ROOT ULTRAVIOLET B-SENSITIVE1/weak auxin response3 is essential for polar auxin transport in Arabidopsis.
The phytohormone auxin regulates virtually every aspect of plant development. To identify new genes involved in auxin activity, a genetic screen was performed for Arabidopsis (Arabidopsis thaliana) mutants with altered expression of the auxin-responsive reporter DR5rev:GFP. One of the mutants recovered in the screen, designated as weak auxin response3 (wxr3), exhibits much lower DR5rev:GFP expression when treated with the synthetic auxin 2,4-dichlorophenoxyacetic acid and displays severe defects in root development. The wxr3 mutant decreases polar auxin transport and results in a disruption of the asymmetric auxin distribution. The levels of the auxin transporters AUXIN1 and PIN-FORMED are dramatically reduced in the wxr3 root tip. Molecular analyses demonstrate that WXR3 is ROOT ULTRAVIOLET B-SENSITIVE1 (RUS1), a member of the conserved Domain of Unknown Function647 protein family found in diverse eukaryotic organisms. Our data suggest that RUS1/WXR3 plays an essential role in the regulation of polar auxin transport by maintaining the proper level of auxin transporters on the plasma membrane.


A mutant Pfu DNA polymerase designed for advanced uracil-excision DNA engineering.
The combined use of restriction enzymes with PCR has revolutionized molecular cloning, but is inherently restricted by the content of the manipulated DNA sequences. Uracil-excision based cloning is ligase and sequence independent and allows seamless fusion of multiple DNA sequences in simple one-tube reactions, with higher accuracy than overlapping PCR. Here, the addition of a highly efficient DNA polymerase and a low-background-, large-insertion- compatible site-directed mutagenesis protocol is described, largely expanding the versatility of uracil-excision DNA engineering. The different uracil-excision based molecular tools that have been developed in an open-source fashion, constitute a comprehensive, yet simple and inexpensive toolkit for any need in molecular cloning.


Changes in mast cell infiltration: a possible mechanism in detrusor overactivity induced by visceral hypersensitivity.
To establish the detrusor overactivity (DO) model induced by visceral hypersensitivity (VH) and investigate the relationship between mast cell (MC) infiltration and DO. Sixty rats are divided into 4 groups randomly: Group 1:Baseline group; Group 2: DO group; Group 3: CON group; Group 4: VH group. The colorectal distension (CRD) and abdominal withdral reflex (AWR) scores are performed to evaluate VH. The cystometric investigation and histological test of MC infiltration are assessed. The threshold pressure of CRD in the VH group is significantly lower than that in the CON group (P<0.001). At the distension pressure ≥20 mmHg, the AWR scores of the VH group are significantly higher than those of the CON group (10 mmHg: P=0.33; 20 mmHg: P=0.028; 40 mmHg: P<0.001; 60 mmHg: P<0.001; 80 mmHg: P<0.001). DO model is successfully established in the VH group (DO rate=100%). Compared with the CON group, the numbers of MC infiltration are significantly increased in the VH group, including submucosa of bladder (P<0.001), mucosa lamina propria/mesentery of small intestine (P<0.001), and mucosa lamina propria/mesentery of large intestine (P<0.001). Furthermore, more MC activation as well as degranulation are observed in the VH group. It is indicated that DO model can be established in the VH rats. The MC infiltration may play an important role in DO induced by VH, and may be helpful to understand the mechanisms of DO in VH patients.


Weighing density and kinship: Aggressive behavior and time allocation in fire salamander (Salamandra infraimmaculata).
Kin-biased behavior (that is responding differentially to kin and non-kin) is thought to be adaptive in many social interactions. One example of this kin bias is behaving less aggressively toward a relative than a non-relative, a behavior which yields inclusive fitness benefits. However, data are lacking about the ability of animals to weigh their preference for kinship and the density of conspecifics simultaneously and to respond accordingly. Fire salamanders (Salamandra infraimmaculata) larviposit in high densities in ponds. Thus, larvae of different females confront competition and predation by other larvae. We studied whether larvae prefer their kin over particular density or vice versa. We experimentally used a transparent glass aquarium with inner chambers to test the responses of a focal larva toward its siblings and non-siblings. Specifically, we quantified the time a focal larva spent near its siblings or non-siblings, presented in varying densities, and the aggression level it demonstrated. We found that focal larvae spent more time near non-siblings if non-sibling and sibling groups were of equal density. The focal larvae were also more aggressive toward non-siblings. The results may be explained by the cannibalistic nature of these larvae: high density may provide more opportunities for food, especially when non-siblings are present. Further explanations for these findings may include other advantages of staying in a larger group and/or the stronger olfactory and visual stimulation offered by groups compared to a single individual. These findings suggest that larvae make differential responses toward conspecifics depending simultaneously on the level of relatedness and the density of the group. Such responses have important implications for social-aggregation decisions and may especially affect the fitness of cannibalistic species.


Decreased plasma and tissue isoleucine levels after simulated gastrointestinal bleeding by blood gavages in chronic portacaval shunted rats.
Previously, arterial concentrations of the essential branched chain amino acid isoleucine (Ile) were found to have decreased by more than 50% after gastrointestinal haemorrhage in patients and after intragastric blood administration in healthy humans and pigs. Hypothetically, this induced hypoisoleucinaemia could deplete tissue Ile pools. To study the effect of repeated blood gavages on arterial and tissue Ile levels during normal and impaired liver function. Male Wistar rats. 14 days after portacaval shunting or sham surgery, rats received 3 ml bovine erythrocytes or saline at 0, 1, 2, and 3 hours via a gastrostomy catheter in the duodenum. At 0, 2, 4, 6 and 8 hours arterial blood and at 8 hours intestine, liver, muscle, and cerebral cortex were sampled for determination of ammonia and amino acid concentrations. In both groups repeated blood administration resulted in a marked decrease in plasma Ile (40-60%). This was accompanied by decreased tissue Ile concentrations in liver (50%), muscle (40-60%), and cerebral cortex (40-50%), but unaltered intestinal Ile levels. In contrast, the arterial and tissue concentrations of ammonia, urea, and of most amino acids increased, most strikingly of the other two branched chain amino acids, valine and leucine. Simulated gastrointestinal bleeding by blood gavages in rats with and without impaired liver function leads to hypoisoleucinaemia and decreased tissue Ile pools.


Discrete confidence levels revealed by sequential decisions.
Humans can meaningfully express their confidence about uncertain events. Normatively, these beliefs should correspond to Bayesian probabilities. However, it is unclear whether the normative theory provides an accurate description of the human sense of confidence, partly because the self-report measures used in most studies hinder quantitative comparison with normative predictions. To measure confidence objectively, we developed a dual-decision task in which the correctness of a first decision determines the correct answer of a second decision, thus mimicking real-life situations in which confidence guides future choices. While participants were able to use confidence to improve performance, they fell short of the ideal Bayesian strategy. Instead, behaviour was better explained by a model with a few discrete confidence levels. These findings question the descriptive validity of normative accounts, and suggest that confidence judgments might be based on point estimates of the relevant variables, rather than on their full probability distributions.


Associations of cytokine concentrations with key osteopathic lesions and clinical outcomes in patients with nonspecific chronic low back pain: results from the OSTEOPATHIC Trial.
Little is known about the role that cytokines play in osteopathic manual treatment (OMT) of patients with chronic low back pain (LBP). To measure the baseline concentrations of interleukin (IL)-1β, IL-6, IL-8, IL-10, and tumor necrosis factor (TNF)-α in patients with chronic LBP; the correlations of these cytokine concentrations with clinical measures, including the number of key osteopathic lesions; the changes in cytokine concentrations with OMT; and the association of such changes with clinical outcomes. Substudy nested within a randomized controlled trial of OMT for nonspecific chronic LBP. University-based study in Dallas-Fort Worth, Texas. Seventy adult research patients with nonspecific chronic LBP. A 10-cm visual analog scale, the Roland-Morris Disability Questionnaire, and the Medical Outcomes Study Short Form-36 Health Survey were used to measure LBP severity, back-specific functioning, and general health, respectively. At baseline, IL-1β (ρ = 0.33; P = .005) and IL-6 (ρ = 0.32; P = .006) were each correlated with the number of key osteopathic lesions; however, only IL-6 was correlated with LBP severity (ρ = 0.28; P = .02). There was a significantly greater reduction of TNF-α concentration after 12 weeks in patients who received OMT compared with patients who received sham OMT (Mann-Whitney U = 251.5; P = .03). Significant associations were found between OMT and a reduced TNF-α concentration response at week 12 among patients who achieved moderate (response ratio, 2.13; 95% confidence interval [CI], 1.11-4.06; P = .006) and substantial (response ratio, 2.13; 95% CI, 1.07-4.25; P = .01) LBP improvements, and improvement in back-specific functioning (response ratio, 1.68; 95% CI, 1.04-2.71; P = .03). This study found associations between IL-1β and IL-6 concentrations and the number of key osteopathic lesions and between IL-6 and LBP severity at baseline. However, only TNF-α concentration changed significantly after 12 weeks in response to OMT. These discordant findings indicate that additional research is needed to elucidate the underlying mechanisms of action of OMT in patients with nonspecific chronic LBP.


Non-contact lens related Acanthamoeba keratitis at a tertiary eye care center in south India: Implications for eye care programs in the region.
The purpose of our research was to determine diagnosis and outcomes for non-contact lens related Acanthamoeba keratitis in south India. A retrospective review of the medical and microbiology records of culture-positive Acanthamoeba cases presenting between 1987 and 2001 to a tertiary eye care center in south India. One hundred and three culture-positive cases of Acanthamoeba were identified during chart review. The majority of these cases (70.9%) were already on treatment for keratitis with antibiotics, antifungal and antiviral regimes prior to our examination; 45.2% were on different combinations of regimes. Cysts could be identified using 10% KOH mount in 83.5% of these cases. Clinical resolution with medical therapy was achieved for 83.5% of the cases; the median duration of treatment was 90.5 days. Outcomes - either clinical or visual - did not differ between Acanthamoeba keratitis cases presenting to this tertiary care center were non-contact lens wearers, and already on empirical treatment for either bacterial or fungal keratitis. A basic lab facility including only microscopy and smear examinations may aid etiological diagnosis of corneal ulcers, and reduce the current practice of using combinations of treatment regimes on an empirical basis.


