Diagnostic performance of 18F-FDG PET/CT in patients with spinal infection: a systematic review and a bivariate meta-analysis.
Diagnosis of spinal infection (SI) is challenging and usually requires multiple tests. We aimed to perform a systematic review and a bivariate meta-analysis on the diagnostic role of 18F-FDG PET/CT in patients with SI. A comprehensive literature search of studies published through February 2019 in PubMed/MEDLINE and Cochrane library databases was carried out. Studies investigating the diagnostic performance of 18F-FDG PET/CT in patients with SI were eligible for inclusion in the qualitative analysis. For the quantitative analysis, pooled sensitivity, specificity, positive and negative likelihood ratio (LR+ and LR-) and diagnostic odds ratio (DOR) of 18F-FDG PET/CT in patients with suspected SI were calculated on a per examination-based analysis. Pooled data were presented with 95% confidence intervals (95% CI). Twenty-six articles (833 patients) using 18F-FDG PET/CT were eligible for the qualitative analysis. Twelve studies (396 patients) were selected for the meta-analysis. Overall, 18F-FDG PET/CT demonstrated a very good diagnostic performance in patients with SI and several studies underlined the value of 18F-FDG PET/CT in assessing the response to treatment. The bivariate meta-analysis on 18F-FDG PET/CT in patients with suspected SI provided the following results: sensitivity 94.8% (95% CI 88.9-97.6%) and specificity 91.4% (95% CI 78.2-96.9%). The pooled LR+, LR- and DOR were 4.7 (95% CI 2.9-7.7), 0.11 (95% CI 0.07-0.16) and 63.4 (95% CI 28.9-139), respectively. No significant heterogeneity or publication bias was found. 18F-FDG PET/CT demonstrated a very good diagnostic performance in patients with SI and can be used in patients in which MRI cannot be performed or is non-diagnostic or inconclusive. Several studies underlined the value of 18F-FDG PET/CT in assessing the response to treatment in patients with SI. Overall, larger multicentre and prospective studies and cost-effectiveness analyses are warranted.


Gastric tube interpostion: a satisfactory alternative to the colon for esophageal replacement in children.
The gastric tube was used as the primary method of esophageal reconstruction in 15 infants and children, 9 with isolated esophageal atresia and 6 with lye stricture. The youngest patient was 8 months old and the oldest, 5 years old at the time of the procedure. The technique of gastric tube construction is described. There have been both major and minor complications but the gastric tube has proved very satisfactory as a conduit from mouth to stomach. Growth and development have been acceptable in all 15 children, although most remain in the lower percentiles for growth and height, a condition that usually predates the esophageal substitution. In our institution the gastric tube is the preferred method of esophageal substitution.


Measurements of the lower uterine segment during gestation.
To establish normal values for the lower uterine segment (LUS) thickness and to recognize factors that may affect these values. In this cross-sectional study, we measured the LUS thickness in women between 11 and 41 weeks gestation. Women with placental abnormalities and fetal anomalies were excluded. Fetal weight, location of placental implantation, and cervical length were estimated. The LUS was examined to identify the thinnest zone and evaluated using the transvaginal approach with an empty urinary bladder. Full LUS thickness was measured with a caliper at the inner surface of the posterior bladder wall and another caliper at the interface between the amniotic fluid and the decidua. The myometrium was measured with the first caliper at the interface between the amniotic fluid and the deciduas and the second between the bladder wall and the myometrium. Normal values for the LUS were established throughout gestation, and correlations between the LUS gestational age, fetal weight, previous cesarean section, and other parameters were examined. Overall, 350 women were included in our study. Median parity was 1 (0-6) and the majority (62%, 218/350) of women have not had a previous cesarean section. The LUS thickness inversely correlated with gestational week (Pearson's r = -0.11, p < 0.03). When stratifying the linear regression model to women with and without a history of a previous cesarean section, it was demonstrated that gestational age was moderately correlated with LUS only in the second group of patients (Pearson's r = -0.16, p = 0.1 and Pearson's r = -0.47, p < 0.0001, respectively). During the post term period, patients who had had a previous cesarean section had significantly thinner LUS compared with patients who had not had a previous cesarean section (46 mm ± 20 versus 59 mm ± 20, p = 0.002, respectively). Neither parity nor the number of previous cesarean sections were found to correlate with the thickness of the LUS (p > 0.05). Multivariate linear regression (R(2) = 0.215, F(2, 63) = 9.021, p < 0.001) demonstrated that both gestational week (β = -0.13, p < 0.04) and cesarean section (β = -0.01, p < 0.0001) were independent factors associated with the thickness of the LUS; for every 1 week increase in gestational week, there was a 1.3 mm decrease in the total thickness of the LUS CONCLUSIONS: We have established reference ranges for LUS thickness throughout gestation. The LUS thickness decreases throughout gestation in singleton pregnancies and is significantly thinner in postterm period pregnant women with a previous cesarean section.


Clinical implication of serum C-reactive protein in patients with uncomplicated acute pyelonephritis as marker of prolonged hospitalization and recurrence.
To analyze the clinical value of C-reactive protein (CRP) as a marker of prolonged hospitalization and a predictor of recurrence in patients after uncomplicated acute pyelonephritis (APN). A total of 202 consecutive adult patients with APN were prospectively enrolled from September 2005 to June 2007. APN was defined as the concomitant presence of 4 major and >/=2 minor clinical or laboratory signs or symptoms suggestive of APN. All patients were treated with parenteral antibiotics. The patients were discharged after normalization of body temperature, serum white blood cell counts, and urinalysis. Correlations among the recurrence of APN and various factors, including CRP, were investigated. Of the 202 patients, 13 were excluded because of the presence of complicating factors or insufficient data. APN recurrence developed in 4 patients (2.1%). The CRP level at discharge correlated significantly with the recurrence of APN on univariate and multivariate analysis. Irrespective of the normalization of body temperature, serum white blood cell counts, and urinalysis, the recurrence of APN was significantly greater in the patients with CRP >4 mg/dL than in those with <4 mg/dL at discharge. Patients with a maximal CRP of >15 mg/dL during admission had a longer hospitalization and required more intravenous antibiotic therapy than did the patients with a maximal CRP of <15 mg/dL. As a marker of prolonged hospitalization and recurrence, CRP can complement the present clinical and laboratory parameters used as guides in the proper treatment of patients with uncomplicated APN.


[Detection of bacterial DNA in blood with three pairs of primers].
To develop a stable and sensitive method to detect gut-derived bacterial DNA present in the blood. Blood culture and PCR were performed simultaneously when temperature of patients (n = 23) was higher than 38.5 degrees C after laparotomy. PCR was performed after DNA extraction, target genes being beta-lactosidase gene of Escherichia coli(E. coli), glutamine synthase gene of Bacteroides Fragilitas, and 16SrRNA gene of most pathogenic bacteria. DNA of standard strains of E. coli and Bacteroides Fragilitas served as positive controls, blank control as negative controls, and healthy volunteers (n = 20) served as normal controls. We performed PCR twice with part of the samples (n = 20) in order to test the repetition of this method. The repetition rate of PCR was 95%. Three of blood cultures were positive (13.0%, 3/23), the corresponding positive ratio of PCR was 43.5% (10/23) which was higher than that of the blood culture (P = 0.016). PCR is more sensitive than blood culture in detection of bacteremia.


Biochemical events associated with inhibition of B-cell proliferation by phorbol diesters.
Phorbol myristate acelate (PMA), a potent tumor promoter, has a variety of effects on cells of the immune system resulting in altered patterns of cell proliferation and differentiation. Although PMA is mitogenic or co-mitogenic for human lymphocytes and murine T-cells, it inhibits proliferation of murine B-cells stimulated by LPS or anti-Ig. PMA, however, does not inhibit the ability of LPS or anti-Ig to activate B-cells, as evidenced by increased Ia antigen expression and RNA synthesis. In the present studies it was shown that inhibition of DNA synthesis by PMA coincided with qualitative and quantitative changes in phosphorylated proteins. In particular, PMA treatment resulted in a unique profile of phosphoproteins independent of LPS or anti-Ig treatment. Inhibition of DNA synthesis occurred over a wide range of PMA concentrations. At concentrations up to 10(-9) M, inhibition of proliferation correlated with decreased phosphatidylinositol turnover and decreased intracellular Ca2+ levels, suggesting that PMA affects the phosphoinositide signal transduction pathway. However, at PMA concentrations less than 10(-10) M, inhibition of anti-Ig- and LPS-mediated proliferation occurred without inhibition of the phosphoinositide transduction signal. At these concentrations, PMA-induced inhibition of DNA synthesis was highly sensitive to recombinant IL-2. These data suggest that the antiproliferative effects of PMA on B-cells stimulated by LPS or anti-Ig may be mediated by two mechanisms. At high concentrations, PMA causes a feedback regulation of the phosphoinositide-dependent messenger system, while at lower concentrations, PMA alters the response to specific growth factors. Since PMA induces unique phosphoproteins and both of these events can be regulated by protein phosphorylation, it is possible that these unique phosphoproteins are responsible for the antiproliferative effects of PMA.


Scaffold-free high throughput generation of quiescent valvular microtissues.
The major challenge of working with valvular interstitial cells in vitro is the preservation or recovery of their native quiescent state. In this study, a biomimetic approach is used which aims to engineer small volume, high quality valve microtissues, having a potential in regenerative medicine and as a relevant 3D in vitro model to provide insights into valve (patho)biology. To form micro-aggregates, porcine valvular interstitial cells were seeded in agarose micro-wells and cultured in medium supplemented with 250μM Ascorbic Acid 2-phosphate for 22days. Histology showed viable aggregates with normal nuclei and without any signs of calcification. Aggregates stained strongly for GAG and collagen I and reticular fibers were present. ECM formation was quantified and showed a significant increase of GAG, elastin and Col I during aggregate culture. Cultivation of VIC in aggregates also promoted mRNA expression of Col I/III/V, elastin, hyaluronan, biglycan, decorin, versican MMP-1/2/3/9 and TIMP-2 compared to monolayer cultured VIC. Phenotype analysis of aggregates showed a significant decrease in α-SMA expression, and an increase in FSP-1 expression at any time point. Furthermore, VIC aggregates did not show a significant difference in OCN, Egr-1, Sox-9 or Runx2 expression. In this study high quality valvular interstitial cell aggregates were generated that are able to produce their own ECM, resembling the native valve composition. The applied and completely cell driven 3D approach overcomes the problems of VIC activation in 2D, by downregulating α-SMA expression and stimulating a homeostatic quiescent VIC state.


