A review of the physicochemical characteristics of ultrafine particle emissions from domestic solid fuel combustion during cooking and heating.
Residential solid fuel combustion has increased because of rising energy costs but little is known about the emission characteristics of unregulated pollutants such as ultrafine particles (UFPs). This review aims to characterise the emissions and chemical composition of UFPs, build an understanding of the particle number size distribution (PSD), assesses the factors affecting pollutants emission, and the efficacy of pollutants mitigation strategies. A systematic appraisal of literature suggests that the pollutants emissions from domestic solid fuel combustion are influenced by the quality and type of fuels, stove types, and combustion conditions. Low volatile matter content fuels such as smokeless fuels emit lesser PM2.5, NOX, SO2 than high volatile matter content fuels such as wood. However, CO emissions does not directly correlate with volatile matter content, but depend on air supply, combustion temperature, and fuel particle size. Majority of UFPs are emitted during the coking and flaming phases of combustion. Since UFPs have a large surface area, they adsorb significant amounts of hazardous metals and chemicals such as PAHs, As, Pb, and NO3 in addition to minor amounts of C, Ca and Fe. Emission factor of solid fuel based on the particle number concentration (PNC) can range from 0.2 to 2 × 1015 # kg-1 of fuel. UFPs were not found to be reduced by improved stoves, mineral additives, or small-scale electrostatic precipitators (ESP). In fact, improved cook stoves were found to increase UFP emissions by a factor of 2 compared with conventional stoves. However, they have demonstrated a 35-66 % reduction in PM2.5 emissions. Using a domestic stove within a home puts occupants at risk of being exposed to significant concentrations of UFPs in a short period of time. As there are limited studies on the topic area, further research on different improved heating stoves is required to better understand their emissions of unregulated pollutants such as the UFPs.


Buccal metastasis in a case of carcinoma breast: A rare case report with review of literature.
Metastatic lesions to oral cavity from distant tumours account for 1% of all oral cavity malignancies. Oral cavity is a rare site of metastasis from the breast. We describe case report of breast cancer patient with metastasis to buccal mucosa. We report a case of pre-menopausal woman with left side infiltrating ductal carcinoma breast - T4aN1M0. She received three cycles of neo-adjuvant chemotherapy followed by modified radical mastectomy (MRM) and three cycles of adjuvant chemotherapy and loco-regional EBRT. She presented with a lump in region of MRM scar and a painful swelling in the right cheek, one year afterwards. Core needle biopsy from scar site revealed infiltrating ductal carcinoma. CECT revealed a heterogeneous lesion (1.1cm×1.7cm) in right masticator space, which on biopsy revealed metastatic deposit consistent with infiltrating ductal carcinoma. Metastatic lesions to oral cavity from distant tumours are uncommon. They mainly involve bony structures. Primary metastases to soft tissues are rare and accounts for 0.1% of oral malignancies. In our case, patient presented with scar recurrence and distant metastasis at an unusual site. Had it not been for scar recurrence, patient might not have presented to the OPD with oral swelling. A high degree of clinical suspicion and previous history of breast cancer led to detection of metastatic deposit. Diagnosis of a metastatic lesion in buccal mucosa is challenging and requires a high degree of clinical suspicion.


Energy performance of an innovative bifacial photovoltaic sunshade (BiPVS) under hot summer and warm winter climate.
The bi-facial photovoltaic sunshade (BiPVS) is an innovative solution that utilizes vertically mounted bi-facial photovoltaic modules to provide shading. The BiPVS is capable of converting incident solar radiation into electricity on both the front and rear sides of the module, resulting in higher electrical efficiency compared to traditional mono-facial PV sunshades. The BiPVS has great potential as a sustainable solution for building shading and energy generation, which allows for improved indoor light/thermal environment and building energy efficiency. In this study, the bi-facial photovoltaic sunshade (BiPVS) was implemented in an office under typical hot summer and warm winter climate of Shenzhen, China. The energy performance of the BiPVS was analyzed using Energyplus. The comprehensive building energy saving was evaluated by comparing the energy consumption of the office with and without the BiPVS. Results showed that the total annual photovoltaic power generation was 133.19 kWh, while the comprehensive building energy savings were 159.65 kWh. Additionally, carbon dioxide emissions were reduced by 83.29 kgCO2 per year. The proposed method can help optimize the design parameters of BiPVS according to specific climate conditions, building types, and orientation, and contribute to the development of high-efficiency BIPV technology and support efforts towards carbon neutrality.


Adverse Cochlear Effects After Head and Neck Cancer Therapy.
This study aims to report the incidence of adverse cochlear effects when treating patients of HNSCC with different radiation techniques and to compare the effect of different treatment modalities on the cochlea. This prospective observational study took place in a tertiary care centre, of 132 individual ears from 66 patients of HNSCC treated with conventional RT (group-1), IMRT (group-2), conventional RT with chemotherapy (group-3) and IMRT in combination with chemotherapy (group-4). Pure tone audiometry was performed during the follow-up period at 3 months and 1 year of completion of therapy. Correlation of audiometric change of both the ears at high frequencies (pure tone average 4 kHz, 6 kHz, 8 kHz), low frequencies (pure tone average 0.5-2 kHz) and BC (average 500-4 kHz) with series of factors were analyzed. There was a significant deterioration of hearing threshold 1 year after complete treatment, in all groups. There was an average drop in BC (0-1 year) by 19.63 ± 31.25% in group-2, 24.57 ± 21.96% in group-1 and a drop of 36.48 ± 43.97% and 70.78 ± 21.11% in group-3 and group-4 respectively. When we compared the audiometric change (PTAv at high and low frequency) from 0 to 1 year of group-1&2 the p value was significant (p = 0.050 at high frequency, p = 0.040 at low frequency). The audiological outcome of the different treatment modalities when compared, it was observed that the maximum hearing loss was in group-4 (IMRT with Chemotherapy) followed by group-3 (RTCT), group-1 (Conventional RT) and group-2 (IMRT).


Association of socioeconomic disadvantage and neighborhood disparities with clinical outcomes in multiple sclerosis patients.
Socioeconomic disadvantage may be an important contributor to clinical outcomes in MS but is not well understood. Our objective was to examine the associations between Area Deprivation Index (ADI), a validated measure of neighborhood-level disadvantage, with clinical outcomes. We assessed the longitudinal association between MS Performance Test (MSPT) and quality of life in Neurological Disorders (Neuro-QoL) measures with ADI quartiles (Q1: lowest deprivation - Q4 highest deprivation) in relapsing remitting MS (RRMS) and progressive MS cohorts. Our study included 2,921 patients (65.8% RRMS and 34.1% progressive MS) with 13,715 visits. Patients living in the most disadvantaged areas had almost universal worsening on baseline MSPT and Neuro-QoL scores (p < 0.05) when compared to patients living in areas of lowest deprivation. Manual Dexterity Test (MDT) illustrated particular disparity as RRMS patients living in the greatest area of deprivation had MDT score which averaged 2.9 seconds longer than someone living in areas of least deprivation. Longitudinal analysis illustrated less favorable MSPT and Neuro-QoL outcomes across visits between Q1 versus Q4 ADI quartiles within in the RRMS cohort but not within the progressive MS cohort. After adjustment, linearly increasing area deprivation scores reflected less favorable Processing Speed Test (PST) and six Neuro-QoL outcomes among the RRMS cohort. Within the progressive cohort, higher deprivation was associated less favorable MDT, PST and 11 of 12 Neuro-QoL outcome measures. This study provides evidence for socioeconomic disadvantage as a risk factor for disability accrual in MS and may be targeted to improve care while informing resource allocation.


Behaviorally specific inhibition of sham feeding by amylin.
To further characterize amylin's inhibitory action on feeding, we examined the effects of intraperitoneal injections of amylin on sham feeding of sucrose in food-deprived male rats with chronic gastric cannulas. Thirty and 100 microg/kg amylin reduced sham feeding, but did not terminate it or elicit the behavioral sequence of satiety. Real feeding of sucrose, but not sham feeding, was reduced after injection of 10 microg/kg amylin. Amylin's inhibitory effect on sham feeding appeared behaviorally specific because neither 30 nor 100 microg/kg amylin affected sham drinking of water in thirsty rats and because no abnormal behaviors occurred. We conclude that amylin has a behaviorally specific satiating effect on sucrose sham feeding that is insufficient to elicit satiety in absence of gastric or postgastric food stimulation.


Revisiting the free nipple graft: an opportunity for nipple sparing mastectomy in women with breast ptosis.
Nipple areolar complex (NAC) sparing mastectomy improves the cosmetic outcome of patients with breast cancer. However, women with significant breast ptosis are not candidates for this technique due toexcessive skin flap length and ensuing risk of NAC ischemia.1 (-) 3 We report a novel technique using free nipple graft during skin sparing mastectomy for patients with significant ptosis while concurrently maintaining oncologic integrity. Case series. Community and tertiary care hospital practices. Women with breast cancer desiring NAC preservation who are otherwise candidates for nipple sparing mastectomy, but with significant breast ptosis that precludes NAC viability. All women underwent immediate, autologous breast reconstruction. Bilateral and unilateral free nipple grafts were harvested, placed on ice during skin sparing mastectomy and free flap reconstruction, grafted at the conclusion of the case and secured with a bolster. Full or partial NAC preservation, ischemia time, local wound complications at NAC grafting site, pathologic outcomes. A total of three patients underwent free nipple grafting at the time of skin sparing mastectomy and free or pedicled flap for breast cancer between March and September 2012. Of five total nipple grafts, one had partial NAC loss but did not require operative debridement. Pathologic review of areolar tissue removed during intraoperative defatting of free nipple graft demonstrated residual duct epithelium. Women with significant breast ptosis that would preclude them from NAC sparing mastectomy can successfully preserve their NAC using a free nipple graft. Duct epithelium present in defatted tissue during preparation of the free nipple graft suggests that oncologic integrity can also be maintained.


Interface Modification of a Perovskite/Hole Transport Layer with Tetraphenyldibenzoperiflanthene for Highly Efficient and Stable Solar Cells.
Interface engineering has been recognized as a very effective method to simultaneously improve both efficiency and stability in perovskite solar cells (PSCs). In this work, we report using an excellent small molecular material tetraphenyldibenzoperiflanthene (DBP) to modify the perovskite/Spiro-OMeTAD interface to achieve significantly improved solar cell performance. It is found that the ultrathin DBP interlayer accelerates hole transfer across the FAxMA1-xPbInBr3-n/Spiro-OMeTAD interface and effectively reduces the nonradiative recombination. The Kelvin probe force microscopy and energy band analyses reveal that the DBP modification helps build better matched energy level alignment and smaller energy loss for more fluent hole transport. Consequently, the DBP-treated PSCs achieve an enhanced open-circuit voltage as high as 1.184 V and fill factor as high as 78.2% as well as the negligible hysteresis. The champion PSC made with DBP gives a PCE of 21.49%, significantly increased compared to 19.68% from the reference cell without the modification. Moreover, DBP also serves as a water-resistant protection for improved moisture stability. The PCE of the DBP-treated cells without encapsulation remains more than 84% of its initial efficiency, which is significantly higher than that of the reference PSCs (65%) after 20 days of storage under an air environment with 50-65% humidity. This study provides an effective interface modification material to address notorious stability problems in Spiro-OMeTAD-based PSCs.