An Ethnographic Observational Study to Evaluate and Optimize the Use of Respiratory Acoustic Monitoring in Children Receiving Postoperative Opioid Infusions.
Respiratory depression in children receiving postoperative opioid infusions is a significant risk because of the interindividual variability in analgesic requirement. Detection of respiratory depression (or apnea) in these children may be improved with the introduction of automated acoustic respiratory rate (RR) monitoring. However, early detection of adverse events must be balanced with the risk of alarm fatigue. Our objective was to evaluate the use of acoustic RR monitoring in children receiving opioid infusions on a postsurgical ward and identify the causes of false alarm and optimal alarm thresholds. A video ethnographic study was performed using an observational, mixed methods approach. After surgery, an acoustic RR sensor was placed on the participant's neck and attached to a Rad87 monitor. The monitor was networked with paging for alarms. Vital signs data and paging notification logs were obtained from the central monitoring system. Webcam videos of the participant, infusion pump, and Rad87 monitor were recorded, stored on a secure server, and subsequently analyzed by 2 research nurses to identify the cause of the alarm, response, and effectiveness. Alarms occurring within a 90-second window were grouped into a single-alarm response opportunity. Data from 49 patients (30 females) with median age 14 (range, 4.4-18.8) years were analyzed. The 896 bedside vital sign threshold alarms resulted in 160 alarm response opportunities (44 low RR, 74 high RR, and 42 low SpO2). In 141 periods (88% of total), for which video was available, 65% of alarms were deemed effective (followed by an alarm-related action within 10 minutes). Nurses were the sole responders in 55% of effective alarms and the patient or parent in 20%. Episodes of desaturation (SpO2 < 90%) were observed in 9 patients: At the time of the SpO2 paging trigger, the RR was >10 bpm in 6 of 9 patients. Based on all RR samples observed, the default alarm thresholds, to serve as a starting point for each patient, would be a low RR of 6 (>10 years of age) and 10 (4-9 years of age). In this study, the use of RR monitoring did not improve the detection of respiratory depression. An RR threshold, which would have been predictive of desaturations, would have resulted in an unacceptably high false alarm rate. Future research using a combination of variables (e.g., SpO2 and RR), or the measurement of tidal volumes, may be needed to improve patient safety in the postoperative ward.


Evaluation of real-time PCR and conventional diagnostic methods for the detection of Clostridium difficile-associated diarrhoea in a prospective multicentre study.
In this prospective multicentre study, an enzyme-linked fluorescent assay (VIDAS CDA2; bioMérieux), an enzyme-linked assay [Premier Toxins A and B (PTAB); Meridian] and an in-house real-time PCR amplifying the tcdB gene were compared with the cell cytotoxicity assay used as the 'gold standard' for diagnosis of Clostridium difficile-associated diarrhoea (CDAD). Faecal samples from patients with a request for C. difficile diagnosis and samples from patients with diarrhoea hospitalized for at least 72 h were collected for 3 consecutive months from four university medical centres in The Netherlands. In total, 547 faecal samples were obtained from 450 patients. Of 540 samples available for all of the assays, 84 (15.6 %) showed a positive result in one or more assays. The cell cytotoxicity assay was positive in 31 samples (5.7 %) from 28 patients. A diagnosis of CDAD was not considered by the physician in 5 (23.8 %) of 21 patients with CDAD who were hospitalized for at least 72 h. Compared with the cell cytotoxicity assay, the sensitivity of VIDAS, PTAB and PCR was 83.9, 96.8 and 87.1 %, respectively. The specificity of VIDAS, PTAB and PCR was 97.1, 94.3 and 96.5 %, respectively. The positive and negative predictive values for VIDAS, PTAB and PCR were 63.4 and 99.0 %, 50.9 and 99.8 %, and 60.0 and 99.2 %, respectively. Of 61 samples that were positive in one, two or three of the assays, 56 were available for discordance analysis. Discordance analysis was performed by culture of toxinogenic strains. The concordance of VIDAS, PTAB and PCR with culture was 53.6 % (30/56), 55.4 % (31/56) and 71.4 % (40/56), respectively. It was concluded that real-time PCR had the highest concordance with toxinogenic culture and is therefore the preferred method for diagnosing CDAD in faecal samples. It was also concluded that diagnosis of patients with diarrhoea who have been hospitalized for more than 72 h should focus mainly on the detection of C. difficile, irrespective of the physician's request.


Intraluminal erosion and migration of the Angelchik antireflux prosthesis.
Despite a paucity of published clinical trials, use of the Angelchik antireflux prosthesis has increased dramatically since its introduction in 1979. Serious complications of this device have begun to appear. We dealt with two cases of erosion of the prosthesis into the gastrointestinal tract, one of which represents, to our knowledge, the first reported case of a gastroenteric fistula secondary to the device. Other complications of the use of this prosthesis have appeared in the literature. Carefully controlled clinical studies with long-term follow-up are needed to assess the overall benefits and safety of this new antireflux prosthesis.


Cholecystosonography--the junctional fold.
Three cases are presented in which a fold occurred along the posterior wall of the gallbladder at the junction of the body and infundibulum at cholecystosonography. On the initial supine scans, this finding suggested a small polyp in 1 case and a calculus in the other 2. Familiarity with this normal variant as well as adherence to correct scan methodology should help to further reduce erroneous diagnoses.


CREBH normalizes dyslipidemia and halts atherosclerosis in diabetes by decreasing circulating remnant lipoproteins.
Loss-of-function mutations in the transcription factor CREB3L3 (CREBH) associate with severe hypertriglyceridemia in humans. CREBH is believed to lower plasma triglycerides by augmenting the activity of lipoprotein lipase (LPL). However, by using a mouse model of type 1 diabetes mellitus (T1DM), we found that greater liver expression of active CREBH normalized both elevated plasma triglycerides and cholesterol. Residual triglyceride-rich lipoprotein (TRL) remnants were enriched in apolipoprotein E (APOE) and impoverished in APOC3, an apolipoprotein composition indicative of increased hepatic clearance. The underlying mechanism was independent of LPL, as CREBH reduced both triglycerides and cholesterol in LPL-deficient mice. Instead, APOE was critical for CREBH's ability to lower circulating remnant lipoproteins because it failed to reduce TRL cholesterol in Apoe-/- mice. Importantly, individuals with CREB3L3 loss-of-function mutations exhibited increased levels of remnant lipoproteins that were deprived of APOE. Recent evidence suggests that impaired clearance of TRL remnants promotes cardiovascular disease in patients with T1DM. Consistently, we found that hepatic expression of CREBH prevented the progression of diabetes-accelerated atherosclerosis. Our results support the proposal that CREBH acts through an APOE-dependent pathway to increase hepatic clearance of remnant lipoproteins. They also implicate elevated levels of remnants in the pathogenesis of atherosclerosis in T1DM.


Development of a Biotechnology Platform for the Fast-Growing Cyanobacterium Synechococcus sp. PCC 11901.
Synechococcus sp. PCC 11901 reportedly demonstrates the highest, most sustained growth of any known cyanobacterium under optimized conditions. Due to its recent discovery, our knowledge of its biology, including the factors underlying sustained, fast growth, is limited. Furthermore, tools specific for genetic manipulation of PCC 11901 are not established. Here, we demonstrate that PCC 11901 shows faster growth than other model cyanobacteria, including the fast-growing species Synechococcuselongatus UTEX 2973, under optimal growth conditions for UTEX 2973. Comparative genomics between PCC 11901 and Synechocystis sp. PCC 6803 reveal conservation of most metabolic pathways but PCC 11901 has a simplified electron transport chain and reduced light harvesting complex. This may underlie its superior light use, reduced photoinhibition, and higher photosynthetic and respiratory rates. To aid biotechnology applications, we developed a vitamin B12 auxotrophic mutant but were unable to generate unmarked knockouts using two negative selectable markers, suggesting that recombinase- or CRISPR-based approaches may be required for repeated genetic manipulation. Overall, this study establishes PCC 11901 as one of the most promising species currently available for cyanobacterial biotechnology and provides a useful set of bioinformatics tools and strains for advancing this field, in addition to insights into the factors underlying its fast growth phenotype.


[Biweekly regimen of high dose of leucovorin, 5-fluorouracil, and paclitaxel for patients with advanced gastric cancer].
Clinical study showed that paclitaxel (PTX) may be used to treat gastric cancer. The combination of PTX and 5-fluorouracil (5-FU) is effective, and safe in treating advanced gastric cancer. This study was to investigate efficacy of biweekly regimen of high dose of leucovorin (CF), 5-FU, and PTX on advanced gastric cancer, and its toxicities. Twenty patients with advanced gastric cancer received biweekly regimen of CF/5-FU/PTX (200 mg/m(2) of CF, intravenous infusion for 2 h, day 1; 500 mg/m(2) of 5-FU, intravenous injection, day 1; 1 500 mg/m(2) of 5-FU, intravenous infusion for 46 h, day 1, 2; 90 mg/m(2) of PTX, intravenous infusion for 3 h,day 1). Efficacy, and toxicities were evaluated after 4 cycles. Total response rate was 65.0% (13/20) with 2 (10.0%) cases of complete remission (CR), and 11 (55.0%) cases of partial remission (PR). No treatment- related death occurred. Stomatitis, hand-foot syndrome, and loss of hair were main toxicities. Biweekly regimen of high dose of CF, 5-FU, and PTX may achieve a high response rate with tolerable toxicities in patients with advanced gastric cancer.


Fast and Bioorthogonal Release of Isocyanates in Living Cells from Iminosydnones and Cycloalkynes.
Bioorthogonal click-and-release reactions are powerful tools for chemical biology, allowing, for example, the selective release of drugs in biological media, including inside animals. Here, we developed two new families of iminosydnone mesoionic reactants that allow a bioorthogonal release of electrophilic species under physiological conditions. Their synthesis and reactivities as dipoles in cycloaddition reactions with strained alkynes have been studied in detail. Whereas the impact of the pH on the reaction kinetics was demonstrated experimentally, theoretical calculations suggest that the newly designed dipoles display reduced resonance stabilization energies compared to previously described iminosydnones, explaining their higher reactivity. These mesoionic compounds react smoothly with cycloalkynes under physiological, copper-free reaction conditions to form a click pyrazole product together with a released alkyl- or aryl-isocyanate. With rate constants up to 1000 M-1 s-1, this click-and-release reaction is among the fastest described to date and represents the first bioorthogonal process allowing the release of isocyanate electrophiles inside living cells, offering interesting perspectives in chemical biology.


