Topologically Precise and Discrete Bottlebrush Polymers: Synthesis, Characterization, and Structure-Property Relationships.
As the complexity of polymer structure grows, so do the challenges for developing an accurate understanding of their structure-property relationships. Here, the synthesis of bottlebrush polymers with topologically precise and fully discrete structures is reported. A key feature of the strategy is the synthesis of discrete macromonomer libraries for their polymerization into topologically precise bottlebrushes that can be separated into discrete bottlebrushes (Đ = 1.0). As the system becomes more discrete, packing efficiency increases, distinct three-phase Langmuir-Blodgett isotherms are observed, and its glass transition temperature becomes responsive to side-chain sequence. Overall, this work presents a versatile strategy to access a range of precision bottlebrush polymers and unravels the impact of side-chain topology on their macroscopic properties. Precise control over side chains opens a pathway for tailoring polymer properties without changing their chemical makeup.


Decreased digitalis receptor activity in acute rejecting canine transplanted heart.
In the course of acute rejection, myocardial tissue undergoes massive transformation and we hypothetized that for digitalis-like substances, receptor binding characteristics might be altered. Ten canine heterotopic cardiac allografts were carried out and were harvested once rejection had developed (8-10 days post-transplant). Microsomal membrane fractions of those grafts and of native hearts were isolated. Radioligand binding studies were carried out in a medium containing 5 mM Tris PO4, 50 mM Tris HCl, 5 mM MgCl2, pH 7.4 at 37 degrees C, using 3H-ouabain as the ligand. Saturation experiments (n = 10) indicate the presence of one homogeneous population of high affinity binding sites with an affinity constant (Kd) of 8-13 nM and a maximum binding capacity (Bmax) of 47 +/- 3.5 pmol/mg protein. Both saturation and competition binding studies illustrate the fact that acute rejection resulted in a significant decrease in Bmax (43%) without significant alteration in Kd value. These studies indicate that digitalis-like substances might not exert significant inotropic activity during rejection, but this hypothesis must be confirmed by in vivo haemodynamic experiments.


Transition from Syringe to Autoinjector Based on Bridging Pharmacokinetics and Pharmacodynamics of the P2Y12 Receptor Antagonist Selatogrel in Healthy Subjects.
Selatogrel is a potent, reversible, and selective antagonist of the platelet P2Y12 receptor currently developed for the treatment of acute myocardial infarction (AMI). In the completed Phase I/II studies, selatogrel was subcutaneously (s.c.) administered as a lyophilizate-based formulation by syringe by a healthcare professional. In the Phase III study, selatogrel will be self-administered s.c. as a liquid formulation with an autoinjector at the onset of AMI symptoms to shorten treatment delay. This clinical bridging study compared the pharmacokinetics (PK) of selatogrel between the different formulations. This was a single-center, randomized, open-label, three-period, cross-over Phase I study in 24 healthy subjects. In each period, a single subcutaneous dose of 16 mg selatogrel was administered as (1) a Phase III liquid formulation by autoinjector (Treatment A), (2) a Phase III liquid formulation by prefilled syringe (Treatment B), or (3) a Phase I/II reconstituted lyophilizate-based formulation by syringe (Treatment C). PK parameters including area under the plasma concentration-time curve from zero to infinity (AUC0-∞), maximum plasma concentration (Cmax), time to reach Cmax(tmax), and terminal half-life (t1/2) were determined using noncompartmental analysis. Pharmacodynamic (PD) parameters were estimated using PK/PD modeling, including the time of first occurrence of inhibition of platelet aggregation (IPA) ≥ 80% (tonset), duration of IPA above 80% (tduration), and responder rate defined as the percentage of subjects with tonset ≤ 30 min and tduration ≥ 3 h. Safety and tolerability were also assessed. Comparing Treatment A to Treatment C, the exposure (AUC0-∞) was bioequivalent with a geometric mean ratio (GMR) (90% confidence interval) of 0.95 (0.92-0.97) within the bioequivalence range (0.80-1.25). Absorption following Treatment A was slightly slower with a tmax occurring approximately 30 min later and a 20% lower Cmax. The autoinjector itself had no impact on the PK of selatogrel, as similar values of Cmax and AUC0-∞ were determined after administration as a Phase III liquid formulation by autoinjector or by prefilled syringe (i.e., GMR [90% confidence interval] of 1.06 [0.97-1.15] and 0.99 [0.96-1.03] for Cmax and AUC0-∞, respectively). PK/PD modeling predicted that the median tonset will occur slightly later for Treatment A (7.2 min) compared to Treatment C (4.2 min), while no relevant differences in tduration and responder rate were estimated between the two treatments. Selatogrel was safe and well tolerated following all three treatments. PK and simulated PD effects of selatogrel were similar across treatments. NCT04557280.


Nanoparticle endothelial delivery of PGC-1α attenuates hypoxia-induced pulmonary hypertension by attenuating EndoMT-caused vascular wall remodeling.
Pulmonary hypertension (PH) induced by chronic hypoxia is characterized by thickening of pulmonary artery walls, elevated pulmonary vascular resistance, and right-heart failure. Dysfunction of endothelial cells is the hallmark event in the progression of PH. Among various mechanisms, endothelial to mesenchymal transition (EndoMT) has emerged as an important source of endothelial cell dysfunction in PH. However, the mechanisms underlying the EndoMT in PH remain largely unknown. Our results showed that peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) expression was decreased in pulmonary arterial endothelial cells (PAECs) in PH patients and hypoxia-induced PH mouse model compared to the normal controls. Endothelial-specific overexpression of PGC-1α using nanoparticle delivery significantly attenuated the progression of PH, as shown by the significantly decreased right ventricular systolic pressure and diminished artery thickness as well as reduced vascular muscularization. Moreover, Endothelial-specific overexpression of PGC-1α blocked the EndoMT of PAECs during PH, indicating that loss of PGC-1α promotes PH development by mediating EndoMT, which damages the integrity of endothelium. Intriguingly, we found that PGC-1α overexpression rescued the expression of endothelial nitric oxide synthase in mouse lung tissues that was deceased by hypoxia treatment in vivo and in endothelial cells treated with TGF-β in vitro. Consistently, PAECs and vascular smooth muscle co-culture showed that overexpression of PGC-1α in PAECs increases nitric oxide release, which would likely diffuse to smooth muscle cells, where it activates specific protein kinases, and initiates SMC relaxation by diminishing the calcium flux. Endothelial-specific overexpression of PGC-1α also attenuated hypoxia-induced pulmonary artery stiffness which appeared to be caused by both the decreased endothelial nitric oxide production and increased vascular remodeling. Taken together, these results demonstrated that endothelial-specific delivery of PGC-1α prevents PH development by inhibiting EndoMT of PAECs and thus restoring endothelial function and reducing vascular remodeling.


Small-Carrion penile prosthesis: a report on 160 cases and review of the literature.
The use of the Small-Carrion penile prosthesis in 160 patients is evaluated. Methods to determine those patients who will benefit from the use of this prosthesis and the size prosthesis needed are discussed. Suggestions are made on how to handle problems or complications that may occur during or after the operation, as well as the antibiotic regimen. The literature is reviewed.


Radiosynthesis and initial in vitro evaluation of [18F]F-PEG6-IPQA--a novel PET radiotracer for imaging EGFR expression-activity in lung carcinomas.
Epidermal growth factor receptor (EGFR)-targeted therapies with antibodies and small molecular EGFR kinase inhibitors have shown poor efficacy in unselected populations of patients with advanced non-small cell lung carcinomas (NSCLC). In contrast, patients with overexpression of EGFR and activating mutations in EGFR kinase domain demonstrated improved responses to EGFR kinase inhibitors. Therefore, we have developed a novel radiotracer, [(18)F]F-PEG(6)-IPQA for PET imaging of EGFR expression-activity in NSCLC, and have described its radiosynthesis and in vitro evaluation in two NSCLC cell lines with wild-type and L858R active mutant EGFR. A mesylate precursor was synthesized in multiple steps and radiofluorinated using K(18)F/Kryptofix. The fluorinated intermediate compound was reduced to an amino derivative then treated with acryloyl isobutyl carbonate, followed by purification by HPLC to obtain the desired product. Decay-corrected radiochemical yields of [(18)F]F-PEG(6)-IPQA were 3.9-17.6%, with an average of 9.0% (n = 11). Radiochemical purity was >97% with specific activity of 34 GBq/μmol (mean value, n = 10) at the end of synthesis. The accumulation of [(18)F]F-PEG(6)-IPQA in H3255 cells was ten-fold higher than in H441 cells, despite a two-fold lower level of activated phospho-EGFR expression in H3255 cells compared with H441 cells. The accumulation of [(18)F]F-PEG(6)-IPQA in both cell lines was significantly decreased in the presence of a small molecular EGFR kinase inhibitor, Iressa, at 100 μM concentration in culture medium. We have synthesized [(18)F]F-PEG(6)-IPQA and demonstrated its highly selective accumulation in active mutant L858R EGFR-expressing NSCLC cells in vitro. Further in vivo studies are warranted to assess the ability of PET imaging with [(18)F]F-PEG(6)-IPQA to discriminate the active mutant L858R EGFR-expressing NSCLC that are sensitive to therapy with EGFR kinase inhibitors vs NSCLC that express wild-type EGFR.


Estimating total morbidity burden of COVID-19: relative importance of death and disability.
Calculations of disease burden of COVID-19, used to allocate scarce resources, have historically considered only mortality. However, survivors often develop postinfectious 'long-COVID' similar to chronic fatigue syndrome; physical sequelae such as heart damage, or both. This paper quantifies relative contributions of acute case fatality, delayed case fatality, and disability to total morbidity per COVID-19 case. Healthy life years lost per COVID-19 case were computed as the sum of (incidence*disability weight*duration) for death and long-COVID by sex and 10-year age category in three plausible scenarios. In all models, acute mortality was only a small share of total morbidity. For lifelong moderate symptoms, healthy years lost per COVID-19 case ranged from 0.92 (male in his 30s) to 5.71 (girl under 10) and were 3.5 and 3.6 for the oldest females and males. At higher symptom severities, young people and females bore larger shares of morbidity; if survivors' later mortality increased, morbidity increased most in young people of both sexes. Under most conditions most COVID-19 morbidity was in survivors. Future research should investigate incidence, risk factors, and clinical course of long-COVID to elucidate total disease burden, and decisionmakers should allocate scarce resources to minimize total morbidity.


