a high score of DNA binding damage. Mechanistic studies demonstrated the apoptotic activity of the most active tricyclic heteroaromatic analogue 24 on HCT-116 cancer cells by inducing a strong S phase cell cycle arrest suggesting that the mechanism of its antiproliferative activity may be through uPA inhibition. Finally, deeper insight illustrated that the hit compounds exhibited characteristic binding interactions in the active site of uPA that are required in the S pocket, which are important for activity Arg 217, Gly 219, and Ser 190.


Effect of interleukin 2 on intractable herpes virus infection and chronic eczematoid dermatitis in a patient with Wiskott-Aldrich syndrome.
Recombinant interleukin 2 (rIL2) was administered to a patient with Wiskott-Aldrich syndrome for the treatment of an intractable facial herpetiform lesion. This treatment appeared to be effective in suppressing the virus activity. At the same time, a transient improvement of the chronic eczematoid dermatitis was observed. During rIL2 administration, the CD3+ and CD4+ subsets of peripheral blood lymphocytes increased in number. These changes might play an important role in the induction of anti-viral immunity and in the improvement of dermatitis.


Tandem Mass Spectrometry Has a Larger Analytical Range than Fluorescence Assays of Lysosomal Enzymes: Application to Newborn Screening and Diagnosis of Mucopolysaccharidoses Types II, IVA, and VI.
There is interest in newborn screening and diagnosis of lysosomal storage diseases because of the development of treatment options that improve clinical outcome. Assays of lysosomal enzymes with high analytical range (ratio of assay response from the enzymatic reaction divided by the assay response due to nonenzymatic processes) are desirable because they are predicted to lead to a lower rate of false positives in population screening and to more accurate diagnoses. We designed new tandem mass spectrometry (MS/MS) assays that give the largest analytical ranges reported to date for the use of dried blood spots (DBS) for detection of mucopolysaccharidoses type II (MPS-II), MPS-IVA, and MPS-VI. For comparison, we carried out fluorometric assays of 6 lysosomal enzymes using 4-methylumbelliferyl (4MU)-substrate conjugates. The MS/MS assays for MPS-II, -IVA, and -VI displayed analytical ranges that are 1-2 orders of magnitude higher than those for the corresponding fluorometric assays. The relatively small analytical ranges of the 4MU assays are due to the intrinsic fluorescence of the 4MU substrates, which cause high background in the assay response. These highly reproducible MS/MS assays for MPS-II, -IVA, and -VI can support multiplex newborn screening of these lysosomal storage diseases. MS/MS assays of lysosomal enzymes outperform 4MU fluorometric assays in terms of analytical range. Ongoing pilot studies will allow us to gauge the impact of the increased analytical range on newborn screening performance.


Feasibility of bionanocomposite films fabricated using capsicum leaf protein and cellulose nanofibers.
In this study, the feasibility of fabricating protein-based bionanocomposite films (PBBFs) was analysed by applying capsicum leaf protein (CLP) and cellulose nanofiber (CNF) as raw materials. The effects of different amounts of CNF (solid content 2%) on physicochemical and material properties of PBBFs were investigated. The results showed nanoscale CNFs exhibited good interfacial compatibility with CLP. The hydroxyl groups on the CNF surface promoted the association of hydrogen bonds between CLP, glycerol and CNF, which improved the crystal structure and thermal stability of PBBFs. Concurrently, the mechanical properties and hydrophobicity of PBBFs are also enhanced. PBBFs with 60% CNF content have maximum flexibility and hydrophobicity. All PBBFs exhibited ultraviolet barrier performance, indicating that PBBFs had potential application prospects in the development of degradable food packaging materials. The results of the present study can provide a theoretical basis for the efficient utilisation of capsicum planting waste while improving the ecosystem.


Pharmacokinetics of Exenatide in nonhuman primates following its administration in the form of sustained-release PT320 and Bydureon.
The time-dependent (30 min - day 84) plasma profile of PT320, a sustained-release (SR)-Exenatide formulation under clinical development for treatment of neurodegenerative disorders, was evaluated in nonhuman primates after a single subcutaneous dose and was compared to Bydureon. Exenatide release from PT320 exhibited a triphasic pharmacokinetic profile. An initial peak occurred at 3 hr post-administration, a secondary peak at 5 days, and achievement of Exenatide steady-state plasma levels from day 10-28. Systemic exposure increased across PT320 doses, and Exenatide levels were maintained above the therapeutic threshold prior to achieving a steady-state. In contrast, Exenatide release from Bydureon exhibited a biphasic profile, with an initial plasma peak at 3 hr, followed by a rapid decline to a sub-therapeutic concentration, and a gradual elevation to provide a steady-state from day 35-49. Exenatide total exposure, evaluated from the area under the time-dependent Exenatide concentration curve, was similar for equivalent doses of PT320 and Bydureon. The former, however, reached and maintained steady-state plasma Exenatide levels more rapidly, without dipping to a sub-therapeutic concentration. Both SR-Exenatide formulations proved well-tolerated and, following a well-regulated initial release burst, generated steady-state plasma levels of Exenatide, but with PT320 producing continuous therapeutic Exenatide levels and more rapidly reaching a steady-state.