A model for dynamics of primer extension by eukaryotic DNA primase.
A mathematical model is proposed for processive primer extension by eukaryotic DNA primase. The model uses available experimental data to predict rate constants for the dynamic behavior of primase activity as a function of NTP concentration. The model also predicts some data such as the binding affinities of the primase for the DNA template and for the RNA primer.


Analysis of an estrogen binding macromolecule in human pancreas by radioimmunoassay.
A radioimmunoassay for quantitation of the human pancreatic estrogen binding protein (hEBP) was developed using polyclonal rabbit hEBP antiserum and iodinated purified hEBP. Parallel dose-response curves were obtained when serial dilutions of human serum and of cytosols obtained from human pancreas, prostate and colon were analyzed simultaneously with serial dilutions of purified hEBP standard. Very high levels of hEBP (500-1000 mg/kg wet weight) were found in normal pancreas. High as well as medium levels were found in pancreatic carcinoma tissue and medium values (0.1-1 mg/kg wet weight) in prostate, colon and ovarian tissue. Other tissues and serum from healthy volunteers showed low values, usually below 0.1 mg/kg. When serial dilutions of rat pancreatic cytosol were analyzed in the hEBP assay, [125I]hEBP was displaced by the rat preparation, but the dose-response curves were not parallel to the standard curves, indicating similarity but non-identity between the estrogen binding proteins in human and in rat pancreas.


Results of AO plate fixation of forearm shaft fractures in adults.
A series of 111 forearm fractures in 108 individuals involving 177 individual bones, and treated by AO plating is reported. There were 18 different surgeons. Open fractures occurred in 24 per cent of limbs. Reviews at a mean of 3 years after the accident showed 97 per cent of bones to be solidly united, and satisfactory function to be achieved in 80 per cent of limbs. Deep infection occurred 6 times, and non-union in 7 bones. Cross-union developed in 6 patients, all of whom had sustained head injuries. Seven patients sustained operative nerve injuries. It is felt that the implant of choice at the moment is the small fragment Dynamic Compression Plate (DCP).


Neonatal Endocrine Labomas - Pitfalls and Challenges in Reporting Neonatal Hormonal Reports.
This review highlights pitfalls and challenges in interpreting neonatal hormone reports. Pre-analytical errors contribute to nearly 50% of all errors. Modern chemiluminescence assay are more accurate, have lower risk of Hook's effect, but continue to have problems of assay interference. Liquid chromatography mass spectroscopy is gold standard for most hormone assays. Neonatal hypoglycemia diagnostic cut-offs are lower than adults. Random growth hormone testing is of value in diagnosing growth hormone deficiency in neonates. 17-hydroxy-progesterone testing in first three days of life for congenital adrenal hyperplasia (CAH) remains a challenge due to cross-reactivity with maternal circulating steroids, prematurity and lack of adrenal maturation. Both T4 and TSH testing is encouraged after 48 hours of delivery for diagnosing neonatal hypothyroidism; repeat testing should be done immediately for confirmation of diagnosis. There is an urgent need to develop age- sex- and ethnicity-based normative data for different hormone parameters in neonates. Laboratory should develop their own neonatal references and avoid using ranges from manufacturers. In neonatal endocrinopathies, the clinical scenario should primarily dictate the treatment formulation with hormonal assay to supplement treatment.


P2X7 receptor-dependent ATP-induced shedding of CD27 in mouse lymphocytes.
The ATP-gated P2X7 cell surface receptor belongs to the P2X purinoreceptor family, and is expressed abundantly by immune cells. This receptor is involved in several inflammatory and immunological processes, including the secretion of IL-1 by activated macrophages. Here, we demonstrate that CD27, a cell surface molecule, which is involved in the interaction between immune cells and implicated in the immunological memory of the T and B cells, is released rapidly upon treatment with low ATP concentrations, via the activation of the P2X7 receptor. The surface expression of CD27 on the T and B cells has been shown to be down-regulated as the result of ATP treatment, and the soluble form of CD27 was detected readily in the supernatants of splenocytes, which were cultured along with ATP treatment. The shedding of CD27 was blocked by KN-62, a chemical P2X7 inhibitor, and was also efficiently triggered by treatment with 2,3-O-(4-benzoyl-benzoyl)-ATP. The shedding of CD27 from mouse splenic T cells was observed to occur within 5 min of treatment with 300 microM ATP, whereas treatment with PMA or ionomycin was not determined to trigger the shedding of CD27 until treatment had been applied for a period of at least 2 h. The ATP-induced shedding of CD27 was inhibited by treatment with the matrix metalloprotease inhibitor, GM6001, but not by treatments with BAPTA-AM, wortmannin, SB202190, or PD 98059. Therefore, we concluded that P2X7 receptor stimulation by extracellular ATP results in rapid CD27 shedding via protease activation.


Peri-implant bony overgrowth as a cause of revision surgery in auditory osseointegrated implantation.
Implantation of auditory osseointegrated implants, also known as bone-anchored hearing systems (BAHS), represents a surgical option for select pediatric patients aged 5 years or older with hearing loss. Functional indications in this patient population include conductive or mixed hearing loss. Common complications of implantation include skin infections, chronic skin irritation, hypertrophic skin overgrowth, and loose abutments. In a case series of 15 pediatric patients, we discovered an unexpectedly high skin-related complication rate requiring surgical revision of 53%. During revision surgery, we discovered 5 patients who exhibited significant bony overgrowth at the abutment site, a complication infrequently noted in past literature.


Independent community pharmacists' attitudes and intentions toward dispensing buprenorphine/naloxone for opioid use disorder.
Buprenorphine/naloxone (BUP/NX) for opioid use disorder (OUD) is associated with positive health outcomes; however, challenges accessing prescribed BUP/NX at community pharmacies have been identified. The theory of planned behavior was applied to determine whether independent community pharmacists' attitudes toward dispensing BUP/NX for OUD predict intentions to dispense. A 40-item survey was administered to 185 Texas Community Pharmacy Enhanced Services Network pharmacists. The survey assessed intentions to dispense BUP/NX (3 items), attitudes toward BUP/NX (24 items), current barriers to dispensing BUP/NX (2 items), and demographics (10 items). Inferential statistics determined associations among pharmacists' attitudes, practice setting characteristics, and intentions to dispense BUP/NX. Regression analysis determined whether attitude predicted intention to dispense BUP/NX, controlling for practice setting and demographic characteristics. Responses were obtained from 82 community independent pharmacists (response rate = 44%). Respondents were predominantly non-Hispanic white (45.8%) and women (56.6%) and practiced in pharmacies with an average 1129.1 (± 1034.5) dispensed prescriptions/week. Pharmacists had positive intentions (6.2 ± 3.5) and attitudes (14.4 ± 24.9) toward dispensing BUP/NX and attitudes did not predict intentions to dispense (P = 0.330). Positive drivers of attitude were related to improving patient outcomes, fulfilling a community need, and absence of conflicts with pharmacists' personal and religious beliefs. A negative driver of attitude was financial reimbursement/loss. Pharmacists dispensing 2000 or more prescriptions/week had higher intentions (b = 3.22, P = 0.014) to dispense than those dispensing less than 500 prescriptions/week. The most common barrier to dispense BUP/NX was "refill was too soon" (54.8%). Community independent pharmacists had positive attitudes toward and intentions of dispensing BUP/NX for OUD. However, attitudes did not predict intentions to dispense. Negative drivers of attitudes were related to factors not within pharmacists' control, such as time to refill or financial reimbursement.Future studies focused on community pharmacy-based access to BUP/NX are warranted to elucidate issues that are impactful in improving pharmacists' dispensing intentions and behavior.


The impact of the COVID-19 pandemic on the provision of HIV/AIDS-related services in Iran: a qualitative study.
Providing services to people living with HIV (PLWH) faced many challenges during the COVID-19 pandemic. This study aimed to examine the impact of the COVID-19 pandemic on providing HIV/AIDS-related services in Iran. In this qualitative study, the participants were included by purposive sampling between November 2021 and February 2022. Virtually focused group discussion (FGD) meetings were conducted with the first group including policymakers, service providers, and researchers (n = 17), and the interviews were conducted telephonic and face-to-face using a semi-structured guide with the second group including people who received services (n = 38). Data were analyzed by content analysis using the inductive method in MAXQDA 10 software. Six categories were obtained, including mostly affected services, ways of the effect of COVID-19, healthcare systems reaction, effects on social inequality, opportunities created by the pandemic, and suggestions for the future. In addition, people who received services believed the COVID-19 pandemic has affected their life in several ways, including getting COVID-19, mental and emotional problems during the pandemic, financial problems, changes in the care plan, and changes in high-risk behaviors. Considering the level of community involvement with the issue of COVID-19 and the shock caused by the pandemic, as mentioned by the world health organization, it is necessary to improve health systems' resilience for better preparedness for similar conditions.


Pre-analytical sample stabilization by different sampling devices for PCR-based COVID-19 diagnostics.
The outbreak of the SARS-CoV-2 pandemic created an unprecedented requirement for diagnostic testing, challenging not only healthcare workers and laboratories, but also providers. Quantitative RT-PCR of various specimen types is considered the diagnostic gold standard for the detection of SARS-CoV-2, both in terms of sensitivity and specificity. The pre-analytical handling of patient specimens is a critical factor to ensure reliable and valid test results. Therefore, the effect of storage duration and temperature on SARS-CoV-2 RNA copy number stability was examined in various commercially available specimen collection, transport and storage devices for naso/oropharyngeal swabs and saliva. The swab specimen transport and storage devices tested showed no significant alteration of viral RNA copy numbers when stored at room temperature, except for one system when stored for up to 96 h. However, at 37 °C a significant reduction of detectable RNA was found in 3 out of 4 of the swab solutions tested. It was also found that detectability of viral RNA remained unchanged in all 7 saliva devices as well as in unstabilized saliva when stored for 96 h at room temperature, but one device showed marked RNA copy number loss at 37 °C. All tested saliva collection devices inhibited SARS-CoV-2 infectivity immediately, whereas SARS-CoV-2 remained infectious in the swab transport systems examined, which are designed to be used for viral or bacterial growth in cell culture systems.