Random urine drug testing among patients receiving opioid therapy for cancer pain.
There is limited information regarding the true frequency of nonmedical opioid use (NMOU) among patients receiving opioid therapy for cancer pain. Data to guide patient selection for urine drug testing (UDT) as well as the timing and frequency of ordering UDT are insufficient. This study examined the frequency of abnormal UDT among patients with cancer who underwent random UDT and their characteristics. Demographic and clinical information for patients with cancer who underwent random UDT were retrospectively reviewed and compared with a historical cohort that underwent targeted UDT. Random UDT was ordered regardless of a patient's risk potential for NMOU. Targeted UDT was ordered on the basis of a physician's estimation of a patient's risk for NMOU. In all, 552 of 573 eligible patients (96%) underwent random UDT. Among these patients, 130 (24%) had 1 or more abnormal results; 38 of the 88 patients (43%) who underwent targeted UDT had 1 or more abnormal results. When marijuana was excluded, 15% of the random group and 37% of the targeted group had abnormal UDT findings (P < .001). It took a shorter time from the initial consultation to detect 1 or more abnormalities with the random test than the targeted test (median, 130 vs 274 days; P = .02). Abnormal random UDT was independently associated with younger age (P < .0001), male sex (P = .03), Cut Down, Annoyed, Guilty, and Eye Opener-Adapted to Include Drugs positivity (P = .001), and higher Edmonton Symptom Assessment System anxiety (P = .01). Approximately 1 in 4 patients receiving opioids for cancer pain at a supportive care clinic who underwent random UDT had 1 or more abnormalities. Random UDT detected abnormalities earlier than the targeted test. These findings suggest that random UDT is justified among patients with cancer pain.


Factors Associated With Hepatitis A Mortality During Person-to-Person Outbreaks: A Matched Case-Control Study-United States, 2016-2019.
During 2016-2020, the United States experienced person-to-person hepatitis A outbreaks that are unprecedented in the vaccine era, during which case-fatality ratios reported by some jurisdictions exceeded those historically associated with hepatitis A. To identify factors associated with hepatitis A-related mortality, we performed a matched case-control study (matched on age [±5 years] and county of residence in a 1:4 ratio) using data collected from health department and hospital medical records of outbreak-associated patients in Kentucky, Michigan, and West Virginia. Controls were hepatitis A outbreak-associated patients who did not die. There were 110 cases (mean age 53.6 years) and 414 matched controls (mean age 51.9 years); most cases (68.2%) and controls (63.8%) were male. Significantly (P < 0.05) higher odds of mortality were associated with preexisting nonviral liver disease (adjusted odds ratio [aOR], 5.2), history of hepatitis B (aOR, 2.4), diabetes (aOR, 2.2), and cardiovascular disease (aOR, 2.2), as well as initial Model for End-Stage Liver Disease (MELD) score ≥ 30 (aOR, 10.0), aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio > 2 (aOR, 10.3), and platelet count < 150,000/μL (aOR, 3.7) among hepatitis A outbreak-associated patients in the independent multivariable conditional logistic regression analyses (each model adjusted for sex). Preexisting liver disease, diabetes, cardiovascular disease, and initial MELD score ≥ 30, AST/ALT ratio ≥ 1, and platelet count < 150,000/μL among hepatitis A patients were independently associated with higher odds of mortality. Providers should be vigilant for such features and have a low threshold to escalate care and consider consultation for liver transplantation. Our findings support the recommendation of the Advisory Committee on Immunization Practices to vaccinate persons with chronic liver disease, though future recommendations to include adults with diabetes and cardiovascular disease should be considered.


Optimization of chitin yield from shrimp shell waste by Bacillus subtilis and impact of gamma irradiation on production of low molecular weight chitosan.
Chitin and chitosan have been produced from the exoskeletons of crustacean shells such as shrimps. In this study, seventy bacterial isolates, isolated from soil, were tested for proteolytic enzymes production. The most efficient one, identified as Bacillus subtilis, was employed to extract chitin from shrimp shell waste (SSW). Following one-variable-at-a-time approach, the relevant factors affecting deproteinization (DP) and demineralization (DM) were sucrose concentration (10%, w/v), SSW concentration (5%, w/v), inoculum size (15%, v/v), and fermentation time (6days). These factors were optimized subsequently using Box-Behnken design and response surface methodology. Maximum DP (97.65%) and DM (82.94%) were predicted at sucrose concentration (5%), SSW concentration (12.5%), inoculum size (10%, containing 35×10(8) CFU/mL), and fermentation time (7days). The predicted optimum values were verified by additional experiment. The values of DP (96.0%) and DM (82.1%) obtained experimentally correlated to the predicted values which justify the authenticity of optimum points. Overall 1.3-fold increase in DP% and DM% was obtained compared with 75.27% and 63.50%, respectively, before optimization. Gamma-irradiation (35kGy) reduced deacetylation time of irradiated chitin by 4.5-fold compared with non-irradiated chitin. The molecular weight of chitosan was decreased from 1.9×10(6) (non-irradiated) to 3.7×10(4)g/mol (at 35kGy).


Sacroiliac joint fusion for low back pain: a systematic review and meta-analysis.
Although pain is generally regarded as originating in the lumbar spine, it has been estimated that in 15-30 % of patients, LBP originates from the sacroiliac joint (SIJ). To determine whether sacroiliac joint fusion (SIJF) for LBP is effective in reducing pain when the SIJ is known to be the pain generator. Systematic review and meta-analysis. A systematic literature review and meta-analysis was performed of observational studies describing outcome of SIJF in patients with LBP. Outcome measures were VAS pain, ODI, SF-36 PCS/MCS and Majeed score. The following databases were searched: PubMed, Web of Science, Embase, Medline and Google scholar. The methodological quality of selected studies was assessed using the National Heart Lung and Blood Institute case series quality assessment tool. Meta-analysis was used to combine the studies for each outcome and forest plots were prepared. Outcomes were expressed as mean difference (MD). Six studies were included in the meta-analysis with a mean follow-up of 17.6 months. All outcomes showed statistical and clinical improvement (VAS pain MD: 54.8; 95 % CI 48.6, 61.0; n = 380; p < 0.001, ODI MD: 14.5; 95 % CI 8.4, 20.6; n = 102; p < 0.001, SF-36 PCS MD: -19.5; 95 % CI -24.7, -14.2; n = 140; p < 0.001, SF-36 MCS MD: -8.5; 95 % CI -12.9, -4.1; n = 198; p < 0.001 and Majeed score MD: -35.4; 95 % CI -48.5, -22.2; n = 140; p < 0.001). SIJF appears to be a satisfactory procedure for alleviating pelvic girdle pain.


Metastatic renal cell carcinoma to the thyroid with cervicothoracic venous tumor thrombosis.
Metastatic renal cell carcinoma (RCC) represents 25%-42% of metastatic thyroid malignancies. Propensity for RCC to demonstrate intravascular extension to the inferior vena cava is well documented. We present an analogous phenomenon of intravascular extension to the internal jugular vein (IJV) from thyroid gland metastasis. A 69-year-old male presented with metastatic RCC of the right thyroid lobe. Imaging demonstrated tumor thrombosis of the ipsilateral IJV, extending inferiorly to the junction of the brachiocephalic, subclavian, and internal jugular veins within the mediastinum. Surgical excision required control of both the IJV in the neck and mediastinal venous great vessels via sternotomy, prior to subtotal thyroidectomy and venotomy for en bloc resection. This case report describes metastatic RCC to the thyroid gland with cervicothoracic venous tumor thrombosis successfully treated with subtotal thyroidectomy, sternotomy for venotomy and tumor thrombectomy, and preservation of IJV conduit.


Altered disposition of fleroxacin in patients with cystic fibrosis.
Thirteen patients with cystic fibrosis and 12 healthy control volunteers received a single oral 800 mg dose of fleroxacin and 800 mg every day for 5 days. Interstitial fluid penetration was studied by the suction-induced blister technique. Fleroxacin and its two major metabolites, N-demethyl and N-oxide, were analyzed in plasma and urine by HPLC. Single-dose absorption parameters (absorption rate constant, normalized peak plasma drug concentration, and time to reach peak concentration) and total urinary excretion indicated that fleroxacin was absorbed more slowly and more completely in patients with cystic fibrosis than in control subjects. Fleroxacin volume of distribution tended to be smaller in patients with cystic fibrosis and it reached statistical significance after a single dose when normalization for lean body mass was applied. When normalized for lean body mass, the formation clearance of N-demethyl fleroxacin and N-oxide fleroxacin was significantly greater in patients with cystic fibrosis than in control subjects (p less than 0.05). These data concur with those of others showing an induction of drug-metabolizing enzymes in cystic fibrosis. Renal clearances of fleroxacin and its metabolites were significantly increased in cystic fibrosis (p less than 0.05), and this seems to be explained by a decreased tubular reabsorption of these compounds. The differences seen in the pharmacokinetics of fleroxacin in cystic fibrosis support the theories of generalized induction of drug metabolism and of a defective renal tubular reabsorptive process of drugs in cystic fibrosis.


Differential expression and activities of cytochrome P450 3A in the rat brain microsomes and mitochondria.
Midazolam (MDZ), a benzodiazepine derivative, is metabolized to 1'- and 4-hydroxylated metabolites (1'-OH-MDZ and 4-OH-MDZ, respectively) by cytochrome P450 3A (CYP3A). The purpose of this study was to investigate the CYP3A-mediated hydroxylation of MDZ in the rat brain mitochondria (MT). Brain microsomes (MC) and MT fractions were prepared from rats (n = 8) using differential and density gradient centrifugations, and the purity of the fractions was evaluated using VDAC1 and calreticulin as markers of MT and MC, respectively. The formation rates of 1'-OH-MDZ and 4-OH-MDZ in the rat brain MC and MT samples were determined using an LC-MS/MS method after validation. Subsequently, Michaelis-Menten kinetics of 1'- and 4-hydroxylation of MDZ were estimated. Western blot (WB) analysis was used to determine the protein expression of CYP3A in the rat brain MC and MT. The MC fractions had 5.93% ± 3.01% mitochondrial impurity, and the MT fractions had 19.3% ± 7.8% microsomal impurity (mean ± SD). The maximum velocity (Vmax ) values of the formation of the hydroxylated metabolites in the brain MT were 2.4-9-fold higher than those in MC. Further, the Vmax values of 4-OH-MDZ in both MC and MT fractions were substantially higher than those of 1'-OH-MDZ. The WB analysis showed that the intensity of the CYP3A immunoreactive band in MT was more than twofold higher than that in MC. It is concluded that compared with MC, rat brain MT contains substantial CYP3A, which may affect the pharmacology or toxicology of centrally acting xenobiotic and endogenous substrates of this enzyme.