Lifetime PTSD is associated with impaired emotion recognition in veterans and their offspring.
PTSD is associated with emotion dysregulation. Studies have found inconsistent impaired facial emotion recognition ability (ERA) in patients with PTSD and intergenerational transmission of PTSD has been reported, although no studies exist regarding ERA. Our objective was to characterise the facial ERA of a group of traumatised war veterans with, and without lifetime PTSD, and also of their respective adult offspring. Sixty-one veterans with, and without lifetime PTSD and 73 offspring were tested for ERA of seven basic facial emotions expressions, 40 years after veterans had been exposed to war-related trauma. Veterans with lifetime PTSD showed impairment of recognition of all emotions, irrespective of the type, when compared with veterans without PTSD. This result was maintained after adjusting for potential confounders-including depressive symptoms. Offspring of veterans with lifetime PTSD also showed impaired recognition of all emotions, including after adjustment for the same variables. Offspring of veterans with lifetime PTSD also showed specific impairment in recognising the emotions of happiness and disgust. These results confirm that PTSD has negative effects with regards to emotion regulation and also on the next generation. This could result in this population being at increased risk of suffering from relationship problems and psychopathology.


Indication.
Should the indications for therapies differ from one nation to the next? What are the reasons behind controversial therapeutic variations? What roles do cultural history and authoritarian conflict among clinicians play in the adoption of therapies? When I worked at a rural hospital in Kenya, a woman experiencing obstructed labor made me ponder many questions-but only after our emergency ended in the death of her newborn son. In recounting and learning from this episode, I listened to the disparate Kenyan voices of the patient, the hospital's director, the consultant obstetrician, and to the even more controversial voices of evidence-based medicine. In reflecting on this process, I have learned at least 3 lessons-about the transmissibility of arrogance, the role of guests in other countries, and the nature of science.


Absence of effect of maternal immunization to paternal antigens on placental weight, fetal weight and litter size in the mouse.
No evidence was obtained that immunization to paternal antigens affected placental weight, fetal weight or litter size on Day 18 of pregnancy in female mice.


Community Surveillance Study--perceived response of rheumatoid arthritis patients to NSAIDs.
The perceived effectiveness of nonsteroidal anti-inflammatory drugs was studied in a community population (n=380). The population characteristics of a sample were similar to previous studies. Most patients were on a single NSAID. Rheumatoid arthritis (RA) was found to have a significant impact in terms of disability and lifestyle. Active inflammation was the main incentive to comply with therapy. However, the patients perceptions about the efficacy of the medication, their attitude towards the medication and their motivations for taking it, also affected compliance. A decreased effectiveness of therapy may also be due in part to tolerance to some medications and some evidence of the induction of salicylate metabolism has been reported. Considerable variation in the patients' perception of other forms of therapy for RA were also observed.


Metal-organic frameworks as template for synthesis of Mn3+/Mn4+ mixed valence manganese cobaltites electrocatalysts for oxygen evolution reaction.
Cobalt-based oxides are among the most promising electrocatalysts for oxygen evolution reactions (OER). In this context, this work reports the synthesis of manganese-doped cobaltites using the Zeolitic-Imidazolate Frameworks 67 (ZIF-67) as template. The incorporation of manganese ions into ZIF-67 structure was evaluated in ethanol and methanol, in order to obtain the best synthetic route. Non-doped (ZIF-67C) and Mn-doped cobaltites (Mn/ZIF-67C(E) and Mn/ZIF-67C(M)) were obtained after thermal treatment at 350 °C. Structural and morphological properties were investigated and presence of Mn3+ and Mn4+ was confirmed by X-ray photoelectron spectroscopy (XPS) data and magnetization curves. The electrocatalytic activity in OER was investigated in alkaline medium for manganese cobaltites, and compared to the ZIF-67C. Overpotentials to generate a current of 10 mA cm-2 were 338 mV and 356 mV for Mn/ZIF-67C(E) and Mn/ZIF-67C(M), respectively. These results are superior to those found for similar materials in the literature. The material obtained in methanol (Mn/ZIF-67C(M)) presents lower overpotential, however, shows superior electrocatalytic performance for current density above 100 mA cm-2, therefore being an efficient electrode for commercial electrolysers.


Reasons and Risk Factors for Failed Same-Day Discharge After Primary Total Knee Arthroplasty.
As ambulatory total knee arthroplasty (TKA) becomes increasingly common, unplanned admission after surgery presents a challenge for the health care system. Studies evaluating the reasons and risk factors for this occurrence are limited. We sought to evaluate the reasons for unplanned admission after surgery and identify risk factors associated with this occurrence. Patients registered in an institutional ambulatory joint arthroplasty program who underwent a TKA from 2017-2020 were retrospectively reviewed. The criteria for enrollment include candidates for unilateral TKA between the ages of 18 and 70 years, with a body mass index (BMI) of less than 35, and appropriate social and material support at home. Patients who had certain comorbidities including coronary artery disease, valvular heart disease, and opioid dependence were not eligible. A total of 274 patients who underwent TKA with planned same-day discharge (SDD) were identified in the medical record and reviewed. In this cohort, 140 patients (51.1%) were discharged on the day of surgery and 134 patients (48.9%) required a minimum 1-night admission. Demographics, comorbidities, and perioperative data were collected. Factors associated with failed SDD were identified using multivariate logistic regression. The most common reasons for failed SDD were failure to meet ambulation goals (25%) and logistical issues related to a late-day case (19%). Risk factors for failed SDD include general anesthesia (odds ratio (OR) 12.60, P = .047), procedure start time after 11:00 am (OR 5.16, P < .001), highest postoperative pain score >8 (visual analogue scale, OR 5.78, P = .001). Willingness to accept a higher pain threshold before discharge (visual analogue scale 4 to 10) was associated with successful SDD (OR 3.0, P < .001). Age and American Society of Anesthesiologists (ASA) classification were not associated with failed SDD. The most common reasons for failed SDD were related to logistical issues and postoperative mobilization. Risk factors for failed SDD involve case timing and pain control. Modifiable perioperative factors may play an important role in successful SDD after TKA.


Antiulcer principle from Zingiber montanum.
Rhizome of Zingiber montanum has been extensively used as a folk medicine to ameliorate peptic ulcer at northern part of Bangladesh. To identify the antiulcer principle of the MeOH extract of the rhizome of Zingiber montanum by an ex vivo bioassay guided chromatographic separation and purification, and structure elucidation of the purified compound by spectroscopic methods. Dried powder of Zingiber montanum rhizomes was extracted with MeOH. The antiulcer activity of the crude extract and its chromatographic fractions were evaluated by the inhibition of 1N HCl induced gastric lesions in Swiss albino mice. The pure compound was purified from the active fraction by crystallization with hexanes. Structure of the pure compound was elucidated by spectroscopic methods. The antiulcer activity of the pure compound was evaluated by the inhibition of 1N HCl, 95% ethanol and indomethacin induced gastric lesions in mice. The MeOH extract of Zingiber montanum showed 61.97% and 83.10% inhibition of the 1N HCl induced gastric lesions at doses of 200mg/kg and 400mg/kg, respectively, in mice. Chromatographic separation on silica gel of the extract was yielded seven fractions and the fraction 2 was found to have most potent antiulcer activity in mice. This fraction showed 77.46% inhibition of the 1N HCl induced gastric lesions at a dose of 40mg/kg in mice. Crystallization of the fraction yielded 1 (zerumbone, 180mg). It showed statistically 45.77% and 92.25% inhibition of 1N HCl induced gastric lesions in mice at doses of 20mg/kg and 40mg/kg, respectively. It also showed 29.07% and 45.35% inhibition of 95% ethanol induced gastric mucosal damage, and 64.76% and 72.38% inhibition of indomethacin induced gastric lesions in mice at doses of 20mg/kg and 40mg/kg, respectively. Zerumbone (1) showed potent cytoprotective effect against necrotizing agent (HCl) and non-steroidal anti-inflammatory drug (indomethacin) induced gastric ulceration. It also exhibited moderate cytoprotective effect against noxious agent (EtOH) induced gastric lesions. It can be considered as a promising new antiulcer natural drug lead.


Post-surgical pain relief with zero-order intravenous infusions of meptazinol and morphine: a double-blind placebo-controlled evaluation of their effects on ventilation.
A double-blind, placebo-controlled study has been made of the analgesic and respiratory effects of constant rate infusions of meptazinol and morphine in 30 patients after abdominal surgery. Group I received meptazinol, loading dose 50 mg followed by i.v. infusion 0.5 mg.kg-1.h-1, Group II received morphine, loading dose 5 mg and then an infusion of 0.05 mg.kg-1.h-1, and Group III received saline. After recovery from inhalation anaesthesia (without opiates or a local anaesthetic) pain relief and chemoreceptor carbon dioxide tolerance were assessed before and at various times after starting the analgesic infusion. A similar degree of pain relief was found after 10 min in Groups I and II, which lasted until the end of observation period (20 h). Heart rate and systolic and diastolic blood pressures were lower in Group II than in Groups I and III, and respiratory rate fell in Groups I and II. After 6 h arterial carbon dioxide tensions (PaCO2) became significantly higher in Group II than Group III. The maximum percentage fall in mean tidal volume (VT) and expired minute volume (VE) from the preinjection values was significant in Groups I and II. End-tidal carbon-dioxide (PETCO2) and PaCO2 were significantly higher after 20 h of infusion in Group II compared to Group I. The slope of VE/PETCO2 (mean value of S) was increased in Group I and it was significantly reduced in Group II. Analysis of derived variables, such as the CO2 intercept (CO2I) and minute ventilation at 7 kPa (VE7), indicated a shift to the right of the slopes in Groups I and II, initially more so in Group I.(ABSTRACT TRUNCATED AT 250 WORDS)


Post-radiation primary hypothyroidism in patients with head and neck cancer: External validation of thyroid gland dose-volume constraints with long-term endocrine outcomes.
Post-radiation primary hypothyroidism is a common late complication in head and neck cancer (HNC) survivors. No radiation dose-volume constraint of the thyroid gland has been externally validated for predicting long-term thyroid function outcomes. This external validation study evaluated the diagnostic properties of 22 radiation dose-volume constraints of the thyroid gland proposed in the literature. Radiation dosimetric data from 488 HNC patients who underwent neck irradiation from January 2013 to December 2015 at two tertiary oncology centers were reviewed. The diagnostic metrics of candidate constraints were computed by inverse probability of censoring weighting and compared using time-dependent receiver operating characteristic (ROC) curves with death designated as a competing event. Multivariable regression analyses were performed using the Fine-Gray sub-distribution hazard model. Over a median follow-up period of 6.8 years, 205 (42.0 %) patients developed post-radiation primary hypothyroidism. The thyroid volume spared from 60 Gy (VS60) had the largest area under ROC curve of 0.698 at 5 years after radiotherapy. Of all evaluated constraints, VS60 at a cutoff value of 10 cc had the highest F-score of 0.53. The 5-year hypothyroidism risks of patients with thyroid VS60 ≥ 10 cc and < 10 cc were 14.7 % and 38.2 %, respectively (p < 0.001). The adjusted sub-hazard ratio for post-radiation primary hypothyroidism for VS60 < 10 cc was 1.87 (95 % confidence interval, 1.22-2.87; p < 0.001). Thyroid VS60 is the best radiation dose-volume parameter to predict the long-term risk of primary hypothyroidism in patients with HNC who underwent neck irradiation. VS60 ≥ 10 cc is a robust constraint that limits the 5-year primary hypothyroidism risk to less than 15 % and should be routinely employed during radiotherapy optimization.