Modeling of oncolytic viruses in a heterogeneous cell population to predict spread into non-cancerous cells.
New cancer treatment modalities that limit patient discomfort need to be developed. One possible new therapy is the use of oncolytic (cancer-killing) viruses. It is only recently that our ability to manipulate viral genomes has allowed us to consider deliberately infecting cancer patients with viruses. One key consideration is to ensure that the virus exclusively targets cancer cells and does not harm nearby non-cancerous cells. Here, we use a mathematical model of viral infection to determine the characteristics a virus would need to have in order to eradicate a tumor, but leave non-cancerous cells untouched. We conclude that the virus must differ in its ability to infect the two different cell types, with the infection rate of non-cancerous cells needing to be less than one hundredth of the infection rate of cancer cells. Differences in viral production rate or infectious cell death rate alone are not sufficient to protect non-cancerous cells.


Liver transplantation for hepatocellular carcinoma: role of biopsy.
Patients with compensated cirrhosis (and low Model for End-Stage Liver Disease score) should not undergo transplantation unless they have small hepatocellular carcinoma (HCC). Therefore, presence of HCC should be definitely ascertained before deciding on transplantation in this group of patients. Current imaging techniques allow detection of small liver nodules (<1 cm). Not all liver nodules between 1 and 2 cm are HCC. In addition, benign regenerative nodules have a relatively low potential for degeneration. It is generally agreed that in patients with evidence of cirrhosis, a definitive diagnosis of HCC can be made without tissue analysis in case of nodules >2 cm with a characteristic pattern on either computed tomography (CT) or magnetic resonance imaging (MRI) (hypervascularity in the arterial phase and washout in the early or delayed venous phase). Two concordant imaging techniques (triphasic CT and MRI) are needed to ascertain HCC in case of nodules between 1 and 2 cm. Biopsy is needed for making a diagnosis of HCC in patients with cirrhosis with nodules that do not fulfill the above criteria. Whatever the characteristics of the nodules, biopsy should also be performed in patients without documented cirrhosis. In case of HCC, percutaneous biopsy carries a risk of needle tract seeding of 1-2%. Percutaneous biopsy carries a potential risk of hematogenous dissemination that has not been clearly assessed. There is no clear evidence that the risk of posttransplantation recurrence is higher in patients who undergo biopsy before transplantation. Therefore, in case of HCC, previous biopsy should not be considered a contraindication for transplantation. Even though the specificity of biopsy is close to 100%, its negative predictive value is low. Negative biopsy findings do not exclude the presence of HCC. Patients with negative biopsy findings should either undergo a second biopsy or an enhanced surveillance protocol.


In vivo Characterization of the Opioid Receptor-Binding Profiles of Samidorphan and Naltrexone in Rats: Comparisons at Clinically Relevant Concentrations.
The atypical antipsychotic olanzapine is approved for the treatment of schizophrenia and bipolar I disorder; however, weight gain and metabolic dysregulation associated with olanzapine therapy have limited its clinical utility. In clinical studies, treatment with the combination of olanzapine and the opioid receptor antagonist samidorphan (OLZ/SAM) mitigated olanzapine-associated weight gain while providing antipsychotic efficacy similar to that of olanzapine. Although samidorphan is structurally similar to the opioid receptor antagonist naltrexone, the two differ in their pharmacokinetics and in vitro binding affinities to mu, delta, and kappa opioid receptors (MOR, DOR, and KOR, respectively). The objective of this series of nonclinical studies was to compare the in vivo binding profiles of samidorphan and naltrexone and their receptor occupancies at MOR, DOR, and KOR in rat brains. Male rats were injected with samidorphan or naltrexone to obtain total and unbound plasma and brain concentrations representing levels observed in humans at clinically relevant oral doses. Subsequently, samidorphan and naltrexone brain receptor occupancy at MOR, DOR, and KOR was measured using ultra-performance liquid chromatography and high-resolution accurate-mass mass spectrometry. A dose-dependent increase in samidorphan occupancy was observed at MOR, DOR, and KOR (EC50: 5.1, 54.7, and 42.9 nM, respectively). Occupancy of naltrexone at MOR (EC50: 15.5 nM) and KOR was dose dependent; minimal DOR occupancy was detected. At the clinically relevant unbound brain concentration of 23.1 nM, samidorphan bound to MOR, DOR, and KOR with 93.2%, 36.1%, and 41.9% occupancy, respectively. At 33.5 nM, naltrexone bound to MOR and KOR with 79.4% and 9.4% occupancy, respectively, with no binding at DOR. At clinically relevant concentrations, samidorphan occupied MOR, DOR, and KOR, whereas naltrexone occupied only MOR and KOR. The binding profile of samidorphan differs from that of naltrexone, with potential clinical implications.