A paramagnetic-reporter two-particle system for amplification-free detection of DNA in serum.
Quantitative nucleic acid detection is used extensively in the management of many pathogenic infections, where viral or bacterial nucleic acid copy number relates directly to disease prognosis. Temperature-cycle or isothermal amplification formats offer excellent performance, but their requirement for purified nucleic acid and accurate temperature control increases costs and renders their migration to resource-limited environments problematic. In contrast, amplification-free nucleic acid assays could allow simplified system design, resulting in reduced costs. In this study, we report a amplification-free herpes simplex virus (HSV) assay where oligoethylene glycol methacrylate (OEGMA) grafted ssDNA capture-probes on paramagnetic nanoparticles are coupled with reporter-probe-modified fluorescent nanoparticles in a target-dependent manner. Following assay and reagent optimization, a sub-pM (25 amol) limit of detection could be achieved in buffer and also in neat, undiluted serum, representing a 160-fold improvement over that achieved using convention detection with a fluorescence plate reader. Equivalent performance in serum and buffer offers the opportunity for simplified diagnostic device design for resource-limited environments.


Prostaglandins and congeners. 16. Synthesis and bronchodilator activity of dl-11-doexy-3-thiaprostaglandins.
The interesting bronchodilator activity of certain dl-11-deoxy-3-thiaprostaglandins and their preparation by the conjugate addition of appropriately substituted (E)-1-alkenyllithio cuprate reagents to requisite cyclopentenones are described.


Endocrine disrupting chemicals and their effects on the reproductive health in men.
Endocrine Disrupting Chemicals (EDCs) are harmful compounds that enter the environment naturally or through anthropogenic activities and disrupt normal endocrine functions in humans, adversely affecting reproductive health. Among the most significant sources of EDC contaminants are the pharmaceutical, cosmetic, and packaging industries. EDCs have been identified to have a deteriorating effect on male reproductive system, as evidenced by the increasing number of male infertility cases. A large number of case studies have been published in which men exposed to EDCs experienced testicular cancer, undescended testicles, a decrease in serum testosterone levels, and poor semen quality. Furthermore, epidemiological evidence suggested a link between prenatal EDC exposure and cryptorchidism or undescended testicles, hypospadias, and decreased anogenital distance in infants. The majority of these findings, however, are incongruent due to the lack of long-term follow-up studies that would demonstrate EDCs to be associated with male reproductive disorders. This review aims to provide an overview on recent scientific progress on the association of EDCs to male reproductive health with special emphasis on its toxicity and possible mechanism of EDCs that disrupt male reproductive system.


A small pulsatile pump for extracorporeal circulation.
A new pulsatile pump was constructed with variable beat rate and the stroke volume, controlled systolic maximum pressure and a very steep built-up curve, to be used for extracorporeal circulation.


The radiology of lymphoma.
The development of new imaging techniques over recent years has improved the accuracy with which the extent of the disease can be demonstrated in patients with lymphoma. These methods either complement or replace existing conventional radiological methods such as plain films, bariums, intravenous urograms or lymphography. CT in particular, and to a lesser extent ultrasound and radionuclides, now plays an important part in helping the clinician to manage patients with lymphoma. It is impractical and unnecessary to use all available imaging studies. More than ever, close co-operation between the clinician and radiologist is essential to derive the maximum amount of information from the studies and to use the techniques effectively and appropriately. This chapter has reviewed the advantages and limitations of each imaging method, stressing the role of each in staging the lymphomas and in monitoring response to treatment. The common radiological appearances of the effects of lymphoma on each organ system have been described. The possible contribution that other techniques may make in the future has been discussed.


The public hospital and its local ecology in the United States: some relationships between the "plight of the public hospital" and the "plight of the cities".
The "plight" of the public hospital in the United States is examined from the point of view of its relationship to the "plight" of the cities. Fifty-five large cities are examined and for 38 of these cities that have such hospitals the relationships of levels of public hospital services to local demographic, government fiscal, and tax structure conditions are analyzed. The principal findings point to the existence of some strong relationships and the implications for public policy of these associations are discussed.


Detection of lesions during capsule endoscopy: physician performance is disappointing.
Limited data guide capsule endoscopists on how to view the many images collected in each capsule. The objective of this study was to compare the detection rates of clinically significant findings in different capsule endoscopy reading modes and speeds. Seventeen capsule endoscopists with experience from 23 to > 1,000 total capsule procedures read 24 clips, 18 of which were abnormal. Clips were read in two different reading modes utilizing two speeds, including SingleView at 15 at frames per second (f.p.s.), SingleView 25 f.p.s., QuadView 20 f.p.s., and QuadView 30 f.p.s. The main outcome measurements were pathology detection rates correlated with reading mode, lesion type, reader experience, and timing order. SingleView 15, QuadView 20, and QuadView 30 had no significant difference in overall detection rate (45, 47, and 43%, respectively). SingleView 25 had a 26% detection rate, which was significantly lower than SingleView 15 (P = 0.04) and QuadView 20 (P = 0.002). The detection rates of angioectasias, ulcers/erosions, masses/polyps, and blood were 69, 38, 46, and 17%, respectively. Reader experience and timing of interpretation did not significantly impact detection rate. Pathology was present on a few frames. Limited modes and speeds were assessed. Lesion types were not confirmed with surgical or deep enteroscopic methods. A relatively small number of readers provided interpretations. Overall, the detection rates in this study are lower than previously reported and not influenced by increasing experience. Detection rates are significantly higher when reading in SingleView 15 and QuadView 20 compared with reading in SingleView 25. Increasing viewing speed from QuadView 20 to QuadView 30 appears to have no significant effect on detection. Quality control measures to compare and improve lesion detection rates need further study.


Physical function and all-cause mortality in patients with chronic kidney disease and end-stage renal disease: a systematic review and meta-analysis.
The loss of skeletal muscle mass and muscle strength is common in patients suffering from chronic kidney disease (CKD) and end-stage renal disease (ESRD) undergoing dialysis. The purpose of this study was to conduct a meta-analysis to explore the relationship between physical functional performance and all-cause mortality in CKD and ESRD patients undergoing dialysis. A systematic literature search was conducted on an electronic database up to January 2022, and all data were analyzed using RevMan5 (version 5.3). Totally, 19 studies involving 6908 patients were enrolled for analysis. Patients with poor physical functional performance in the handgrip strength (HGS) (hazard ratio [HR] = 1.99, P < 0.00001), gait speed (HR = 2.45, P = 0.0005), 6 m walk test (HR = 2.94, P < 0.01), and timed up and go test (HR = 1.69, P = 0.02) showed increased risk of all-cause mortality than those with good physical functional performance. In continuous analyses, both per 1 kg increase in HGS (95% CI 0.94-0.98; P < 0.00001; I2 = 47%) and per 1 SD increase in HGS (HR = 0.47 95% CI 0.35-0.64; P < 0.0001; I2 = 35%) were significantly associated with lower all-cause mortality. The present meta-analysis demonstrated that poor physical function outcomes, including grip strength, gait speed, 6MWT, and TUG test, were significantly associated with high all-cause mortality in patients with CKD and ESRD.


CYP3A4 inhibition by Psoralea corylifolia and its major components in human recombinant enzyme, differentiated human hepatoma HuH-7 and HepaRG cells.
Psoralea corylifolia (P. corylifolia) is a medicinal plant used primarily in herbal dietary supplements to treat skin diseases, such as vitiligo and psoriasis. Case reports of liver toxicity have recently emerged from its use, which often includes co-administration with other herbal products. In this study, CYP3A4 inhibition and hepatotoxicity of P. corylifolia and its major components were evaluated in human recombinant CYP3A4 enzyme, differentiated human hepatoma HuH-7 and HepaRG cells. LC/MS-TOF was used to identify the major components of P. corylifolia fruit methanol-water extract. P. corylifolia and its major bioactive components psoralen and isopsoralen were then incubated with human recombinant CYP3A4 (10 min) or differentiated HuH-7 and HepaRG cells (24 h) prior to CYP3A4 activity and cytotoxicity assays. P. corylifolia extract, psoralen, and isopsoralen concentration dependently inhibited CYP3A4 activity with different potency in the three in vitro systems. No cytotoxicity was observed at any concentration tested. In vitro CYP3A4 inhibition by P. corylifolia and its major components suggests potential drug-dietary supplement interactions that warrant further investigations in vivo.


[Adenosine deaminase activity of lymphocytes during typhoid fever (preliminary data)].
Adenosine deaminase activity has been measured in the peripheral lymphocytes of 12 patients suffering from typhoid fever. The mean activity was found to be significantly higher (P less than 0,001) when compared with normal controls.


L-glutamate and acetylcholine mobilise Ca2+ from the same intracellular pool in cerebellar granule cells using transduction mechanisms with different Ca2+ sensitivities.
Ca2+ mobilisation induced by L-glutamate (Glu) and acetylcholine (ACh) has been studied in cultured cerebellar granule cells using digital fluorescence microscopy. The ability of Glu-receptor activation to mobilise Ca2+ was decreased when [Ca2+]o was lowered to 10 microM (from 1.8 mM). It was enhanced when [Ca2+]i was raised using 25 mM external K+ or by N-methyl-D-aspartate (NMDA), which selectively activates a distinct Glu-receptor subtype. The enhancement was dependent on entry of external Ca2+. In contrast, the ability of ACh receptor activation to mobilise Ca2+ was not affected by these conditions. Furthermore, pretreatment with pertussis toxin inhibited Ca2+ mobilisation in response to Glu-receptor activation without affecting mobilisation in response to ACh. However, activation of both receptors mobilised Ca2+ from a common, thapsigargin-sensitive pool. We conclude that there are differences in the Ca2+ mobilization pathways for the two receptor systems in cerebellar granule cells. The Ca(2+)-sensitivity of this Ca2+ mobilizing Glu receptor may have implications for its function in neuronal synaptogenesis and plasticity.


Comparison of detectability limits for elemental mapping by EF-TEM and STEM-XEDS.
The analytical sensitivity in terms of the signal-to-noise ratio (SNR) was investigated for elemental mapping by a transmission electron microscope equipped with an energy filter (EF-TEM) and a scanning transmission electron microscope with an X-ray energy dispersive spectrometer (STEM-XEDS). To compare the detectability limits of the elemental maps by the two techniques, homogeneous Cu-0.98+/-0.34 wt% Mn and Cu-4.93+/-0.49 wt% Mn thin specimens were used. Elemental maps can be considered as either an image or a spectrum. Therefore, the detectability limits of the elemental maps were characterized by the spectral SNR. To evaluate the detectability limits of the elemental maps with statistical confidence limits such as 1 sigma, 2 sigma and 3 sigma, the SNR values were reviewed from the statistical point of view. In STEM-XEDS mapping, the spectral SNR values improve as the specimen thickness increases since the signal intensity increases. Conversely, the spectral SNR in EF-TEM mapping is maximized at a certain thickness and then reduces as the thickness increases. To compare the two mapping techniques with regard to the analytical sensitivity, a method to estimate the minimum mass fraction (MMF) from measured signal and background intensities was developed. In this experimental approach, the MMF value can be evaluated by selecting the appropriate SNR value corresponding to the statistical confidence limits. In comparing the estimated MMF values from the two mapping approaches, EF-TEM mapping can be more sensitive than STEM-XEDS mapping up to specimen thicknesses <20-30 nm in the 1 sigma confidence limit and < approximately 50 nm in the 3 sigma limits. However, as the specimen thickness increases, the XEDS maps provide better detectability limits in the Cu-Mn dilute alloy specimens.