A database of 5305 healthy Korean individuals reveals genetic and clinical implications for an East Asian population.
Despite substantial advances in disease genetics, studies to date have largely focused on individuals of European descent. This limits further discoveries of novel functional genetic variants in other ethnic groups. To alleviate the paucity of East Asian population genome resources, we established the Korean Variant Archive 2 (KOVA 2), which is composed of 1896 whole-genome sequences and 3409 whole-exome sequences from healthy individuals of Korean ethnicity. This is the largest genome database from the ethnic Korean population to date, surpassing the 1909 Korean individuals deposited in gnomAD. The variants in KOVA 2 displayed all the known genetic features of those from previous genome databases, and we compiled data from Korean-specific runs of homozygosity, positively selected intervals, and structural variants. In doing so, we found loci, such as the loci of ADH1A/1B and UHRF1BP1, that are strongly selected in the Korean population relative to other East Asian populations. Our analysis of allele ages revealed a correlation between variant functionality and evolutionary age. The data can be browsed and downloaded from a public website ( https://www.kobic.re.kr/kova/ ). We anticipate that KOVA 2 will serve as a valuable resource for genetic studies involving East Asian populations.


Phase Ib single- and multiple-dose pharmacokinetic study of oral NV-52 in healthy volunteers.
NV-52 is a novel synthetic flavonoid thromboxane synthase (TXS) inhibitor that may be useful for the maintenance of remission in inflammatory bowel disease (IBD). This study was conducted to determine the single- and multiple-dose pharmacokinetics of NV-52 in nine healthy volunteers (five men, four women; mean [+/- SD] age 23 +/- 2 years). NV-52 400 mg was administered once daily for 10 days (excluding day 2) in an open-label study. Plasma was sampled and urine was collected for 48 hours after the first and last doses. Plasma and urine unconjugated and total (unconjugated plus glucuronide and sulphate conjugated) NV-52 concentrations were measured using liquid chromatography-mass spectrometry. No adverse events were observed. Unconjugated and total NV-52 appeared and rose rapidly in plasma following the first dose. Time to maximum concentration values were 1.92 +/- 1.17 and 2.72 +/- 1.52 hours for unconjugated and total NV-52, respectively. Unconjugated and total NV-52 were eliminated with plasma half-lives of 13.12 +/- 17.31 and 18.03 +/- 19.06 hours, respectively, following the first dose. Pre-dose levels following multiple-dose administration were 135.17 +/- 120.03 and 751.9 +/- 679.74 ng/mL for unconjugated and total NV-52, respectively. Multiple-dose administration did not significantly alter the pharmacokinetics of NV-52. Renal elimination accounted for about 20-35% of the total (largely conjugated) drug but only 1% of unconjugated NV-52. Plasma concentrations of unconjugated NV-52 following single- and multiple-dose administration were well above the range found to be associated with suppression of colitis in a murine model of IBD.


Results of a Phase 1/2 Study in Metastatic Renal Cell Carcinoma Patients Treated with a Patient-specific Adjuvant Multi-peptide Vaccine after Resection of Metastases.
Treatment of metastatic renal cell carcinoma comprises metastasectomy±systemic medical treatment. Specific immunotherapy after metastasectomy could be a complementary option. In this phase 1/2 study, safety and tolerability of an adjuvant multi-peptide vaccine (UroRCC) after metastasectomy was evaluated together with immune response and efficacy, compared with a contemporary cohort of patients (n=44) treated with metastasectomy only. Nineteen metastatic renal cell carcinoma patients received UroRCC via intradermal or subcutaneous application randomized to immunoadjuvants (granulocyte-macrophage colony-stimulating factor or Montanide). Adverse events of UroRCC were mainly grade I and II; frequency of immune response was higher for major histocompatibility complex class II peptides (17/19, 89.5%) than for major histocompatibility complex class I peptides (8/19, 42.1%). Median overall survival was not reached in the UroRCC group (mean: 112.6 mo, 95% confidence interval [CI]: 92.1-133.1) and 58.0 mo (95% CI: 32.7-83.2) in the control cohort (p=0.015). UroRCC was an independent prognosticator of overall survival (hazard ratio=0.19, 95% CI: 0.05-0.69, p=0.012). Adjuvant UroRCC multi-peptide vaccine after metastasectomy was well tolerated, immunogenic, and indicates potential clinical benefit when compared with a contemporary control cohort (NCT02429440). PATIENT SUMMARY: The application of a patient-specific peptide vaccine after complete resection of metastases in metastatic renal cell carcinoma patients resulted in favorable tolerability and outcome.


Comparison between two different protocols of negative pressure therapy for healing of chronic ulcers.
Negative pressure therapy plays an important role in the healing process of different types of wounds. this study aimed to compare between modified and traditional method of vacuum wound closure for chronic wounds. Thirty participants with chronic ulcers completed the study, their ages ranged from 47 to 65 years, from Benha city, divided randomly into two groups, it was carried out from December 2017 to March 2019. The first group treated by the traditional method of vacuum assisted wound closure for 8 weeks; dressing was changed 3 times weekly, at 125 mmHg. The mode of 2 min off and 5 min on was used. The second group treated by the modified method by switching off the device at the fifth week and applying traditional dressing for one week then ended by three weeks of vacuum wound closure. Assessment was performed before and after the study. Student t-test was used for analysis. Paired t-test showed a significant improvement in wound surface area as well as volume for pre and post treatment in each group (p < 0.05). On the other hand independent t-test revealed a non-significant difference between the two groups pre as well as post treatment (p > 0.05). There is no significant difference between the two programs on healing of chronic ulcers. NCT03701152 - at Clinicaltrials.gov.


A weight reduction model for mildly retarded adults living in semi-independent care facilities.
A behavioural weight reduction treatment model for use with retarded adults is discussed. The model describes five stages of the treatment programme. Instructional components and techniques are reviewed. The model was designed for implementation by nurses, dieticians, and other nutritional health educators.


Composition and diversity of weed communities in Al-Jouf province, northern Saudi Arabia.
The aim of this study was to identify the main weed communities in Al-Jouf province in northern Saudi Arabia. Moreover, the composition and diversity of these communities were studied in relation to soil variables and crop type. Some 54 stands representing olive orchards, date palm orchards, wheat crop and watermelon crop were studied, using ten quadrats (1 × 1 m) per stand. A total of 71 species belonging to 22 families and 61 genera were observed. The classification of vegetation using the Two Way Indicator Species Analysis (TWINSPAN) resulted in the recognition of four vegetation groups representing wheat crop, orchards in winter season, orchards in summer season and watermelon crop. These results suggested the importance of both crop and season for the formation of weed community. Detrended Correspondence Analysis (DCA) showed that these groups are clearly distinguished by the first two DCA axes. The species richness was higher in both olive and date palm orchards than in wheat and watermelon crops. This pattern of species richness could be related to farm management practices and habitat micro-heterogeneity. Soil electrical conductivity, organic carbon and soil texture showed significant correlations with species richness and the cover values of some dominant species, suggesting the significant role of soil characteristics in weed community structure and diversity.


Do urodynamics predict urinary retention after sling placement in the complex patient: the value of reproducing symptoms on urodynamics.
To examine urinary retention (UR) after female urethral sling placement in patients with or without detrusor underactivity (DU) or Valsalva voiding whose urodynamics (UDS) accurately reproduced voiding symptoms to determine whether the reproduction of voiding symptoms on UDS in those with DU is predictive of UR after sling placement. We performed a review of patients undergoing urethral sling procedures for stress urinary incontinence (SUI) looking specifically at the occurrence of short- and long-term urinary retention. Preoperative UDS data were obtained from a prospectively acquired UDS database in which patients were directly queried at the time of the UDS study about whether the filling and/or storage phase of the study reproduced their usual symptoms. Of the 141 women who had a urethral sling procedure, 124 (87.9%) had preoperative UDS. Of those who had UDS, 41 (33%) had de novo UR at some point postoperatively. Compared to those without DU, patients with DU and/or Valsalva voiding were more likely to have UR (75.6% vs. 56.6%, p = 0.04). There was no difference in association of UR in patients with DU/Valsalva voiding whose UDS reproduced voiding symptoms compared to those with DU/Valsalva voiding whose UDS did not reproduce symptoms (OR 1.01, CI 0.32-3.19, p 0.98). This study found that patients with DU/Valsalva voiding had an increased association with UR but did not find reproduction of symptoms on UDS to correlate with UR in either those with DU/Valsalva voiding or with normal bladder contractility.


Biomarkers of human papillomavirus (HPV)-driven head and neck cancer in Latin America and Europe study: Study design and HPV DNA/p16INK4a status.
Human papillomavirus (HPV)-driven head/neck squamous cell carcinomas (HNSCC) prevalence varies globally. We evaluated HPV DNA and p16INK4a in formalin fixed paraffin embedded (FFPE) HNSCC from Argentina, Brazil, Colombia, and Peru. HPV was genotyped by PCR-hybridization. All HPV DNA positive and some HPV DNA negative cases underwent p16INK4a immunohistochemistry. HPV DNA was detected in 32.8%, 11.1%, and 17.8% of oropharyngeal (OPC), oral cavity (OCC) and laryngeal (LC) cancers, respectively. OPC HPV prevalence was higher in Colombia (94.7%), and Argentina (42.6%) compared to Brazil (10.6%) and Peru (0.0%). HPV-16 was the most detected. Other HPVs were found in LC. Higher rates of p16INK4a positivity were observed among HPV positive OPC/OCC cases compared to LC cases. Our results support a role for HPV-16 in a subset of HNSCC, corroborate the heterogeneity observed in samples from different countries, and contribute additional etiological and biomarkers information in tumors of significant impact worldwide.


Measuring Apathy in Alzheimer's Disease in the Apathy in Dementia Methylphenidate Trial 2 (ADMET 2): A Comparison of Instruments.
Diagnostic criteria for apathy have been published but have yet to be evaluated in the context of clinical trials. The Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) operationalized the diagnostic criteria for apathy (DCA) into a clinician-rated questionnaire informed by interviews with the patient and caregiver. The goal of the present study was to compare the classification of apathy using the DCA with that using the Neuropsychiatric Inventory-apathy (NPI-apathy) subscale in ADMET 2. Comparisons between NPI-Apathy and Dementia Apathy Interview Rating (DAIR) scale, and DCA and DAIR were also explored. ADMET 2 is a randomized, double-blind, placebo-controlled phase III trial examining the effects of 20 mg/day methylphenidate on symptoms of apathy over 6 months in patients with mild to moderate Alzheimer's disease (AD). Participants scoring at least 4 on the NPI-Apathy were recruited. This analysis focuses on cross-sectional correlations between baseline apathy scale scores using cross-tabulation. Of 180 participants, the median age was 76.5 years and they were predominantly white (92.8%) and male (66.1%). The mean (±standard deviation) scores were 7.7 ± 2.4 on the NPI-apathy, and 1.9 ± 0.5 on the DAIR. Of those with NPI-defined apathy, 169 (93.9%, 95% confidence interval [CI] 89.3%-96.9%) met DCA diagnostic criteria. The DCA and DAIR overlapped on apathy diagnosis for 169 participants (93.9%, 95% CI 89.3%-96.9%). The measurements used for the assessment of apathy in patients with AD had a high degree of overlap with the DCA. The NPI-apathy cut-off used to determine apathy in ADMET 2 selects those likely to meet DCA criteria.