Preoperative hemoglobin and perioperative blood transfusion in major head and neck surgery: a systematic review and meta-analysis.
There is a growing concern with inappropriate, excessive perioperative blood transfusions. Understanding the influence of low preoperative hemoglobin (Hgb) on perioperative blood transfusion (PBT) in head and neck cancer (HNC) surgery with free flap reconstruction may help guide clinical practice to reduce inappropriate treatment among these patients. The objective is to synthesize evidence regarding the association between preoperative Hgb and PBT among major HNC free flap surgeries. Terms and synonyms for HNC surgical procedures, Hgb and PBT were used to search MEDLINE, Embase, CINAHL, Cochrane Central Register of Controlled Trials and Cochrane Database of Reviews from inception to February 2020. Reference lists of included full texts and studies reporting the preoperative Hgb, anemia or hematocrit (exposure) and the PBT (outcome) in major HNC surgery with free flap reconstruction were eligible. Studies examining esophageal, thyroid and parathyroid neoplasms were excluded; as were case reports, case series (n < 20), editorials, reviews, perspectives, viewpoints and responses. Two independent, blinded reviewers screened titles, abstracts and full texts in duplicate. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses was followed. A random-effects model was used to pool reported data. The primary outcome was the proportion of patients who had a PBT. Subgroup analysis examined sources of heterogeneity for perioperative predictors of PBT (age, sex, flap type, flap site and preoperative Hgb). We also examined mean preoperative Hgb in the PBT and no PBT groups. Patients with low preoperative Hgb were transfused more than those with normal Hgb (47.62%, 95% CI = 41.19-54.06, I2 = 0.00% and 13.92%, 95% CI = 10.19-17.65, I2 = 20.69%, respectively). None of the predictor variables explained PBT. The overall pooled mean preoperative Hgb was 12.96 g/dL (95% CI = 11.33-14.59, I2 = 0.00%) and was 13.58 g/dL (95% CI = 11.95-15.21, I2 = 0.00%) in the no PBT group and 12.05 g/dL (95% CI = 10.01 to 14.09, I2 = 0.00%) in the PBT group. The heterogeneity between studies, especially around the trigger for PBT, highlights the need for additional research to guide clinical practice of preoperative Hgb related to PBT to enhance patient outcomes and improve healthcare stewardship.


Sequential Evaluation of Pancreato-Biliary Findings in a Case with IgG4-Associated Cholangiopathy and Autoimmune Pancreatitis during Corticosteroid Treatment.
Immunoglobulin G4 (IgG4)-associated diseases mostly involve the pancreaticobiliary tree and pancreatic parenchyma. This disease complex is characterized by marked response to corticosteroid therapy and response to steroids is incorporated in the diagnostic algorithm of IgG4 associated diseases. However, there is much unknown about the sequences and duration of healing during the corticosteroid therapy in the literature. In this case report, we report a young male patient with IgG4 associated extrahepatic biliary stricture and autoimmune pancreatitis successfully treated with corticosteroids. Recovery in the laboratory and radiological findings seemed to correlate well with the decrease in serum IgG4 levels in this patient. We also discussed sequences and the duration of healing in the pancreaticobiliary tree and pancreatic parenchymal manifestations in this case report. There is a gap in our knowledge about the evaluation of response criteria after steroid trial with regard to the duration and sequences of healing in the pancreaticobiliary involvement in diagnosing IgG4-related biliary and pancreatic diseases.


Cation-doping matters in caesium lead halide perovskite nanocrystals: from physicochemical fundamentals to optoelectronic applications.
All-inorganic caesium lead halide perovskite nanocrystals (PeNCs) with different dimensionalities have recently fascinated the research community due to their extraordinary optoelectronic properties including tunable bandgaps over the entire visible spectral region, high photoluminescence quantum yields (PLQYs) close to unity and narrow emission line widths down to 10-20 nm, making them particularly suitable as promising candidates for numerous applications ranging from light-emitting diodes (LEDs), solar cells to scintillators. Despite the considerable progress made in the past six years, the real-world applications of caesium lead halide PeNCs themselves especially in the category of CsPbX3 (X = Cl, Br and I) are still restricted by their labile crystal lattices and downgraded luminescence when exposed to ambient air conditions. Recent experimental and theoretical studies on cation doping have proven to be an effective way to significantly improve the physicochemical properties of cesium lead halide PeNCs, which would have profound implications for a range of applications. In this review, we provide a brief overview of the most recent advances in cation-doped all-inorganic caesium lead halide PeNCs, aimed at developing high-performance and long-term stable optoelectronic and photovoltaic devices, which covers areas from their fundamental considerations of cation doping, controlled synthesis methodology and novel physicochemical properties to the optoelectronic applications with an emphasis on perovskite-based LEDs and solar cells. And finally, some possible directions of future efforts toward this active research field are also proposed.


Cladribine Analogues via O⁶-(Benzotriazolyl) Derivatives of Guanine Nucleosides.
Cladribine, 2-chloro-2'-deoxyadenosine, is a highly efficacious, clinically used nucleoside for the treatment of hairy cell leukemia. It is also being evaluated against other lymphoid malignancies and has been a molecule of interest for well over half a century. In continuation of our interest in the amide bond-activation in purine nucleosides via the use of (benzotriazol-1yl-oxy)tris(dimethylamino)phosphonium hexafluorophosphate, we have evaluated the use of O⁶-(benzotriazol-1-yl)-2'-deoxyguanosine as a potential precursor to cladribine and its analogues. These compounds, after appropriate deprotection, were assessed for their biological activities, and the data are presented herein. Against hairy cell leukemia (HCL), T-cell lymphoma (TCL) and chronic lymphocytic leukemia (CLL), cladribine was the most active against all. The bromo analogue of cladribine showed comparable activity to the ribose analogue of cladribine against HCL, but was more active against TCL and CLL. The bromo ribose analogue of cladribine showed activity, but was the least active among the C6-NH₂-containing compounds. Substitution with alkyl groups at the exocyclic amino group appears detrimental to activity, and only the C6 piperidinyl cladribine analogue demonstrated any activity. Against adenocarcinoma MDA-MB-231 cells, cladribine and its ribose analogue were most active.


Hypertension is harmful to dialysis patients and should be controlled.
Managing hypertension is among the commonest and most challenging features of end-stage renal disease and many clinical trials have shown the benefit of treating hypertension in the general population. If associations between blood pressure levels and cardiovascular outcomes in dialysis patients mirrored those seen in general population studies, one could argue that dialysis population-specific antihypertensive trials are unnecessary. Associations between blood pressure levels and outcomes are complex in this population. Naturally, comparisons of observational and experimental findings within intervention in patients with chronic kidney disease often show a surprising degree of disparity. In addition, the possibility of serious unmeasured co-morbid illnesses masking the true causal relationship between blood pressure and outcomes in this population looms large. Unfortunately, therefore, observational studies appear to be highly unreliable guides to identifying the truth regarding optimal management of hypertension. It appears, then, that controlled trials, alone, can inform appropriate treatment. Of late, intervention trials of antihypertensives in dialysis patients have begun to emerge. Though mostly small, less than definitive, and heterogeneous regarding patient selection, interventions and outcomes, several suggest net benefit and none suggests net harm. As dialysis patients are at vast cardiovascular risk, these findings suggest that aggressive treatment of hypertension should be the default approach, until large clinical trials show otherwise.


A randomized controlled study of conventional TBNA versus EBUS-TBNA for diagnosis of suspected stage I and II sarcoidosis.
The aim of this study was to compare the diagnostic yield of TBNA and EBUS-TBNA in the patients with suspected stage I and II sarcoidosis in the case of the same number of needle aspiration lymph nodes and the same lymph nodes needle aspiration times. A total of 62 patients with suspected stage I and II sarcoidosis were randomly divided into TBNA group and EBUS-TBNA group, based on the clinical and radiologic manifestations. Biopsy specimens of each patient in both groups were taken from two lymph nodes with two needle passes per lymph node. The diagnostic yields of subgroup were separately calculated including the 4th and 7th lymph nodes (referred to as group A), in other stations (group B), greater than 15 mm and less than 15 mm in the shortest diameter. The diagnostic yield of TBNA and EBUS-TBNA for sarcoidosis was 64% and 93%, respectively (χ2=7.12, P<0.05). Subgroup analysis showed that the percentages of positive pathological diagnosis in group A for TBNA and EBUS-TBNA were 79% and 95% (χ2=3.47, P>0.05). The percentages of positive pathological diagnosis greater than 15 mm in the shortest diameter were 78% and 94% (χ2=2.29, P>0.05). The overall diagnostic yield of EBUS-TBNA for stage I and II sarcoidosis was higher than TBNA. However, Conventional TBNA has very high diagnostic yield similar to EBUS-TBNA, if the lymph nodes located on the 4th and 7th group or the shortest diameter was greater than 15 mm.


Transition from Intravenous to Subcutaneous Daratumumab Formulation in Clinical Practice.
Daratumumab is an anti-CD38 monoclonal antibody widely used for treating patients with newly diagnosed or relapsed/refractory multiple myeloma. The subcutaneous formulation of daratumumab was developed with the purpose of minimizing the treatment burden (to patients and health care system) associated with intravenous daratumumab. Given its recent approval, there is a knowledge gap regarding the best practices that should be instituted for safe administration of subcutaneous daratumumab. A retrospective chart review was performed from August 2020 until November 2020 to identify patients either switched to or treated upfront (daratumumab naive) with any subcutaneous daratumumab-based treatment regimen. All patients received appropriate premedications per institutional standards of care. The study end points were to report real-world data regarding administration-related reaction rates (at or following discharge from infusion center), as well as compare their incidence rates to those noted in the COLUMBA study (historical cohort). The study included 58 patients, of whom 38% (n = 22) were daratumumab naive. The majority (84%, n = 49) received subcutaneous daratumumab in combination with various antimyeloma regimens. There were no cases of administration-related reactions at infusion center or after discharge irrespective of previous exposure to intravenous daratumumab. None of the patients included herein required rescue home medications or visited the emergency department within 24 to 48 hours after subcutaneous daratumumab administration. These translated into a significant difference in incidence of administration-related reactions compared with historical cohort (0% vs. 13%, P = .003). Subcutaneous daratumumab was extremely well tolerated and could be safely administered without need for monitoring or rescue home medications.