Single-layer CVD-grown graphene decorated with metal nanoparticles as a promising biosensing platform.
A new approach to the development of a single-layer graphene sensor decorated with metal nanoparticles is presented. Chemical vapor deposition is used to grow single layer graphene on copper. Decoration of the single-layer graphene is achieved by electroless deposition of Au nanoparticles using the copper substrate as a source of electrons. Transfer of the decorated single-layer graphene on glassy carbon electrodes offers a sensitive platform for biosensor development. As a proof of concept, 10 units of glucose oxidase were deposited on the surface in a Nafion matrix to stabilize the enzyme as well as to prevent interference from ascorbic acid and uric acid. Amperometric linear response calibration in the μmoll(-1) is obtained. The presented methodology enables highly sensitive platforms for biosensor development, providing a scalable roll-to-roll production with a much more reproducible scheme when compared to the graphene biosensors reported previously based on drop-cast of multi-layer graphene suspensions.


Non-immersed zigzag microalgae biofilm overcoming high turbidity and ammonia of wastewater for muti-pollutants bio-purification.
Biological treatment that utilizes microalgae technology has demonstrated outstanding efficacy in the wastewater purification and nutrients recovery. However, the high turbidity of the digested piggery wastewater (DPW) leads to serious light attenuation and the culture mode of suspended microalgae results in a huge landing area. Thus, to overcome light attenuation in DPW, a non-immersed titled zigzag microalgae biofilm was constructed by attaching it onto a porous cotton cloth. As a result, the light could directly irradiate microalgae biofilm that attached on both sides of the cotton cloth, and the microalgal biofilm area was up to 6 m2 per bioreactor landing area. When the non-immersed zigzag microalgae biofilm bioreactor (N-Z-MBP) was used to treat wastewater with an ammonia nitrogen (NH4+-N) concentration of 362 mg L-1, the NH4+-N was completely removed in just 5 days and the maximum growth rate of microalgae biofilm reached 7.02 g m-2 d-1. After 21 days of long-term sequencing batch operation for the N-Z-MBP, the biomass density of the biofilm reached 52 g m-2 and remained at this high value for the next 14 days. Most importantly, during the 35 days' running, the NH4+ -N maximum removal rate of single batch reached up to 65 mg L-1 d-1 and its concentration in the effluent was always below the discharge standard value (80 mg L-1 form GB18596-2001 of China) and total phosphorus was completely removed in each batch. Furthermore, the biomass concentration of microalgae cells in the effluent of the N-Z-MBP was almost zero, indicating that the non-submerged biofilm achieved in situ separation of microalgae from the wastewater. This work suggests that the N-Z-MBP can effectively purify DPW over a long period, providing a possible strategy to treat wastewater with high ammonia nitrogen and high turbidity.


Antibiotics versus no therapy in kidney transplant recipients with asymptomatic bacteriuria (BiRT): a pragmatic, multicentre, randomized, controlled trial.
Many transplant physicians screen for and treat asymptomatic bacteriuria (ASB) during post-kidney-transplant surveillance. We investigated whether antibiotics are effective in reducing the occurrence of symptomatic urinary tract infection (UTI) in kidney transplant recipients with ASB. We performed this multicentre, randomized, open-label trial in kidney transplant recipients who had ASB and were ≥2 months post-transplantation. We randomly assigned participants to receive antibiotics or no therapy. The primary outcome was the incidence of symptomatic UTI over the subsequent 12 months. One hundred and ninety-nine kidney transplant recipients with ASB were randomly assigned to antibiotics (100 participants) or no therapy (99 participants). There was no significant difference in the occurrence of symptomatic UTI between the antibiotic and no-therapy groups (27%, 27/100 versus 31%, 31/99; univariate Cox model: hazard ratio 0.83, 95%CI: 0.50-1.40; log-rank test: p 0.49). Over the 1-year study period, antibiotic use was five times higher in the antibiotic group than in the no-therapy group (30 antibiotic days/participant, interquartile range 20-41, versus 6, interquartile range 0-15, p < 0.001). Overall, 155/199 participants (78%) had at least one further episode of bacteriuria during the follow-up. Compared with the participant's baseline episode of ASB, the second episode of bacteriuria was more frequently caused by bacteria resistant to clinically relevant antibiotics (ciprofloxacin, cotrimoxazole, third-generation cephalosporin) in the antibiotic group than in the no-therapy group (18%, 13/72 versus 4%, 3/83, p 0.003). Applying a screen-and-treat strategy for ASB does not reduce the occurrence of symptomatic UTI in kidney transplant recipients who are more than 2 months post-transplantation. Furthermore, this strategy increases antibiotic use and promotes the emergence of resistant organisms.


Investigation of the association between CT detection of early gastric cancer and ultimate histology.
To evaluate the association between computed tomography (CT) detection of early gastric cancer (EGC) and various parameters, including the depth of invasion, lesion extent, morpholgical type, location, and histological type. One hundred and ten patients with 114 EGCs were preoperatively examined using multidetector CT (MDCT). All patients received 500 ml water as an oral contrast agent approximately 15 min before the examination and an additional 500 ml immediately prior to the study. Portal venous phase, contrast-enhanced, helical scans with multiplanar reformation were obtained. All patients underwent surgery. For location and size of tumour, the CT findings were compared with the histopathological results. The association between CT detection of EGC and various parameters were assessed. In addition, we performed a stepwise forward logistic regression to identify which variables significantly increased the CT detection rate of EGC. The detection rate of all EGCs using MDCT was 36.4%. The detection rate for EGCs confined to the superficial layer (mucosa or SM1) was 14.3%, whereas the detection rate for EGCs that involved the deep layer (SM2 or more than SM2) was 86.5%. All three of the protruded lesions and five of the six excavated lesions were readily detected using CT. Stepwise forward logistic regression showed that the best parameter for CT detection of EGCs was the depth of invasion; more EGCs were detected when the lesion was deep. MDCT has advantages in acceptable evaluation of the depth invasion of EGCs. EGC that is undetectable using CT suggests an EGC confined to the superficial layer, whereas EGC detectable using CT suggests deep lesions.


The psychiatric services in Cremona: a case study of the Italian reform law.
Italy's mental health law of 1978 provided for the gradual phasing out of psychiatric hospitals (PH) and the creation of comprehensive community-based systems. However, these changes have taken place at different times and in different forms. There are now three different organizational and care models operating in Italy: in the first, common in Southern Italy, the former PH and the new general hospital general wards (GHPW) coexist; in the second, outpatient departments complement the above facilities, but the hospital activity remains central; in the third model, a community model has been given priority--the so-called "community priority." While many reports have been published describing the activity of some of the services adhering to the third model, no report has been published specifically describing the activity of services which work according to the second model, such as Cremona. In this paper, the activity of the Cremona psychiatric services is described, and the consequences of the reform law and the problems related to an hospital-based activity are emphasized.


The anthelmintic efficacy of fenbendazole in the control of Moniezia expansa and Trichuris ovis in sheep.
The anthelmintic efficacy of fenbendazole (methyl 5-(phenyl-thio)-2-benzimidazole-carbamate) against Moniezia expansa and Trichuris ovis was tested. At dose rates of 5 mg per kg and above, efficacies were found to be greater than 91 percent against M expansa and greater than 92 per cent against T ovis. At these dose rates efficacy on egg suppression was 100 per cent for Moniezia and greater than 97 per cent for Trichuris.


The effect of variation in perfusion pressure on the capillary blood flow (microflow) in the cerebral cortex of the isolated cat's head preparation.
The results of the present experiments show that capillary blood flow in the cerebral cortex fluctuates, whether the cat's head is supplied by the animal's intact circulation or by an artificial circulation system. These variations in blood flow last about 5 to 15 min and range from about 10% below to 10% above the mean. When the perfusion pressure is gradually reduced from 140 mmHg to 60 mmHg, the cortical microflow and the electrical activity of the brain remain almost constant. However, a reduction in perfusion pressure of this magnitude causes a 75% fall in total blood flow through the isolated head.


Erionite-Na upon heating: dehydration dynamics and exchangeable cations mobility.
Erionite is a fibrous zeolite significantly more tumorigenic than crocidolite asbestos upon inhalation. In recent years, several papers have been published aimed at characterizing from the crystal-chemical point of view erionite fibres. As their toxicity has been ascribed to Fe acquired within the human body, studies aimed at characterizing the iron topochemistry have also been published, suggesting a possible important role played by the ionic exchange properties and cations mobility of this zeolite on developing carcinogenicity. Here we report the analysis results of the thermal behaviour of erionite-Na, which has been found to deviate significantly from that of erionite-K. This result is in contrast with the current scientific view that differences in weighted ionic potential, Si/Al ratio and size of exchangeable cations result in significantly different thermal behaviours, all those parameters being nearly identical or very similar in both species. The different mobility of the extraframework cations observed in erionite samples with dissimilar chemistry is of particular interest within the frame of the hypothesis that their biological activity could depend, apart from surface interactions, also on bulk effects.


Risk factors for jaw osteoradionecrosis: a case control study.
There are divergences among studies regarding features associated to increased risk of osteoradionecrosis (ORN). Our objective was to identify factors that predispose to the development of ORN of the jaw. This was a retrospective, hospital-based, case-control study involving patients with head and neck cancer who had been treated with ≥ 60 Gy external radiotherapy (RT) to the jaw. A total of 19 cases of ORN and 43 controls were included. The patients' demographic data, tumor type, staging, treatment and outcome information, and pre-treatment oral status were collected. Univariate analysis showed that the oral cavity/oropharynx sites were associated with 9.77-fold increased risk of ORN development compared to other sites (p = 0.005). Being an active smoker was associated with 3.95-fold increased risk of ORN development (p = 0.01). A tendency towards increased risk of ORN was observed particularly when tooth extraction occurred after RT (odds ratio (OR): 3.04; p = 0.08). Multivariable analysis showed that tumor site was the only significant risk factor (OR: 21.03, p = 0.01). The oral and oropharyngeal primary site is an important risk factor for ORN. Dental extraction, which did not occur in 28% of the sample, was not an essential event for ORN development.


