One-pot synthesis of an organic-inorganic hybrid affinity monolithic column for specific capture of glycoproteins.
An inorganic-organic hybrid affinity monolithic column was synthesized by a novel "one-pot" approach. The resulting hybrid affinity monoliths have potential applications in specific recognition and enrichment of glycoproteins.


Accessory ovary in the utero-ovarian ligament: an incidental finding.
So far, only 21 descriptions of accessory ovary have been reported since 1959. However, the true incidence of this condition is probably underestimated because the pathologic forms (ovarian tumors and endometriosis) are probably more often diagnosed and reported. We report the incident discovery of one right accessory ovary during a laparoscopic tubal sterilization. This accessory ovary was asymptomatic and structurally normal. It was connected serial to the right utero-ovarian ligament and left in situ. There was no other anomaly. Gynaecologic surgeons must be aware of this possibility when removal of the whole ovarian tissue is needed.


Analysis of 2141 pediatric craniopharyngioma admissions in the USA utilizing the Kids' Inpatient Database (KID): predictors of discharge disposition.
To recognize the national trends in management of pediatric craniopharyngioma and to address the significant predictors of discharge disposition. We utilized the Kids' Inpatient Database (KID), a pediatric inpatient sample generated by the Healthcare Cost and Utilization Project (HCUP) triennially from 1997 to 2016. KID contains 2141 pediatric craniopharyngioma admissions. Patient demographics had no effect on discharge disposition. Based on the multivariable logistic regression analysis, we confirmed a significantly higher non-routine discharge rate among patients with hydrocephalus (P = 0.01). Patients who developed diabetes insipidus were at higher risk for non-routine discharge (P = 0.02). Admission of patients to a freestanding children's hospital increased the likelihood of routine discharge (P = 0.001). Hydrocephalus, diabetes insipidus, and admission to a freestanding children's hospital are significant independent predictors of discharge disposition.


Complete opioid transition to sublingual Buprenorphine after abdominal surgery is associated with significant reductions in opioid requirements, but not reduction in hospital length of stay: a retrospective cohort study.
The use of sublingual buprenorphine (SLBup) for acute pain after major abdominal surgery may offer the potential advantages of unique analgesic properties and more reliable absorption during resolving ileus. We hypothesized that complete opioid transition to SLBup rather than oral oxycodone (OOxy) in the early postoperative period after major abdominal surgery would reduce hospital length of stay, and acute pain and total OMEDD (Oral Morphine Equivalent Daily Dose) requirements in the first 24 h from post-parenteral opioid transition. We reviewed 146 patients who had undergone elective and emergency abdominal surgery under our quaternary referral centre's Upper Gastro-Intestinal and Colo-Rectal Surgical Units 6 months before and after the introduction of complete postoperative transition to sublingual buprenorphine, rather than oral oxycodone, in July 2017. Our primary endpoint was 24-hourly post-transition OMEDDs; secondary endpoints were 24-hourly post-transition Mean NRS-11 pain scores on movement (POM) and length of hospital stay (LOS). Univariate analysis and linear multivariate regression analyses were used to quantify effect size and identify surgical, patient & other analgesic factors associated with these outcome measures. Patients transitioning to SLBup had reduced 24-hourly post-transition OMEDD requirements on postoperative day 2 (POD) (26 mg less, p = 0.04) and NRS-11 POM at POD1 (0.7 NRS-11 units less, p = 0.01). When adjusting for patient, surgical and special analgesic factors, SLBup was associated with a similar reduction in OMEDDs (Unstandardised beta-coefficient -26 mg, p = 0.0001), but not NRS-11 POM (p = 0.47) or hospital LOS (p = 0.16). Our change of practice from use of OOxy to SLBup as primary transition opioid from patient-controlled analgesia delivered full opioid agonists was associated with a clinically significant decrease in 24-hourly post-parenteral opioid transition OMEDDs and improved NRS-11 POM, but without an association with hospital LOS after major abdominal surgery. Further prospective randomized work is required to confirm these observed associations and impact on other important patient-centred outcomes.