Phospholipid--driven gene regulation.
Phospholipids (PLs), well known for their fundamental role in cellular structure, play critical signaling roles via their derivatives and cleavage products acting as second messengers in signaling cascades. Recent work has shown that intact PLs act as signaling molecules in their own right by modulating the activity of nuclear hormone transcription factors responsible for tuning genes involved in metabolism, lipid flux, steroid synthesis and inflammation. As such, PLs have been classified as novel hormones. This review highlights recent work in PL-driven gene regulation with a focus on the unique structural features of phospholipid-sensing transcription factors and what sets them apart from well known soluble phospholipid transporters.


The RAR1 interactor SGT1, an essential component of R gene-triggered disease resistance.
Plant disease resistance (R) genes trigger innate immune responses upon pathogen attack. RAR1 is an early convergence point in a signaling pathway engaged by multiple R genes. Here, we show that RAR1 interacts with plant orthologs of the yeast protein SGT1, an essential regulator in the cell cycle. Silencing the barley gene Sgt1 reveals its role in R gene-triggered, Rar1-dependent disease resistance. SGT1 associates with SKP1 and CUL1, subunits of the SCF (Skp1-Cullin-F-box) ubiquitin ligase complex. Furthermore, the RAR1-SGT1 complex also interacts with two COP9 signalosome components. The interactions among RAR1, SGT1, SCF, and signalosome subunits indicate a link between disease resistance and ubiquitination.


[Complications of treatment of adult's groin hernia: a report of 100 cases comparative study between Bassini and Mac Vay's technics].
The authors report a prospective study comparing pre and immediate post operative complications of non complicated hernia of the groin in adult treated by operations based on Bassini and Mac Vay technics. It concerned a total of 100 patients made up of two groups of 50 age ranging from 13 to 84 years with an average age of 47 years of whom were 93 males and 7 females. No mortality was registered. The rate of complications was 20% in Bassini's technic and 22% in Mac Vay's technic. There were: bladder injurie, accidental skin wound incurred by the electric surgical blade, meningeal irritation, urinary retention, scrotal sac hematoma, parietal suppuration, intestinal occlusion and immediate recidivation before 6 months. As well as our study as in literature, specific complications related to both technics were rare. We could draw the conlusion that there is no significant superiority of one technic in comparison with the other one.


Diagnostic Performance of Risk of Malignancy Algorithm (ROMA), Risk of Malignancy Index (RMI) and Expert Ultrasound Assessment in a Pelvic Mass Classified as Inconclusive by International Ovarian Tumour Analysis (IOTA) Simple Rules.
The accurate prediction of malignancy for a pelvic mass detected on ultrasound allows for appropriate referral to specialised care. IOTA simple rules are one of the best methods but are inconclusive in 25% of cases, where subjective assessment by an expert sonographer is recommended but may not always be available. In the present paper, we evaluate the methods for assessing the nature of a pelvic mass, including IOTA with subjective assessment by expert ultrasound, RMI and ROMA. In particular, we investigate whether ROMA can replace expert ultrasound when IOTA is inconclusive. This prospective study involves one cancer centre and three general units. Women scheduled for an operation for a pelvic mass underwent a pelvic ultrasound pre-operatively. The final histology was obtained from the operative sample. The sensitivity, specificity and accuracy for each method were compared with the McNemar test. Of the 690 women included in the study, 171 (25%) had an inconclusive IOTA. In this group, expert ultrasound was more sensitive in diagnosing a malignant mass compared to ROMA (81% vs. 63%, p = 0.009) with no significant difference in the specificity or accuracy. All assessment methods involving IOTA had similar accuracies and were more accurate than RMI or ROMA alone. In conclusion, when IOTA was inconclusive, assessment by expert ultrasound was more sensitive than ROMA, with similar specificity.


Exploiting docetaxel-induced tumor cell necrosis with tumor targeted delivery of IL-12.
There is strong evidence that chemotherapy can induce tumor necrosis which can be exploited for the targeted delivery of immuno-oncology agents into the tumor microenvironment (TME). We hypothesized that docetaxel, a chemotherapeutic agent that induces necrosis, in combination with the bifunctional molecule NHS-IL-12 (M9241), which delivers recombinant IL-12 through specific targeting of necrotic regions in the tumor, would provide a significant antitumor benefit in the poorly inflamed murine tumor model, EMT6 (breast), and in the moderately immune-infiltrated tumor model, MC38 (colorectal). Docetaxel, as monotherapy or in combination with NHS-IL-12, promoted tumor necrosis, leading to the improved accumulation and retention of NHS-IL-12 in the TME. Significant antitumor activity and prolonged survival were observed in cohorts receiving docetaxel and NHS-IL-12 combination therapy in both the MC38 and EMT6 murine models. The therapeutic effects were associated with increased tumor infiltrating lymphocytes and were dependent on CD8+ T cells. Transcriptomics of the TME of mice receiving the combination therapy revealed the upregulation of genes involving crosstalk between innate and adaptive immunity factors, as well as the downregulation of signatures of myeloid cells. In addition, docetaxel and NHS-IL-12 combination therapy effectively controlled tumor growth of PD-L1 wild-type and PD-L1 knockout MC38 in vivo, implying this combination could be applied in immune checkpoint refractory tumors, and/or tumors regardless of PD-L1 status. The data presented herein provide the rationale for the design of clinical studies employing this combination or similar combinations of agents.


Analysis of cutaneous somatic mosaicism.
Laser Dissection Microscopy (LDM) is a valuable technique to identify the genetic event that underlies cutaneous mosaicism. Isolation of a selected cell population is key to the detection of a somatic mutation. Advantages of the LDM technique are that stored skin biopsies can be analyzed without the necessity of culturing cells. Here, we describe the preparation of skin sections and cells for LDM, followed by dissection, and subsequent DNA and RNA analysis in order to detect the underlying somatic mutation.


Switching from vitamin K antagonist to dabigatran in atrial fibrillation: differences according to dose.
In atrial fibrillation (AF) patients 150 mg b.i.d. dabigatran is the standard dose, yet guidelines recommend 110 mg b.i.d. when bleeding risk is high. It is unknown to which extend these recommendations are followed in patients switching from vitamin K antagonist (VKA) to dabigatran. The aim of this study was to investigate if AF patients are switched from VKA to the appropriate dose of dabigatran. Using nationwide registries (22 August 2011 to 31 December 2012), we identified VKA-experienced AF patients with available creatinine values who switched to dabigatran. European guidelines criteria 2012 on dabigatran dosing were examined: age ≥80 years, HAS-BLED ≥3, estimated glomerular filtration rate (eGFR)<50 mL/min/1.73 m2, or use of interacting drugs. We identified 1626 VKA-experienced AF patients who switched to dabigatran 110 mg (820 patients) or 150 mg (806 patients). Patients who switched to 110 mg compared with 150 mg were older [median age 82 years (Q1-Q3: 77-86) vs. 68 years (Q1-Q3: 64-74)], more often females (54% vs. 35%), had a higher comorbidity burden, higher proportion with CHA2DS2-VASc score ≥2 (98% vs. 80%), and more with a HAS-BLED score ≥3 (46% vs. 28%). Patients switched to 110 mg had a higher absolute risk of mortality compared with patients switched to 150 mg. Overall, 26% were inappropriately dosed and 14% were switched to 110 mg although the higher dose was indicated. Furthermore, 39% of patients switched to 150 mg fulfilled one or more criteria for 110 mg, this mostly driven by high HAS-BLED scores (28.2% of patients on 150 mg). Female sex, age ≥80 years, eGFR < 50 mL/min/1.73 m2, drugs interacting with dabigatran, and prior bleeding were associated with switch to 110 mg. Patients inappropriately dosed had similar risk of mortality as patients appropriately dosed. Among VKA-experienced AF patients one in four were switched to a dabigatran dose contrary to guideline recommendations.


Are pregnancy planning and timing associated with preterm or small for gestational age births?
To investigate whether unplanned or poorly timed pregnancies (self-reported at enrollment) are associated with preterm or small for gestational age births. Prospective cohort study. Not applicable. Two thousand six hundred fifty-four pregnant women <18 weeks estimated gestational age with a singleton pregnancy. None. Preterm and small for gestational age births. In adjusted analyses, pregnancy planning was not statistically significantly associated with preterm (odds ratio [OR] 1.18; 95% confidence interval [CI], 0.85-1.65) or small for gestational age birth (OR 1.17; 95% CI, 0.69-1.97). Similarly, poorly timed pregnancies were not statistically significantly associated with preterm (OR 0.85; 95% CI, 0.53-1.38) or small for gestational age birth (OR 0.92; 95% CI, 0.65-1.29). Combining pregnancy planning (yes/no) and timing (yes/no) into a 4-level category showed no statistically significant association with preterm birth or small for gestational age. In a large cohort with antenatally assessed pregnancy planning and timing, outcome data collected from medical record abstraction, and robust analysis adjusting for multiple confounding factors including maternal demographics, medical conditions, and other risk factors, neither pregnancy planning nor pregnancy timing showed a statistically significant association with preterm or small for gestational age infants. This study improves upon previous analyses that lacked adjustment for confounding and used retrospective self-reporting to assess pregnancy planning and timing, and preterm and small for gestational age births. Findings may differ in higher risk populations with higher prevalence of preterm or small for gestational age births.


Safety considerations for patients with communication disorders in rehabilitation medicine settings.
Communication barriers can pose a significant safety risk for patients. Individuals in a communication-vulnerable state are commonly seen in rehabilitation settings. These patients cannot adequately communicate their symptoms, wants, and needs to providers. Causes of communication barriers include neurologic impairments, such as stroke, cerebral palsy, and Parkinson disease, and language barriers. The ability of clinicians to adequately diagnose, treat, and monitor these patients is also hindered. This article identifies key communication barriers and strategies that clinicians can use to effectively communicate with these patients.