Absorption of nutrients in lactase deficiency.
The influence of malabsorption of lactose, as a result of primary lactase deficiency, on the absorption of the nutrients in milk was tested in four healthy controls and four subjects with lactase deficiency. An ileal perfusion technique was used to quantify arrival in the ileum of nutrients and a nonabsorbable marker (polyethylene glycol, PEG 4000) ingested as a test meal of milk. The meal was 250 ml of whole milk or milk in which the lactose had been hydrolyzed to glucose and galactose. In the fasting state, ileal flow of volume, protein, carbohydrate, and electrolytes was small and not different in controls and lactase-deficient subjects. Ileal flow increased in all subjects after the test meal of milk; more fluid and nutrient was recovered from the ileum in lactase-deficient subjects after whole milk than in control subjects or in lactase deficiency after hydrolyzed milk. Two deficient subjects showed marked malabsorption of lactose (35 and 50%); two did not. Protein, calcium, magnesium, and phosphorus were also recovered from the ileum in greater quantities in lactase deficients after whole milk. However, apart from decreased absorption of lactose, the nutritional consequences of malabsorption in association with primary lactase deficiency in adults are probably minimal.


MicroRNA-139-5p Promotes Functional Recovery and Reduces Pain Hypersensitivity in Mice with Spinal Cord Injury by Targeting Mammalian Sterile 20-like Kinase 1.
Currently, there is no cure for spinal cord injury (SCI), a heavy burden on patients physiology and psychology. We found that microRNA-139-5p (miR-139-5p) expression was significantly downregulated in damaged spinal cords in mice. So, we aimed to test the effect of treatment with miR-139-5p on functional recovery and neuropathic pain in mice with SCI and investigate the underlying mechanism. The luciferase reporter assay revealed that miR-139-5p directly targeted mammalian sterile 20-like kinase 1 (Mst1), and miR-139-5p treatment suppressed Mst1 protein expression in damaged spinal cords of mice. Wild-type mice and Mst1(-/-) mice were exposed to SCI and treated with miR-139-5p agomir via intrathecal infusion. Treatment of SCI mice with miR-139-5p accelerated locomotor functional recovery, reduced hypersensitivities to mechanical and thermal stimulations, and promoted neuronal survival in damaged spinal cords. Treatment with miR-139-5p enhanced phosphorylation of adenosine monophosphate-activated protein kinase alpha (AMPKα), improved mitochondrial function, and suppressed NF-κB-related inflammation in damaged spinal cords. Deficiency of Mst1 had similar benefits in mice with SCI. Furthermore, miR-139-5p treatment did not provide further protection in Mst1(-/-) mice against SCI. In conclusion, miR-139-5p treatment enhanced functional recovery and reduced pain hypersensitivity in mice with SCI, possibly through targeting Mst1.


A numerical method for biphasic curve fitting with a programmable calculator.
Elimination kinetics of bromsulphalein (BSP) after a single injection into the circulation of rats were examined by means of a four-compartment model. BSP plasma concentrations were measured colorimetrically. A program written for the Texas Instruments TI-59 programmable calculator is presented, which will calculate the fractional blood clearance of BSP using an iteration procedure. A simple method of fitting biphasic decay curves to experimental data is also proposed.


Plant nanotoxicology.
The anthropogenic release of nanoparticles (NPs) to the environment poses a potential hazard to human health and life. The interplay between NPs and biological processes is receiving increasing attention. Plants expose huge interfaces to the air and soil environment. Thus, NPs are adsorbed to the plant surfaces, taken up through nano- or micrometer-scale openings of plants and are translocated within the plant body. Persistent NPs associated with plants enter the human food chain. In this Opinion, we document the occurrence and character of NPs in the environment and evaluate the need for future research on toxicological effects. Plant nanotoxicology is introduced as a discipline that explores the effects and toxicity mechanisms of NPs in plants, including transport, surface interactions and material-specific responses.


Inter-institutional comparison of treatment practice for cervical cancer with special emphasis on brachytherapy.
To compare the cervical cancer treatment outcome and toxicities between two different institutions. We analysed the clinical outcome of cervical cancer patients treated at two different centres from January 2015 to December 2016. Centre A treated 72 patients by external beam radiotherapy (EBRT) to a dose of 45 Gy in 25 fractions followed by intracavitary brachytherapy (ICBT) 6.5 Gy × 4 fractions and centre B treated 89 patients by EBRT to a dose of 50.4 Gy in 28 fractions followed by ICBT 9 Gy × 2 fractions. The local control, distant metastases and treatment toxicities were compared. The median follow-up in centre A was 12 months and in centre B was 18 months. The median overall treatment time in centre A was 52 days and in centre B was 61 days. The mean equieffective doses in 2 Gy (EQD2) for high risk target volume (CTVHR) and point A in centre A were 84.59 and 64.5 Gy, respectively. The mean EQD2 for point A in centre B was 78.5 Gy. One patient out of 72 (1.38%) had local recurrence in centre A and five patients out of 89 (5.6%) had local recurrence in centre B. Local control in centre A was 98.6% and in centre B was 94.3%. The local recurrence rate was higher in centre B but it was not statistically significant (p = 0.15). One patient developed brain metastasis in centre B. One patient developed grade 3 proctitis in centre A. A high dose rate brachytherapy fractionation schedule of 6.5 Gy × 4 fractions over 2 days for CTVHR is associated with reduced overall treatment time, a slightly higher local control rate and lesser dose to OARs compared to 9 Gy × 2 fractions given one week apart to point A.


Exposure to Crystal Violet, Its Toxic, Genotoxic and Carcinogenic Effects on Environment and Its Degradation and Detoxification for Environmental Safety.
Crystal Violet (CV), a triphenylmethane dye, has been extensively used in human and veterinary medicine as a biological stain, as a textile dye in textile processing industries and also used to provide a deep violet color to paints and printing ink. CV is also used as a mutagenic and bacteriostatic agent in medical solutions and antimicrobial agent to prevent the fungal growth in poultry feed. Inspite of its many uses, CV has been reported as a recalcitrant dye molecule that persists in environment for a long period and pose toxic effects in environment. It acts as a mitotic poison, potent carcinogen and a potent clastogene promoting tumor growth in some species of fish. Thus, CV is regarded as a biohazard substance. Although, there are several physico-chemical methods such as adsorption, coagulation and ion-pair extraction reported for the removal of CV, but these methods are insufficient for the complete removal of CV from industrial wastewaters and also produce large quantity of sludge containing secondary pollutants. However, biological methods are regarded as cost-effective and eco-friendly for the treatment of industrial wastewaters, but these methods also have certain limitations. Therefore, there is an urgent need to develop such eco-friendly and cost-effective biological treatment methods, which can effectively remove the dye from industrial wastewaters for the safety of environment, as well as human and animal health.


Comparison of tissue artifacts in punch and scalpel biopsies of oral and maxillofacial lesions: A systematic review and meta-analysis.
The aim of this systematic review and meta-analysis was to compare the occurrence of tissue artifacts in punch and scalpel biopsies of oral and maxillofacial lesions. Electronic searches were conducted in four databases (PubMed, Scopus, Web of Science and Ovid). Study selection, data extraction, and quality assessment of the included articles were performed independently by two authors. An evaluation of the strength of the evidence (GRADE) and meta-analysis were conducted. Odds ratio and confidence intervals (CI) were provided. After the removal of duplicates, 466 references were identified. Four studies evaluating artifacts, such as crush, fragmentation, splits, hemorrhage, curling, and orientation artifacts and also those induced by improper surgical removal, were included. Specimens obtained using scalpel biopsy were 2.98 times more likely (CI=1.53-5.80) to present crushes and 12.36 times more likely (CI=2.64-57.83) to present splits than specimens procured using punch biopsy. Scalpel biopsies were also 2.40 times more likely to present fragmentation than punch biopsies (CI=1.01-5.72). No significant differences between scalpel and punch biopsies were found concerning the presence of hemorrhage, curling, or orientation artifacts and those induced by improper surgical removal. After sensitivity analysis, samples obtained from scalpel biopsy were 6.18 times more likely to present hemorrhage than those from a punch biopsy (CI=2.21-17.28). Based on the GRADE evaluation, the confidence in the effect estimate of the sub-group analysis of crush and fragmentation was moderate. For the other subgroup analysis, the confidence was low or very low. Punch biopsies were less likely to produce artifacts, such as crush, fragmentation, splits, and hemorrhage, than biopsies obtained with a scalpel.


Distribution of Gc subtypes in Aragon (north-east Spain).
Group-specific component (Gc) polymorphism was investigated in 559 individuals from Aragon. The gene frequencies were compared to those reported for other European populations.


International Pediatric Otolaryngology group (IPOG) consensus on the diagnosis and management of pediatric obstructive sleep apnea (OSA).
To develop an expert-based consensus of recommendations for the diagnosis and management of pediatric obstructive sleep apnea. A two-iterative Delphi method questionnaire was used to formulate expert recommendations by the members of the International Pediatric Otolaryngology Group (IPOG). Twenty-six members completed the survey. Consensus recommendations (>90% agreement) are formulated for 15 different items related to the clinical evaluation, diagnosis, treatment, postoperative management and follow-up of children with OSA. The recommendations formulated in this IPOG consensus statement may be used along with existing clinical practice guidelines to improve the quality of care and to reduce variation in care for children with OSA.


Novel mechanisms of selenite reduction in Bacillus subtilis 168:Confirmation of multiple-pathway mediated remediation based on transcriptome analysis.
Selenite biotransformation by microorganisms is an effective detoxification and assimilation process. Bacillus subtilis is a probiotic bacterium that can reduce Se(IV) to SeNPs under aerobic conditions. However, current knowledge on the molecular mechanisms of selenite reduction by B. subtilis remains limited. Here, the reduction of Se(IV) by probiotic bacterium Bacillus subtilis 168 was systematically analysed, and the molecular mechanisms of selenium nanoparticle (SeNPs) formation were characterised in detail. B. subtilis 168 reduced 5.0 mM selenite by nearly 40% in 24 h, and the produced SeNPs were spherical and localised intracellularly or extracellularly. FTIR (Fourier transform infrared) spectroscopy suggested the presence of proteins, lipids, and carbohydrates on the surface of the isolated SeNPs. Transcriptome data analysis revealed that the expression of genes associated with the proline metabolism, glutamate metabolism, and sulfite metabolism pathways was significantly up-regulated. Gene mutation and complementation revealed the ability of PutC, GabD, and CysJI to reduce selenite in vivo. In vitro experiments demonstrated that PutC, GabD, and CysJI could catalyse the reduction of Se(IV) under optimal conditions using NADPH as a cofactor. To the best of our knowledge, our study is the first to demonstrate the involvement of PutC and GabD in selenite reduction. Particularly, our findings demonstrated that the reduction of Se(IV) was mediated by multiple pathways both in vivo and in vitro. Our findings thus provide novel insights into the molecular mechanisms of Se(VI) reduction in aerobic bacteria.