Cannabidiol, extracted from Cannabis sativa, selectively inhibits inflammatory hypermotility in mice.
Cannabidiol is a Cannabis-derived non-psychotropic compound that exerts a plethora of pharmacological actions, including anti-inflammatory, neuroprotective and antitumour effects, with potential therapeutic interest. However, the actions of cannabidiol in the digestive tract are largely unexplored. In the present study, we investigated the effect of cannabidiol on intestinal motility in normal (control) mice and in mice with intestinal inflammation. Motility in vivo was measured by evaluating the distribution of an orally administered fluorescent marker along the small intestine; intestinal inflammation was induced by the irritant croton oil; contractility in vitro was evaluated by stimulating the isolated ileum, in an organ bath, with ACh. In vivo, cannabidiol did not affect motility in control mice, but normalized croton oil-induced hypermotility. The inhibitory effect of cannabidiol was counteracted by the cannabinoid CB1 receptor antagonist rimonabant, but not by the cannabinoid CB2 receptor antagonist SR144528 (N-[-1S-endo-1,3,3-trimethyl bicyclo [2.2.1] heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide), by the opioid receptor antagonist naloxone or by the alpha2-adrenergic antagonist yohimbine. Cannabidiol did not reduce motility in animals treated with the fatty acid amide hydrolase (FAAH) inhibitor N-arachidonoyl-5-hydroxytryptamine, whereas loperamide was still effective. In vitro, cannabidiol inhibited ACh-induced contractions in the isolated ileum from both control and croton oil-treated mice. Cannabidiol selectively reduces croton oil-induced hypermotility in mice in vivo and this effect involves cannabinoid CB1 receptors and FAAH. In view of its low toxicity in humans, cannabidiol may represent a good candidate to normalize motility in patients with inflammatory bowel disease.


Scattered radiation from trimmer bars in the cobalt-60 teletherapy machines.
The amount of scattered radiation resulting from four Cobalt-60 teletherapy units in four different hospitals when trimmer bars were fully extended was studied. Scatter was present for all machines checked at between 10% and 20% of the central axis dose. Clinical significance is also discussed.


Prevalence, risk factors and association with glycemic levels of presbyopia in South Indian population.
To determine the prevalence of presbyopia and its association with elevated glycemic levels in subjects ≥40 years of age in the South Indian population of Chennai. This was a retrospective study. Subjects were included from the Sankara Nethralaya Diabetic Retinopathy Epidemiology And Molecular genetics Study (SN-DREAMS 1). Demographic data, detailed medical and ocular history, comprehensive eye examination, and biochemical investigations were performed. Glycosylated hemoglobin results were categorized as controls (4%-5.6%), prediabetic (5.7%-6.4%), and diabetic (≥6.5%) groups. The given presbyopic correction was divided into two groups as within and outside donders limit. Prevalence rates and mean values were determined and compared among the three glycemic groups. The Student t test, the Chi-square test, and multivariate logistic regression analyses were performed. The overall prevalence of presbyopia from our previously conducted SN-DREAMS 1 population of 1414 patients was 79.77% (95% CI: 0.775-0.818). In total, 1128 participants were included for our current secondary analysis with a mean age of 54.40 years (range: 40-83). The number of subjects within and outside donders limit was 1044 (92.55%) and 84 (7.44%), respectively. In each age group (40-49, 50-59, ≥60) regardless of being within or outside donders limits, an increasing trend in the prevalence of presbyopia was noted based on increasing glycemic levels. Our study demonstrated a high prevalence of presbyopia in the South Indian population of Chennai. Findings show that the prevalence of presbyopia in different age groups increases with worsening diabetes status.