Cerebral CT findings in male opioid-dependent patients: stereological, planimetric and linear measurements.
Cerebrospinal fluid (CSF) space enlargement has been demonstrated in substance-related disorders like alcohol and cocaine dependence. Experimental animal studies showed a reduction in shape and size of mesolimbic dopaminergic neurons after chronic morphine administration. Other studies indicated a change of neurofilament and glial fibrillary acid proteins after chronic opiate administration. Furthermore, frequent overdosing and toxicological effects of 'street'-heroin may lead to CSF space enlargement in opioid dependence. In our study the pericortical and ventricular CSF space of 21 male opioid-dependent patients was compared with an age- and sex-matched normal control group. Considering serious problems with ratio and proportion measures, we used a battery of linear (cella media index, Huckman number, frontal horn index), planimetric (cortical atrophy score) and stereological volumetric measures in order to detect differences in cranial computerized tomography scans. We found a significant ventricular and cortical volume loss of the brain in opioid-dependent patients. A higher degree of frontal lobe volume loss seemed to be associated with a shorter period of abstinence before relapse. However, the etiology of volume loss of the brain in opioid-dependent patients is still unclear, but experimental animal studies provide some evidence that long-term, chronic opiate exposure is associated with visible changes of specific structures in the brain.


Nanoemulsion curcumin injection showed significant anti-inflammatory activities on carrageenan-induced paw edema in Sprague-Dawley rats.
Medicinal plants are candidates for the discovery of potential new anti-inflammatory agents. Curcumin is the active compound found in turmeric root, which has high anti-inflammatory activity. One of the limitations of curcumin as a therapeutic agent is its low solubility in water and extensive first-pass effect metabolism. The aim of this study was to formulate curcumin nanoemulsion for parenteral injection. We prepared curcumin nanoemulsions with a homogenizer using three surfactant concentrations (1.8%; 2.4%; and 3%) and two curcumin concentrations (1% and 3%). Formulas were evaluated for droplet diameter, polydispersity index, zeta potential, viscosity, pH, entrapment efficiency (EE), osmolality, sterility, and morphology. The nanoemulsion containing 1% curcumin and 3% surfactant (F3) demonstrated good stability. Curcumin nanoemulsions at 20 and 40 mg/kg doses showed anti-inflammatory activity on carrageenan-induced paw edema in male Sprague-Dawley rats. These two doses inhibited paw edema by 33% and 56% respectively at 5 h after carrageenan induction. Inhibition of edema volume by curcumin nanoemulsion at a dose of 40 mg/kg did not show a significant difference (P > 0.05) compared to the activity of the standard drug ketorolac at a dose of 2.7 mg/kg. We conclude that curcumin nanoemulsion has anti-inflammatory activity and can be a promising anti-inflammatory agent.


Early-life stress induces EAAC1 expression reduction and attention-deficit and depressive behaviors in adolescent rats.
Neonatal maternal separation (NMS), as an early-life stress (ELS), is a risk factor to develop emotional disorders. However, the exact mechanisms remain to be defined. In the present study, we investigated the mechanisms involved in developing emotional disorders caused by NMS. First, we confirmed that NMS provoked impulsive behavior, orienting and nonselective attention-deficit, abnormal grooming, and depressive-like behaviors in adolescence. Excitatory amino acid carrier 1 (EAAC1) is an excitatory amino acid transporter expressed specifically by neurons and is the route for the neuronal uptake of glutamate/aspartate/cysteine. Compared with that in the normal control group, EAAC1 expression was remarkably reduced in the ventral hippocampus and cerebral cortex in the NMS group. Additionally, EAAC1 expression was reduced in parvalbumin-positive hippocampal GABAergic neurons in the NMS group. We also found that EAAC1-knockout (EAAC1-/-) mice exhibited impulsive-like, nonselective attention-deficit, and depressive-like behaviors compared with WT mice in adolescence, characteristics similar to those of the NMS behavior phenotype. Taken together, our results revealed that ELS induced a reduction in EAAC1 expression, suggesting that reduced EAAC1 expression is involved in the pathophysiology of attention-deficit and depressive behaviors in adolescence caused by NMS.


The variable lipoprotein family participates in the interaction of Mycoplasma hyorhinis with host extracellular matrix and plasminogen.
Mycoplasma hyorhinis (Mhr) infects pigs, typically causing polyserositis and polyarthritis. It has also been reported in various human tumors. The variable lipoprotein (Vlp) family is a vital surface component mediating the immune evasion of Mhr. We have previously reported its functions in the adherence of Mhr to pig cells. Herein, we further evaluated its role in interacting with host extracellular matrix (ECM) components (fibronectin, collagen type Ⅳ and laminin) and plasminogen. Consequently, the recombinant Vlp proteins of all the seven members (VlpA-VlpG) were able to bind most of the tested host molecules. Further experiment showed that region Ⅱ of all Vlp members has a strong binding ability, while the binding ability of region Ⅲ of each member varied between different host molecules. Comparing the Vlps containing short (rVlpX3) or long (rVlpX12) region Ⅲ, we found that the ability of most Vlps binding NCI-H292 cell membrane proteins became weaker as the molecule grows, except VlpG. However, the binding of VlpA, VlpB, VlpC and VlpG to tested ECM components and plasminogen tended to increase as Vlps became longer, and those of VlpE and VlpF decreased, and that of VlpD did not change. Furthermore, the activation of Vlp-bound plasminogen was proved. In summary, the Vlp family participates in the interaction of Mhr with host ECM and plasminogen in addition to cytoadhesion. The size variation of Vlps is likely to further regulate these interactions. The results may help to elucidate the roles of Vlps in the persistent infection of Mhr.


Increased beta-cell apoptosis and impaired insulin signaling pathway contributes to the onset of diabetes in OLETF rats.
Inappropriate adaptation of beta-cell mass is a primary cause of the development of diabetic hyperglycemia. However, the mechanisms underlying regulation of the beta-cell mass in response to insulin resistance or in the development of type 2 diabetes remain unclear. We determined the insulin signaling in the beta-cells and the adaptation of the beta-cell mass in response to the progression of insulin resistance in OLETF rats. By 25 weeks of age, at the onset of diabetes, compared to control LETO rats, OLETF rats developed obesity (Body weight: LETO vs OLETF = 474.0+/-9.5 vs 581.3+/-21.8 g, P < 0.001, n=6), hyperlipidemia (Cholesterol: LETO vs OLETF = 1.67+/-0.07 vs 2.19+/-0.20 mM, P < 0.05, n=6; triglyceride: LETO vs OLETF = 0.36+/-0.05 vs 1.36+/-0.12 mM, P < 0.001, n=6), and impaired glucose tolerance (AUC: LETO vs OLETF = 10.3+/-3.4 vs 29.6+/-7.8 mM, P < 0.001, n=6). Insulin sensitivities as assessed by the insulin sensitivity index (ISI) and the homeostasis model assessment (HOMA) indicated that OLETF rats developed severe insulin resistance. The measurement of plasma insulin levels by ELISA demonstrated, at the onset of diabetes, that fasting insulin levels were increased by 1.2-fold, and 2 hr postprandial insulin levels were increased by 3-fold (P < 0.05, n=6) in OLETF rats compared to age-matched LETO mates which is suggestive of hyperinsulinemia. Immunostaining detected a significant reduction in the insulin receptor substrate 1 (IRS1) (by 54%, P < 0.001) and IRS2 (by 55%, P < 0.001) in the beta-cells of the OLETF rats. Interestingly, while the beta-cell mass was found to be increased (by 2.2-fold; P < 0.001), the beta-cell insulin content as determined by immunostaining was significantly reduced by 32% (P < 0.001) in the OLETF rats when compared to the controls. Our findings suggest that despite increasing beta-cell mass the impaired beta-cell insulin signaling and reduced beta-cell insulin content may contribute to the onset of overt diabetes in OLETF rats.


The Fe-type nitrile hydratase from Rhodococcus equi TG328-2 forms an alpha-activator protein complex.
An Fe-type nitrile hydratase α(ɛ) protein complex from Rhodococcus equi TG328-2 (ReNHase) was discovered and shown by MALDI-TOF to form a 1:1 complex. As isolated, the α(ɛ) protein complex exhibited no detectable NHase activity even in the presence of iron. The addition of the ReNHase β-subunit and Fe(II) to the ReNHase apo-α(ε) complex, provided an enzyme with a kcat value of 0.7 ± 0.1 s-1 using acrylonitrile as the substrate, indicating that the β-subunit is important for the reconstitution of NHase activity. The addition of the reducing agent TCEP enhanced the activity by more than 50% (kcat of 1.7 ± 0.2 s-1). As the (ɛ) protein was previously shown to bind and hydrolyze GTP, the addition of GTP to the as-purified α(ε) complex provided a kcat value of 1.1 ± 0.2 s-1, in the presence of Fe(II) and β-subunit. The addition of TCEP to this combination further enhanced the activity (kcat of 2.1 ± 0.3 s-1). Apo α-subunit was expressed in purified and added to the (ɛ) protein and β-subunits plus Fe(II) and TCEP resulting in a kcat value of 0.7 ± 0.2 s-1 suggesting an α(ɛ) complex can form in vitro. The addition of GTP to this sample increased the observed rate of nitrile hydration by ~ 30%, while TCEP free samples exhibited no activity. Taken together, these data provide insight into the role of the (ɛ) protein and the newly discovered α(ɛ) complex in NHase metallocenter assembly.