Efficacy of first-line atezolizumab combination therapy in patients with non-small cell lung cancer receiving proton pump inhibitors: post hoc analysis of IMpower150.
Proton pump inhibitors (PPIs) are commonly used concomitant to cancer treatment and they induce gut microbiota changes. It is increasingly apparent that gut dysbiosis can reduce the effectiveness of immune checkpoint inhibitors (ICI). However, little is known about PPI effects on outcomes with ICIs, particularly in combination, ICI approaches. Post hoc, Cox proportional hazard analysis of phase III trial, IMpower150 was conducted to assess the association between PPI use and overall survival (OS) and progression-free survival (PFS) in chemotherapy-naive, metastatic non-squamous non-small cell lung cancer participants randomised atezolizumab plus carboplatin plus paclitaxel (ACP), bevacizumab plus carboplatin plus paclitaxel (BCP), or atezolizumab plus BCP (ABCP). PPI use was defined as any PPI administration between 30 days prior and 30 days after treatment initiation. Of 1202 participants, 441 (37%) received a PPI. PPI use was independently associated with worse OS (n = 748; hazard ratio (HR) [95% confidence interval (CI)] = 1.53 [1.21-1.95], P < 0.001) and PFS (1.34 [1.12-1.61], P = 0.002) in the pooled atezolizumab arms (ACP plus ABCP). This association was not apparent for BCP (n = 368; OS 1.01 [0.73-1.39], P = 0.969; PFS 0.97 [0.76-1.25], P = 0.827). The observed OS treatment effect (HR 95% CI) of the atezolizumab (ACP plus ABCP) arms vs BCP was 1.03 (0.77-1.36) for PPI users compared to 0.68 (0.54-0.86) for non-users (P [interaction] = 0.028). A similar association was noted for ABCP vs BCP (PPI users 0.96 [0.68-1.35]; PPI non-users 0.66 [0.50-0.87]; P [interaction] = 0.095). PPI use was a negative prognostic marker in patients treated with ACP or ABCP, but not BCP. The analysis suggests that PPIs negatively influence the magnitude of ICI efficacy.


Human Genome Editing in the Clinic: New Challenges in Regulatory Benefit-Risk Assessment.
As genome editing rapidly progresses toward the realization of its clinical promise, assessing the suitability of current tools and processes used for its benefit-risk assessment is critical. Although current regulations may initially provide an adequate regulatory framework, improvements are recommended to overcome several existing technology-based safety and efficacy issues.


Decelerative treatment practices with persons who have mental retardation: a review of five years of the literature.
The literature from 1981 through 1985 in seven major journals on the treatment of behavior problems in persons with mental retardation was reviewed. We included all studies designed to decrease a target behavior that included formal pre- and posttreatment data. Behavior problems were categorized into seven classes. Treatment procedures were grouped into three levels by degree of restrictiveness according to the model proposed by Brazier and MacDonald (1981). We reported the problems treated with various procedures and the frequencies and effectiveness values for all the problem--procedure combinations. Differential reinforcement and overcorrection were the two most widely used procedures. We drew conclusions about treatment of specific classes of problem behaviors based on the results of this review.


Somatostatin potentiates voltage-dependent K+ and Ca2+ channel expression induced by nerve growth factor in PC12 cells.
It has been proposed that neurotransmitters and neuromodulators may function as neurotrophic factors during the development of the nervous system. Somatostatin (SS) was known to increase neurite outgrowth in PC12 cells, rat pheochromocytoma cell line, and cerebellar granule cells as well as Helisoma neuron. To further investigate a neurotrophic role of SS, voltage-dependent K+ and Ca2+ channel expression was studied using whole-cell patch-clamp in PC12 cells and the effect of SS was compared to that of nerve growth factor (NGF). Cyclic AMP (cAMP) level and mitogen-activated protein (MAP) kinase phosphorylation were also studied following the treatment with SS and/or NGF. Whereas NGF (50 ng/ml) increased continually the current density of the voltage-dependent K+ channel throughout 8 days treatment, SS (1 microM) increased the K+ current density on day 2 to the peak. K+ current density was decreased thereafter and was not different on day 6 from that of undifferentiated cells. Although SS did not increase voltage-dependent Ca2+ current density, it potentiated NGF-induced increase of voltage-dependent Ca2+ channel current density as well as the K+ current density. cAMP level was decreased by NGF and/or SS treatment. An increased phosphorylation of MAP kinase induced by NGF was not changed by SS treatment. These results support functionally that SS may function as a neurotrophic factor in developing nervous system.


A fast and inexpensive method for N-terminal fluorescein-labeling of peptides.
A new method has been developed to synthesize fluorescein labeled peptides, compounds of increasing importance in bioorganic chemistry, cell biology, pharmacology, drug targeting and medicinal chemistry. We show, that 4(5)-carboxyfluorescein is much more efficient than the hitherto predominantly utilized reagents 4(5)-carboxyfluorescein-N-succinimidylester and 4(5)-fluoresceinisothiocyanate.


[The Global Patient Safety Action Plan 2021-2030: Identifying actions for safer primary health care].
The 74th World Health Assembly adopted in May 2021 the "Global Patient Safety Action Plan: 2021-2030" to enhance patient safety as an essential component in the design, procedures and performance evaluation of health systems worldwide. It is a strategic plan that guides country governments, health sector entities, health organisations and the World Health Organisation secretariat on how to implement the assembly's patient safety resolution. Deployment of the plan will strengthen the quality and safety of health systems worldwide by spanning the entire continuum of people's health care from diagnosis to treatment and care, reducing the likelihood of harm in the course of care. The Declaration on Primary Health Care during the Global Conference on Primary Health Care in Astana, 2018, urged countries to strengthen their primary health care systems as an essential step towards achieving universal health coverage and providing access to safe, quality care without financial loss. The deployment of the Global Patient Safety Action Plan in primary care is therefore a high-priority health policy action. The Action Plan is structured into 6 strategic objectives with 35 strategic actions. We present an analysis of the strategic actions regarding healthcare organizations and the challenges ahead for their particular deployment in primary health care settings.


Performance, microbial growth and community interactions of iron-dependent denitrification in freshwaters.
Iron-dependent denitrification is a safe and promising technology for nitrogen removal in freshwaters. However, the understanding of microbial physiology and interactions during the process was limited. Denitrifying systems inoculated with freshwater samples were operated with and without iron(II) at a low C/N ratio for 54 days. Iron addition improved nitrogen removal. Batch experiments confirmed that microbially mediated reaction rather than abiotic reaction dominated during the process. Metagenomics recovered genomes of the five most abundant microorganisms, which accounted for over 99% of the community in every triplicate of the iron-based system. Based on codon usage bias, all of them were fast-growing organisms. The total abundance of fast-growing organisms was 38% higher in the system with iron than in the system without iron. Notably, the most abundant organism Diaphorobacter did not have enzymes for asparagine and aspartate biosynthesis, whereas Rhodanobacter could not produce serine and cobalamin. Algoriphagus and Areminomonas lost synthesis enzymes for more amino acids and vitamins. However, they could always obtain these growth-required substances from another microorganism in the community. The two-partner relationship minimized the limitation on microbial reproduction and increased community stability. Our results indicated that iron addition improved nitrogen removal by supplying electron donors, promoting microbial growth, and building up syntrophic interactions among microorganisms with timely communications. The findings provided new insights into the process, with implications for freshwater remediation.


Prostatitis.
Prostatitis is a poorly defined group of syndromes with multiple causes, some of which are not yet determined. Although treatment of acute prostatitis is well defined and almost uniformly successful, chronic prostatitis, either of bacterial or undetermined etiology, remains a perplexing problem in both diagnosis and treatment. Identification of the etiologic agent of chronic "nonbacterial" prostatitis, if one exists, has not yet been accomplished. Undoubtedly, more than one organism may be responsible for these cases. Treatment is ineffective for a high percentage of patients with chronic prostatitis, both from proven bacterial and nonbacterial causes. Few drugs penetrate the prostatic tissues well, and few of those that do have an appropriate antimicrobial spectrum. An excellent, or even adequate, antibiotic for chronic prostatic infections has yet to be developed. Prostatodynia remains as a "wastebasket" syndrome of miscellaneous pains, aches, and pelvic discomforts. With this collection of symptoms, no easy approach to diagnosis or treatment is possible. Only when more detailed diagnosis has been developed can one hope for better therapy of this condition.


Spatiotemporal distributions and oceanic emissions of short-lived halocarbons in the East China Sea.
Coastal waters are important sources of volatile halocarbons, which are important in atmospheric chemistry. Here, in May (spring) and October (autumn) 2020, we studied the surface, bottom, and sediment-pore seawater concentrations, atmospheric mixing ratios, and sea-to-air fluxes of the three primary short-lived atmospheric halocarbons (CH3I, CH2Br2, and CHBr3) in the East China Sea (ECS). The highest concentrations of the three short-lived halocarbons occurred in coastal waters, such as the Changjiang estuary and Zhejiang coastal waters, reflecting the influence of excessive anthropogenic inputs on the distributions of these gases. Interestingly, the aqueous levels of these gases seemed to be lower compared to previous measurements in this oceanic region, probably due to reduced contributions from local anthropogenic emission sources. The concentrations of CH3I, CH2Br2, and CHBr3 in pore water were significantly higher than those in bottom water, suggesting that sediment could be a source of these short-lived halocarbons. Additionally, the atmospheric mixing ratios of these gases occasionally increased in coastal areas. An air-mass back trajectory analysis showed this was due to continental anthropogenic sources and emissions from enriched waters. The atmospheric mixing ratios of these halocarbons exhibited significant seasonal variability, with significant correlations among atmospheric CH3I, CH2Br2, and CHBr3 in spring, but not in autumn. The sea-to-air fluxes of CH3I, CH2Br2, and CHBr3 indicated that the ECS is a source of these gases. Seasonal differences in CH3I and CH2Br2 fluxes were driven by changes in wind speed and sea surface temperature, while CHBr3 flux changes were associated with changes in its surface seawater concentration.


Staged laparoscopic infusion of hyperthermic intraperitoneal chemotherapy after cytoreductive surgery.
Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (HIPC) is a promising treatment for patients with peritoneal malignancies. Traditionally, HIPC is performed concurrently with cytoreductive surgery. However, this strategy is associated with significant morbidity and mortality. In this report, we describe our initial experience with staged laparoscopic infusion of HIPC. Five patients underwent complete open cytoreductive surgery followed by staged laparoscopic HIPC several weeks later. Primary malignancies included adenocarcinoma of the ileum (one patient), adenocarcinoma of the appendix (three patients), and adenocarcinoma of the gallbladder (one patient). At a subsequent operation, we performed laparoscopic HIPC. Quality of life was measured with the Functional Assessment of Cancer Therapy-Colon Subscale (FACT-C). Mean inflow and outflow cannula temperatures were 42.1 degrees C and 40.5 degrees C, respectively. Mean peritoneal perfusion flow rates were 689.8 ml/minute. The hospital stay for all patients was 1 to 2 days. One patient developed postoperative cellulitis, one patient died of progressive tumor, and four patients are alive without tumor progression. Quality-of-life measurements had returned to baseline 4 months after treatment. Staged laparoscopic HIPC after open cytoreductive surgery is safe, feasible, and can achieve uniform temperatures and perfusion flow rates. Although the results of this pilot study are encouraging, additional studies are required to determine long-term survival and quality of life.