The nephrotoxicity and renal accumulation of amikacin, tobramycin and gentamycin in rats, rabbits and guinea pigs.
The nephrotoxicity and renal concentrations of amikacin, tobramycin and gentamycin were studied in rat, rabbit and guinea pig. The nephrotoxicity was estimated by histological examination and by measuring the relative weight of the kidneys (mg/100 mg body weight). These two systems had a significant correlation (r = 0.87; p less than 0.001). The concentrations of aminoglycosides were determined by the cylinder-plate method measuring free aminoglycosides. The renal toxicity of the aminoglycosides in equal doses weight by weight followed the order amikacin less than tobramycin less than gentamycin in the rat. The same order was observed in the renal accumulation of the aminoglycosides in rat, rabbit and guinea pig. The critical kidney damaging concentration of free aminoglycoside in the whole rat kidney was estimated to be 160--190 microgram/g.


Assessment of Health Facilities for Airborne Infection Control Practices and Adherence to National Airborne Infection Control Guidelines: A Study from Kerala, Southern India.
Nosocomial transmission of airborne infections, such as H1N1, drug-resistant tuberculosis, and Nipah virus disease, has been reported recently and has been linked to the limited airborne infection control strategies. The objective of the current study was to assess the health facilities for airborne infection control (AIC) practices and adherence to the National AIC (NAIC) guidelines, 2010. A cross-sectional study was conducted in 25 public and 25 private hospitals selected from five randomly selected districts in the state of Kerala. A checklist with 62 components was developed based on the NAIC guidelines. Frequencies, percentages, and mean with standard deviation were used to summarize facility risk assessment and compliance to guidelines. Most of the facilities had infection control committees 35 (70%). Annual infection control trainings were held for staff in 21 (42%) facilities. Twenty (40%) facilities were not familiar with NAIC guidelines. Counseling on cough etiquette at registration was practiced in 5 (10%) institutions. Cross ventilation was present in outpatient departments in 27 (54%) institutions. Sputum was disposed properly in 43 (86%) institutions. N95 masks were available in high-risk settings in 7 (14%) health facilities. There exist deficiencies in adherence to all components of NAIC guidelines including administrative, environmental, and use of personal protective equipment in both government and private hospitals in the state.


Photochemical transformation of ibuprofen into harmful 4-isobutylacetophenone: pathways, kinetics, and significance for surface waters.
The harmful compound 4-isobutylacetophenone (IBAP) can be formed photochemically from the anti-inflammatory drug ibuprofen (IBP), upon direct photolysis (yield 25 ± 7%, μ ± σ), reaction with ·OH (yield 2.3 ± 0.1%) and reaction with triplet states of chromophoric dissolved organic matter, (3)CDOM* (yield 31 ± 4%). In the latter case, anthraquinone-2-sulphonate was used as CDOM proxy. The three processes would account for most of the photochemical transformation of IBP and IBAP in surface waters. IBAP formation from IBP involves the propanoic acid chain, which is more reactive than the aromatic ring as shown by quantum mechanical calculations. IBAP is expected to undergo slightly faster photochemical transformation than IBP in surface waters, with a modelled pseudo-first order rate constant that is higher by 1.5-1.9 times compared to IBP. Due to fairly high formation yields and depending on IBP emission scenarios, photochemical modelling suggests that IBAP could reach concentration values up to ~15% of IBP in surface waters, thus being a potentially important transformation intermediate. This issue prompts for the need of field studies that provide information on IBAP environmental occurrence, which is virtually unknown at the present moment.


Self-reported skin cancer protection strategies and location of skin cancer in retired cricketers: a case study from membership of the Emu Cricket Club.
Cricket is one of Australia's most popular sports with approximately 470,000 registered participants. Played as a summer sport, participants can spend long periods in the sun with potential skin damage a possible contributor to skin cancer. Three hundred and sixty-eight retired regional representative players received and were invited to complete a comprehensive survey that included questions relating to their individual playing history, injury rate, sun protection strategies and reported location of skin cancer. A total of 164 players (mean age 45.2+/-12.1 years) responded to the survey representing a response rate of 44.6%. Of these, 61.6% reported no diagnosis of skin cancer. However, 38.4% had been diagnosed with at least one skin cancer with the most common site being the face followed by the arms. Of those respondents reporting the diagnosis of a skin cancer, 7.9% had skin cancer on 4 or more separate locations. Proportionally, the 45-55 years group had the highest incidence, with 55.8% of this group indicating they had a skin cancer in at least one anatomical location. By comparison those in the under 35 years age group reported an incidence rate of 16.7%. The incidence of skin cancer among respondents (n=63) reporting either, occasionally, very rarely or never wearing sunscreen, a hat or long sleeved shirt was (n=27) 42.9, (n=14) 22.2 and (n=39) 61.9%, respectively. The results suggest that skin protection strategies, such as wearing a wide brimmed hat, long sleeved shirt and the use of sunscreen, may help to reduce the risk of skin cancer in cricketers.