Diagnosis of von Willebrand disease in Western Mexico.
Von Willebrand disease (VWD) is the most common inherited bleeding disorder with a prevalence of 0.1%, characterised by quantitative or functional deficiency of von Willebrand factor (VWF). VWD diagnosis is based on symptomology, biochemical and genetic tests, but limited laboratory resources and VWD heterogeneity still generate an important subdiagnosis gap worldwide and in our country. To identify the type and subtype of VWD in a cohort of patients with a history of excessive bleeding in Western Mexico. This prospective cohort study from 2012 to 2019 included patients with mucocutaneous bleeding or abnormal laboratory tests. A standardised questionnaire and confirmatory tests were applied: FVIII:C, VWF activity, VWF antigen, and VWF multimeric analysis. Of the 297 patients recruited, 207 (69.7%) were excluded because their values exceeded 50% in VWF activity and VWF antigen. Of those 90 remaining, 54 (18.2%) had low VWF, and only 36 patients (12.1%) were diagnosed with VWD. Among them, 17 (47.2%) had quantitative deficiencies, of whom 14 were assigned as type 1 and 3 as type 3.The remaining 19 cases were diagnosed as type 2 (52.8%): type 2A and 2B were the most frequent with 6 and 7 cases respectively; 4 cases were possible type 2M and two suggestive of 2N, however, this was not confirmed. This study highlights the challenges of VWD diagnosis using a comprehensive panel of diagnostic tests which should extend to supplemental tests of VWF:CB, VWF:FVIIIB, and sequencing the VWD gene to confirm the results from the panel assays.


Understanding Ash Sintering Variation Behaviors of Low-Rank Coals with Municipal Sludge Addition Based on Mineral Interactions.
Co-gasification with coal provides an economically viable way to use sludge. To investigate the effect of municipal sludge (MS) on the sintering behaviors of low-rank coals (LRCs) and their modification mechanisms, the initial sintering temperature (T s) of three LRCs and their mixtures with MS addition were tested by a T s analyzer, an X-ray diffractometer, and FactSage calculation. The results show that the T s values of Xiaolongtan coal (XLT), Xiangyuan coal (XY), and Daliuta coal (DLT) all increase with MS addition. The 9-12% MS mass ratio is suitable during LRC fluidized-bed gasification to mitigate ash-related issues. The T s is closely related to the liquid-phase content or the transmissions of microparticles (e.g., atoms and ions) or blank spots during heating, while the ash fusion temperatures (AFTs) are mainly determined by acid/base ratios. The T s values of high-Fe XLT and XY mixed ashes increased gradually with increasing MS proportion because the sintering mechanisms transferred from liquid phase to solid phase, while for relatively high-Mg DLT ashes, the T s values increased with increasing MS proportions, which might result from the formations of high-melting-point minerals (e.g., Ca3(PO4)2 and Mg2SiO4). The results deepen the understanding of ash sintering behaviors and provide references to alleviate ash-related issues during gasification.


Hazardous elements present in coal nanoparticles in a Caribbean port region in Colombia.
Scientific works examining coal-derived nanoparticles (NPs) containing potentially toxic elements (PTEs) confined in marine suspended sediments (MSSs) in port regions worldwide is an understudied topic, despite the fact that coal NPs have tremendous negative impacts on marine estuaries. The general objective of this study is to analyze the NP levels of coal, including PTEs, contained within MSSs in the general vicinity of the largest Caribbean port in Colombia. The morphology, size, chemical composition, and agglomeration states of NPs within MSSs of the sampled beaches were calculated through modern electron microscopy. The methodology used to detect chemical elements, unfortunately with EDS, it is not possible to precisely specify the chemical elements of low atomic weight (e.g. H, O, F, etc.) Therefore, with the EDS available today, it is only possible to have an idea of the chemical composition of each detected particle. Thus, it was possible to obtain the average frequency of the chemical elements identified in the 23 analyzed sampling points. Through the results, more than one thousand particles were detected in the most abundant phases, thus, the most frequent particles in the results of this manuscript were described. Sample point 8, located closest to the coal export port, had a higher concentration of nano-toxic elements (Al, Fe, Si, K, Mg, K) most concerning for human health in addition to being harmful to marine life. This study suggests that public policies dealing with MSS pollution need to be discussed by public managers to avoid further and sustained environmental degradation. The need to create projects will subsidize legacy liabilities generated by coal in seaports in other regions of the world.


Phospholipase D-mediated diradylglycerol formation coincides with H2O2 and lactoferrin release in adherent human neutrophils.
Polymorphonuclear leukocytes (PMNs) adherent to fibrinogen exhibit a delay in the onset of the respiratory burst in response to N-formyl-methionyl-leucyl-phenylalanine (fMLP). Previously, we demonstrated that H2O2 release in adherent PMNs coincides with the exocytosis of lactoferrin-containing specific granules. Since diradylglycerol (DRG) has been implicated in PMN secretion and oxidant release, we measured DRG formation during PMN adhesion to fibrinogen. PMNs were added to fibrinogen-coated plastic in the presence of fMLP, and H2O2 release, lactoferrin release, and DRG formation measured over a time course of 120 min. H2O2 and lactoferrin release were not apparent until 45-60 min, reaching maximal levels by 120 min. In contrast, DRG concentration increased by 15-30 min, from 275 +/- 27 pmol/mg of protein in resting cells to 600 +/- 173 pmol/mg protein in cells exposed to fMLP. DRG levels returned to base line by 30-45 min (383 +/- 32 pmol/mg of protein) before increasing again between 60 and 120 min (944 +/- 230 pmol/mg of protein and 1632 +/- 351 pmol/mg of protein, respectively). Propranolol, an inhibitor of phosphatidate phosphohydrolase, caused a dose-dependent inhibition of both H2O2 and lactoferrin release, with maximal inhibition at 50-100 microM. Propranolol also inhibited the second, but not the first phase of DRG formation. Similarly, ethanol treatment completely blocked H2O2 and lactoferrin release, and the second phase of DRG formation. In the presence of ethanol, phospholipase D (PLD)-mediated formation of [3H]phosphatidylethanol from 3H-O-alkyl-phosphatidylcholine corresponded to the second, but not the first, phase of DRG formation (23,169 +/- 2,017 cpm/mg protein, ethanol versus 2,696 +/- 261 cpm/mg protein, control). These data indicate that DRG, generated through the activation of PLD, plays an important role in degranulation and oxidant release in adherent PMNs.


Elective Surgical Cancellations in a Tertiary Hospital in the Middle East: Quality Improvement Process.
Cancellation of elective surgery negatively affects patient outcomes and the efficiency of the work environment. The purpose of this project was to analyze the cancellation of elective surgeries and identify the best evidence-based interventions to address cancellations in a tertiary hospital in the Middle East. A quality improvement study design. A retrospective review of cancellations conducted over two 3-month periods in 2016 and 2017. In both phases of the audit, patient-related reasons were the leading cause of cancellations. Conducting a preoperative call 2 days before surgery and doing a weekly review of the surgery schedule reduced cancellations from 3.8% to 3.5%. Cancellations because of patient-related reasons reduced from 81% to 79.7% whereas cancellations because of hospital-related reasons reduced from 17.5% to 15.9%. Cancellation of surgeries is a worldwide health care issue and without understanding the causes of cancellations, it is difficult to devise an effective intervention to address this issue.


Efficacy of Bortezomib as an Adjunctive Therapy for Refractory Chronic Active Antibody-Mediated Rejection in Kidney Transplant Patients: A Single-Center Experience.
Chronic active antibody-mediated rejection (CAMR) has unsatisfactory prognosis in spite of intensive standard antihumoral treatment. Efficacy of additional bortezomib in CAMR remains uncertain. A retrospective chart review was conducted among kidney transplant patients with biopsy-proven CAMR. Our standard CAMR protocol included plasma exchange, intravenous immunoglobulin, and rituximab. Repeated treatment was provided for refractory cases. Patients receiving at least 1 course of bortezomib were enrolled as the bortezomib group. Allograft outcome was compared among patients receiving repeated standard protocol alone and the bortezomib group. Thirteen and 15 patients were assigned to the bortezomib and control groups, respectively. Repeated bortezomib protocol was given for 1, 2, 3, and 4 courses in 6, 4, 1, and 2 patients, respectively. With a median follow-up time after treatment of 41.8 (18.3-47.4) months, the bortezomib group had a lower rate of glomerular filtration rate declination (-4.20 ± 4.89 mL/min/y vs -12.33 ± 10.44 mL/min/y; P = .014), a higher rate of disappearance of donor specific antibodies (69.2% vs 25%; P = .03), a lower rate of allograft loss (15.4% vs 66.7%; P = .006), and better allograft survival (P = .006). In CAMR, additional bortezomib treatment was more effective in eliminating donor specific antibodies and improving allograft survival than standard protocol treatment.


Risk factors for recurrent urinary tract infection in 4,332 Belgian schoolchildren aged between 10 and 14 years.
To analyse the risk factors for recurrent urinary tract infection (UTI) and the possible influence of potty-training, a questionnaire with 41 questions was completed by 4,332 parents of children completing the last 2 years of normal primary school. Statistical analysis was done with the Chi-squared test and Yates correction. Three groups of children emerged: one without any history of UTI ( n=3818), a group with one actual or former UTI ( n=382) and a group with recurrent UTI ( n=132). Mean age was 11.5+/-0.56 years. A strong correlation between daytime and/or night-time wetting, voiding frequency of more than 10 times a day and nocturia and recurrent UTI was found. No correlation between these factors and a single UTI could be demonstrated. In the 343 bed-wetting children, equal infections for boys and girls were found. Potty-training started significantly earlier in children without UTI. Parents of children with recurrent UTIs insisted more when the first attempt to void was unsuccessful: in the group without UTI, most parents just postponed and had the child try later again. In the group with recurrent UTI, more parents asked the child to strain, made special noises or turned on a tap. Daytime with/without night-time wetting, more than 10 voidings a day and nocturia are indicators of recurrent urinary tract infections. If they are simultaneously present, the relative risk for recurrent urinary tract infections is 60%. Consequently, paediatricians should take urinary symptoms very seriously into account, and as incontinence is still a hidden condition, question the child on this topic.


Peer attachment formation by systemic redox regulation with social training after a sensitive period.
Attachment formation is the most pivotal factor for humans and animals in the growth and development of social relationships. However, the developmental processes of attachment formation mediated by sensory-motor, emotional, and cognitive integration remain obscure. Here we developed an animal model to understand the types of social interactions that lead to peer-social attachment formation. We found that the social interaction in a sensitive period was essential to stabilise or overwrite the initially imprinted peer affiliation state and that synchronised behaviour with others based on common motivations could be a driver of peer social attachment formation. Furthermore, feeding experience with supplementation of ubiquinol conferred peer social attachment formation even after the sensitive period. Surprisingly, the experience of feeding beyond the cage window was also effective to reduce the required amount ubiquinol, suggesting that peri-personal space modulation may affect socio-emotional cognition and there by lead to attachment formation.