A new look at osteogenesis imperfecta. A clinical, radiological and biochemical study of forty-two patients.
In a clinical, radiological and biochemical study of forty-two patients from Oxford with osteogenesis imperfecta, it was found that patients could be divided simply into mild, moderate and severe groups according to deformity of long bones. In the severe group (seventeen patients) a family history of affected members was uncommon and fractures began earlier and were more frequent than in the mild group (twenty-two patients); sixteen patients in the severe group had scoliosis and eleven had white sclerae; no patients in the mild group had white sclerae or scoliosis. Radiological examination of the femur showed only minor modelling defects in patients in the mild group, whereas in the severe group five distinct appearances of bone (thin, thick, cystic and buttressed bones, and those with hyperplastic callus) were seen. The polymeric (structural) collagen from skin was unstable to depolymerisation in patients in the severe group, but normal in amount, whereas the reverse was found in the mild group. This division according to long bone deformity may provide, a basis for future research more useful than previous classifications.


Changes in somatic cell structure during senescence of Volvox carteri.
Senescence of the terminally differentiated somatic cells of the green alga, Volvox carteri f. weismannia, was investigated by light, fluorescence, and electron microscopy. Viability of the somatic cell population, as determined by trypan blue or erythrosin B exclusion, showed a sharp reduction beginning 144 h after the somatic cells had lost the ability to divide. This increased mortality rate was correlated at the light microscopic level with a retraction of the somatic cell cytoplasm, a reduction in chloroplast autofluorescence (and total chlorophyll content), and a decline in the number of vacuoles which could be localized with 9-aminoacridine fluorescence microscopy. Nuclear fluorescence with acridine orange remained unaffected during this time. Lipid bodies increased in older cells, and total lipid analysis showed a sharp increase beginning 96 h after the somatic cells had stopped dividing. Electron microscopic comparison between young (48--72 h) and old (168 h) somatic cells showed a disorganization of chloroplast structure, a decline in the number of cytoplasmic ribosomes, and, substantiating the light microscopy, and accumulation of lipid bodies in the cytoplasm of the older cells. The results demonstrate progressive changes in somatic cell structure with age and are suggestive of cells under nutrient stress even though they are in nutrient medium. Therefore senescence and death of the V. carteri somatic cells may be caused, in part, by an inability to take up or utilize nutrients present in the culture medium.


Histone Adduction and Its Functional Impact on Epigenetics.
Bioactive electrophiles generated from the oxidation of endogenous and exogenous compounds are a contributing factor in numerous disease states. Their toxicity is largely attributed to the covalent modification of cellular nucleophiles, including protein and DNA. With regard to protein modification, the side-chains of Cys, His, Lys, and Arg residues are critical targets. This results in the generation of undesired protein post-translational modifications (PTMs) that can trigger dire cellular consequences. Notably, histones are Lys- and Arg-rich proteins, providing a fertile source for adduction by both exogenous and endogenous electrophiles. The regulation of histone PTMs plays a critical role in the regulation of chromatin structure and thus gene expression. This perspective focuses on the role of electrophilic protein adduction within the context of chromatin and its potential consequences on cellular law and order.


Solitary invasive orchid bee outperforms co-occurring native bees to promote fruit set of an invasive Solanum.
Our understanding of the effects of introduced invasive pollinators on plants has been exclusively drawn from studies on introduced social bees. One might expect, however, that the impacts of introduced solitary bees, with much lower population densities and fewer foragers, would be small. Yet little is known about the potential effects of naturalized solitary bees on the environment. We took advantage of the recent naturalization of an orchid bee, Euglossa viridissima, in southern Florida to study the effects of this solitary bee on reproduction of Solanum torvum, an invasive shrub. Flowers of S. torvum require specialized buzz pollination. Through timed floral visitor watches and two pollination treatments (control and pollen supplementation) at three forest edge and three open area sites, we found that the fruit set of S. torvum was pollen limited at the open sites where the native bees dominate, but was not pollen limited at the forest sites where the invasive orchid bees dominate. The orchid bee's pollination efficiency was nearly double that of the native halictid bees, and was also slightly higher than that of the native carpenter bee. Experiments using small and large mesh cages (to deny or allow E. viridissima access, respectively) at one forest site indicated that when the orchid bee was excluded, the flowers set one-quarter as many fruit as when the bee was allowed access. The orchid bee was the most important pollinator of the weed at the forest sites, which could pose additional challenges to the management of this weed in the fragmented, endangered tropical hardwood forests in the region. This specialized invasive mutualism may promote populations of both the orchid bee and this noxious weed. Invasive solitary bees, particularly species that are specialized pollinators, appear to have more importance than has previously been recognized.


Peroxisome proliferator-activated receptor β/δ induces myogenesis by modulating myostatin activity.
Classically, peroxisome proliferator-activated receptor β/δ (PPARβ/δ) function was thought to be restricted to enhancing adipocyte differentiation and development of adipose-like cells from other lineages. However, recent studies have revealed a critical role for PPARβ/δ during skeletal muscle growth and regeneration. Although PPARβ/δ has been implicated in regulating myogenesis, little is presently known about the role and, for that matter, the mechanism(s) of action of PPARβ/δ in regulating postnatal myogenesis. Here we report for the first time, using a PPARβ/δ-specific ligand (L165041) and the PPARβ/δ-null mouse model, that PPARβ/δ enhances postnatal myogenesis through increasing both myoblast proliferation and differentiation. In addition, we have identified Gasp-1 (growth and differentiation factor-associated serum protein-1) as a novel downstream target of PPARβ/δ in skeletal muscle. In agreement, reduced Gasp-1 expression was detected in PPARβ/δ-null mice muscle tissue. We further report that a functional PPAR-responsive element within the 1.5-kb proximal Gasp-1 promoter region is critical for PPARβ/δ regulation of Gasp-1. Gasp-1 has been reported to bind to and inhibit the activity of myostatin; consistent with this, we found that enhanced secretion of Gasp-1, increased Gasp-1 myostatin interaction and significantly reduced myostatin activity upon L165041-mediated activation of PPARβ/δ. Moreover, we analyzed the ability of hGASP-1 to regulate myogenesis independently of PPARβ/δ activation. The results revealed that hGASP-1 protein treatment enhances myoblast proliferation and differentiation, whereas silencing of hGASP-1 results in defective myogenesis. Taken together these data revealed that PPARβ/δ is a positive regulator of skeletal muscle myogenesis, which functions through negatively modulating myostatin activity via a mechanism involving Gasp-1.


Beneficial and adverse psychotropic effects of antiepileptic drugs in patients with epilepsy: a summary of prevalence, underlying mechanisms and data limitations.
Antiepileptic drugs (AEDs) can have both beneficial and adverse psychotropic effects. They act on neurotransmitter systems, neuronal ion permeability and other targets, although the exact mechanisms are not generally fully elucidated. A systematic review of the literature reveals evidence for both positive and negative effects on depression, anxiety, aggression, psychosis and sleep in patients with epilepsy. Topiramate, vigabatrin, levetiracetam, tiagabine and zonisamide have been associated primarily with adverse psychotropic effects, whilst gabapentin, pregabalin, lacosamide and lamotrigine, in particular, have demonstrated a more beneficial psychotropic profile, especially with regard to affective symptoms. This review, however, identifies specific methodological issues with studies that have reported on the psychotropic effects of AEDs, suggesting that some of the findings might be inconclusive or unreliable because of confounding factors, particularly the presence of psychiatric history. More rigorous double-blind, randomized, placebo-controlled trials on larger numbers of patients with epilepsy, with clear inclusion/exclusion criteria, that are specifically designed to investigate psychotropic changes are more likely to produce results that inform clinical practice and direct future research.


Antibacterial resistance, macrophage influx, and activation induced by bacterial rRNA with dimethyldioctadecylammonium bromide.
Intraperitoneally injected rRNA from Pseudomonas aeruginosa combined with dimethyldioctadecylammonium bromide (DDA) increased nonspecifically the resistance of mice against an intraperitoneal challenge with extracellular (P. aeruginosa, Escherichia coli) and intracellular (Listeria monocytogenes) bacteria. This study concerns the mechanism underlying the nonspecific resistance. RNA with DDA (RNA-DDA) induced a cell influx and activated peritoneal macrophages (M phi) as judged by the decreased 5'-nucleotidase and alkaline phosphodiesterase activities in M phi lysates, the enhanced O2- release, and the increased antitumor activity in comparison with unstimulated M phi. RNA without DDA did not enhance the resistance and did not influence the peritoneal cell numbers or M phi properties. DDA without RNA enhanced the resistance of mice only slightly; it induced a cell influx, yielding elicited M phi as judged by the decreased 5'-nucleotidase activity and increased alkaline phosphodiesterase activity, the slightly enhanced O2- release, and the absence of increased antitumor activity. Both RNA-DDA and DDA M phi showed an enhanced capacity to ingest and kill L. monocytogenes in vitro, DDA M phi being slightly less effective than RNA-DDA M phi with respect to killing. We conclude that the enhanced killing capacity of M phi for L. monocytogenes is characteristic of both elicited DDA M phi and activated RNA-DDA M phi. The relationship between nonspecific resistance, peritoneal cell numbers, and antibacterial M phi activity is discussed. In addition, it is shown that RNA and DDA retain their activity when they are injected apart, suggesting that they activate M phi by sequential action.


CHIR-258, a novel, multitargeted tyrosine kinase inhibitor for the potential treatment of t(4;14) multiple myeloma.
The t(4;14) translocation that occurs uniquely in a subset (15%) of patients with multiple myeloma (MM) results in the ectopic expression of the receptor tyrosine kinase (RTK), fibroblast growth factor receptor 3 (FGFR3). Inhibition of activated FGFR3 in MM cells induces apoptosis, validating FGFR3 as a therapeutic target in t(4;14) MM and encouraging the clinical development of FGFR3 inhibitors for the treatment of these patients, who have a poor prognosis. We describe here the characterization of a novel, small-molecule inhibitor of class III, IV, and V RTKs, CHIR-258, as an inhibitor of FGFR3. CHIR-258 potently inhibits FGFR3 with an inhibitory concentration of 50% (IC50) of 5 nM in in vitro kinase assays and selectively inhibited the growth of B9 cells and human myeloma cell lines expressing wild-type (WT) or activated mutant FGFR3. In responsive cell lines, CHIR-258 induced cytostatic and cytotoxic effects. Importantly, addition of interleukin 6 (IL-6) or insulin growth factor 1 (IGF-1) or coculture on stroma did not confer resistance to CHIR-258. In primary myeloma cells from t(4;14) patients, CHIR-258 inhibited downstream extracellular signal-regulated kinase (ERK) 1/2 phosphorylation with an associated cytotoxic response. Finally, therapeutic efficacy of CHIR-258 was demonstrated in a xenograft mouse model of FGFR3 MM. These studies support the clinical evaluation of CHIR-258 in MM.