Superoxide anion radical induced phototoxicity of 2,4,5,6-Tetraminopyrimidine sulfate via mitochondrial-mediated apoptosis in human skin keratinocytes at ambient UVR exposure.
2,4,5,6-Tetraaminopyrimidine sulfate (TAPS) is worldwide the most commonly used developer in hair dyes. As skin is the major organ, which is directly exposed to these permanent hair dyes, a comprehensive dermal safety assessment is needed. Hereto, we studied the photosensitization potential and mechanism involved in dermal phototoxicity of TAPS exposed to the dark and UVA/UVB/Sunlight by using different in-chemico and mammalian (HaCaT) cells, as test systems. Our experimental outcomes illustrate that TAPS get photodegraded (LC-MS/MS) and specifically generated superoxide anion radical (O2•-) under UVA and UVB via type-I photodynamic reaction. The phototoxic potential of TAPS is measured through MTT, NRU, and LDH assays that depicted a significant cell viability reduction at 25 μg/ml concentration and higher. Different cellular stainings (PI uptake, AO/EB, JC-1, NR uptake) suggested the role of mitochondrial-mediated apoptosis. Further, the transcriptomics study revealed upregulation of Apaf-1, Bax, Cytochrome c, Caspase 3, Caspase 9 and downregulation of Catalase and Bcl-2 by TAPS treated cells that strengthen our findings. Thus, the above findings suggest that chronic application of TAPS may be hazardous for human skin and promote various skin diseases.


Indications for sentinel lymph node biopsy in node-negative oral cancers.
We aimed to define the indications for sentinel lymph node biopsy (SLNB), the third option for cervical treatment in oral cancer with negative cervical lymph nodes. The greatest depth of invasion (DOI) and long diameter (LD) of the primary site were used as exposures. SLN metastasis was considered the outcome. In three trials conducted between 2009 and 2016, 158 patients were eligible and reassigned to this study group. The scatterplot based on the respective values of DOI and LD would eventually be divided into three sections. In cases of sections T1, T2, and T3, the proportions of SLN metastasis positivity were 21.3%, 35.3%, and 51.2%, respectively. In certain cases of T1 with 2 mm < DOI ≤ 5 mm and 8 mm < LD ≤ 20 mm, the proportion of SLN metastasis positivity was 40.9%. SLNB-navigated or assisted neck dissection can be added as an effective procedure for N0 neck control.


Role of ultralow dose of naloxone as an adjuvant to fentanyl-bupivacaine in thoracic paravertebral block analgesia after modified radical mastectomy: Randomized controlled trial.
We evaluated the effect of the addition of 100 ng of naloxone to fentanyl-bupivacaine mixture used in thoracic paravertebral block (PVB) on the duration and the quality of post-mastectomy analgesia. A randomized double-blinded trial. Oncology surgery unit. This study included 135 patients, aged 40-60 years of either sex presented for elective unilateral-modified radical mastectomy. Patients were divided randomly into three groups: group I, received 0.3 mL/kg of 0.25 percent bupivacaine; group II, received 0.3 mL/kg of 0.25 percent bupivacaine, fentanyl 50 µg, and naloxone 100 ng; group III, received 0.3 mL/kg of 0.25 percent bupivacaine and fentanyl 50 µg. The visual analog scale was assessed immediately post-operative, every 2 hours till 12 hours, and then every 6 hours for 24 hours; the time of first and total amount of rescue analgesia and side effects during the first 24 hours were recorded. Group II showed a significant prolonged analgesia with a delayed first request of rescue analgesia and lower amount of morphine (592.1 ± 14.9 minutes and 7.28 ± 7.81 mg, respectively) than groups I (127.7 ± 35.1 minutes and 19.84 ± 2.56 mg, respectively) and III (232.2 ± 9.27 minutes and 13.52 ± 1.74 mg, respectively) as p < 0.001. Using naloxone as additives in PVB has been promising and effective in controlling post-mastectomy pain.


Hepatitis C virus core protein modulates fatty acid metabolism and thereby causes lipid accumulation in the liver.
We studied the roles of hepatitis C virus (HCV) core protein in hepatic steatosis and changes in hepatic lipid metabolism. HCV core protein expression plasmid was transfected in HepG2. Triacylglyceride (TG) and mRNA level associated with lipid metabolism were measured. Male C57BL/6 mice were infected with HCV core recombinant adenovirus and used for lipids and mRNA studies. In HCV core protein-expressing cells, peroxisome proliferator-activated receptor (PPAR)alpha, multidrug resistance protein (MDR) 3, and microsomal triglyceride transfer protein (MTP) were down-regulated 48 hr after transfection. In HCV core protein-expressing mice, hepatic TG content and hepatic thiobarbituric acid-reactive substances increased. PPARalpha, MDR2, acyl-CoA oxidase (AOX), and carnitine palmitoyl transferase-1 (CPT-1) were down-regulated. HCV core protein down-regulated lipid metabolism-associated gene expression, Mdr2, CPT, and AOX, accompanied by down-regulation of PPARalpha. There findings may contribute to the understanding of HCV-related steatosis, induction of reactive oxygen species, and carcinogenesis.


Author Correction: OutPredict: multiple datasets can improve prediction of expression and inference of causality.
An amendment to this paper has been published and can be accessed via a link at the top of the paper.


The YPEL5-PPP1CB fusion transcript is detected in different hematological malignancies and in normal samples.
Chronic lymphocytic leukemia (CLL) is the most frequent leukemia in Western adults. It was suggested that transcripts from a reciprocal trans-splicing event between YPEL5 and PPP1CB were present exclusively in CLL patients (more than 90%). Here we show that the YPEL5-PPP1CB fusion is not specific for CLL but is also detected in other hematological malignancies such as chronic myeloid leukemia, monoclonal B cell lymphocytosis or acute leukemia and also in normal samples. As such, it is unlikely that the YPEL5-PPP1CB fusion is a good drug target in CLL or a suitable target to monitor disease.


Mutations affecting acetylcholine levels in the nematode Caenorhabditis elegans.
Gene cha-1.unc-17 of the nematode Caenorhabditis elegans is a complex gene, consisting of at least two complementation groups. One part (cha-1 region) of the gene encodes the enzyme choline acetyltransferase (ChAT), but the function of the other part (unc-17 region) is still unclear. We measured the ChAT activity and ACh levels of the cha-1 and unc-17 complex gene mutants. We show here that alterations in ACh levels, rather than the ChAT activity, reflect abnormal phenotypes accompanying cha-1.unc-17 mutations, that is, the decreased ACh levels in cha-1 mutations and abnormal accumulation in unc-17 mutations. Our results suggest that the unc-17 region may encode functions necessary for storage and/or release of ACh at the presynaptic level.


Review of outpatient procedural sedation clinics in a tertiary paediatric hospital in South Australia.
Procedures, such as immunisation and venepuncture, can be distressing for paediatric patients, especially those with needle phobia and neurodevelopmental disorders. Procedural sedation helps provide access to equitable health care in this population. The aim of this study was to evaluate the pilot outpatient procedural sedation clinics at the Women's and Children's Hospital and the impact on patient care and outcomes. A prospective review was undertaken between July 2021 and May 2022 on all patients who attended the procedural sedation clinics at the Women's and Children's Hospital. These clinics were the COVID Specialist Immunisation Sedation Clinic (SISC) and Paediatric Sedation Clinic (PSC). There were 182 visits in a total of 110 children with a 92% primary procedure success rate. Sixty-three per cent of patients had neurodevelopmental disorders with autism spectrum disorder being most common. There was a significant reduction in anxiety scores pre- and post-sedation and a reduction in anxiety scores if patients were to return without the use of sedation. Outpatient procedural sedation is beneficial for a specific cohort of the paediatric population. This can also have a significant positive impact on patient care and potentially, long-term outcomes.


Diverse model systems reveal common principles of meiosis.
A meeting report on the 14th Gordon Research Conference on Meiosis, held at Colby Sawyer College, New London, NH, USA, 9-15 June 2018, chaired by Monica Colaiacovo, Harvard Medical School.


Measuring and tracking education program implementation: the Minnesota Heart Health Program experience.
In an overall framework uniting program planning and evaluation, process evaluation can assist community-based health promotion programs in establishing participation objectives, monitoring their achievement and the quality of interventions used, and translating these into useful information for managing and developing programs. This research reports on efforts by the Minnesota Heart Health Program to develop a system that permitted tracking educational program contacts, its implementation, and its use to make management decisions about program activities. The system was developed as part of a planning and evaluation framework with specific criteria for developing and tracking educational programs drawn from the social-learning literature. Overall, the system helped to make participation objectives more concrete, aided decision making about allocation of personnel and material resources, and encouraged the development of innovative programs.


Freeze-fracture and immunohistochemical studies of gap junctions in human gastric mucosa with special reference to their relationship to gastric ulcer and gastric carcinoma.
Our aim was to determine whether the development of gap junctions in the human gastric mucosa has any relation to gastric ulcer and gastric carcinoma. Freeze-fracture replicas were prepared from the endoscopic biopsy specimens of 20 patients with gastric ulcer and 7 healthy volunteers. Large fractured areas of lateral cell membranes of surface mucous cells were examined randomly under an electron microscope. Small gap junctions were observed between gastric surface mucous cells in all healthy volunteers. Gap junctions in the patients with gastric ulcer were significantly fewer than in the healthy volunteers. In addition, gap junctions in patients with recurrent ulcer were significantly fewer than in those with first-onset ulcer. There was no obvious relationship between age and the development of gap junctions in patients with gastric ulcer or in healthy volunteers. In the areas of intestinal metaplasia, gap junctions were occasionally seen between absorptive cells of the villi, but not in the lateral membranes of goblet cells. Fresh frozen sections for indirect immunofluorescence were prepared from the endoscopic biopsy specimens of 19 patients with gastric ulcer and 5 patients with gastric cancer. Monoclonal antibody against liver gap junction protein (anti-connexin 32, 6-3G11) was used for the indirect immunofluorescence. On the border of gastric ulcer, fluorescent spots in the surface mucous cells were significantly fewer than in the surface mucous cells of the body and antrum which were distant from the ulcer area in the same patients. In gastric cancer tissue specimens, fluorescent spots were not observed at all.(ABSTRACT TRUNCATED AT 250 WORDS)


Regulation of cell cycle proteins by chemokine receptors: A novel pathway in human immunodeficiency virus neuropathogenesis?
In order to test the hypothesis that alteration of cell cycle proteins are involved in the neuronal damage caused by human immunodeficiency virus (HIV), the authors have been studying the effect of chemokines on the CDK/Rb/E2F-1 pathway--which is involved in neuronal apoptosis and differentiation. First, they have asked whether CXCR4, the specific receptor for the chemokine SDF-1 and X4-using gp120s, can regulate Rb and E2F-1 activity in cultures of differentiated rat neurons. Although CCR3 and CCR5 are known to mediate infection of microglia by HIV-1, recent evidence indicate that CXCR4 also play important roles in HIV-induced neuronal injury, and dual-tropic isolates that use CXCR4 to infect macrophages have recently been reported. The authors have focused on two specific brain areas in which CXCR4 is physiologically relevant, i.e., the cerebellum and the hippocampus. So far, the data indicate that changes in the nuclear and cytosolic levels of Rb, which result in the functional loss of this protein, are associated with apoptosis in these neurons, and that SDF-1alpha and gp120IIIB affect this pathway. A summary of the findings are presented.