Letter to the editor, "Validation and clinical value of the MANAGE-PD tool: A clinician-reported tool to identify Parkinson's disease patients inadequately controlled on oral medications".
The MANAGE-PD tool may help general neurologists in deciding whether a patient with advanced Parkinson's disease should be referred for an advanced therapy. Although the development and clinical validation of MANAGE-PD would appear to serve an important need, we urge the reader to be aware of several methodological concerns.


Sub-chronic exposure to chlorpyrifos induces hematological, metabolic disorders and oxidative stress in rat: attenuation by glutathione.
The current work aimed to investigate the different toxic effects of chlorpyrifos (CPF) in subchronic exposure. Two groups of Sprague-Dawley male rats were exposed to CPF alone in a dose of 30 mg/kg body weight, or CPF dose as previous plus glutathione (GSH) in a dose of 100 mg/kg body weight, for 90 days, twice weekly, orally. Another two groups of rat were given corn oil (control) or GSH. There is a significant decrease in hemoglobin concentration, haematocrit percentage, thrombocytic indices, total protein and albumin levels in CPF-exposed group. CPF induced hyperglycemia and significant increase in total cholesterol, but a significant decrease in triglyceride levels was obtained. A significant increase in the levels of lipid peroxidation was obtained while a significant decrease of the total antioxidant was recorded. The decrease in glycogen content and some histopathological changes were observed in liver after CPF exposure. Furthermore, co-administration of GSH can restore some of these alterations.


Bridging the gap between the Rayleigh and Thomson limits for spheres and spheroids.
An exact transform of the scattering coefficients that removes the m-related refractive-index restrictions of the Rayleigh and Thomson approximations is presented. The resulting series is valid for all m and small x. A similar but approximate transform for spheroids also is presented.


V3S4 Nanosheets Anchored on N, S Co-Doped Graphene with Pseudocapacitive Effect for Fast and Durable Lithium Storage.
Construction of a suitable hybrid structure has been considered an important approach to address the defects of metal sulfide anode materials. V3S4 nanosheets anchored on an N, S co-coped graphene (VS/NSG) aerogel were successfully fabricated by an efficient self-assembled strategy. During the heat treatment process, decomposition, sulfuration and N, S co-doping occurred. This hybrid structure was not only endowed with an enhanced capability to buffer the volume expansion, but also improved electron conductivity as a result of the conductive network that had been constructed. The dominating pseudocapacitive contribution (57.78% at 1 mV s-1) enhanced the electrochemical performance effectively. When serving as anode material for lithium ion batteries, VS/NSG exhibits excellent lithium storage properties, including high rate capacity (480 and 330 mAh g-1 at 5 and 10 A g-1, respectively) and stable cyclic performance (692 mAh g-1 after 400 cycles at 2 A g-1).


[Similarity of pathological alterations in insects during infection by microsporidia, other parasites and under different adverse environmental factors].
Striking resemblance of pathological alterations in the development of insects caused by 1) infection with microsporidia, 2) infection with other parasites, and 3) variety of adverse environmental factors is discussed.


Prime-boost immunization with cruzipain co-administered with MALP-2 triggers a protective immune response able to decrease parasite burden and tissue injury in an experimental Trypanosoma cruzi infection model.
Cruzipain (Cz), a key Trypanosoma cruzi enzyme, is a main candidate antigen for vaccines against Chagas' disease. We evaluated a vaccination protocol based on intradermal priming with recombinant Cz and intranasal boosting with rCz co-administered with a derivative of the TLR2/6 agonist MALP-2. Vaccination triggered strong systemic and mucosal antibody responses, and a vigorous cell-mediated immunity characterized by lymphoproliferation, DTH reactivity and IFN-gamma production. The immune responses protected against a lethal trypomastigote challenge and, upon sub-lethal infection, immunized mice showed reduction of tissue damage and normal enzymatic markers of muscle injury. This prime-boost regimen appears promising for further development, since warranted survival, provided efficient control of parasite load and restricted inflammatory myopathy.


Cathepsin B containing cells in the rabbit mesentery during invasion of V2 carcinoma cells.
Localization of cathepsin B was studied in the rabbit mesentery during invasion of V2 carcinoma cells. Cathepsin B was visualized immunohistochemically by using monospecific sheep antibodies and the avidin-biotin-peroxidase complex (ABC) method. Horizontal and vertical semithin Epon embedded sections of stained mesenteries showed that histiocytes always displayed the strongest staining reaction independently of the presence of V2 carcinoma cells. Fibroblasts, mesothelial cells and the invaded V2 cells were less stained. Strongly stained peritoneal monocytes were frequently found on the surface of the mesentery in association with tumor foxi. The role of these various cathepsin B containing cells with respect to extracellular matrix degradation during tumor invasion in the mesentery is not clear; some aspects of this problem are presented in the discussion.


DNA Damage Signalling and Repair Inhibitors: The Long-Sought-After Achilles' Heel of Cancer.
For decades, radiotherapy and chemotherapy were the two only approaches exploiting DNA repair processes to fight against cancer. Nowadays, cancer therapeutics can be a major challenge when it comes to seeking personalized targeted medicine that is both effective and selective to the malignancy. Over the last decade, the discovery of new targeted therapies against DNA damage signalling and repair has offered the possibility of therapeutic improvements in oncology. In this review, we summarize the current knowledge of DNA damage signalling and repair inhibitors, their molecular and cellular effects, and future therapeutic use.


Existence, uniqueness and regularity of the projection onto differentiable manifolds.
We investigate the maximal open domain E ( M ) on which the orthogonal projection map p onto a subset M ⊆ R d can be defined and study essential properties of p. We prove that if M is a C 1 submanifold of R d satisfying a Lipschitz condition on the tangent spaces, then E ( M ) can be described by a lower semi-continuous function, named frontier function. We show that this frontier function is continuous if M is C 2 or if the topological skeleton of M c is closed and we provide an example showing that the frontier function need not be continuous in general. We demonstrate that, for a C k -submanifold M with k ≥ 2 , the projection map is C k - 1 on E ( M ) , and we obtain a differentiation formula for the projection map which is used to discuss boundedness of its higher order differentials on tubular neighborhoods. A sufficient condition for the inclusion M ⊆ E ( M ) is that M is a C 1 submanifold whose tangent spaces satisfy a local Lipschitz condition. We prove in a new way that this condition is also necessary. More precisely, if M is a topological submanifold with M ⊆ E ( M ) , then M must be C 1 and its tangent spaces satisfy the same local Lipschitz condition. A final section is devoted to highlighting some relations between E ( M ) and the topological skeleton of M c .


Plasma and leukemic cell pharmacokinetics of high-dose N4-behenoyl-1-beta-D-arabinofuranosylcytosine in acute leukemia patients.
The pharmacokinetics of N4-behenoyl-1-beta-D-arabinofuranosylcytosine (BHAC), a lipophilic antitumor analog of 1-beta-D-arabinofuranosylcytosine (ara-C), was investigated, by assay of plasma and leukemic cells of ten acute leukemic patients receiving 60-minute intravenous (IV) infusion of 700 mg/m2 BHAC, for BHAC and 1-beta-D-arabinofuranosylcytosine 5'-triphosphate (ara-CTP) by high-performance liquid chromatography, ara-C by radioimmunoassay, and 1-beta-D-arabinofuranosyluracil (ara-U) by gas chromatography-mass fragmentography. The plasma concentration of BHAC reached a maximum (173.4 +/- 75.3 micrograms/mL) at the end of the infusion and then declined in a biphasic pattern with an initial-phase half-life (t1/2 alpha) of 1.00 +/- .36 hours and a second-phase half-life (t1/2 beta) of 4.28 +/- 2.35 hours. That of ara-C similarly reached a maximum (102.2 +/- 39.9 mg/mL) at the end of the infusion and then declined with t1/2 alpha of 1.37 +/- 1.11 hours and t1/2 beta of 11.2 +/- 4.31 hours. Intracellular ara-CTP concentration increased in a linear-accumulation manner for the first 4 hours after the infusion, reached a maximum of .081 +/- .112 micrograms/10(7) cells at approximately 7 hours, and then declined very slowly in accordance with a one-compartment model with t1/2 of 13.56 +/- 9.62 hours.


Metastatic cervical carcinoma presenting as primary thyroid cancer. Case report.
Secondary neoplasm of the thyroid mimicking a primary thyroid lesion is a very rare finding. A case of squamous and anaplastic cell carcinoma of the uterine cervix metastatic to the thyroid is described.


Comparative evaluation and assessment of the diagnostic usefulness of four commercial HIV-1/HIV-2 antibody assays using two well-characterized serum panels from Blood Transfusion Service and the National Health Laboratory Services in Zimbabwe.
To evaluate four Enzyme Linked Immunosorbent Assay (ELISA) HIV kits for possible use as a combination at the National Health Laboratory Services (NHLS) in Zimbabwe. Laboratory evaluation, sensitivity, specificity and cost effectiveness of HIV diagnostic kits. Blood Transfusion Service (BTS) and Parirenyatwa Hospital in Zimbabwe. A total of 346 samples from 245 patients referred to Parirenyatwa Hospital and 101 blood donors at BTS. The main goal was to come out with the best combination of ELISA kits in terms of sensitivity, specificity and cost effectiveness for use in diagnosis of HIV infection in Zimbabwe. The best combination kit was the Murex/Innotest with 100% sensitivity and 98.9% specificity, being slightly superior to the Genelavia/Vironostika combination kits in current use at NHLS. In addition, the Murex/Innotest combination has the shortest assay running time and requires fewer internal controls thereby increasing the number of test specimens per run. We recommend the use of the Murex/Innotest kits as a suitable combination for HIV infection diagnosis in Zimbabwe. The combination has a relatively low number of discordant results, drastically reducing the cost of running a third confirmatory test to resolve the discordant results. Most importantly, this combination maximizes HIV infection diagnosis by its ability to detect antibodies to HIV-1 groups M and O as well as HIV-2.


Profilin-1 regulates DNA replication forks in a context-dependent fashion by interacting with SNF2H and BOD1L.
DNA replication forks are tightly controlled by a large protein network consisting of well-known core regulators and many accessory factors which remain functionally undefined. In this study, we report previously unknown nuclear functions of the actin-binding factor profilin-1 (PFN1) in DNA replication, which occur in a context-dependent fashion and require its binding to poly-L-proline (PLP)-containing proteins instead of actin. In unperturbed cells, PFN1 increases DNA replication initiation and accelerates fork progression by binding and stimulating the PLP-containing nucleosome remodeler SNF2H. Under replication stress, PFN1/SNF2H increases fork stalling and functionally collaborates with fork reversal enzymes to enable the over-resection of unprotected forks. In addition, PFN1 binds and functionally attenuates the PLP-containing fork protector BODL1 to increase the resection of a subset of stressed forks. Accordingly, raising nuclear PFN1 level decreases genome stability and cell survival during replication stress. Thus, PFN1 is a multi-functional regulator of DNA replication with exploitable anticancer potential.