Mitral regurgitation after anthracycline-based chemotherapy in an adult patient with breast cancer: A case report.
Anthracyclines cardiotoxicity characterized by dilated myocardiopathy has been well described in the literature. However, anthracyclines-induced valvular diseases have been seldom reported. In this study, we present the case of a 62-year-old Chinese female patient with breast cancer developing severe mitral regurgitation after anthracycline exposure. The patient was diagnosed with mitral regurgitation with preserved left ventricular ejection fraction and normal cardiac chamber dimensions in the sixth month after the last course of anthracycline-containing chemotherapy. However, continued decrease in LVEF with normal left ventricular wall thickness, and serial increases in left atrial and ventricular dimensions were observed in the follow-up echocardiography. Treatments with oral itraconazole at a dose of 75 mg/day and local wound care with ciclopirox olamine ointment were administered. The patient responded well to the treatment with perindopril, metoprolol succinate, spirolactone, and furosemide, and symptoms associated with heart failure were dramatically relieved. The incipient mitral regurgitation may serve as an early sign of myocardial dysfunction that can facilitate a timely recognition of cardiotoxicity, which is crucial to a timely change of chemotherapy regimen and an appropriate initiation of antiremodeling therapy that could limit anthracycline cardiotoxicity and improve overall outcome.


[The search of miRNA genes in Bombyx mori nuclear polyhedrosis virus genomes regions complementary to the latest genes].
The search of miRNA genes in Bombyx mori nuclear polyhedrosis virus genome region complementary to very late genes has been carried out. The search miRNA algorithm in silico was developed by us. It was shown that NPV B. mori genome region containing orf4 gene complementary to ph gene encodes the potential miRNA. NPV B. mori genome region containing p74 gene complementary to p10 gene encodes mature miRNA and potential miRNA. The genome region containing orf1629 encodes two small non-coding RNAs complementary to orf 5'-end of polyhedrin miRNA. From obtained results it is proposed that two small noncoding RNAs complementary to regions of polyhedrin miRNA are included in polyhedra.


New data on the ultrastructure of the corpus amylaceum (polyglucosan body).
During the semiquantitative evaluation of the occurrence of the corpus amylaceum (CA) in a large quantity of autopsy and biopsy material (1,407 cases), electromicroscopical (EM) and scanning EM examinations were carried out on 8 autopsied cases where CA was demonstrated. The EM examinations appeared to underline the astrocytic origin of the CA formation, which is initiated in the astrocytic fiber system by glycogen and other carbohydrate polymers. The biophysics of the development of the CA is indicative of the same mechanisms as for (mainly intracellular) inclusion bodies. The large amount of CA that develops at the predilection sites is a consequence of metabolic damage, a large quantity of cerebrospinal fluid and recurring disturbances in the barrier functions. The abundant CA may cause secondary blood-brain barrier disturbances. This working hypothesis demands further investigations and the continuation of research by modern immunocytochemical and ultrastructural methods recommended.


Effect of Selected Biopesticides in Reducing Soybean Rust (Phakopsora pachyrhizi) Development.
The intensive use of fungicides in controlling soybean rust (SBR), a damaging foliar fungal disease of soybean caused by the obligate fungus Phakopsora pachyrhizi, may have accelerated the insensitivity of P. pachyrhizi populations to fungicides. The objective of this study was to determine the effect of selected biopesticides and their application time on reducing SBR infection. There were differences (P < 0.05) in percent rust reduction values for application times, biopesticide treatments, and their interaction in detached-leaf and whole-plant greenhouse experiments. All application times and nearly all biopesticide treatments reduced (α = 0.05) fungal infection compared with the nonfungicide control. Among the treatments, Bacillus subtilis QST 713 and acibenzolar-S-methyl often reduced fungal sporulation more than the other treatments in detached-leaf and whole-plant greenhouse experiments. The identification of biopesticides effective to P. pachyrhizi may be a valuable alternative or complement to synthetic fungicides and may be useful in integrated pest management programs for SBR control.


Linear and nonlinear identification of the carotid sinus baroreflex in the very low-frequency range.
Since the arterial baroreflex system is classified as an immediate control system, the focus has been on analyzing its dynamic characteristics in the frequency range between 0.01 and 1 Hz. Although the dynamic characteristics in the frequency range below 0.01 Hz are not expected to be large, actual experimental data are scant. The aim was to identify the dynamic characteristics of the carotid sinus baroreflex in the frequency range down to 0.001 Hz. The carotid sinus baroreceptor regions were isolated from the systemic circulation, and carotid sinus pressure (CSP) was changed every 10 s according to Gaussian white noise with a mean of 120 mmHg and standard deviation of 20 mmHg for 90 min in anesthetized Wistar-Kyoto rats (n = 8). The dynamic gain of the linear transfer function relating CSP to arterial pressure (AP) at 0.001 Hz tended to be greater than that at 0.01 Hz (1.060 ± 0.197 vs. 0.625 ± 0.067, p = 0.080), suggesting that baroreflex control was largely maintained at 0.001 Hz. Regarding nonlinear analysis, a second-order Uryson model predicted AP with a higher R2 value (0.645 ± 0.053) than a linear model (R2 = 0.543 ± 0.057, p = 0.025) or a second-order Volterra model (R2 = 0.589 ± 0.055, p = 0.045) in testing data. These pieces of information may be used to create baroreflex models that can add a component of autonomic control to a cardiovascular digital twin for predicting acute hemodynamic responses to treatments and tailoring individual treatment strategies.


Colonic Epithelial Circadian Disruption Worsens Dextran Sulfate Sodium-Induced Colitis.
Disruption of central circadian rhythms likely mediated by changes in microbiota and a decrease in gut-derived metabolites like short chain fatty acids (SCFAs) negatively impacts colonic barrier homeostasis. We aimed to explore the effects of isolated peripheral colonic circadian disruption on the colonic barrier in a mouse model of colitis and explore the mechanisms, including intestinal microbiota community structure and function. Colon epithelial cell circadian rhythms were conditionally genetically disrupted in mice: TS4Cre-BMAL1lox (cBMAL1KO) with TS4Cre as control animals. Colitis was induced through 5 days of 2% dextran sulfate sodium (DSS). Disease activity index and intestinal barrier were assessed, as were fecal microbiota and metabolites. Colitis symptoms were worse in mice with peripheral circadian disruption (cBMAL1KO). Specifically, the disease activity index and intestinal permeability were significantly higher in circadian-disrupted mice compared with control animals (TS4Cre) (P < .05). The worsening of colitis appears to be mediated, in part, through JAK (Janus kinase)-mediated STAT3 (signal transducer and activator of transcription 3), which was significantly elevated in circadian-disrupted (cBMAL1KO) mice treated with DSS (P < .05). Circadian-disrupted (cBMAL1KO) mice also had decreased SCFA metabolite concentrations and decreased relative abundances of SCFA-producing bacteria in their stool when compared with control animals (TS4Cre). Disruption of intestinal circadian rhythms in colonic epithelial cells promoted more severe colitis, increased inflammatory mediators (STAT3 [signal transducer and activator of transcription 3]), and decreased gut microbiota-derived SCFAs compared with DSS alone. Further investigation elucidating the molecular mechanisms behind these findings could provide novel circadian directed targets and strategies in the treatment of inflammatory bowel disease.


Magnetogenetic cell activation using endogenous ferritin.
The ability to precisely control the activity of defined cell populations enables studies of their physiological roles and may provide therapeutic applications. While prior studies have shown that magnetic activation of ferritin-tagged ion channels allows cell-specific modulation of cellular activity, the large size of the constructs made the use of adeno-associated virus, AAV, the vector of choice for gene therapy, impractical. In addition, simple means for generating magnetic fields of sufficient strength have been lacking. Toward these ends, we first generated a novel anti-ferritin nanobody that when fused to transient receptor potential cation channel subfamily V member 1, TRPV1, enables direct binding of the channel to endogenous ferritin in mouse and human cells. This smaller construct can be delivered in a single AAV and we validated that it robustly enables magnetically induced cell activation in vitro . In parallel, we developed a simple benchtop electromagnet capable of gating the nanobody-tagged channel in vivo . Finally, we showed that delivering these new constructs by AAV to pancreatic beta cells in combination with the benchtop magnetic field delivery stimulates glucose-stimulated insulin release to improve glucose tolerance in mice in vivo . Together, the novel anti-ferritin nanobody, nanobody-TRPV1 construct and new hardware advance the utility of magnetogenetics in animals and potentially humans.


Characterization of the interaction between endostatin short peptide and VEGF receptor 3.
Corneal angiogenesis and lymphangiogenesis are induced by vascular endothelial growth factors (VEGFs) signaling through its receptors VEGFR-1, -2, and -3. Endostatin is a peptide antagonist of these receptors that causes inhibition of bFGF-induced corneal angiogenesis and lymphangiogenesis. Here we show that binding of VEGF-C and endostatin to recombinant VEGFR-3 is competitive. Alignments of the primary amino acid sequences of VEGF-C and the C-terminal endostatin peptide (mEP: LEQKAASCHNSYIVLCIENSFMTSFSK) identified two conserved cysteine residues separated by seven amino acids. Peptides of VEGF-C and mEP containing these conserved residues bound to VEGFR-3. However, substitution of alanine for either of the cysteines in the mEP peptide perturbed the secondary structure, and this mutated peptide was unable to bind to VEGFR-3. Analysis by surface plasmon resonance demonstrated that the binding of the mEP peptide for recombinant VEGFR-3 had a Ka of 1.41 x 10⁷ M⁻¹ s⁻¹, Kd of 0.6718 s⁻¹, and a KD of 4.78 x 10⁻⁸ M. Characterization of the mechanism of endostatin binding to VEGFR-3 may lead to the development of novel therapies for lymphangiogenesis-related disorders, such as transplant rejection, lymphedema, and cancer metastasis.


Hematin-hematin self-association states involved in the formation and reactivity of the malaria parasite pigment, hemozoin.
The malaria parasite pigment, hemozoin, is a crystal of ferriprotoporphyrin IX (FP-Fe(III)), a product of hemoglobin digestion. Hemozoin formation is essential for FP-Fe(III) detoxification in the parasite; it is the main target of quinoline antimalarials and can modulate immune and inflammation responses. To gain further insight into the likely mechanisms of crystal formation and hemozoin reactivity, we have reanalyzed the crystal structure data for beta-hematin and solved the crystal structure of Plasmodium falciparum hemozoin. The analysis reveals that the structures are very similar and highlights two previously unexplored modes of FP-Fe(III) self-association involving pi-pi interactions that may initiate crystal formation and help to stabilize the extended structure. Hemozoin can be considered to be a crystal composed of pi-pi dimers stabilized by iron-carboxylate linkages. As a result, it is predicted that two surfaces of the crystal would consist of pi-pi dimers with Fe(III) partly exposed to solvent and capable of undergoing redox reactions. Accordingly, we demonstrate that the crystal possesses both general peroxidase activity and the ability to cause lipid oxidation.