Rat proximal small intestinal Golgi membranes: lipid composition and fluidity.
The present studies were conducted to examine and characterize the lipid composition and physical state of the membrane lipids of rat proximal small intestinal Golgi membranes. Golgi membranes were purified from isolated enterocytes; lipids were extracted from these membranes and analyzed by thin-layer and gas-liquid chromatography. The 'static' and 'dynamic' components of fluidity of Golgi membranes and their liposomes were assessed by steady-state fluorescence polarization techniques utilizing r infinity and S values of 1,6-diphenyl-1,3,5-hexatriene and r values of DL-2-(9-anthroyl)- and DL-12-(9-anthroyl)stearic acid, respectively. Additional studies were also performed on these membranes, using benzyl and methyl alcohol, to examine the relationship between alterations in lipid fluidity and glycosphingolipid glycosyltransferase activities. The results of these studies demonstrated that: (1) the principal phospholipids and neutral lipids of intestinal Golgi membranes, respectively, were phosphatidylcholine, phosphatidylethanolamine and sphingomyelin, and unesterified cholesterol and fatty acids; (2) the major fatty acids of Golgi membranes were palmitic (16:0), stearic (18:0), linoleic (18:2), arachidonic (20:4) and oleic (18:1) acids; (3) fluorescence polarization studies using diphenylhexatriene detected a thermotropic transition at 24-26 degrees C in Golgi membranes and liposomes prepared from lipid extracts of these membranes; (4) benzyl alcohol (25 and 50 mM) but not methyl alcohol (50 mM) significantly increased the fluidity of these membranes; and (5) at these same concentrations, benzyl alcohol was also found to increase significantly the specific activity of UDP-galactosyllactosylceramide galactosyltransferase but not CMP-acetylneuraminic acid: lactosylceramide sialyltransferase. Methyl alcohol was not found to influence either enzyme's activity in these membranes.


Lycorine attenuates lipopolysaccharide-induced acute lung injury through the HMGB1/TLRs/NF-κB pathway.
Lung injury associated with systemic inflammatory response is a common problem affecting human health. Previous studies have shown that lycorine exerts a anti-inflammatory effect. However, whether lycorine alleviates lung injury remains unclear. To explore this issue, BALB/c mice and MLE-12 cells were treated with lipopolysaccharide (LPS) to establish lung injury mouse model and cell model, respectively. Glycyrrhizic acid, known as an inhibitor of ALI, was also used to study the effects of lycorine in vitro. Our results showed that after LPS treatment, the lung injury score, lung wet-to-dry weight ratio, and malondialdehyde (MDA) production in the lung tissues and the expression levels of tumor necrosis factor-α, interleukin-1β, and interleukin-6 in bronchoalveolar lavage fluid were significantly increased, whereas their levels were decreased by lycorine. Additionally, LPS injection activated the high-mobility group box 1 (HMGB1)/Toll-like receptors (TLRs)/NF-κB pathway. However, lycorine treatment attenuated the activity of the HMGB1/TLRs/NF-κB pathway in the lung tissues. In vitro studies showed that lycorine administration significantly decreased the levels of inflammatory cytokines and MDA and attenuated the activity of the HMGB1/TLRs/NF-κB pathway in LPS-treated cells. Moreover, the inhibitory effects of lycorine on the inflammatory response and oxidative stress in LPS-treated lung cells were similar with that of glycyrrhizic acid, and this inhibition was intensified by both lycorine and glycyrrhizic acid treatment. We suggest that lycorine could alleviate LPS-induced lung injury of inflammation and oxidative stress by blocking the HMGB1/TLRs/NF-κB pathway, which gives a new perspective for ALI therapy to treat lycorine as a potential treatment clinically.