Pharmacology and neurochemistry of bombesin-like peptides.
The pharmacology and neurochemistry of bombesin-like peptides was investigated. Synthetic analogues which had modifications near the N-terminal inhibited specific binding of (125I-Tyr4)BN with high affinity in rat brain and these peptides were potent hypothermic agents after central injection. In comparison, BN-like peptides with modifications near the C-terminal bound with low affinity and were not potent hypothermic agents. These data indicate that the C-terminal of BN is required for central high affinity binding and biological potency. Because substitution of D for L-amino acids at the 8, 10, 13 or 14 positions greatly reduced receptor binding affinity and ability to induce hypothermia, central receptors for BN show marked stereospecificity. Also, the pharmacology of BN in the periphery was investigated using dispersed guinea pig pancreatic acini and found to be similar to that of the brain. Because endogenous BN-like peptides extracted from brain tissue possess appreciable biological activity, these receptors are likely activated by endogenous BN-like peptides in vivo.


Association of residential greenness with chronotype among children.
The association between residential greenness and chronotype remains unclear, especially among children. The current study aimed to explore the associations between residential greenness and chronotype parameters in children and examine potential pathways for these associations. In this cross-sectional study, 16,421 children ages 3-12 were included. Two satellite-derived vegetation indices, i.e., the normalized difference vegetation index (NDVI) and the enhanced vegetation index (EVI), were used to estimate residential greenness. The mid-sleep point on a workday (MSW) and the mid-sleep point on free days (MSF) were considered. And mid-sleep time on free days adjusted for sleep debt (MSFsc) was used as an indicator of chronotype. In addition to multivariable linear regression models, subgroup analyses were conducted to explore effect modifiers, and mediation analyses were used to explore possible mediating mechanisms of air pollutants underlying the associations. An interquartile range (IQR) increase in both NDVI500-m and EVI500-m was significantly associated with an earlier MSFsc of -0.061 (95 % confidence interval (CI): -0.072, -0.049) and -0.054 (95 % CI: -0.066, -0.042), respectively. Non-linear dose response relationships were discovered between greenness indices and MSFsc and MSF. The results of stratified analyses showed the effect of residential greenness on MSW was stronger among primary school children and individuals with higher household income than among kindergarten children and those with lower household income. The joint mediation effects of PM2.5, PM1, PM10, NO2, and SO2 on the associations of NDVI500-m and EVI500-m with MSFsc were 89.6 % and 76.0 %, respectively. Higher levels of residential greenness may have beneficial effects on an earlier chronotype in the child population, by reducing the effects of air pollutants, especially PM2.5. Our research hopes to promote the deployment of green infrastructure and healthy urban design strategies.


Folding research recruits unconventional help.
A denatured protein chain can find its well-ordered three-dimensional structure, the native state, in under a second, using only the information contained in the sequence. For researchers, however, the prediction of structures from sequences is a hard problem, so they are now recruiting all the help they can get, including idle computers and game consoles, game players, and little hints from evolution. Michael Gross reports.


Neurological manifestations in patients with COVID-19: A systematic review and meta-analysis.
The intensification of coronavirus disease 2019 (COVID-19) complications, severe symptoms, and high mortality rate has led researchers to focus on this significant issue. While respiratory and cardiac complications have been described as high-risk manifestations in patients with COVID-19, neurological complications can also enhance mortality. This study aimed to evaluate the prevalence of neurological complications arises from SARS-CoV-2 and assess the mortality rate from neurological complications. Literature review was conducted by searching in PubMed/Medline, Web of Sciences, and Embase. After performing search strategies with relevant terms, a number of articles were excluded, including review articles, systematic review or meta-analysis, duplicate publication of same researchers, congress abstracts, animal studies, case reports, case series, and articles reporting a history of neurological features prior to COVID-19 infection. After retrieving the data, statistical analysis was performed using the STATA Version 14 software. From 4455 retrieved publications, 20 articles were selected for further analysis. Among 18,258 included patients, 2791 showed neurological symptoms, which were classified into different groups. Headache, confusion, and fatigue were reported as the most non-specific neurological features in confirmed COVID-19 patients. Psychiatric symptoms, CNS disorders, cerebrovascular disorders, CNS inflammatory disorders, PNS disorders, neuromuscular disorders, etc., were defined as specific neurological manifestations. The pooled prevalence of neurological manifestations and mortality rate of COVID-19 patients with neurological features were estimated to be 23.0% (95% CI: 17.8-29.2) and 29.1% (95% CI: 20.3-39.8), respectively. Neurological manifestations may commonly happen in patients with COVID-19. This study reported a high prevalence of neurological complications and mortality rates in COVID-19 patients. Therefore, patients with COVID-19 who indicated neurological symptoms should be taken seriously and should receive early treatment to prevent undesirable events.


Abyssicoccus albus gen. nov., sp. nov., a novel member of the family Staphylococcaceae isolated from marine sediment of the Indian Ocean.
A Gram-stain positive, aerobic, non-motile, asporogenous, coccoid shaped bacterium, designated YIM M12140(T), was isolated from a marine sediment sample collected from the Indian Ocean. Phylogenetic analysis showed that strain YIM M12140(T) forms a separate clade within the family Staphylococcaceae. Strain YIM M12140(T) shares high 16S rRNA gene sequence similarity with Macrococcus brunensis DSM 19358(T) (92.9 %). The isolate was found to grow at 0-10 % (w/v) NaCl (optimum, 2-3 %), pH 6.0-10.0 (optimum, pH 8.0) and temperature 5-40 °C (optimum, 28 °C). The polar lipids were identified as diphosphatidylglycerol, phosphatidylglycerol, one unidentified aminophospholipid and two unidentified polar lipids. The major cellular fatty acids of the strain were identified as anteiso-C15:0, -C17:0, iso-C16:0, anteiso-C19:0 and C20:0. The respiratory menaquinones were found to be MK-6 (94 %) and MK-7 (6 %). The cell wall amino acids were found to contain Lys, Ala, Glu, Gly, Asp, Ser and Thr. Whole cell sugars were identified as mannose, ribose, rhamnose, glucose, galactose and xylose. The G+C content of the genomic DNA of strain YIM M12140(T) was determined to be 42.4 mol %. Based on phenotypic, chemotaxonomic data and phylogenetic analysis, it is proposed that strain YIM M12140(T) represents a novel species of a new genus in the family Staphylococcaceae, for which the name Abyssicoccus albus gen. nov., sp. nov. is proposed. The type strain is YIM M12140(T) (= DSM 29158(T) = CCTCC AB 2014213(T)).


Low-density lipoprotein concentration in interstitial fluid from human atherosclerotic lesions. Relation to theories of endothelial damage and lipoprotein binding.
Increased endothelial permeability to low-density lipoprotein (LDL) is believed to be an initiating factor for atherosclerotic lesions. Concentrations of LDL, alpha 2-macroglobulin and albumin were measured by immunoassay in interstitial fluid collected from normal intima and atherosclerotic lesions of human aortas. The concentration of LDL in interstitial fluid from normal intima was twice the concentration in the patient's serum. In early proliferative (gelatinous) lesions the amount of interstitial fluid was consistently increased but its LDL concentration varied between 80 and 200% of adjacent normal intima. Highest concentrations of LDL were found in interstitial fluid from more advanced proliferative lesions, but the amount was reduced, suggesting a shift in tissue water. LDL was consistently low in interstitial fluid from fatty streaks comprised of lipid-filled cells, and in four of 12 lesions it was absent although alpha 2-macroglobulin and albumin concentrations were normal. Electrophoretic mobility of LDL, reflecting surface charge, was unchanged or increased in interstitial fluid from normal intima and fatty streaks, but decreased in gelatinous lesions. The ratio of LDL to alpha 2-macroglobulin and albumin in interstitial fluid was higher than in adjacent intact tissue. The results do not support the idea that increased endothelial permeability to LDL initiates atherogenesis.


Synthesis of some phenothiazine derivatives as potential affinity ligands for the central dopamine receptors.
Syntheses of several phenothiazine ligands as potential affinity probes for the D1- and D2-dopamine receptors derived from 4-(3-(10-(2-trifluoromethyl)phenothiazinyl)propyl)-1-(2-aminoethyl )-piperazine hydrochloride are described and their interactions with D1- and D2-dopamine receptors of the bovine caudate nucleus have been characterized. The bromoacetylamido-, maleinimido-, and isothiocyanato-derivatives expressed low selectivity and moderate affinity for both categories of dopamine receptors. 4-(3-(10-(2-Trifluoromethyl)phenothiazinyl)propyl)-1-(2- (isothiocyanatobenzoyl)ethyl)-piperazine hydrochloride did not discriminate among the two subclasses of the dopamine receptors, but showed an extremely strong irreversible binding to the D1-receptors and thus is promising as a highly specific affinity ligand for biochemical and pharmacological studies of the D1-dopamine receptors.


Feasibility of Anterior Fixation with Single Screw for Odontoid Fractures in Pediatrics: A Computed Tomographic Study.
Although it is an effective fixation technique for an unstable odontoid, anterior fixation remains challenging in pediatric populations. Our study measures the anatomical parameters of the odontoid to identify the feasibility of anterior fixation with a single screw for children. We retrospectively collected data from 112 normal male and female children (aged between 2 and 18) in our institute from January 1, 2022 to December 31, 2022. Subjects were divided into a youth group (2-6 years old), a juvenile group (7-12 years old), and an adolescent group (13-18 years old). Sagittal and coronal computed tomography images of the upper cervical spine were used to measure the screw length, angle, and inner and outer diameters of the odontoid. One-way analysis of variance with the Tukey test was used to analyze the parameters among the groups, while the t-test was used to analyze gender differences. Correlations between parameters and age were assessed using Pearson's test. There were significant differences between male and female subjects in screw length and inner and outer diameters (of both sagittal and coronal views) but not in screw angle. The narrowest diameter of the odontoid was 4.0 ± 1.5 mm in the youth group, 5.5 ± 1.5 mm in the juvenile group, and 5.6 ± 1.1 mm in the adolescent group, respectively. There were significant differences among the three groups in screw length (p < 0.0001). The screw angle of the adolescent group was significantly smaller than that of the youth and juvenile groups. More than 90% of children aged 7-18 years old had an odontoid diameter greater than 4 mm, while only half of the youth group had an odontoid with diameter >4 mm. Screw length and inner and outer diameters in lateral view were positively correlated with age, and screw angle was negatively correlated with age. It is feasible to insert a standard single screw (Φ 3.5 mm) into the odontoid of children aged 7-18 years old but not those aged 2-6 years old. How the anatomical parameters of the odontoid change with age, especially the narrowest diameters, is worthy of attention.