Fine Motor Assessment in Upper Extremity Using Custom-Made Electronic Pegboard Test.
A fine motor test involves the manipulation of smaller objects with fingers, hands, and wrists. This test is an integral part of the evaluation of an upper extremity function. Nine Hole Peg Test (NHPT) is one among such tests which assess the ability to manipulate pegs with the thumb and finger. There is a need to develop a fine motor assessment tool which is reproducible and mimics closely the natural movement of hands. The aim of this work is to develop an electronic pegboard which is easy to administer and efficient in terms of time. Pegboard device is modified and standardized by (1) Adding electronic circuits to custom-made pegboard and programmed using a microcontroller (ATmega2560), (2) Following a specific sequence in placing and picking the pegs from the board, and (3) Using Infrared sensor and robust algorithm to ensure one peg movement at a time. The setup is administered on 15 healthy participants (nine females, six males aged between 21 and 80) and the outcome is compared with the results of traditional NHPT. Predefined sequence in moving the pegs and electronic timer features provide reliable results for repeated measurements and facilitate storing test score in a digital repository. This data could be used as reference data during the follow-up visits. The maximum difference between the measured timing between the present setup and traditional NHPT is about 6.7%. It is important to note that, due to inherent delay (response time) in the traditional NHPT, when compared to present setup the measured timing is always on the higher side. Nondependency on the manual stopwatch to record the time and hands-free of any wearable device are the advantages of the present setup.


Human milk oligosaccharide 2'-fucosyllactose links feedings at 1 month to cognitive development at 24 months in infants of normal and overweight mothers.
Infant cognitive development is influenced by maternal factors that range from obesity to early feeding and breast milk composition. Animal studies suggest a role for human milk oligosaccharide (HMO), 2'-fucosyllactose (2'FL), on learning and memory, yet no human studies have examined its impact on infant cognitive development relative to other HMOs and maternal factors. To determine the impact of 2'FL from breast milk feeding on infant cognitive development at 24 months of age relative to maternal obesity and breast milk feeding frequency. Hispanic mother-infant pairs (N = 50) were recruited across the spectrum of pre-pregnancy BMI. Breast milk was collected at 1 and 6 months, and feedings/day were reported. Nineteen HMOs were analyzed using high-performance liquid chromatography, with initial interest in 2'FL. Infant cognitive development score was assessed with the Bayley-III Scale at 24 months. Linear regressions were used for prediction, and bootstrapping to determine mediation by 2'FL. Maternal pre-pregnancy BMI was not related to feedings/day or HMOs, but predicted poorer infant cognitive development (β = -0.31, P = 0.03). Feedings/day (β = 0.34) and 2'FL (β = 0.59) at 1 month predicted better infant cognitive development (both P≤ 0.01). The association of feedings/day with infant cognitive development was no longer significant after further adjustment for 2'FL (estimated mediation effect = 0.13, P = 0.04). There were no associations of feedings/day and 2'FL at 6 months with infant cognitive development. Our findings suggest that maternal factors influence infant cognitive development through multiple means. Though maternal obesity may be a separate negative influence, greater frequency of breast milk feeding at 1 month contributed to infant cognitive development through greater exposure to 2'FL relative to other HMOs. The influence of 2'FL was not significant at 6 months, indicating that early exposure to 2'FL may be a critical temporal window for positively influencing infant cognitive development.


Self-Organized Near-Zero-Lag Synchronization Induced by Spike-Timing Dependent Plasticity in Cortical Populations.
Several cognitive tasks related to learning and memory exhibit synchronization of macroscopic cortical areas together with synaptic plasticity at neuronal level. Therefore, there is a growing effort among computational neuroscientists to understand the underlying mechanisms relating synchrony and plasticity in the brain. Here we numerically study the interplay between spike-timing dependent plasticity (STDP) and anticipated synchronization (AS). AS emerges when a dominant flux of information from one area to another is accompanied by a negative time lag (or phase). This means that the receiver region pulses before the sender does. In this paper we study the interplay between different synchronization regimes and STDP at the level of three-neuron microcircuits as well as cortical populations. We show that STDP can promote auto-organized zero-lag synchronization in unidirectionally coupled neuronal populations. We also find synchronization regimes with negative phase difference (AS) that are stable against plasticity. Finally, we show that the interplay between negative phase difference and STDP provides limited synaptic weight distribution without the need of imposing artificial boundaries.


Systematic review of the prevalence of mental illness stigma within the Greek culture.
A number of primary studies have now assessed mental illness stigma within the Greek culture. A synthesis and appraisal of all available evidence is now required and will contribute to our growing understanding of the relationship between the cultural context and the formation of stigmatising attitudes. To systematically review the prevalence of mental illness public stigma within the Greek and Greek Cypriot culture. Empirical articles with primary data pertaining to the prevalence of mental illness public stigma among Greek and/or Greek Cypriot populations were retrieved. Included studies were assessed for quality and extracted data were narratively synthesised. A total of 18 studies met the inclusion criteria. Methodological quality was highly variable; only 1 study was adequately statistically powered, 10 studies employed at least some element of probability sampling and obtained response rates of at least 70%, while 10 and 13 studies employed reliable and validated prevalence tools, respectively. Studies sampled the general population (n = 11), students (n = 4), healthcare professionals (n = 2), police officers, employers and family members (all n = 1). Stigma was consistently identified in moderate and high proportions across all of these groups, particularly in terms of social discrimination and restrictiveness, social distance and authoritarianism. However, some evidence of benevolence and positivity towards high-quality social care was also identified. The review highlights the wide-scale prevalence of mental illness stigma within the Greek culture and the need for further rigorous research including culturally tailored stigma interventions.


Predicting attitudes toward a restrictive alcohol policy: Using a model of distal and proximal predictors.
Previous research on attitudes toward a restrictive alcohol policy has mainly focused on variables such as demographics and own drinking as possible predictors. The present article adds to the existing literature by examining the impact of a set of beliefs and personal experiences with the harm caused by other peoples' drinking. We suggest and test an analytic model in which the predictors are ranked according to their conceptual proximity to attitudes. The data stem from a Web survey in the Norwegian adult population (N = 1,951), mapping the respondents' attitudes toward pricing policy and availability restrictions, belief in the harm-limiting effect of such measures, belief in the harm caused by drinking, and personal experiences with harm from others' drinking. In line with the suggested model, belief in the effectiveness of restrictive measures and belief in the harm caused by drinking appeared as the strongest predictors. Attitudes were less strongly related to own drinking, and particularly to demographics. Altogether, 41% of the variance in attitudes was explained. Negative experience with other peoples' drinking was a statistically significant predictor only among young respondents. The strong relationships between proximal predictors, such as belief in the harm caused by drinking and belief in the harm-limiting effect of restrictive measures and attitudes, indicate that support for a restrictive policy may be increased by focusing on awareness of such issues rather than on more distal predictors. However, further research is needed to acquire more knowledge about the mechanisms behind these associations. (PsycINFO Database Record


[Possibilities of the treatment of biliary dyskinesia by laser irradiation].
The examination of 68 patients with biliary dysfunction determined hypokinesia of the gallbladder in 40, sphincter of Oddi spasm in 15 and combination of the two conditions in 13 patients. Blood biochemical indices showed no differences in patients with biliary dyskinesia compared to normal subjects except for alkaline phosphatase levels elevated in 35.3% of patients. This suggests the development of biliary hypertension and cholestasis. All the patients demonstrated disturbed colloid stability of the bile, in those with combined dyskinesia it became lithogenic. Helium-neon and semiconductor laser radiation of biologically active points and the hepatic region, respectively, improved the patients' performance status. The pain and dyspepsia discontinued. The function of the gallbladder and sphincter of Oddi recovered. Positive changes occurred in the blood and bile biochemistry. Laser therapy promoted bilirubin and bile cholesterol decrease. Cholic acid concentration grew, lithogenic characteristics of the bile returned to normal. It is inferred that laser therapy of biliary dyskinesia proved effective.


Allozyme-specific modification of a maize seed chitinase by a protein secreted by the fungal pathogen Stenocarpella maydis.
Stenocarpella maydis causes both dry-ear rot and stalk rot of maize. Maize inbred lines have varying levels of resistance to ear rot caused by S. maydis. The genetic basis of resistance appears to rely on multiple genetic factors, none of which are known. The commonly used stiff-stalk inbred line B73 has been shown to be strongly susceptible to ear rot caused by S. maydis. Here, we report that the ChitA protein alloform from B73, ChitA-F, encoded by a known allele of the chiA gene, is susceptible to modification by a protein (Stm-cmp) secreted by S. maydis. We also identify a new allele of chiA (from inbred line LH82) which encodes ChitA-S, an alloform of ChitA that is resistant to Stm-cmp modification. Chitinase zymogram analysis of seed from a commercial field showed the presence of both ChitA alloforms in healthy ears, and showed that ChitA-F but not ChitA-S was modified in ears rotted by S. maydis. The ChitA-F protein was purified from inbred line B73 and ChitA-S from LH82. ChitA-F was modified more efficiently than ChitA-S by S. maydis protein extracts in vitro. The chiA gene from LH82 was cloned and sequenced. It is a novel allele that encodes six polymorphisms relative to the known allele from B73. This is the first demonstration that the susceptibility to modification of a fungal targeted plant chitinase differs among inbred lines. These findings suggest that the LH82 chiA allele may be a specific genetic determinant that contributes to resistance to ear rot caused by S. maydis whereas the B73 allele may contribute to susceptibility.


The microRNA-processing enzyme Dicer is essential for thyroid function.
Dicer is a type III ribonuclease required for the biogenesis of microRNAs (miRNAs), a class of small non-coding RNAs regulating gene expression at the post-transcriptional level. To explore the functional role of miRNAs in thyroid gland function, we generated a thyrocyte-specific Dicer conditional knockout mouse. Here we show that development and early differentiation of the thyroid gland are not affected by the absence of Dicer, while severe hypothyroidism gradually develops after birth, leading to reduced body weight and shortened life span. Histological and molecular characterization of knockout mice reveals a dramatic loss of the thyroid gland follicular architecture associated with functional aberrations and down-regulation of several differentiation markers. The data presented in this study show for the first time that an intact miRNAs processing machinery is essential for thyroid physiology, suggesting that deregulation of specific miRNAs could be also involved in human thyroid dysfunctions.