Does MRI scan acceleration affect power to track brain change?
The Alzheimer's Disease Neuroimaging Initiative recently implemented accelerated T1-weighted structural imaging to reduce scan times. Faster scans may reduce study costs and patient attrition by accommodating people who cannot tolerate long scan sessions. However, little is known about how scan acceleration affects the power to detect longitudinal brain change. Using tensor-based morphometry, no significant difference was detected in numerical summaries of atrophy rates from accelerated and nonaccelerated scans in subgroups of patients with Alzheimer's disease, early or late mild cognitive impairment, or healthy controls over a 6- and 12-month scan interval. Whole-brain voxelwise mapping analyses revealed some apparent regional differences in 6-month atrophy rates when comparing all subjects irrespective of diagnosis (n = 345). No such whole-brain difference was detected for the 12-month scan interval (n = 156). Effect sizes for structural brain changes were not detectably different in accelerated versus nonaccelerated data. Scan acceleration may influence brain measures but has minimal effects on tensor-based morphometry-derived atrophy measures, at least over the 6- and 12-month intervals examined here.


Female sex workers as health educators with men who buy sex: utilising narratives of rationalisations.
This paper reports on findings from an ethnographic study of female sex workers who work in the indoor sex markets in a British city. An unexpected finding was the collective narratives that sex workers construct to rationalise their involvement in the sex industry. Fifty-five respondents who took part in in-depth interviews maintained that prostitution is a useful occupation and function in society. Narratives included providing emotional support to male clients; a service for men who are socially or physically disabled; preventing men having adulterous affairs; and health education, disease prevention and as therapists for sexual dysfunction. This paper evaluates how the latter narrative of sexual health promotion is an example of how sex workers are ideally placed to work as health educators with men who buy sex. Arguing against gender specific sexual health policies, men who buy sex are described as a 'high risk' group who are also a hidden population. Limitations posed by ideological, ethical and practical concerns relating to the specific conditions of the sex industry suggest that this proposal could be partially successful. In conclusion, I suggest the sexual health of the nation and the place of sex workers in society must be considered with regard to recent policy debates on the management of prostitution and the cultural construction of the sex worker.


Key challenges in providing services to people who use drugs: The perspectives of people working in emergency departments and shelters in Atlantic Canada.
Many people who use drugs (PWUD) have multiple health and social needs, and research suggests that this population is increasingly accessing emergency departments (EDs) and shelters for health care and housing. This qualitative study explored the practices of those working in EDs and shelters when providing services to PWUD, with a particular focus on key challenges in service provision. EDs and shelters were conceptualized as 'micro environments' with various components (i.e. social, physical and resource). One-on-one interviews were conducted with 57 individuals working in EDs and shelters in Atlantic Canada. The social, physical and resource environments within some EDs and shelters are key forces in shaping the challenges facing those providing services. For example, the social environments within these settings are focused on acute health care in the case of EDs, and housing in the case of shelters. These mandates do not encompass the complex needs of many PWUD. Resource issues within the wider community (e.g. limited drug treatment spaces) further contribute to the challenges. Structural issues, internal and external to EDs and shelters need to be addressed to reduce the challenges facing many who work in these settings when providing services to PWUD.


Screening blood donors for Plasmodium falciparum malariae. Application of ready-to-use homologous antigens.
Prevention of post-transfusion malaria remains a worrying problem. Until now it was very difficult to obtain homologous antigens, and immunologic methods used to detect malaria were expensive. We tested the ready-to-use Plasmodium falciparum prepared slides using the IFA (indirect fluorescent antibody) test on 866 selected potentially dangerous donors and known malaria cases. We found that it is a simple, quick, reliable and inexpensive method that can be easily used by blood banks and improve blood transfusion safety.


Factors associated with access and approach to esophagectomy for cancer: a National Cancer Database study.
Minimally invasive esophagectomy (MIE) for esophageal cancer has been associated with decreased pain, less blood loss, and shorter hospital stay with comparable survival to open surgery. To date, there is minimal information regarding what factors are associated with access to MIE. The National Cancer Database (NCDB) was used to compare rates of MIE (either robotic or laparoscopic) and open esophagectomy (OE) by demographic and clinical factors. Continuous variables were compared using a linear trend test, and categorical variables were compared using Mantel-Haenszel tests. Binomial regression was performed to examine significant factors after adjusting for confounding variables. There were 18,366 patients included in the analysis. Of all esophagectomies performed in the US, 49% were performed by OE and 51% were performed by MIE. Patients who had undergone MIE were more likely to live in the Eastern US as compared with the Midwest [odds ratio (OR) 1.72; 95% confidence interval (CI) 1.58, 1.88] or the South (OR 1.31; 95% CI 1.19, 1.44). They were also more likely to be treated at an academic center (OR 1.64; 95% CI 1.53, 1.75) rather than a community hospital, and to be of White race as compared with Asian race (OR 1.46; 95% CI 1.10, 1.92). There was not a significant difference in the rates of MIE between White and Black patients (OR 1.12; 95% CI 0.96, 1.32). MIE was more likely with each passing year, and higher TNM stages of cancer were less likely to be treated with MIE (P < 0.001 for all). While MIE is evolving, OE is still considered standard of care with robotic approaches representing a minority of MIE. While there are several factors associated with access to MIE, including race, facility type and geographic location, these factors should be further explored to help increase access to MIE.