The use of metallochromic Ca indicators in skeletal muscle.
Absorbance signals recorded with metallochromic indicators in skeletal muscle fibers show rapid time courses that probably closely track the fast kinetic process of Ca++ release and retrapping by the sarcoplasmic reticulum. However, the formation of more than one complex in cuvette calibrations, both for Arsenazo III (ArIII) and Antipyrylazo III (ApIII), suggest that care needs to be taken in the deconvolution of in vivo absorbance signals. Since the kinetic rate constants have not yet been obtained for these probes, attempts to deconvolute absorbance signals should be considered approximate. The evidence suggesting that more than one complex is formed during a skeletal muscle transient with ArIII is more compelling than for the case of ApIII. The differences between the ArIII and ApIII signals may not be readily explained assuming 1:1 dye:Ca complexation and kinetic differences between the probes. Competition for Ca++ with cell Ca buffers and/or multiple complex formation by at least one of these probes needs to be invoked. Based on a simple model to simulate the behavior of the Ca signals in muscle, it may be suggested that an ApIII-like probe would more closely track pCa changes in the fiber than would an ArIII-like probe, which would show more interference with intracellular buffers; an even higher affinity probe would tend to sense the total release of Ca by the SR.


An unusual presentation of prosthetic valve endocarditis: Utility of 3D transillumination rendering.
Prosthetic valve endocarditis is a rare but serious complication of cardiac valve replacement, and echocardiography plays a fundamental role in its diagnosis and management. However, there is not much information about the use of the 3D transillumination rendering in this context. In this report, we present an unusual case of prosthetic valve endocarditis that exemplifies the utility of this new tool.


The role of iodination in the formation of hormone-rich peptides from thyroglobulin.
Reduced thyroglobulins from several animal species contain hormone-rich iodopeptides of 20,000-26,000 and 15,000-18,000 daltons. The present study has investigated the role of iodination in their production. Experimental approaches have included: iodination in vitro of thyroglobulin from rabbit thyroid slices incubated with [3H]leucine and subsequent analysis of 3H distribution by gel electrophoresis; iodination in vitro of low iodine thyroglobulin from a human goiter, followed by isolation of the major iodopeptides and quantitation of their peptide content; and injection of iodine-deficient rats with Na125I and assessment of the distribution of isotope among the iodopeptides at successive time intervals. From these experiments the following general pattern has emerged: 1) at low levels of iodine (less than 5 atoms/molecule of thyroglobulin) in vitro or at short time intervals after iodine administration in vivo (less than 4 h), the principal iodinated component of reduced thyroglobulin is a approximately 230,000-dalton peptide; 2) with moderate increases in iodine (5-40 atoms/molecule) or longer time intervals after administration (greater than or equal to 4 h) there is less of the 230,000-dalton iodopeptide, and an iodothyronine-rich approximately 20,000- to 26,000-dalton iodopeptide appears; 3) at higher levels of iodine (greater than 40 atoms/molecule) the amount of approximately 230,000-dalton iodopeptide decreases further, the amount of 20,000- to 26,000-dalton iodopeptides may decrease, and an iodothyronine-rich 15,000- to 18,000-dalton peptide appears. Progressive iodination gives the same changes in distribution of peptide material among these iodopeptides as it does in iodine distribution, and the changes seen with iodination in vitro are similar to those occurring over time in vivo. We conclude that during the process of iodination discrete peptide bonds of thyroglobulin are cleaved to produce the hormone-rich iodopeptides. This is probably a normal part of thyroglobulin maturation in vivo and may be a necessary event preceding hormone formation.


Clinical strains of Streptococcus agalactiae carry two different variants of pathogenicity island XII.
Streptococcus agalactiae or Group B streptococci (GBS) are a common cause of serious diseases of newborns and adults. GBS pathogenicity largely depends on genes located on the accessory genome including several pathogenicity islands (PAI). The present paper is focused on the structure and molecular epidemiological analysis of one of the GBS pathogenicity islands-the pathogenicity island PAI XII (Glaser et al. Mol Microbiol 45(6):1499-1513, 2002). This PAI was found to be composed of three different mobile genetic elements: a composite transposon (PAI-C), a genomic islet (PAI-B), and a pathogenicity island associated with gene sspB1 (PAI-A). PAI-A in GBS has a homolog--PAI-A1 with similar, but a different genetic constellation. PCR-based analysis of GBS collections from different countries revealed that a strains lineage with PAI-A is less common than PAI-A1 and was determined to be present only among the strains obtained from Russia. Our results suggest that PAI-A and PAI-A1 have the same progenitor, which evolved independently and appeared in the GBS genome as separate genetic events. Results of this study reflect specific geographical distribution of the GBS strains with the mobile genetic element under study.


[Free total skin graft in loss of cutaneous substance of the hand. Apropos of 60 cases].
We report 60 cases of free total skin graft--taken from the corresponding forearm--in loss of cutaneous substances of the hand, following hand injury seen in the emergency room, or after removal of a massive skin tumor. The results were interesting.


G2, G3, and complete basis set calculations on the thermodynamic properties of triazane.
As a follow-up study to our study on tetrazane (N(4)H(6)), we present computed thermodynamic properties of triazane (N(3)H(5)). Calculated properties include optimized geometries, infrared vibrations, enthalpy of formation, enthalpy of combustion, and proton affinities. We have also mapped the potential energy surface as the molecule is rotated about the N-N bond. We have predicted a specific enthalpy of combustion for triazane of about -20 kJ g(-1). Figure Schematic diagram of the dielectric barrier discharge (left) and typical temporal profiles of voltage and current, as obtained from the simulations (right).


Biomimetic design of inhibitors of immune checkpoint LILRB4.
Immune checkpoint inhibitors have become a hot spot in the treatment of acute myeloid leukemia (AML), the most common acute leukemia (blood cancer) in adults. In the present study, molecular insights into the molecular interactions between an immune checkpoint leukocyte immunoglobulin-like receptor b4 (LILRB4) and its mAb h128-3 was explored using molecular dynamics (MD) simulation for the biomimetic design of peptide inhibitor of LILRB4. Both hydrophobic interaction and electrostatic interaction were found favorable for the binding of the mAb h128-3 on LILRB4, and hydrophobic interaction was identified as the main driving force. The key amino acid residues for the binding of mAb h128-3 on LILRB4 were identified as Y93, D94, D106, Y34, S103, W107, Y61, N30, E27, Y33, Y59, W95, S92 through MM-PBSA (molecular mechanics-Poisson-Boltzmann surface area) method. Based on this, an inhibitor library with the sequence of SXDXYXSY (Where X is an arbitrary amino acid residue) were designed. Two peptide inhibitors, SADHYHSY and SVDWYHSY were obtained through screening using molecular docking and MD simulations, and then validated by successful blocking of LILRB4 through the covering of LILRB4 surface by these inhibitors. These results would be helpful for the research and development of therapies for AML.


Pleiotropic effects of moonlighting glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in cancer progression, invasiveness, and metastases.
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) may represent the quintessential example of a moonlighting protein. The latter are a new, intriguing class of cell proteins which exhibit multiple activities in different subcellular locales apart from their initially, well-characterized function. As such, apart from its classical role in energy production, membrane-bound GAPDH is required for membrane fusion, endocytosis and, intriguingly, for iron transport. Cytoplasmic GAPDH regulates mRNA stability and is required for ER to Golgi trafficking. Nuclear GAPDH is involved in apoptosis, transcriptional gene regulation, the maintenance of DNA integrity, as well as nuclear tRNA export. Paradoxically, the etiology of a number of human pathologies is dependent upon GAPDH structure and function. In particular, recent evidence indicates a significant role for moonlighting GAPDH in tumorigenesis. Specifically, these include its role in the survival of tumor cells, in tumor angiogenesis, as well as its control of tumor cell gene expression and posttranscriptional regulation of tumor cell mRNA. Each of these activities correlates with increased tumor progression and, unfortunately, a poor prognosis for the afflicted individual.


Ionization of imidazole in the gas phase, microhydrated environments, and in aqueous solution.
Hydration of neutral and cationic imidazole is studied by means of ab initio and molecular dynamics calculations, and by photoelectron spectroscopy of the neutral species in a liquid microjet. The calculations show the importance of long range solvent polarization and of the difference between the structure of water molecules in the first shell around the neutral vs cationic species for determining vertical and adiabatic ionization potentials. The vertical ionization potential of neutral imidazole of 8.06 eV calculated using a nonequilibrium polarizable continuum model agrees well with the value of 8.26 eV obtained experimentally for an aqueous solution at pH 10.6.


Ectopic pregnancy. Diagnostic and therapeutic algorithms minimizing surgical intervention.
Presented are the results of a diagnostic algorithm for ectopic pregnancy incorporating history, physical examination, quantitative human chorionic gonadotropin (hCG), serum progesterone, color-flow vaginal Doppler sonography and endometrial curettage as well as a treatment algorithm combining expectant, medical and surgical management. These algorithms resulted in: (1) earlier diagnosis of ectopic pregnancy, with fewer ruptured ectopic pregnancies; (2) virtual elimination of diagnostic laparoscopy; (3) elimination of culdocentesis; (4) greater use of methotrexate; and (5) increased use of expectant (i.e., nonsurgical and nonmedical) treatment. These algorithms are potentially applicable in other clinical settings and should be considered for use on at-risk populations or when the diagnosis of ectopic pregnancy is in question.


TNF-related apoptosis-inducing ligand (TRAIL) protects against diabetes and atherosclerosis in Apoe ⁻/⁻ mice.
TNF-related apoptosis-inducing ligand (TRAIL) is implicated in the regulation of diabetes and is reduced in patients with cardiovascular disease. Although TRAIL receptors are widespread, and TRAIL can promote cell proliferation and apoptosis, it is not known how TRAIL might protect against diabetes and atherosclerosis. We examined the development of atherosclerosis and diabetes in Apoe (-/-), Trail (also known as Tnfsf10)( -/- ) Apoe ( -/- ) and Trail ( -/- ) mice that were fed a high-fat diet. Plasma cholesterol, triacylglycerol, glucose and insulin, as well as changes in various metabolic enzymes and regulators were assessed. Glucose and insulin tolerance tests were performed. Pancreatic islets were examined for insulin and beta cell dysfunction (apoptosis and macrophage infiltration). Compared with Apoe ( -/- ) mice, Trail ( -/- ) Apoe ( -/- ) and Trail ( -/- ) mice exhibited several features of diabetes, including increased weight, hyperglycaemia, reduced plasma insulin, impaired glucose tolerance, beta cell dysfunction, reduced islet insulin, macrophage infiltration and increased apoptosis. Trail ( -/- ) Apoe ( -/- ) mice had increased plasma cholesterol, triacylglycerol, and VLDL- and LDL-cholesterol, and increased expression of genes involved in cholesterol synthesis and lipogenesis. Trail ( -/- ) Apoe ( -/- ) mice also had increased atherosclerosis, with several features of plaque instability. We show for the first time that TRAIL deficiency promotes numerous features of diabetes that are typical of human disease, and are associated with reduced insulin and pancreatic inflammation/apoptosis. TRAIL also regulates cholesterol and triacylglycerol homeostasis in Apoe ( -/- ) mice by increasing the expression of genes involved in (1) cholesterol synthesis and absorption, and (2) triacylglycerol production.