Towards clinically feasible relaxation-diffusion correlation MRI using MADCO.
Multidimensional relaxation-diffusion correlation (REDCO) NMR is an assumption-free method that measures how water is distributed within materials. Although highly informative, REDCO had never been used in clinical MRI applications because of the large amount of data it requires, leading to infeasible scan times. A recently suggested novel experimental design and processing framework, marginal distributions constrained optimization (MADCO), was used here to accelerate and improve the reconstruction of such MRI correlations. MADCO uses the 1D marginal distributions as a priori information, which provide powerful constraints when 2D spectra are reconstructed, while their estimation requires an order of magnitude less data than conventional 2D approaches. In this work we experimentally examined the impact the complexity of the correlation distribution has on the accuracy and robustness of the estimates. MADCO and a conventional method were compared using two T1-D phantoms that differ in the proximity of their peaks, leading to a relatively simple case as opposed to a more challenging one. The phantoms were used to vet the achievable data compression using MADCO under these conditions. MADCO required ~43 and ~30 less data than the conventional approach for the simple and complex spectra, respectively, making it potentially feasible for preclinical and even clinical applications.


Oral administration of allergen extracts from mugwort pollen desensitizes specific allergen-induced allergy in mice.
Clinically, sublingual immunotherapy (SLIT) using allergen extracts effectively alleviates the symptoms of allergic rhinitis and asthma. We hypothesized that oral administration of a high-dose of allergen extracts imitates SLIT, which may prevent IgE-related responses in allergic diseases. In the present study, we investigated the effects of oral administration of allergen extracts from mugwort pollen (MP) on allergen-induced inflammation and airway hyperresponsiveness (AHR) in an allergic mouse model. After administration of MPdrop containing Art v 1 and Art v 4 extracts derived from MP specifically in MP-sensitized mice, the effects of MPdrop on AHR, inflammatory cell accumulation, cytokine production in the bronchoalveolar lavage fluid and lung tissue, and serum IgE and IgG levels were investigated. The results indicated that MPdrop not only prevented the AHR in response to methacholine in a dose-dependent manner but also significantly reduced the total serum and allergen-specific IgE levels. All of the maximal effects were achieved at a dose of 100μg/(kgd) and were comparable to the effects of dexamethasone at a dose of 0.5mg/(kgd). Furthermore, oral administration of MPdrop dose-dependently elevated allergen-specific serum IgG2a levels, reduced total and allergen-specific IgE levels and normalized the imbalance between the Th1 cytokine IL-12 and Th2 cytokines IL-4 and IL-5. Finally, oral administration of MPdrop significantly reduced goblet cell hyperplasia and eosinophilia in the MP-sensitized allergic mouse model. These data suggest that MPdrop effectively improves specific allergen-induced inflammation and AHR in MP-sensitized and -challenged mice and provides the rationale for clinical use of MPdrop in the specific allergen-induced asthma.


Determination of Soft Tissue Breakpoint Based on Its Temperature Enhancement Pattern: In Vivo and In Vitro Experiments.
The breakpoint of fresh commercial meats and in vivo mice has been assessed using tissue temperature enhancement pattern. A 1 cm length and 0.1 cm diameter gold rod was implanted in fresh chicken breast, beef, fish, and in vivo Mus musculus white mice and was insonated with ultrasound. The temperature enhancement of gold rods was measured with a needle type thermistor over a temperature range from 35 to 50 °C. From these results the breakpoints were determined by plotting the gold rod temperature versus ultrasound exposure duration using the interception point of two curves fitted by a linear regression equations of thermal response above and below 43 °C. The linear correlation coefficients for all fitted curves lie within 0.985 and 0.997. The breakpoints were found to be 42.1 ± 1.1, 42.3 ± 0.9, 42.6 ± 0.8 and 43.5 ± 0.6 for fish, chicken breast, beef and in vivo Mus musculus white mice, respectively. The interception of the thermal response curves above and below 43 °C. Soft tissue temperature enhancement pattern has demonstrated to be a fast method to determine breakpoint. It denotes the temperature where cells may start to be destroyed and may be used to spot the startup point in dosimetry of hyperthermia cancer therapy.