MRI-based quantification of posterior ocular globe flattening during 60 days of strict 6° head-down tilt bed rest with and without daily centrifugation.
Spaceflight associated neuro-ocular syndrome (SANS) is associated with acquired optic disc edema, hyperopia, and posterior globe flattening in some astronauts during long-duration spaceflight possibly due to the headward fluid redistribution in microgravity. The goal of this study was to assess whether strict head-down tilt (HDT) bed rest as a spaceflight analog would produce globe flattening and whether centrifugation could prevent these changes. Twenty-four healthy subjects separated into three groups underwent 60 days of strict 6° HDT bed rest: one control group with no countermeasure (n = 8) and two countermeasure groups exposed to 30 min daily of short-arm centrifugation as a means of artificial gravity (AG), either intermittent (iAG, n = 8) or continuous (cAG, n = 8). Magnetic resonance images (MRI) were collected at baseline, HDT-day 14, HDT-day 52, and 3 days after bed rest. An automated method was applied to quantify posterior globe volume displacement compared with baseline scans. On average, subjects showed an increasing degree of globe volume displacement with bed rest duration (means ± SE: 1.41 ± 1.01 mm3 on HDT14 and 4.04 ± 1.19 mm3 on HDT52) that persisted post-bed rest (5.51 ± 1.26 mm3). Application of 30 min daily AG did not have a significant impact on globe volume displacement (P = 0.42 for cAG and P = 0.93 for iAG compared with control). These results indicate that strict 6° HDT bed rest produced displacement of the posterior globe with a trend of increasing displacement with longer duration that was not prevented by daily 30 min exposure to AG.NEW & NOTEWORTHY Head-down tilt (HDT) bed rest is commonly used as a spaceflight analog for investigating spaceflight associated neuro-ocular syndrome (SANS). Posterior ocular globe flattening has been identified in astronauts with SANS but until now has not been investigated during HDT bed rest. In this study, posterior ocular globe volume displacement was quantified before, during, and after HDT bed rest and countermeasures were tested for their potential to reduce the degree of globe flattening.


Molecular Chaperones in Neurodegenerative Diseases: A Short Review.
Stress and misfolded proteins result to dysfunction in the cell, often leading to neurodegenerative diseases and aging. Misfolded proteins form toxic aggregates that threaten cell's stability and normal functions. In order to restore its homeostasis, the cell activates the UPR system. Leading role in the restoration play the molecular chaperones which target the misfolded proteins with the purpose of either helping them to unfold and refold to their natural state or lead them degradation. This paper aims to present some of the most known molecular chaperones and their relation with diseases associated to protein misfolding and neurodegeneration, as well as the role of chaperones in proteostasis.


Autoantibodies mimicking anti-Jkb plus anti-Jk3 associated with autoimmune hemolytic anemia in a primipara who delivered an unaffected infant.
A serum sample from a nontransfused 25-year-old Caucasian primipara contained weak anti-Jkb plus anti-Jk3. The direct antiglobulin test on the patient's red cells was strongly positive. Anti-Jkb was recovered in a heat eluate. An ether eluate contained anti-Jk3. Her red cells types as Jk(a-b+)Jk:3. The anti-Jkb and anti-Jk3 reactivity was completely absorbed both by red cell samples lacking and red cells possessing the corresponding antigens, indicating these antibody specificities to be of the mimicking variety. At 41 weeks gestation she delivered a normal, healthy infant with no detectable serum or cell bound antibody.


Interaction of ICRF 159 with radiation, and its effect on sub-lethal and potentially lethal radiation damage in vitro.
ICRF 159 has been shown to increase the X-radiation sensitivity of exponentially growing EMT6 mouse tumour cells in vitro. This was found only with ICRF 159 exposure times longer than 10 h and only when the drug was given before irradiation. The increase in radiation sensitivity was expressed as a reduction of the shoulder of the radiation survival curve. As ICRF 159 was shown to have no effect on the repair of sub-lethal radiation damage, it was concluded that the drug reduced the capacity to accumulate such damage. ICRF 159 was also shown to have no effect on the repair of potentially lethal radiation damage in late plateau cells.


Therapeutic jurisprudence and the desistance paradigm: Theoretical and practical convergences for social reintegration.
This paper discusses in theoretical and practical terms how the Desistance Paradigm offers a powerful and underexplored potential alliance with Therapeutic Jurisprudence, especially regarding the social reintegration of those who break the law. As such, this paper presents a description of the Therapeutic Justice and Desistance Paradigm, along with their main findings and theoretical scope, to then present a discussion of how these two approaches share a common horizon (which are not only limited to practices and techniques, but also to legal structures and procedures). Finally, it concludes with some future challenges for which the convergence of these two paradigms can offer fruitful developments within the criminal justice system.


Clinical, immunophenotypic, and molecular profiling of trisomy 12 in chronic lymphocytic leukemia and comparison with other karyotypic subgroups defined by cytogenetic analysis.
In a cohort of 130 unselected chronic lymphocytic leukemia (CLL) patients, 73 cases had normal karyotypes, 57 cases had abnormal karyotypes, and 22/57 cases carried more than one abnormality. Trisomy 12 (+12) was the most common abnormality (26/130 cases; 20%), and 17/26 cases had isolated +12. Del(13q)/t13q/-13 was detected in 19/130 cases (14.6%), and 5/19 cases had isolated del(13)(q12q14). Deletion (11)(q23) and del(17p)/-17 were detected in 5/130 cases, respectively. CD38 expression was significantly more frequent in the +12/11q/17p versus the normal/del(13q) subgroups. A significant association was detected between +12 and FMC7 positivity. IGHV-unmutated cases were significantly more frequent in the +12/11q/17p subgroups. Patients with normal karyotype/del(13q) had a longer median time to progression versus the patients in the +12/11q/17p subgroups. According to multivariate analysis, only IGHV mutation status remained a statistically significant variable for progression-free survival (PFS). Furthermore, IGHV mutation status and clinical stage at diagnosis were the only significant prognostic factors for overall survival. Among Binet-A patients, significant parameters for shorter PFS were +12 or 11q/17p aberrations, CD38 expression, and IGHV unmutated status. In multivariate analysis, only CD38 expression and IGHV-unmutated status retained statistical significance for PFS. In conclusion, trisomy 12 in CLL is characterized by considerable heterogeneity and seems to be associated with disease progression.


Do pioneers have r-selected traits? Life history patterns among colonizing terrestrial gastropods.
We examine whether pioneer species of terrestrial gastropods (snails and slugs) possess particular life history traits commonly associated with r-selection, using data on gastropod colonization in four areas in north-west Europe (the Kvarken and Tvärminne archipelagos in the Baltic, polder woods in IJsselmeer, and a rehabilitated quarry near Maastricht). Data on age at first reproduction, longevity, clutch size, egg size and lifetime fecundity were gathered from the literature. In order to control for potentially confounding effects of body size on life history traits, we compared the residuals from the allometric relations between life history traits and body size for pioneers and non-pioneers. In snails, all life history traits examined were related to body size. In slugs, all traits except age at first reproduction scaled with body size. Body sizes did not differ between pioneers and non-pioneers in any area. In all four areas, there were no significant differences between pioneers and non-pioneers in any of the life history traits examined, after body size had been taken into account. This indicates that pioneer terrestrial gastropods generally cannot be regarded as r-selected. Pioneer species may possess any of several life history strategies, and the combinations of traits shown by them may have little in common with the r-K selection concept.


An acute psychiatric rating scale for the clinical assessment of functionally disturbed inpatients.
A 28-item behavioral rating scale, the Acute Psychiatric Rating Scale (APRS), was developed using factor-analytic methods for the assessment of functionally disturbed psychiatric inpatients. Fifty-eight staff rated 74 patients on the scale. Seven factorial dimensions were extracted comprising neuroticism, aggression, emotional withdrawal, cognitive impairment, schizophrenia, hypomania and self-injuriousness. The scale was evaluated in 4 different psychiatric inpatient units: two acute admission wards, an intensive care unit and a regional secure unit. Behavioral ratings on the scale were related to several patient demographic and treatment variables, including age, sex, marital status, legal status, length of admission and electroconvulsive therapy. The scale was found to possess a clear factorial structure, good interrater reliability and promising clinical validity for further research use in psychiatric inpatient settings.


A reproducible robust likelihood approach to inference about marginal characteristics of binary data in paired settings.
We introduce a robust likelihood approach to inference about marginal distributional characteristics for paired data without modeling correlation/joint probabilities. This method is reproducible in that it is applicable to paired settings with various sizes. The virtue of the new strategy is elucidated via testing marginal homogeneity in paired triplet scenario. We use simulations and real data analysis to demonstrate the merit of our robust likelihood methodology.


Electroacupuncture-driven endogenous circulating serum exosomes as a potential therapeutic strategy for sepsis.
Sepsis poses a serious threat to human life and health, with limited options for current clinical treatments. Acupuncture plays an active role in treating sepsis. However, previous studies have focused on the neuromodulatory effect of acupuncture, neglecting its network modulatory effect. Exosomes, as a new way of intercellular communication, may play an important role in transmitting acupuncture information. This paper explores the possibility of electroacupuncture-driven endogenous circulating serum exosomes and their carried miRNAs as a potential treatment for sepsis. The sepsis mouse model was established by intraperitoneal injection of lipopolysaccharide (LPS) (12 mg/kg, 24 mg/kg), and EA (continuous wave, 10 Hz, intensity 5) or intraperitoneal injection of Acupuncture Exosomes (Acu-exo) were performed before the model establishment. The therapeutic effect was evaluated by survival rate, ELISA, H&E staining and lung wet/dry weight ration (W/D). In vivo imaging of small animals was used to observe the accumulation of Acu-exo in various organs of sepsis mice. LPS was used to induce macrophages in cell experiments, and the effect of Acu-exo on macrophage inflammatory cytokines was observed. In addition, The miRNA sequencing method was further used to detect the serum exosomes of normal and EA-treated mice, and combined with network biology analysis methods to screen possible key targets. EA and Acu-exo reduced the W/D and lung tissue damage in sepsis mice, down-regulated the expression of serum inflammatory cytokines TNF-α and IL-6, and increased the survival rate of sepsis mice. In vivo imaging of small animals found that Acu-exo were accumulated in the lungs of sepsis mice. Cell experiments proved that Acu-exo down-regulated the expression of inflammatory cytokines TNF-α, IL-6 and IL-1β to alleviate the inflammatory response induced by LPS in macrophages. MiRNA sequencing revealed 53 differentially expressed miRNAs, and network biology analysis revealed the key targets of Acu-exo in sepsis treatment. Electroacupuncture-driven endogenous circulating serum exosomes and their carried miRNAs may be a potential treatment for sepsis.