Recognition of open conformers of classical MHC by chaperones and monoclonal antibodies.
There is considerable evidence that the conformation and stability of class I and class II major histocompatibility complex (MHC) proteins is dependent upon high-affinity peptide ligation, but structural data for an empty MHC protein unfortunately is lacking. However, several monoclonal antibodies (mAbs) that specifically detect open MHC conformers have been characterized, and they provide insights into the changes associated with peptide loading and unloading. Here, the structural changes make the argument that certain of these open conformer-specific mAbs recognize analogous MHC segments as the molecular chaperones tapasin and DM. MHC residues located in regions flanking the peptide-terminal anchoring pockets have been implicated in both chaperone and monoclonal antibody binding. Indeed, we propose these regions serve as peptide-binding hinges that are uniquely accessible in open MHC.


[Characteristics of older versus younger emergency patients : Analysis of over 356,000 visits from the AKTIN German emergency department data registry].
This nationwide study aims to analyze age-specific differences and characteristics of emergency patients with a special focus on older patients. In 2019, data were obtained from 11 emergency departments (EDs), all part of the German Emergency Department Data (AKTIN) registry. All patients 18 years and older visiting the EDs were included. In addition to demographic data, variables such as referral, type of transport, primary assessment, diagnoses, length of stay and type of transfer were recorded and compared by age group and specifically by younger (18-64 years) and older patients (65+ years). Data from 356,354 patients (39.1% were aged 65+ years) were included. Compared to younger patients, older ED patients were more likely to be accompanied by emergency medical services (15.4 vs. 34.3%) and almost twice as often by an emergency physician (6.4 vs. 12.2%). The need for treatment increased with age; 47.1% of younger and 66.1% of older people were classified as yellow, orange or red. The proportion of patients with internal diseases was higher for patients 65+ years (22.5 vs. 38.8%). Older patients were more often hospitalized (27.5 vs. 60.3%) and were more frequently transferred to an intensive care unit (4.5 vs. 11.9%). About 40% of adult emergency patients are 65+ years. They require more urgent treatment and are more often hospitalized than younger patients. In older patients, internal diseases were more common.


Peculiar pattern of glial fibrillary acidic protein production in extracranial metastatic tumor cells of malignant astrocytoma.
An 83-year-old woman suffered from malignant astrocytoma originating in the temporal lobe. Autopsy revealed its extracranial metastasis to the liver, lung and bone marrow. The tumor tissue at the primary site was composed of plump, process-forming cells and small cells with scanty cytoplasm, and showed dural invasion. In the metastatic areas, most of the tumor cells were small cells, although proliferation of the plump cells in contact with perivascular connective tissue was marked, particularly in the liver. These plump cells were positively stained with antiserum to glial fibrillary acidic protein (GFAP), showing that the collagenous tissue was able to induce increased production of GFAP by the glial tumor cells.


Multifractal analysis of weighted networks by a modified sandbox algorithm.
Complex networks have attracted growing attention in many fields. As a generalization of fractal analysis, multifractal analysis (MFA) is a useful way to systematically describe the spatial heterogeneity of both theoretical and experimental fractal patterns. Some algorithms for MFA of unweighted complex networks have been proposed in the past a few years, including the sandbox (SB) algorithm recently employed by our group. In this paper, a modified SB algorithm (we call it SBw algorithm) is proposed for MFA of weighted networks. First, we use the SBw algorithm to study the multifractal property of two families of weighted fractal networks (WFNs): "Sierpinski" WFNs and "Cantor dust" WFNs. We also discuss how the fractal dimension and generalized fractal dimensions change with the edge-weights of the WFN. From the comparison between the theoretical and numerical fractal dimensions of these networks, we can find that the proposed SBw algorithm is efficient and feasible for MFA of weighted networks. Then, we apply the SBw algorithm to study multifractal properties of some real weighted networks - collaboration networks. It is found that the multifractality exists in these weighted networks, and is affected by their edge-weights.


Ill-defined: Concepts of mental health and illness are becoming broader, looser, and more benign.
We argue that mental health-related concepts have become degraded within professional circles and in the wider community. We identify three trends: concept creep, the rise of broad umbrella concepts (e.g. distress and trauma), and the conflation of mental health with well-being, which marginalises serious mental illness. We speculate on the causes of these trends, including cultural shifts towards greater sensitivity to harm and the rise of wellness industries. Contributing factors within psychiatry include overdiagnosis, dimensional models and transdiagnostic perspectives. These trends may lead to inflated demands on services from those at the milder end of the psychopathological spectrum. We set out seven measures that mental health professionals can take to resist trends towards broad concepts of mental illness and limit some of their adverse consequences.


The dependence of ipsilesional aiming deficits on task demands, lesioned hemisphere, and apraxia.
Neuroimaging studies as well as neurophysiological and lesion data indicate that the ipsilateral hemisphere plays a role in controlling the active limb. However, the nature and the conditions of this ipsilateral control are not well understood. We measured aiming movements with the ipsilesional limb toward targets with different characteristics which were made by patients with unilateral left brain damage (LBD) or right brain damage (RBD). The movement kinematics were analysed. Performance measures of the pointing movements were impaired in LBD patients, whereas RBD patients performed normally. LBD patients had obvious deficits during all tasks; however, they were exacerbated when high accuracy was required, and when an exocentric target had to be reached without visual feedback. Thus, the motor-dominant hemisphere plays a specific role in the programming and execution of ipsilateral aiming movements, and the importance of ipsilateral control increases with increasing task demands. To assess the relationship between pointing deficits and apraxia in LBD patients, the imitation of meaning gestures was tested. We replicated a recent study, showing that deviations of the final hand position from the demonstration were not correlated with abnormal kinematics of the corresponding arm movement when LBD patients performed this test. However, there were correlations between related kinematic measures during pointing and gesture imitation. These findings suggest a deficit of motor programming and execution after damage to the motor-dominant brain which is unrelated to the spatial errors characteristic of apraxia. This deficit affects different types of goal-directed aiming movements and its severity depends on task demands.


Molecular symmetry and biological activities of new symmetrical tris(2-aminoethyl)amine derivatives.
In terms of molecular symmetry and bioactivity, new C3- and CS-symmetrical derivatives based on the tris(2-aminoethyl)amine scaffold were designed and synthesized. The synthesized compounds were evaluated for antiviral activity with herpes simplex virus type 1 (HSV-1) by a plaque reduction assay and for cytotoxic activity with Vero cells. Most of the compounds showed no significant anti-HSV-1 activity, but some of the symmetrical derivatives showed high levels of cytotoxic activitiy.


Coupling between myosin head conformation and the thick filament backbone structure.
The recent high-resolution structure of the thick filament from Lethocerus asynchronous flight muscle shows aspects of thick filament structure never before revealed that may shed some light on how striated muscles function. The phenomenon of stretch activation underlies the function of asynchronous flight muscle. It is most highly developed in flight muscle, but is also observed in other striated muscles such as cardiac muscle. Although stretch activation is likely to be complex, involving more than a single structural aspect of striated muscle, the thick filament itself, would be a prime site for regulatory function because it must bear all of the tension produced by both its associated myosin motors and any externally applied force. Here we show the first structural evidence that the arrangement of myosin heads within the interacting heads motif is coupled to the structure of the thick filament backbone. We find that a change in helical angle of 0.16° disorders the blocked head preferentially within the Lethocerus interacting heads motif. This observation suggests a mechanism for how tension affects the dynamics of the myosin heads leading to a detailed hypothesis for stretch activation and shortening deactivation, in which the blocked head preferentially binds the thin filament followed by the free head when force production occurs.


Mutagenicity of diesel exhaust particle extracts: influence of driving cycle and environmental temperature.
General Motors and Volkswagen diesel passenger cars (1980 and 1981 model year) were operated on a climate controlled chassis dynomometer and the particulate portion of the exhaust was collected on high volume filters. Dichloromethane extracts of the exhaust particles (soot) collected while the cars were operated under simulated highway, urban and congested urban driving cycles were assayed for mutagenicity in Salmonella strains TA-98 and TA-100. Driving pattern did not significantly influence the mutagenic potency of the exhaust particle extracts or estimates of the amount of mutagenicity emitted from the exhaust despite large differences in particle emission rates and extractable fraction of the particles. Mutagenicity of extracts of exhaust particles collected while the vehicles were operated at test chamber temperatures of 25, 50, 75 and 100 degrees F were also very similar. The results suggest that driving pattern and environmental temperature do not significantly alter the emission of genotoxic combustion products from the exhaust.


Pin-site care: can we reduce the incidence of infections?
This study was conducted to determine the pin-site care protocols currently in use and to analyse their effectiveness and outcomes. PubMed, the Cochrane Library and Embase databases were screened for manuscripts that described comparative studies of different methods of pin-site care and referred to complications related to any kind of external fixator application. A total of 369 manuscripts were screened and only 13 of these met the inclusion criteria evaluating different protocols of pin-site care. This review is based on a total of 574 patients. Infection rates were very variable depending on the type of implant used and the protocol of pin-site care applied. None of the different protocols of pin-site care that were evaluated in this study were associated with a 0% infection rate. There is currently no consensus in the international literature about which protocol should be applied universally. Meticulous surgical technique during pin insertion and implementation of one of the existing protocols of pin-site care are the mainstay of prevention and/or reduction of the incidence of pin-site infections.


The mechanism of antiproliferative activity of the oxaliplatin pyrophosphate derivative involves its binding to nuclear DNA in cancer cells.
(1R,2R-diaminocyclohexane)(dihydropyrophosphato) platinum(II), also abbreviated as RRD2, belongs to a class of potent antitumor platinum cytostatics called phosphaplatins. Curiously, several published studies have suggested significant mechanistic differences between phosphaplatins and conventional platinum antitumor drugs. Controversial findings have been published regarding the role of RRD2 binding to DNA in the mechanism of its antiproliferative activity in cancer cells. This prompted us to perform detailed studies to confirm or rule out the role of RRD2 binding to DNA in its antiproliferative effect in cancer cells. Here, we show that RRD2 exhibits excellent antiproliferative activity in various cancer cell lines, with IC50 values in the low micromolar or submicromolar range. Moreover, the results of this study demonstrate that DNA lesions caused by RRD2 contribute to killing cancer cells treated with this phosphaplatin derivative. Additionally, our data indicate that RRD2 accumulates in cancer cells but to a lesser extent than cisplatin. On the other hand, the efficiency of cisplatin and RRD2, after they accumulate in cancer cells, in binding to nuclear DNA is similar. Our results also show that RRD2 in the medium, in which the cells were cultured before RRD2 accumulated inside the cells, remained intact. This result is consistent with the view that RRD2 is activated by releasing free pyrophosphate only in the environment of cancer cells, thereby allowing RRD2 to bind to nuclear DNA.