Inhalational delivery of induced pluripotent stem cell secretome improves postpneumonectomy lung structure and function.
Cell-free secretory products (secretome) of human induced pluripotent stem cells (iPSCs) have been shown to attenuate tissue injury and facilitate repair and recovery. To examine whether iPSC secretome facilitates mechanically induced compensatory responses following unilateral pneumonectomy (PNX), litter-matched young adult female hounds underwent right PNX (removing 55%-58% of lung units), followed by inhalational delivery of either the nebulized-conditioned media containing induced pluripotent stem cell secretome (iPSC CM) or control cell-free media (CFM); inhalation was repeated every 5 days for 10 treatments. Lung function was measured under anesthesia pre-PNX and 10 days after the last treatment (8 wk post-PNX); detailed quantitative analysis of lung ultrastructure was performed postmortem. Pre-PNX lung function was similar between groups. Compared with CFM control, treatment with iPSC CM attenuated the post-PNX decline in lung diffusing capacity for carbon monoxide and membrane diffusing capacity, accompanied by a 24% larger postmortem lobar volume and distal air spaces. Alveolar double-capillary profiles were 39% more prevalent consistent with enhanced intussusceptive angiogenesis. Frequency distribution of the harmonic mean thickness of alveolar blood-gas barrier shifted toward the lowest values, whereas alveolar septal tissue volume and arithmetic septal thickness were similar, indicating septal remodeling and reduced diffusive resistance of the blood-gas barrier. Thus, repetitive inhalational delivery of iPSC secretome enhanced post-PNX alveolar angiogenesis and septal remodeling that are associated with improved gas exchange compensation. Results highlight the plasticity of the remaining lung units following major loss of lung mass that are responsive to broad-based modulation provided by the iPSC secretome.NEW & NOTEWORTHY To examine whether the secreted products of human induced pluripotent stem cells (iPSCs) facilitate innate adaptive responses following loss of lung tissue, adult dogs underwent surgical removal of one lung, then received repeated administration of iPSC secretory products via inhalational delivery compared with control treatment. Inhalation of iPSC secretory products enhanced capillary formation and beneficial structural remodeling in the remaining lung, leading to improved lung function.


Development of inverted organic solar cells with TiO₂ interface layer by using low-temperature atomic layer deposition.
Organic solar cells (OSCs) with inverted structure have attracted much attention in recent years because of their improved device air stability due to the use of stable materials for electrodes and interface layers. In this work, TiO(2) films, fabricated using low temperature (e.g., 130-170 °C) atomic layer deposition (ALD) on ITO substrates, are used as electron selective interface layers to investigate inverted OSCs. It is found that though the as-deposited TiO(2) films are high resistive due to the presence of oxygen defects, the defects can be significantly reduced by light soaking. PV cells with 15-nm-thick amorphous-TiO(2) layers fabricated at low temperature show better performance than those with poly crystal TiO(2) with same thickness deposited at 250 °C. The low temperature ALD-grown TiO(2) films are dense, stable and robust with capability of conformal coating on nanostructural surfaces, showing a promising interface layer for achieving air-stable plastic OSCs with roll-to-roll mass production potential.


Hypoxic-preconditioning enhances the regenerative capacity of neural stem/progenitors in subventricular zone of newborn piglet brain.
Perinatal hypoxia-ischemia (HI) results in brain injury, whereas mild hypoxic episodes result in preconditioning, which can significantly reduce the vulnerability of the brain to subsequent severe hypoxia-ischemia. Hypoxic-preconditioning (PC) has been shown to enhance cell survival and differentiation of progenitor cells in the central nervous system (CNS). The purpose of this study was to determine whether pretreatment with PC prior to HI stimulates subventricular zone (SVZ) proliferation and neurogenesis in newborn piglets. One-day-old piglets were subjected to PC (8% O2/92% N2) for 3h and 24h later were exposed to HI produced by combination of hypoxia (5% FiO2) for a pre-defined period of 30min and ischemia induced by a period of 10min of hypotension. Here we demonstrate that SVZ derived neural stem/progenitor cells (NSPs) from PC, HI and PC+HI piglets proliferated as neurospheres, expressed neural progenitor and neurodevelopmental markers, and that greater proportion of the spheres generated are multipotential. Neurosphere assay revealed that preconditioning pretreatment increased the number of NSP-derived neurospheres in SVZ following HI compared to normoxic and HI controls. NSPs from preconditioned SVZ generated twice as many neurons and astrocytes in vitro. Injections with 5-Bromo-2-deoxyuridine (BrdU) after PC revealed a robust proliferative response within the SVZ that continued for one week. PC also increased neurogenesis in vivo, doublecortin positive cells with migratory profiles were observed streaming from the SVZ to striatum and neocortex. These findings show that the induction of proliferation and neurogenesis by PC might be a positive adaptation for an efficient repair and plasticity in the event of a hypoxic-ischemic insult.


The role of anticomplement therapy in lupus nephritis.
The complement system plays crucial roles in homeostasis and host defense against microbes. Deficiency of early complement cascade components has been associated with increased susceptibility to systemic lupus erythematosus (SLE), whereas excessive complement consumption is a hallmark of this disease. Although enhanced classical pathway activation by immune complexes was initially thought to be the main contributor to lupus nephritis (LN) pathogenesis, an increasing body of evidence has suggested the alternative and the lectin pathways are also involved. Therapeutic agents targeting complement activation have been used in LN patients and clinical trials are ongoing. We review the mechanisms by which complement system dysregulation contributes to renal injury in SLE and summarize the latest evidence on the use of anticomplement agents to manage this condition.