Innovative 2-Step Management Strategy Utilizing EXIT Procedure for a Fetus With Hypoplastic Left Heart Syndrome and Intact Atrial Septum.
Hypoplastic left heart syndrome (HLHS) with intact atrial septum (HLHS-IAS) carries a high risk of mortality and affects about 6% of all patients with HLHS. Fetal interventions, postnatal transcatheter interventions, and postnatal surgical resection have all been used, but the mortality risk continues to be high in this subgroup of patients. We describe a novel, sequential approach to manage HLHS-IAS and progressive fetal hydrops. A 28-year-old, gravida 4 para 2 mother was referred to Mayo Clinic for fetal HLHS. Fetal echocardiography at 28 weeks of gestation demonstrated HLHS-IAS with progressive fetal hydrops. The atrial septum was thick and muscular with no interatrial communication. Ultrasound-guided fetal atrial septostomy was performed with successful creation of a small atrial communication. However, fetal echocardiogram at 33 weeks of gestation showed recurrence of a pleural effusion and restriction of the atrial septum. We proceeded with an Ex uteroIntrapartum Treatment (EXIT) delivery and open atrial septectomy. This was performed successfully, and the infant was stabilized in the intensive care unit. The infant required venoarterial extracorporeal membrane oxygenator support on day of life 1. The patient later developed hemorrhagic complications, leading to his demise on day of life 9. This is the first reported case of an EXIT procedure and open atrial septectomy performed without cardiopulmonary bypass for an open-heart operation and provides a promising alternative strategy for the management of HLHS-IAS in select cases.


Increased miR-21a provides metabolic advantages through suppression of FBP1 expression in non-small cell lung cancer cells.
Lung cancer is the most common solid tumor and the leading cause of cancer-related mortality worldwide. miR-21 is one of the most commonly observed aberrant miRNAs in human cancers. However, the biological roles of miR-21 in glucose metabolism of non-small cell lung cancer (NSCLC) cells remain unknown. In the present study, our findings demonstrated that miR-21 promoted glucose uptake and increased TXNIP expression. miR-21 increased lactate generation and decreased oxygen consumption in NSCLC cells. Moreover, we found that miR-21 promoted glycolysis and decreased OXPHOS. Mechanistically, fructose-1,6-biphosphatase (FBP1) was a direct target of miR-21 and observed a negative correlation between miR-21 and FBP1 in NSCLC samples. Restoring FBP1 expression reversed the effects induced by miR-21 overexpression in NSCLC cells. Together, our findings suggest the critical role of miR-21 in glucose metabolism through suppression of FBP1 in NSCLC cells. miR-21 may be a potential target of NSCLC treatment.


Activation of cannabinoid CB2 receptor negatively regulates IL-12p40 production in murine macrophages: role of IL-10 and ERK1/2 kinase signaling.
1 Cannabinoid (CB) receptor agonists have potential utility as anti-inflammatory drugs for the treatment of many disease conditions. In the present study, we investigated the effects of the synthetic CB(2) ligand, JWH-133 on the production of interleukins (ILs), IL-12 and IL-10 by lipopolyssacharide (LPS) or Theiler's virus (TMEV)-activated macrophages. 2 JWH-133 evoked a concentration-related inhibition (10 nM-5 microM) of LPS/IFN-gamma induced IL-12p40 release. The effect of JWH-133 (100 nM) was significantly blocked by the CB2 antagonist SR-144528 (1 microM). Macrophages infected with TMEV increased IL-12p40 production and activation of CB2 receptors by JWH-133 (100 nM) inhibited it. 3 The inhibitory effect of JWH-133 (100 nM) on IL-12p40 production may involve extracellular-regulated kinase (ERK1/2) signaling: (i) JWH-133 induced a greater and sustained activation of ERK1/2 kinase in comparison with the level of activation observed following LPS; (ii) the inhibition of ERK1/2 by the specific inhibitor PD98059 increased LPS-induced IL-12p40 production in the presence or absence of JWH-133 suggesting a negative regulation of ERK pathway on IL-12p40 biosynthesis. 4 Activation of CB2 receptors by JWH-133 (10 nM-5 microM) enhanced IL-10 release by LPS/IFN-gamma-activated macrophages and addition of SR144558 (1 microM) totally blocked the effect of JWH (100 nM). 5 Inhibition of ERK by PD98059 significantly suppressed IL-10 production by LPS-activated macrophages. Endogenous IL-10 plays a modulatory role in IL-12 production. Blocking IL-10 with neutralizing antibody resulted in increased IL-12p40 secretion by LPS-activated macrophages in the absence or presence of JWH-133. In contrast, the addition of exogenous mIL-10 reduced the secretion of IL-12p40 in response to LPS.


Psychophysiologic symptom relief therapy for chronic back pain: a pilot randomized controlled trial.
Chronic back pain is the leading cause of disability in the United States. Based on the hypothesis that nonspecific back pain may be rooted in a psychophysiologic etiology, we propose a new approach to chronic back pain. A pilot study was conducted to assess whether psychophysiologic symptom relief therapy (PSRT) can reduce disability and back pain bothersomeness for patients with chronic back pain. This was a three-armed, randomized trial for adults with nonspecific chronic back pain that compared PSRT with usual care and an active comparator (mindfulness-based stress reduction [MBSR]). Psychophysiologic symptom relief therapy-randomized participants received a 12-week (36 hours) course based on the psychophysiological model of pain. All groups were administered validated questionnaires at baseline and at 4, 8, 13, and 26 weeks. The primary outcome was the reduction in pain disability measured by the Roland-Morris Disability Questionnaire. The mean Roland-Morris Disability Questionnaire score for the PSRT group (n = 11) decreased from 9.5 (±4.3 SDs) to 3.3 (±5.1) after 26 weeks which was statistically significant compared with both MBSR (n = 12) (P = 0.04) and usual care (n = 12) (P = 0.03). Pain bothersomeness scores and pain-related anxiety decreased significantly over 26 weeks in PSRT compared with MBSR and usual care (data in manuscript). At 26 weeks, 63.6% of the PSRT arm reported being pain free (0/10 pain) compared with 25.0% and 16.7% in MBSR and usual care arms, respectively. Psychophysiologic symptom relief therapy attendance was 76%, and there was 100% follow-up of all groups. Psychophysiologic symptom relief therapy is a feasible and potentially highly beneficial treatment for patients with nonspecific back pain.


Continuous measurement of left ventricular volume in animals and humans by conductance catheter.
An eight-electrode conductance catheter previously developed by us and used to determine stroke volume in dogs was applied in human beings and dogs to measure absolute left ventricular volume quantitatively. For calibration we developed the formula V(t) = (1/alpha)(L2/sigma b)G(t) - Vc, where V(t) is time-varying left ventricular volume, alpha is a dimensionless constant, L is the electrode separation, sigma b is the conductivity of blood obtained by a sampling cuvette, and G(t) is the measured conductance within the left ventricular cavity. Vc is a correction term caused by the parallel conductance of structures surrounding the cavity and is measured in two ways. The first method, applicable in the anesthetized animal, consists of temporary reduction of volume to zero by suction. The second method uses a transient change in sigma b by injection of a small bolus of hypertonic saline (dogs) or 10 ml of cold glucose (humans) into the pulmonary artery. The validity of the formula was previously established for the isolated postmortem canine heart. The predicted linearity, slope constant alpha, and accuracy of Vc for the left ventricle in vivo were investigated by comparing the conductance volume data with results from independent methods: electromagnetic blood flow measurement for stroke volume and indicator dilution technique for ejection fraction (dogs), thermal dilution for cardiac output (12 patients), and single-plane cineventriculography for V(t) (five patients). In all comparisons, linear regression showed high correlation (from r = .82 [n = 46] to r = .988 [n = 20]) while alpha, with one exception, ranged from 0.75 to 1.07 and the error in Vc ranged from 0.5% to 16.5% (mean 7%). After positioning of the catheter, no arrhythmias were observed. It is concluded that the conductance catheter provides a reliable and simple method to measure left ventricular volume, giving an on-line, time-varying signal that is easily calibrated. Together with left ventricular pressure obtained through the catheter lumen, the instrument may be used for instantaneous display of pressure-volume loops to facilitate assessment of left ventricular pump performance.


Co-Modification of commercial TiO2 anode by combining a solid electrolyte with pitch-derived carbon to boost cyclability and rate capabilities.
The bad electrochemical performance circumscribes the application of commercial TiO2 (c-TiO2) anodes in Li-ion batteries. Carbon coating could ameliorate the electronic conductivity of TiO2, but the ionic conductivity is still inferior. Herein, a co-modification method was proposed by combining the solid electrolyte of lithium magnesium silicate (LMS) with pitch-derived carbon to concurrently meliorate the electronic and ionic conductivities of c-TiO2. The homogeneous mixtures were heated at 750 °C, and the co-modified product with suitable amounts of LMS and carbon demonstrates cycling capacities of 256.8, 220.4, 195.9, 176.4, and 152.0 mA h g-1 with multiplying current density from 100 to 1600 mA g-1. Even after 1000 cycles at 500 mA g-1, the maintained reversible capacity was 244.8 mA h g-1. The superior rate performance and cyclability correlate closely with the uniform thin N-doped carbon layers on the surface of c-TiO2 particles to favor the electrical conduction, and with the ion channels in LMS as well as the cation exchangeability of LMS to facilitate the Li+ transfer between the electrolyte, carbon layers, and TiO2 particles. The marginal amount of fluoride in LMS also contributes to the excellent cycling stability of the co-modified c-TiO2.


Pentosidine, an advanced glycation end-product, may reflect clinical and morphological features of hand osteoarthritis.
The study investigates pentosidine levels, an advanced glycation end-product, in patients with erosive and non-erosive hand osteoarthritis (HOA) and determine its potential association with clinical findings and imaging-defined joint damage.Pentosidine was measured by HPLC in serum and urine of 53 females with HOA (31 erosive and 22 non-erosive HOA) and normalised to the total serum protein or urinary creatinine, respectively. Pain, joint stiffness and disability were assessed by the Australian/Canadian OA hand index (AUSCAN). The hand radiographs scored according to the Kallman grading scale were assessed to determine a baseline value and reassessed after two years.The levels of urine pentosidine, but not of serum pentosidine, were higher in patients with erosive HOA than in non-erosive HOA (p=0.039). Urinary pentosidine correlated with CRP (r=0.302, p=0.031), ESR (r=0.288, p=0.041) and AUSCAN (r=0.408, p=0.003). Serum pentosidine, but not in urine, significantly correlated with the Kallman radiographic score in erosive HOA at the baseline (r=0.409, p=0.022) and after 2 years (r=0.385, p=0.032). However, when corrected for age and disease duration, only correlation between urine pentosidine and AUSCAN remained significant (r=0.397, p=0.004).Our data suggest that serum and urine pentosidine levels may relate to the distinctive clinical and morphological features of HOA.