STAT3 mediates TGF-β1-induced TWIST1 expression and prostate cancer invasion.
TGF-β1 induces epithelial-mesenchymal transition (EMT) to stimulate cancer cell progression, and TWIST1 is a critical regulator of EMT. In the present study, we determined the underlying mechanisms of TGF-β1-induced TWIST1 expression and its effect on prostate cancer cell invasion. TGF-β1 stimulated STAT3 phosphorylation and HIF-1α expression. Silencing either STAT3 or HIF-1α efficiently attenuated TGF-β1-induced TWIST1 expression. Further ectopic expression of a dominant negative mutant of STAT3 reduced TGF-β1-induced TWIST1 expression. In addition, STAT3 and HIF-1α up-regulated TWIST1 expression by direct binding to a TWIST1 promoter. Strikingly, STAT3 also enhanced TGF-β1-induced TWIST1 expression through HIF-1α stabilization. Collectively, we demonstrate a mechanistic cascade of TGF-β1 up-regulating STAT3 activation and HIF-1α stabilization and subsequent TWIST1 expression, leading to prostate cancer invasion.


Myoclonic epilepsy and ragged-red fiber disease (MERRF) is associated with a mitochondrial DNA tRNA(Lys) mutation.
An A to G transition mutation at nucleotide pair 8344 in human mitochondrial DNA (mtDNA) has been identified as the cause of MERRF. The mutation alters the T psi C loop of the tRNA(Lys) gene and creates a CviJI restriction site, providing a simple molecular diagnostic test for the disease. This mutation was present in three independent MERRF pedigrees and absent in 75 controls, altered a conserved nucleotide, and was heteroplasmic. All MERRF patients and their less-affected maternal relatives had between 2% and 27% wild-type mtDNAs and showed an age-related association between genotype and phenotype. This suggests that a small percentage of normal mtDNAs has a large protective effect on phenotype. This mutation provides molecular confirmation that some forms of epilepsy are the result of deficiencies in mitochondrial energy production.


Natural history of corneal topography after excimer laser photorefractive keratectomy.
To investigate the natural history of corneal topography after excimer laser photorefractive keratectomy (PRK). A prospective, single center clinical study. A total of 40 eyes of 34 patients with myopia were studied. Excimer laser photorefractive keratectomy and computer-assisted videokeratography were performed. Preoperative, 1 week, and 1, 2, and 3 months postoperative topography patterns were compared and changes assessed by averaging defined sectors of the ablation zone in individual maps to produce composite "average" topography maps. Corneal topography was generally not homogeneous at 1 week after PRK. By 3 months, there had been considerable smoothing of corneal contour. A general "central island" effect early in the postoperative period flattened over time. When right and left eyes were evaluated independently, a tendency toward a keyhole-semicircular pattern was seen on average; the maximum flattening was nasal and the least flattening was inferotemporal for both right and left eyes. A tendency, on average, toward central island and keyhole-semicircular patterns is seen early in the postoperative course after PRK. Central islands tend to evolve into the keyhole-semicircular pattern, and the corneal topography in general after PRK tends to smooth considerably with time.


Cancer Stem Cell-Based Models of Colorectal Cancer Reveal Molecular Determinants of Therapy Resistance.
Colorectal cancer (CRC) therapy mainly relies on the use of conventional chemotherapeutic drugs combined, in a subset of patients, with epidermal growth factor receptor [EGFR]-targeting agents. Although CRC is considered a prototype of a cancer stem cell (CSC)-driven tumor, the effects of both conventional and targeted therapies on the CSC compartment are largely unknown. We have optimized a protocol for colorectal CSC isolation that allowed us to obtain CSC-enriched cultures from primary tumor specimens, with high efficiency. CSC isolation was followed by in vitro and in vivo validation, genetic characterization, and drug sensitivity analysis, thus generating panels of CSC lines with defined patterns of genetic mutations and therapy sensitivity. Colorectal CSC lines were polyclonal and maintained intratumor heterogeneity in terms of somatically acquired mutations and differentiation state. Such CSC-enriched cultures were used to investigate the effects of both conventional and targeted therapies on the CSC compartment in vivo and to generate a proteomic picture of signaling pathways implicated in sensitivity/resistance to anti-EGFR agents. We propose CSC lines as a sound preclinical framework to test the effects of therapies in vitro and in vivo and to identify novel determinants of therapy resistance. Colorectal cancer stem cells (CSCs) have been shown to be responsible for tumor propagation, metastatic dissemination, and relapse. However, molecular pathways present in CSCs, as well as mechanisms of therapy resistance, are mostly unknown. Taking advantage of genetically characterized CSC lines derived from colorectal tumors, this study provides an extensive analysis of CSC response to EGFR-targeted therapy in vivo and an overview of factors implicated in therapy response or resistance. Furthermore, the implementation of a biobank of molecularly annotated CSC lines provides an innovative resource for future investigations in colorectal cancer.


Sphingosine 1-Phosphate Receptors in Cerebral Ischemia.
Sphingosine 1-phosphate (S1P) is an important lipid biomolecule that exerts pleiotropic cellular actions as it binds to and activates its five G-protein-coupled receptors, S1P1-5. Through these receptors, S1P can mediate diverse biological activities in both healthy and diseased conditions. S1P is produced by S1P-producing enzymes, sphingosine kinases (SphK1 and SphK2), and is abundantly present in different organs, including the brain. The medically important roles of receptor-mediated S1P signaling are well characterized in multiple sclerosis because FTY720 (Gilenya™, Novartis), a non-selective S1P receptor modulator, is currently used as a treatment for this disease. In cerebral ischemia, its role is also notable because of FTY720's efficacy in both rodent models and human patients with cerebral ischemia. In particular, some of the S1P receptors, including S1P1, S1P2, and S1P3, have been identified as pathogenic players in cerebral ischemia. Other than these receptors, S1P itself and S1P-producing enzymes have been shown to play certain roles in cerebral ischemia. This review aims to compile the current updates and overviews about the roles of S1P signaling, along with a focus on S1P receptors in cerebral ischemia, based on recent studies that used in vivo rodent models of cerebral ischemia.


Pattern of invasion and lymphovascular invasion in squamous cell carcinoma of the floor of the mouth: an interobserver variability study.
Lymphovascular invasion (LVI) and the histological pattern of invasion (POI) at the invasive tumour front have been reported as adverse prognosticators in oral squamous cell carcinoma (SCC). However, assessment of these parameters is hampered by variation in the criteria used for their evaluation. Our objective was to evaluate interobserver variability in the assessment of the POI and LVI in SCC of the floor of the mouth (FOM), and to study the impact of the POI on clinical outcomes by using varying quantitative cut-offs. Fifty-eight cases of FOM SCC were independently evaluated for the POI and LVI by three pathologists. Interobserver variability was analysed by the use of Fleiss kappa statistics. Interobserver agreement was substantial for the assessment of LVI [κ = 0.64, 95% confidence interval (CI) 0.60-0.68]. Interobserver agreement was moderate for evaluation of the POI with a 50% cut-off (κ = 0.58, 95% CI 0.54-0.62), a 20% cut-off (κ = 0.58, 95% CI 0.54-0.62) cut-off, and worst POI (κ =0 .43, 95% CI 0.39-0.46). A consensus diagnosis of the POI was a significant predictor of locoregional recurrence (LRR), disease-specific survival (DSS) and overall survival (OS) on univariate analysis when a 50% cut-off was used (LRR, P = 0.01; DSS, P = 0.01; OS, P = 0.01) and when a 20% cut-off was used (LRR, P = 0.02; DSS, P = 0.02; OS, P = 0.03), but was not significant when worst POI was used (LRR, P = 0.18; DSS, P = 0.16; OS, P = 0.17). Interobserver agreement in the diagnosis of LVI was substantial. The POI at the 50% and 20% cut-offs is moderately reproducible, and has prognostic value in FOM SCC. Further studies are necessary to establish the optimum quantitative cut-off for the POI.


Interview assessment of critically Ill patients regarding resuscitation decisions. A case study in ethics research.
To examine how patients perceive and decide their resuscitation status, we monitored 113 admissions to a coronary care unit. We review the research process, including Institutional Review Board concerns, sampling bias and permission by physicians, informed consent, and the patient interview. In-depth psychiatric interviews on 16 patients demonstrated marked misperceptions about resuscitation procedures. Although standardized psychologic measures indicated distress in some of these critically ill patients, the interview itself induced no detected untoward physiologic or emotional reactions. This pilot study demonstrates the feasibility of assessing patients regarding resuscitation status and also identifies relevant methodologic problems to guide future research of resuscitation decision-making.


Rapid and sensitive detection of viral particles by coupling redox cycling and electrophoretic enrichment.
The COVID-19 pandemic has highlighted the need for rapid, low-cost, and sensitive virus detection platforms to monitor and mitigate widespread outbreaks. Electrochemical sensors are a viable choice to fill this role but still require improvements to the signal magnitude, especially for early detection and low viral loads. Herein, finite element analysis of a novel biosensor concept for single virion counting using a generator-collector microelectrode design is presented. The proposed design combines a redox-cycling amplified electrochemical current with electrophoresis-driven electrode-particle collision for rapid virus detection. The effects of experimental (e.g. scan rate, collector bias) and geometric factors are studied to optimize the sensor design. Two generator-collector configurations are explored: a ring-disk configuration to analyze sessile droplets and an interdigitated electrode (IDE) design housed in a microchannel. For the ring-disk configuration, we calculate an amplification factor of ∼5 and collector efficiency of ∼0.8 for a generator-collector spacing of 600 nm. For the IDE, the collector efficiency is even larger, approaching unity. The dual-electrode mode is critical for increasing the current and electric field strength. As a result, the current steps upon virus capture are more than an order of magnitude larger compared to single-mode. Additionally, single virus capture times are reduced from over 700 s down to ∼20 s. Overall, the frequency of virus capture and magnitude of the electrochemical current steps depend on the virus properties and electrode configuration, with the IDE capable of single virus detection within seconds owing to better particle confinement in the microchannel.


Assignment of the rat genes coding for alpha 1-antitrypsin (PI), phosphoenolpyruvate carboxykinase (PEPCK), alcohol dehydrogenase (ADH), and fructose-1,6-bisphosphatase (FDP).
The chromosomal localization of four genes which are expressed mainly in the liver has been undertaken for the rat. Using a panel of hybrid clones segregating rat chromosomes, and Southern blot analysis, alpha 1-AT (PI), PEPCK, ADH and FDP are assigned to rat Chromosomes (Chr) 6, 3, 2 and 17, respectively. Groups of synteny among rat, mouse and human species are discussed in relationship to the new assignments.