Effect of different levels of phosphorus on rumen microbial fermentation and synthesis determined using a continuous culture technique.
A continuous culture technique was used to study the phosphorus requirements of rumen micro-organisms. Solutions of artificial saliva containing 120, 80, 40 and 0 mg inorganic phosphorus (Pi)/l were infused into the reaction vessels previously inoculated with rumen contents, resulting in Pi concentrations in the vessel contents of 48, 28, 4 and less than 1 mg/l respectively. Various fermentative and synthetic characteristics were examined. In the vessel contents, concentrations of protozoa (about 0.9 X 10(5)/ml) were not significantly affected by Pi concentration. Total volatile fatty acids (VFA) produced averaged about 6.83 mmol/h with Pi levels of 48 and 28 mg/l. Reduction in Pi concentrations to 4 and less than 1 mg/l resulted in significant reductions in total VFA to approximately 6.25 and 3.75 mmol/h respectively, accompanied by a rise in pH from 6.5 to 7.3. Ammonia-nitrogen values, which averaged about 131 mg/l at the higher Pi concentrations, also increased with the lowest level of Pi to about 240 mg/l. ATP concentrations averaged about 14 mumol/l at the highest Pi concentration and fell progressively with each reduction in Pi concentration to a final value of 2.5 mumol/l with the Pi level less than 1 mg/l. At Pi concentrations of 48 and 28 mg/l, the digestibilities of xylose, arabinose and cellulose-glucose were maintained at about 0.90, 0.62 and 0.70 g/g input respectively. At lower Pi concentrations these digestibilities fell significantly and corresponding values at Pi less than 1 mg/l were 0.73, 0.41 and 0.31 respectively. Starch digestion was unaffected by Pi concentration and remained at about 0.90 g/g input. The amount of microbial-N synthesized averaged 0.48 g/d and was maintained with Pi concentrations down to 4 mg/l. There was, however, a significant reduction to 0.26 g/d with Pi concentrations of less than 1 mg/l. The efficiency of microbial protein synthesis was variable but averaged approximately 25 g N/kg total carbohydrate fermented. It was estimated that the minimum Pi concentrations required in rumen fluid in vivo to maintain maximum degradative and synthetic microbial activities was in the range 75-100 mg/l and that over-all P requirement of the microbes was of the order of 5.1 g/kg apparently digested organic matter intake.


A case of severe acute pancreatitis treated with CTR-001 direct hemoperfusion for cytokine apheresis.
Severe acute pancreatitis is a clinical entity that can develop into multiple organ failure (MOF), and still has a poor prognosis. It is generally agreed that excessive humoral mediators such as pro-inflammatory cytokines play important roles in the pathogenesis of organ failure in patients with severe acute pancreatitis (SAP). Furthermore, it has been reported that continuous hemodiafiltration (CHDF) can remove the excess humoral mediators during the hypercytokinemic state of systemic inflammatory response syndrome (SIRS). We experienced a case of severe acute pancreatitis induced by alcohol abuse, on whom we performed cytokine apheresis. The patient was a 46 year-old male. He received 14 cytokine apheresis procedures, for about 4 hours in each session, using a CTR-001 direct hemoperfusion (DHP) cartridge. His serum levels of pro-inflammatory cytokines such as interleukin-6 (IL-6; 1649.1+/-667.1-1257.1+/-489.4 pg/mL, P=0.013) decreased significantly after the CTR-001 procedures. However tumor necrosis factor-alpha (TNF-alpha) (26.2+/-1.7-24.3+/-1.9 pg/mL, P=0.087), IL-1beta (6.1+/-2.9-3.49+/-1.1 pg/mL, P=0.477), IL-8 (192.5+/-33.4-229.5+/-51.8 pg/mL, P=0.754) and IL-10 (14.4+/-2.7-14.0+/-1.9 pg/mL, P=0.726) did not decrease statistically. Therefore, we conclude that in this case, cytokine apheresis using a CTR-001 cartridge was effective for reducing the pro-inflammatory cytokines during severe acute pancreatitis.


Aging change of left ventricular function in children evaluated by acoustic quantification method.
There are few reports about acoustic quantification (AQ) in the area of pediatrics. We aim to determine normal values of AQ analysis and investigate the aging change of left ventricular function in children. The subjects in this study included 137 patients (aged 29 days to 18 years) who had normal cardiac function and no cardiac load. None of the patients were receiving medical therapy. The instrument used was a PH-6500 (Philips, Andevor). Change of left ventricular area in short-axis view was detected by AQ analysis. From the mitral inflow, peak early (E) and peak late (A) diastolic velocities were measured, and E/A was calculated. End-diastolic area (EDA) and end-systolic area (ESA) increased with age. Fractional area change (FAC) decreased with age. Peak ejection rate (PER) and peak rapid filling rate (PRFR) decreased with age up to 10 years. Atrial filling fraction (AFF) decreased and E/A increased with age up to 5 years. Maturational or developmental alterations in LV diastolic properties were found up to 5 years old. AQ analysis is one of the useful indexes for investigating left ventricular diastolic function.


Shotgun proteomics and molecular simulations on multifunctional bioactive peptides derived from the whey of unexplored "Gaddi" goat of Himalayas.
The very first time, whey protein from the Himalayan goat breed "Gaddi" was hydrolyzed with alcalase, flavourzyme, and a combination of both in this study. The degree of hydrolysis (DH) ranged from 28 to 53%, with sequential hydrolysis by combination achieving the highest DH. The sequential hydrolysis demonstrated antimicrobial activity against all pathogens used with 3 kDa permeate showed significantly higher (p < 0.05) activity against S. aureus, E. coli, B. cereus and C. sakazakii. The antioxidant activity was in the range of IC50 = 0.49 to 2.00 mg protein/mL, flavourzyme and sequential hydrolysates showed significant ABTS radical and FRAP inhibition. The α-amylase inhibitory activity was highest in 3 kDa permeate of flavourzyme with IC50 values of 0.34 mg protein/mL. Bioactive peptides DDSPDLPK, EMPFPK and TPEVDKEALEK were identified most significant in the hydrolysates. In molecular docking, the DDSPDLPK interacted most efficiently with enzymes involved in microbial growth, oxidative stress, and hyperglycemia.


Progressive fibrosis in interstitial lung diseases - proposed definition and management.
Interstitial lung diseases may have an unpredictably progressive course, which is manifested as progression of pulmonary fibrosis, causing an increasing impairment of lung function affecting a poor prognosis. The possibility of an effective antifibrotic treatment is a chance for patients to slow down the progression of the disease, perhaps even extend their life. For this reason, standardization of the definition as well as identification criteria for progressive fibrosis interstitial lung disease is a method for optimizing the management in this group of patients.


Virus-cell interactions in the nervous system and the role of the immune response.
The outcome of a viral infection within the nervous system depends on a complex interplay between the virus, its target cell and the immune system. Recent research has elucidated a variety of mechanisms involved in these interactions and their role in the production of disease.


Mortality by Admission Diagnosis in Children 1-60 Months of Age Admitted to a Tertiary Care Government Hospital in Malawi.
Diagnosis-specific mortality is a measure of pediatric healthcare quality that has been incompletely studied in sub-Saharan African hospitals. Identifying the mortality rates of multiple conditions at the same hospital may allow leaders to better target areas for intervention. In this secondary analysis of routinely collected data, we investigated hospital mortality by admission diagnosis in children aged 1-60 months admitted to a tertiary care government referral hospital in Malawi between October 2017 and June 2020. The mortality rate by diagnosis was calculated as the number of deaths among children admitted with a diagnosis divided by the number of children admitted with the same diagnosis. There were 24,452 admitted children eligible for analysis. Discharge disposition was recorded in 94.2% of patients, and 4.0% (N = 977) died in the hospital. The most frequent diagnoses among admissions and deaths were pneumonia/bronchiolitis, malaria, and sepsis. The highest mortality rates by diagnosis were found in surgical conditions (16.1%; 95% CI: 12.0-20.3), malnutrition (15.8%; 95% CI: 13.6-18.0), and congenital heart disease (14.5%; 95% CI: 9.9-19.2). Diagnoses with the highest mortality rates were alike in their need for significant human and material resources for medical care. Improving mortality in this population will require sustained capacity building in conjunction with targeted quality improvement initiatives against both common and deadly diseases.


Scaphoid osteosynthesis: early experience with the Herbert bone screw.
The results of our first fourteen patients with fractured scaphoids treated with the Herbert bone screw have been disappointing. Six have failed to unite. The operation is technically demanding and there is a high incidence of malpositioning of the screw which correlates with failure to achieve union. This is predictable from initial radiographs and peroperative radiology is advised. The osteosynthesis should be protected until union has occurred radiologically, especially in manual workers.


[Use of inflammatory markers for monitoring paediatric asthma].
The assessment of asthma control takes into account the symptoms, quality of life, lung function, and inflammatory markers. In the last few years, there has been a large increase in the number of publications related to the study of biomarkers in the management of paediatric asthma. Despite the large variety of inflammatory markers described in research studies, only a small group has shown to be useful in monitoring the disease. Induced sputum eosinophils offer the most solid evidence in assessing asthma control. Exhaled breath condensate and urinary leucotrienes could be useful in the future if there is standardisation in their procedures and interpretation of the results. Nitric oxide, basic eosinophil cationic protein, and bronchial biopsy with bronchoalveolar lavage, only appeared to be useful in a reduced group of patients.


Direct amide 15N to 13C transfers for solid-state assignment experiments in deuterated proteins.
The assignment of protein backbone and side-chain NMR chemical shifts is the first step towards the characterization of protein structure. The recent introduction of proton detection in combination with fast MAS has opened up novel opportunities for assignment experiments. However, typical 3D sequential-assignment experiments using proton detection under fast MAS lead to signal intensities much smaller than the theoretically expected ones due to the low transfer efficiency of some of the steps. Here, we present a selective 3D experiment for deuterated and (amide) proton back-exchanged proteins where polarization is directly transferred from backbone nitrogen to selected backbone or sidechain carbons. The proposed pulse sequence uses only 1H-15N cross-polarization (CP) transfers, which are, for deuterated proteins, about 30% more efficient than 1H-13C CP transfers, and employs a dipolar version of the INEPT experiment for N-C transfer. By avoiding HN-C (HN stands for amide protons) and C-C CP transfers, we could achieve higher selectivity and increased signal intensities compared to other pulse sequences containing long-range CP transfers. The REDOR transfer is designed with an additional selective π pulse, which enables the selective transfer of the polarization to the desired 13C spins.