The health economics of Helicobacter pylori infection.
Economic considerations are becoming increasingly important as health care becomes more expensive. Evidence for effectiveness is usually gained from randomised controlled trials (RCTs) but often there is insufficient evidence of the costs of alternative strategies in trials. Often, therefore, economic models are needed to extrapolate data from a variety of sources to give an indication of which strategy is cost effective. Helicobacter pylori (H. pylori) testing and treating in a wide variety of upper gastrointestinal diseases is a good example of the application of economic analyses to health care interventions. H. pylori eradication in peptic ulcer disease is very effective with systematic reviews giving a number needed to treat of around two compared to no therapy. RCTs have also suggested that treating H. pylori is also more effective and less expensive than continuous H(2) receptor antagonist therapy and is therefore the dominant strategy in treating peptic ulcer disease. The impact of H. pylori eradication in infected patients with functional dyspepsia is less dramatic, with systematic reviews suggesting a number needed to treat of 14. Economic models suggest that in Europe H. pylori eradication is cost-effective compared to offering no treatment (e.g. in the UK we can be 95% certain this approach is cost effective if you are willing to pay $51/month free from dyspepsia). In the USA it is less certain that this is a cost-effective approach due to the higher cost of eradication therapy. H. pylori test and treat has been proposed as an alternative to early endoscopy in patients with uninvestigated dyspepsia. We have conducted an individual patient data meta-analysis of five RCTs that has addressed the cost effectiveness of this approach. Endoscopy was slightly more effective than H. pylori test and treat at relieving dyspepsia at one year but was not cost-effective as it cost $9000/dyspepsia cure at one year. Population H. pylori test and treat has been proposed as a strategy to prevent noncardia gastric cancer. RCTs have suggested this approach may be cost saving but more data are needed on whether H. pylori eradication will reduce gastric cancer mortality before this strategy can be recommended.


Facile synthesis of multivalent folate-block copolymer conjugates via aqueous RAFT polymerization: targeted delivery of siRNA and subsequent gene suppression.
Cell specific delivery of small interfering ribonucleic acid (siRNA) using well-defined multivalent folate-conjugated block copolymers is reported. Primary amine functional, biocompatible, hydrophilic-block-cationic copolymers were synthesized via aqueous reversible addition-fragmentation chain transfer (RAFT) polymerization. N-(2-hydroxypropyl)methacrylamide) (HPMA), a permanently hydrophilic monomer, was copolymerized with a primary amine containing monomer, N-(3-aminopropyl)methacrylamide (APMA). Poly(HPMA) confers biocompatibility, while APMA provides amine functionality, allowing conjugation of folate derivatives. HPMA-stat-APMA was chain extended with a cationic block, poly(N-[3-(dimethylamino)propyl]methacrylamide), to promote electrostatic complexation between the copolymer and the negatively charged phosphate backbone of siRNA. Notably, poly(HPMA) stabilizes the neutral complexes in aqueous solution, while APMA allows the conjugation of a targeting moiety, thus, dually circumventing problems associated with the delivery of genes via cationically charged complexes (universal transfection). Fluorescence microscopy and gene down-regulation studies indicate that these neutral complexes can be specifically delivered to cancer cells that overexpress folate receptors.


The experiences of gay and bisexual men diagnosed with prostate cancer: results from an online focus group.
Research concerning gay and bisexual men diagnosed with prostate cancer is sparse. An online focus group was conducted over a 4-week period with participants responding to a range of discussion questions concerning their experiences following a prostate cancer diagnosis. Emerging themes were identified and consensus reached. A summary of each of the themes was produced which the coders agreed conveyed the essence of the online discussion. All men who took part in the online focus group reported that prostate cancer significantly impacted their lives. Unexpectedly, some participants actually gained a positive perspective and adopted a sense of empowerment. Participants spoke about emotional responses to a diagnosis of prostate cancer, accessing help and support, the impact of incontinence, the impact of sexual changes on identity, a re-evaluation of life, changed sexual relationships, the need to find the most suitable healthcare professionals and identification of current needs to improve quality of care. These areas of disquiet suggest that the psychological impact of this disease may be quite significant over an extended time-frame. Further research needs to be undertaken to assess the degree of distress accompanying the treatment of gay and bisexual men with prostate cancer.


Development and In vivo Pharmacokinetic and Pharmacodynamic Evaluation of an Oral Innovative Cyclodextrin Complexed Lipid Nanoparticles of Irbesartan Formulation for Enhanced Bioavailability.
Background: Irbesartan (IR) is used in the treatment of hypertension, heart failure, and nephropathy in Type II diabetes. IR bioavailability is limited by poor solubility and presystemic metabolism. In our previous investigations, cyclodextrin (HPβCD) complexed solid lipid nanoparticles (SLNs) of IR were prepared, optimized, and characterized. The current study aimed to confirm the reproducibility of the previous methodology and to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) performance of the selected lead formulations in an experimental animal model. Methods: SLNs were prepared by hot homogenization followed by probe sonication with IR/HPβCD inclusion complex loaded into a solid lipid (Dynasan 112). SLNs were evaluated for physical characteristics, drug content, entrapment efficiency, in vitro release profile, and surface morphology. The pharmacokinetic and pharmacodynamic behavior of the SLNs were evaluated in Wistar rats. Results: Photon correlation spectroscopy, drug content, entrapment efficiency, and dissolution studies results were reproducible and consistent with our earlier investigation. PK studies showed 2.1-, 6.6-, and 9.9-fold improvement in the relative oral bioavailability of the drug from IR-HPβCD, IR-SLN, and IR-HPβCD-SLN formulations, respectively compared to IR suspension. However, IR-HPβCD-SLNs showed 1.5- and 4.7-fold improvement in the relative oral bioavailability of the drug compared to IR-SLN and IR-HPβCD formulations, respectively. PD studies in hypertensive Wistar rats showed a good control over systolic blood pressure for 48 h for SLN formulations compared to 2 h for IR suspension. However, the IR-HPβCD inclusion complex exhibited immediate antihypertensive activity (0.5 h) with a period of systolic blood pressure control similar to IR suspension. Conclusions: The current approach exhibited improved oral bioavailability along with improved and prolonged pharmacodynamic effect.


Family practice residents and the elderly: fostering positive attitudes.
The population of elderly patients is steadily growing. Because physician attitudes toward caring for elderly patients are often negative, it is important to identify aspects of training that lead to favorable attitudes toward the practice of geriatrics. This study investigated the relationships among past casual experiences, educational experiences, level of training, faculty attitudes, and current resident attitudes. All Louisiana family practice residents (72) and program faculty members (35) were surveyed, with response rates of 69% and 86%, respectively. Residents generally held positive attitudes toward the elderly. Variables associated with positive resident attitudes were the amount of didactic training and faculty attitudes. No differences were found among the attitudes of residents at different levels of training. These findings highlight the importance of cognitive training and role modeling in geriatrics. Educational settings in which training occurs--classrooms, ambulatory care facilities, hospitals, and nursing homes--deserve careful consideration.


The doctor's deputizing service in a single-handed practice.
The out-of-hours calls received by a doctor's deputizing service on behalf of a single-handed general practitioner were studied over the course of one year.It was found that the overall rate of call (66.3 per 1,000 patients per year) and the rate of night call (10 per 1,000 patients per year) differed little from the rates found by general practitioners who did their own out-of-hours calls. The main users of the service were children under five and women. The time when the service was used least was between 23.00 and 07.00.It is concluded that employing a deputizing service did not necessarily increase the rate of out-of-hours calls, but that the rate was influenced by the age/sex structure of the practice list. The most economical time to employ the service was found to be from 23.00 to 07.00.


Surface coverage of alcohols on carbon nanomembranes under ambient conditions.
Molecular adsorption on 2D membranes plays a key role in surface-mediated permeation offering selectivity benefits for chemical separation. As many vaporous compounds are demonstrated to pass through 2D membranes faster than ordinary gases, it is important to determine their surface coverage on flat substrates under realistic conditions. Here we present a viable reference system to quantify polarization-modulation infrared reflection-absorption spectroscopy (PM-IRAS) measurements with organic vapors. Microscopic deposits of poly(1-trimethylsilyl-1-propyne) (PTMSP) onto metallic films are introduced as a matrix that soaks up liquid substances and accommodates them during the spectral acquisition. The corresponding molar uptake is obtained with a microbalance and converted into an areal density allowing for direct coverage-intensity relationships. We probe room-temperature physisorption of methanol, ethanol, and n-propanol on supported carbon nanomembranes and correlate the number of adsorbates with the mass transfer rates in free-standing layers. This work opens a new dimension for adsorption controlled permeation (ACP) studies.


Efficacy of 6-diazo-5-oxo-L-norleucine and N-[N-gamma-glutamyl-6-diazo-5-oxo-norleucinyl]-6-diazo-5-oxo-norleucine against experimental tumors in conventional and nude mice.
The chemotherapeutic effects of 6-diazo-5-oxo-L-norleucine (DON) and N-[N-gamma-glutamyl-6-diazo-5-oxo-norleucinyl]6-diazo-5-oxo-norleucine (azotomycin) were evaluated in a spectrum of transplantable experimental tumor systems including xenografts of human tumors in athymic mice. Both drugs displayed remarkable activity against the murine leukemia L1210 and P388, the Colon Tumors C26 and C38 and the CD8F1 mammary tumor. No significant activity was observed against Lewis lung carcinoma, B16 carcinoma, B16 melanoma, and intracranial ependymoblastoma. DON and azotomycin also exhibited striking inhibitory effects on the growth of s.c. human tumor (MX-1 mammary, LX-1 lung and CX-1 and CX-2 colon) xenografts in athymic mice. With the exception of one colon xenograft (CX-1), all tumor lines were markedly responsive to both drugs. Tumor regressions below the initial tumor sizes of 100 to 300 mg, albeit temporary, were brought about by one course of treatment every 4 days for 3 doses (at optimal dose) with either drug. Although these drugs have been tested previously in the clinic and have shown only limited therapeutic effectiveness, they seem to worthy of a second and closer look in light of the recent laboratory results.