Coronary artery abnormalities in children.
Although coronary artery abnormalities are somewhat rare in children, they constitute a population at significant risk for morbidity and/or mortality. The expeditious and accurate diagnosis of these lesions is imperative for optimum management. The ability of two-dimensional and Doppler echocardiography to accurately evaluate coronary artery abnormalities in children will be discussed under three headings: (1) major congenital coronary artery anomalies, (2) coronary artery anomalies associated with specific congenital heart lesions, and (3) acquired coronary artery abnormalities.


Relationship of global assessment of change to AUSCAN and pinch and grip strength among individuals with hand osteoarthritis.
This study assessed the utility and construct validity of a new patient global assessment of symptom change for hand osteoarthritis (OA) by examining its associations with change over time in grip strength, pinch strength, and AUStralian CANadian Osteoarthritis Hand Index (AUSCAN). Participants (N=531, 80% female, mean age=68) were part of a study on the Genetics of Generalized Osteoarthritis (GOGO) and completed two assessments (average 4 years apart). At the second assessment, participants described change in their right and left hand pain, aching, and stiffness on a 15-point scale with descriptors ranging from "Great deal worse" to "Great deal better". Linear regression models examined associations of global change scores with changes in hand strength and AUSCAN, controlling for age, gender, number of hand joints with OA, and time between assessments. Both right and left hand global assessment of change scores were significantly associated with change in AUSCAN, grip strength, and right hand pinch strength (P<0.05), and approached significance for left hand pinch strength (P=0.06). The strongest associations were between global change scores and AUSCAN change (right hand: beta=0.29, P<0.001; left hand: beta=0.27, P<0.001). Associations of change scores with grip and pinch strength were stronger among participants with greater radiographic OA severity at baseline. Results support the validity of this new global assessment of symptom change. This measure is particularly useful for assessing change over time when no baseline data are available. Additional research should examine this measure's responsiveness in the context of clinical trials.


Crystal deposition disease. Diagnosis by electron microscopy.
The diagnosis of gout and pseudogout has traditionally been established by the identification, in synovial fluid, of monosodium urate and calcium pyrophosphate dihydrate crystals with compensated polarizing light microscopy. In this paper the utility of electron microscopy in establishing these diagnosis in two cases, when the conventional means of synovial fluid analysis had failed to do so, is discussed. The application of ultrastructural analysis of synovial fluid increases diagnostic capability in the crystal deposition diseases, and it is recommended for those patients in whom the more usual studies have not established a diagnosis.


Preliminary study on antifertility activity of Calotropis procera roots in female rats.
The effect of ethanolic extract of the roots of Calotropis procera has been studied in albino rats to explore its antifertility and hormonal activities. A strong antiimplantation (inhibition 100%) and uterotropic activity was observed at the dose level of 250 mg/kg (1/4 of LD(50)). No antiestrogenic activity could be detected.


Pore size distributions of ion exchangers and relation to protein binding capacity.
The pore structure of chromatographic media directly influences macromolecular transport and adsorption, and consequently separation resolution and loading capacity in chromatographic separations. The pore size distribution (PSD) is therefore a central structural characteristic of chromatographic materials and a critical determinant of chromatographic behavior. In this work the PSDs of a set of commercial anion exchangers were determined by inverse size-exclusion chromatography (ISEC). The PSDs were further utilized to develop relations to functional properties of adsorbents, such as intraparticle diffusivity, and static and dynamic binding capacities. We find that the detailed PSD is useful in semi-quantitative understanding of chromatographic behavior. However, more accurate prediction of column behavior requires more thorough knowledge of the pore structure, specifically the connectivity of the pore network, as well as improved understanding of the function of grafted resins.


Treating non-ST-segment elevation ACS. Pros and cons of current strategies.
NSTE-ACS is a complex clinical event characterized by a variable degree of myocardial ischemia and triggered, in most patients, by a rupture of a vulnerable plaque that leads to acute intraluminal nonocclusive thrombosis. Traditionally, acute management strategies for NSTE-ACS have been aimed at identification of vascular areas with discrete atheroma and revascularization of the affected myocardium. Studies that have evaluated invasive strategies in NSTE-ACS suggest that the rates of hard clinical events are similar for both intensive medical treatment and early invasive management strategies. As shown recently in the Cooperative Cardiovascular Project study, intensive therapy with beta-blockers appears to be a viable management option that has comparable outcomes in most patients with NSTE-ACS. Although several different treatment strategies have been advocated in the management of NSTE-ACS, the available evidence-based information does not fully support some of these traditional approaches. Future prospective, well-controlled trials are needed to fully ascertain the role of invasive and other medical management strategies in patients with NSTE-ACS. Long-term aggressive management of established risk factors for CAD is unquestionably the most prudent and cost-effective therapeutic approach in the long-term management in patients recovering from NSTE-ACS.


Differential effect of Mn2+ on the hemin-controlled translational repressor and the double-stranded RNA-activated inhibitor.
The inhibition of protein synthesis that occurs when rabbit reticulocyte lysate is incubated in the absence of hemin is due to the activation of a protein kinase termed the hemin-controlled translational repressor, and that occurring when reticulocyte lysate is incubated with a low level of double-stranded RNA is mediated by the activation of a separate protein kinase termed the double-stranded RNA-activated inhibitor. Both the hemin-controlled translational repressor and the double-stranded RNA-activated inhibitor act by phosphorylating the Mr = 35,000 (alpha) subunit of eIF-2. MnCl2 (0.5 mM) partly reverses the inhibition of protein synthesis produced by hemin deficiency but not that induced by double-stranded RNA. In addition, Mn2+ reverses the inhibition of binding of [35S]Met-tRNAf to reticulocyte ribosomal components, isolated on Sepharose 6B, produced by the hemin-controlled translational repressor but not by the double-stranded RNA-activated inhibitor. The effect of Mn2+ is mediated at the level of activation and eIF-2 alpha kinase activity of these two regulatory protein kinases. Specifically, Mn2+ inhibits activation of the hemin-controlled translational repressor in the absence of hemin and the phosphorylation of eIF-2 alpha by pre-activated translational repressor. In contrast, the phosphorylation of eIF-2 alpha by the double-stranded RNA-activated inhibitor is not suppressed by Mn2+, and the activation and autophosphorylation of this inhibitor is enhanced by Mn2+. Finally, while the activation and inactivation of the hemin-controlled translational repressor does not appear to be mediated by autophosphorylation and dephosphorylation, the activation of the double-stranded RNA-activated inhibitor does appear to require autophosphorylation.


Effects of restraint stress and intra-ventral tegmental area injections of morphine and methyl naltrexone on the discriminative stimulus effects of heroin in the rat.
The effect of restraint stress on the discriminative stimulus properties of heroin and the role of the opioid receptor activation in the ventral tegmental area in heroin discrimination were examined. In Experiment 1, male rats were trained to discriminate heroin (0.5 mg/kg, SC) from saline under conditions of exposure to restraint (15 min/day; three times a week) or no stress. Dose-response curves were subsequently determined under conditions of no stress, restraint, corticosterone (3 mg/kg, IP), and saline. Exposure to restraint during training did not alter heroin discrimination under any of the conditions tested. In contrast, administration of restraint or the stress hormone corticosterone just prior to drug injections decreased sensitivity to the heroin cue. In Experiment 2, injections of morphine (5-10 micrograms/side) into the ventral tegmental area (VTA, the cell body region of the mesocorticolimbic dopamine neurons) did not result in heroin-appropriate responding in animals trained to discriminate heroin injected systemically from saline. Furthermore, intra-VTA injections of the opioid antagonist methyl naltrexone (0.75-3.0 micrograms/side) did not block the discriminability of heroin given systemically. These results indicate that exposure to restraint stress or the stress hormone corticosterone in close temporal contiguity to the drug injection may reduce the sensitivity to the opioid cue. In addition, under the condition of the present experiment activation of opioid receptors in the VTA does not appear to mimic the discriminative stimulus effects of systemically administered heroin.


Fibrinogen Sevilla, a congenital dysfibrinogenemia characterized by an abnormal monomer aggregation and a defective plasmin lysis.
A dysfibrinogenemia (fibrinogen Sevilla) was detected in a 64-yr-old woman with no previous history of hemorrhagic diathesis or thrombosis. Thrombin and reptilase times were prolonged. The aggregation of fibrin monomers showed a prolonged latency time with a defective slope although fibrinopeptide release and clot stabilization were found to be normal. Plasmin proteolysis was abnormal with a much slower plasmic degradation in patient's purified fibrinogen. By chromatofocussing the patient's fibrinogen showed an abnormality in pattern elution with a second peak eluting at a pH slightly more basic than the normal one (pH 5.5). Likewise, the isoelectrofocussing of purified non-reduced patient's fibrinogen in agarose gel showed an abnormal distribution in its focussed bands, especially in a group which focussed in a pI-interval between 5.20-5.85. By two-dimensional electrophoresis we did not find any abnormality in the fibrinogen-reduced chains. These results could indicate that the abnormal monomer aggregation, as well as the defective plasmin lysis, could be due to conformational aspects of fibrinogen rather than to structural defects.


Bromalites from the Upper Triassic Polzberg section (Austria); insights into trophic interactions and food chains of the Polzberg palaeobiota.
A rich assemblage of various types of bromalites from the lower Carnian "Konservat-Lagerstätte" from the Reingraben Shales in Polzberg (Northern Calcareous Alps, Lower Austria) is described for the first time in detail. They comprise large regurgitalites consisting of numerous entire shells of ammonoid Austrotrachyceras or their fragments and rare teuthid arm hooks, and buccal cartilage of Phragmoteuthis. Small coprolites composed mainly of fish remains were also found. The size, shape and co-occurrence with vertebrate skeletal remains imply that regurgitalites were likely produced by large durophagous fish (most likely by cartilaginous fish Acrodus). Coprolites, in turn, were likely produced by medium-sized piscivorous actinopterygians. Our findings are consistent with other lines of evidence suggesting that durophagous predation has been intense during the Triassic and that the so-called Mesozoic marine revolution has already started in the early Mesozoic.