Patterns of Relapse and Complications of Immunoglobulin G4-Related Disease.
Immunoglobulin G4-related disease (IgG4-RD) is a multisystemic fibroinflammatory condition potentially resulting in organ dysfunction. We aimed to evaluate imaging characteristics of disease relapse and complications in this cohort of patients. This was a cohort study of IgG4-RD patients imaged between 2010 and 2020. Radiological manifestations of disease activity (remission/stability vs. relapse and complications) were correlated with clinical symptoms. Univariate analyses were performed with χ2 , Fisher exact, and Mann-Whitney U tests. Times to relapse and organ atrophy were studied with Kaplan-Meier analyses. A total of 69 patients had imaging surveillance over a median duration of 47 months. Radiological relapse occurred in 50.7% (35/69) with median time to relapse at 74 months (95% confidence interval, 45-122 months); 42.8% (15/35) of this cohort had different-site relapse with the following recognized primary-secondary patterns: pancreas-hepatobiliary ( p = 0.005), hepatobiliary-pancreas ( p = 0.013), and periaortitis-mesenteric ( p = 0.006). Clinical symptoms were significantly associated with imaging characteristics ( p < 0.001). Abdominal complications were detected in 52.2% (36/69) of patients, mostly solid organ atrophy (97.2% [35/36]). New-onset diabetes was more likely in pancreatic IgG4-RD (n = 51) when accompanied by gland atrophy (4/21 vs. 0/30 nonatrophy, p = 0.024). Radiological relapse of IgG4-RD is common over prolonged imaging surveillance and is significantly associated with symptomatic relapse. A multisystem review to detect new/different sites of disease and abdominal complications may help predict future organ dysfunction.


Deep Vein Thrombosis after Cement Intravasation during Hip Hemiarthroplasty.
Cement intravasation occurs in hemiarthroplasty when pressurization of cement through the medullary canal backflows through the nutrient vessels. This case report describes a 70-year-old woman who underwent hip hemiarthroplasty for a displaced left femoral neck fracture. Postoperative radiographs demonstrated radio-opacity consistent with local cement intravasation. A Doppler ultrasound study subsequently revealed a mobile thrombus at the confluence of the femoral and profunda femoris veins, as well as a nonmobile thrombus within the profunda femoris vein. The more proximal thrombus was determined to be cement that had intravasated during the index operation. The cement likely impeded venous flow, ultimately leading to the development of deep vein thrombosis just distal to the site of cement occlusion.


Healthy lifestyles are associated with better vitamin D status in community-dwelling older men: The Health In Men Study (HIMS).
Older people are more prone to vitamin D deficiency than younger populations. Individual lifestyle factors have been associated with vitamin D status. We examined the influence of a combination of lifestyle factors on vitamin D status in older men. In a population-based cohort study of older men (age ≥65 years), a lifestyle score was calculated from eight prudent health-related behaviours (smoking, exercise, alcohol, fish and meat consumption, adding salt, milk choices and obesity) collected via questionnaire at baseline. Blood samples were collected 5 years afterwards to measure plasma 25-hydroxyvitamin D (25OHD) levels. Associations between lifestyles and the likelihood of having plasma 25OHD levels of ≥75 versus <75 nmol/L and ≥50 versus <50 nmol/L were tested using logistic regression models. Of the 2717 men analysed, mean plasma 25OHD was 69.0 ± 23.5 nmol/L, with 20.7% having plasma 25OHD <50 nmol/L. Men engaging in ≥4 healthy lifestyle behaviours had 20% higher odds of plasma 25OHD ≥75 nmol/L (adjusted OR = 1.20, 95% CI: 1.01-1.45) compared to those with <4 healthy behaviours. No association was found for 25OHD ≥50 nmol/L. Higher physical activity was the only individual component significantly associated with vitamin D sufficiency (highest vs. lowest quintiles of physical activity, adjusted OR = 2.01, 95% CI: 1.47-2.74 for 25OHD ≥50 nmol/L, adjusted OR = 2.35, 95% CI: 1.81-3.06 for 25OHD ≥75 nmol/L). Multiple healthy lifestyle behaviours are associated with better vitamin D status in older men. Further work is needed to determine the effects of promoting healthy lifestyle behaviours, including physical activity, on vitamin D sufficiency.