Anti-Helicobacter pylori activity of derivatives of the phthalide-containing antibacterial agents spirolaxine methyl ether, CJ-12,954, CJ-13,013, CJ-13,102, CJ-13,104, CJ-13,108 and CJ-13,015.
The naturally occurring phthalide-containing antibiotics spirolaxine methyl ether, CJ-12,954, CJ-13,013, CJ-13,015, CJ-13,102, CJ-13,103, CJ-13,104 and CJ-13,108, have been reported to exhibit anti-H. pylori activity. However, the exact stereochemistry of spirolaxine methyl ether, CJ-12,954 or CJ-13,013, contributing to this observed activity has not been confirmed. The anti-H. pylori activity of several analogues of spirolaxine methyl ether, CJ-12,954 and CJ-13,013 of defined stereochemistry together with the anti-H. pylori activity of several indole analogues of the simpler phthalide-containing antibiotics CJ-13,102, CJ-13,104, CJ-13,108 and CJ-13,015 is reported herein. A 1:1 mixture of spiroacetals 5b and 6b in which the phthalide substituent exhibited (3R)-stereochemistry was sixty times more active than the corresponding 1:1 mixture of spiroacetals with (3S)-stereochemistry. Notably, the unnatural (2''S)-diastereomer of spirolaxine methyl ether exhibited more potent anti-H. pylori activity than the natural product spirolaxine methyl ether. The 4,6-dimethoxyindoles 9, 10, 11 and 13 were all found to be less active than their parent compounds 1, 2, 3 and 4, respectively. Chain-shortened 4,6-dimethoxyindole analogue 12 of CJ-13,108 3 and 4,6-dimethoxyindole-spiroacetal 13 exhibited weak anti-H. pylori activity thus providing future opportunity for drug discovery programs.


Real-world use of ofatumumab to treat multiple sclerosis 9 months post-FDA approval during COVID-19 pandemic.
Relapsing multiple sclerosis (MS) is an inflammatory, demyelinating, neurodegenerative disease of the central nervous system that causes episodes of neurological dysfunction (relapse) alternating with variable intervals of stability. Disease-modifying therapies (DMTs) aim to reduce the rate of relapse and slow disease progression in people with MS, particularly in those with relapsing MS. Ofatumumab is a fully human anti-CD20 monoclonal antibody approved to treat patients with relapsing forms of MS. This study describes the demographics, clinical characteristics, and prior DMT use of patients with at least one ofatumumab prescription claim following approval by the United States (US) Food and Drug Administration (FDA). Understanding ofatumumab utilization patterns and patient characteristics can help define the journey of patients with MS and aid future clinical decision-making. This retrospective study is based on data from IQVIA's Longitudinal Prescription Data (LRx) and Medical Claims (Dx) databases in the US, collected between August 01, 2019 and May 31, 2021. The index date was defined as the date of the first ofatumumab prescription. The pre-index period was defined as the 12 months prior to the index date. Adult patients (aged ≥18 years) with a diagnosis of MS and at least one prescription for ofatumumab between August 2020 and May 2021 in the LRx database were included. Only patients with at least one medical claim in the Dx database and a diagnosis of MS 24 months prior to the index date were included. Descriptive analyses were conducted 3, 6, and 9 months after FDA approval. Overall, 3,600 patients with a prescription for ofatumumab were identified in the LRx claims database, and 2,101 patients remained in the study after inclusion and exclusion criteria had been applied. At the 9-month post-approval time point, patients with ofatumumab claims were characterized as primarily female (74%) and middle-aged (median age: 48 years); two-thirds (64.7%) had a mild MS disability level. Patients were otherwise generally healthy with limited comorbid conditions. Most patients (81.7%) in the study did not experience relapse during the pre-index period. DMT-naïve patients who were prescribed ofatumumab at 3, 6, and 9 months post-approval accounted for 46.9%, 54.8%, and 58.4% of the study population, respectively. Over time, this increase in DMT-naïve ofatumumab initiators was statistically significant (p = 0.0003). Among patients who had been treated with DMTs during the previous year, most had taken them orally (50.6%), some had received them via intravenous infusion (32.2%), and some via subcutaneous/intramuscular injection (21.1%). Intravenous ocrelizumab was the most common DMT switch observed (n = 205, 23.4%) among these patients. This real-world study is the first to describe patients treated with ofatumumab since FDA approval during the COVID-19 pandemic. The majority of patients in this study were middle-aged women with mild MS symptoms. Ofatumumab was increasingly used as a first-line DMT. Additionally, a number of patients aged ≥55 years (beyond the trial population) used ofatumumab, which may suggest expanding clinician confidence in the safety and clinical utility of ofatumumab therapy. However, future long-term observational studies are needed to confirm these results.


An electrochemical biosensor based on network-like DNA nanoprobes for detection of mesenchymal circulating tumor cells.
The identification and detection of mesenchymal circulating tumor cells (mCTCs) is important for early warning of tumor metastasis. The majority of conventional detection methods for CTCs rely on the recognition of epithelial biomarkers, which is technically challenging for detecting CTCs with epithelial-mesenchymal transition (EMT)-induced phenotypic alteration. In this work, we have constructed a label-free biosensor for sensitive electrochemical assay of mCTCs. In our design, the capture probe can recognize the vimentin overexpressed on the surface of mCTCs with high specificity. Meantime, the network-like DNA nanoprobes with multiple G-quadruplex/hemin complexes and multiple cholesterol molecules can be grafted to the cell surface based on the high affinity between cholesterol molecules and cell membrane. Owing to the mimic horseradish peroxidase of G-quadruplex/hemin complexes, strong electrochemical responses will be obtained for sensitive quantification of mCTCs with a detection limit of 8 cell mL-1. Moreover, the biosensor can effectively overcome the interference of vimentin negative cells or secretory vimentin, and realize the recovery tests in whole blood with high accuracy, thereby may further promoting the diagnosis and personalized treatment of cancer in clinic.


Medical cost savings for participants and nonparticipants in health risk assessments, lifestyle management, disease management, depression management, and nurseline in a large financial services corporation.
To compare changes in medical costs between participants and nonparticipants in five different health and productivity management (HPM) programs. Quasi-experimental pre/post intervention study. A large financial services corporation. A cohort population of employees enrolled in medical plans (n = 49,723) [corrected]. A comprehensive HPM program, which addressed health risks, acute and chronic conditions, and psychosocial disorders from 2005 to 2007. Incentives were used to encourage health risk assessment participation in years 2 and 3. Program participation and medical claims data were collected for members at the end of each program year to assess the change in total costs from the baseline period. Analysis . Multivariate analyses for participation categories were conducted comparing baseline versus program year cost differences, controlling for demographics. All participation categories yielded a lower cost increase compared to nonparticipation and a positive return on investment (ROI) for years 2 and 3, resulting in a 2.45∶1 ROI for the combined program years. Medical cost savings exceeded program costs in a wide variety of health and productivity management programs by the second year.


Quantitative and qualitative studies on the major extracellular antigen of Mycobacterium tuberculosis H37Rv and Mycobacterium bovis BCG.
The Mycobacterium tuberculosis antigen 85 is a biologically important antigen. Tuberculosis patients may have strong antibodies against it, and their peripheral blood mononuclear cells respond to it with gamma-interferon production and lymphocyte proliferation. Antigen 85 is actively secreted into the culture medium during culture in vitro and is known to bind human fibronectin. A double-antibody enzyme-linked immunosorbent assay (ELISA) for quantification of antigen 85 is described. A mouse monoclonal antibody, HYT27, was used as capture antibody in the assay. HYT27 was characterized in crossed immunoelectrophoresis and found to bind all three components of the antigen 85 complex. By radioimmunoassay, HYT27 was found to bind equally well to antigens 85A and 85B. In the ELISA assay, a rabbit anti-antigen 85 antiserum was used in the second antibody layer. The specificity of the assay was tested using several different antigen preparations. The purified BCG 85A and 85B components were compared, and there was a 10 times lower sensitivity for antigen 85A due to weaker rabbit antibodies toward this component. The purified components MPT44 and MPT59 from M. tuberculosis H37Rv were compared with the components of BCG and found to correspond to BCG 85A and 85B, respectively. Mycobacterium kansasii and Mycobacterium avium both contained partially identical antigens. Small amounts of antigen 85 were detected in Mycobacterium leprae sonicates. Detecting antigen 85 by sensitive methods may be of great value in the early diagnosis of mycobacterial disease.


Accuracy of visual on-site evaluation (Vose) In predicting the adequacy of Eus-guided fine needle biopsy: A single center prospective study.
Endoscopic ultrasound is the standard procedure for the diagnosis of pancreatic lesions and new needles have been developed to improve tissue acquisition (FNB). Rapid onset evaluation (ROSE) decreases the number of needle passes but is not always available. We introduced an easy and rapid method of direct classification of EUS-FNB sample namely Visual on-site evaluation (VOSE). To assess the accuracy of VOSE in predicting the histological adequacy of specimens. To evaluate the diagnostic power of FNB and the rate of core tissue obtained. Prospective single center study on patients with pancreatic lesions that underwent EUS-FNB. VOSE parameters were presence of blood, macroscopic visible core (MVC), number, color and length of specimen. The association between VOSE tool and histological adequacy was assessed. Fisher's exact test and Student's t-test used to compare categorical and continuous variables. Logistic regression analysis was used to assess association between variables. 99 patients (58.6% male; mean age 68.4 ± 10) enrolled, including 102 lesions. Total number of passes was 358 with median number of 4 (range, 2-4). The 92.7% of samples were adequate and it was higher with the 22-G needle than with 25G (96.5% vs 89.2% p 0.01). VOSE "red-mixed specimen" was associated with a higher probability of histological adequacy (OR 2.39 95% CI 1.03-5.42 p = 0.04). The VOSE tool "red-mixed specimen" can be used to predict the histological adequacy and guide the number of needle passes. Overall, FNB provides a high rate of adequate and diagnostic specimen and high rate of core tissue especially with the 22G needle.


Biochemical pathogenesis of post-traumatic epilepsy.
Head trauma is often followed by epilepsy and may be related to the breakdown of red blood cells and hemoglobin within the CNS. Injection of hemoglobin or iron salts into the rat cortex is known to induce a chronic epileptic focus. We observed the formation of superoxide anion (O2) and hydroxyl radical (.OH) after ferric chloride injection into the rat cerebral cortex and suggest that these radicals, especially .OH, may be responsible for the initiation of lipid peroxidation in neuronal membranes and for the accelerated production of guanidine compounds in the brain, which may in turn lead to epileptogenicity. Then, we found that treatment with epigallocatechin (EGC) or a phosphate diester of vitamins E and C (EPC), which are potent .OH scavengers, significantly inhibited the formation of malondialdehyde and epileptic discharges in the iron-induced epileptic focus.