Prenatal closure of the ductus arteriosus and maternal ingestion of anthocyanins.
Prenatal closure of the ductus arteriosus (DA) is associated with maternal ingestion of cyclooxygenase inhibitors during pregnancy. We report a case of prenatal DA closure after maternal ingestion of MonaVie, a juice blend containing the cyclooxygenase and nitric oxide synthase inhibitors anthocyanins and proanthocyanidins. A G(2)P(0)Ab(1) woman had an uncomplicated first and second trimester and normal 20-week fetal ultrasound. At 37 weeks, she developed polyhydramnios; a fetal echocardiogram showed right atrial and ventricular (RV) enlargement with RV dysfunction. Immediately after birth, there was pulmonary hypertension by echocardiogram with DA closure, severe RV hypertrophy and dysfunction, and marked right-to-left atrial shunting. Improvement occurred over 3 weeks with the neonate tolerating room air and a follow-up echocardiogram showing minimal atrial shunting and improved RV function. This report shows an association between MonaVie ingestion throughout pregnancy and prenatal DA closure resulting in cardiac dysfunction and pulmonary hypertension at birth.


The distribution of radio-activity in rats given [3H]bishydroxymethyl-1-methylpyrrole and its relationship to that from [3H]synthanecine A bis-N-ethylcarbamate.
The distribution of radioactivity was measured in rats various times after single intravenous doses of tritium-labelled 2,3-bis-hydroxymethyl-1-methylpyrrole (BHMP). Over half the dose was excreted in urine during the first day; less than a seventh this amount was found in the faeces. The level in glandular stomach was much higher than in any other organ and there was evidence that this was related to the acidity of this tissue. With this exception, the radioactivity in other tissues was lower than after an equivalent dose of tritiated synthanecine A bis-N-ethylcarbamate, and that in liver tissue was more easily solubilised than after the latter compound. The results indicate it is unlikely that more than a small amount of free BHMP is released into the bloodstreams of rats given synthanecine A bis-N-ethylcarbamate. When [3H]BHMP is given by stomach tube much radioactivity remains within the gut and there is no exceptional binding to glandular stomach tissue. Whereas the tissue binding as well as chemical and toxicological properties of BHMP are similar to those of dehydroretronecine, the binding properties of synthanecine A bis-N-ethylcarbamate are likely to resemble those of monocrotaline and similar pyrrolizidine alkaloids.


Flexibility in individualized, competency-based workplace curricula with EPAs: Analyzing four cohorts of physician assistants in training.
Entrustable professional activities (EPAs) were introduced as a principle for individualized physician assistant (PA) workplace curricula at the University of Applied Sciences (UAS) Utrecht in 2008. We studied how the focus on EPAs served the competency-based flexibility intention of the program. We analyzed data of those 119 students who enrolled in the program 2010 through 2013, and completed the program before April 2016. We analyzed the number of EPAs per student at start and end of the program, number changed during training and the reasons for change. Data of 101 students were suitable for evaluation. Excluded were 16 students ending the program prematurely and two with study delay. Mean number of EPAs per student at the start was 6.8 (range 4-12) and at the end 6.6 (range 3-13). On average 1.5 EPAs were altered (range 0-13). Reasons included extension of the EPA package during training (n = 10), lack of proficiency at planned moments of summative entrustment decisions (n = 9) and procedures not being suitable for PAs at closer look (n = 6). All changes resulted in a curriculum meeting the school's standards for graduation. The flexibility of the EPA concept enabled changes in the individualized curriculum of students, according to the intended competency-based nature of the educational program.


Radial extracorporeal shock wave reduces myogenic contracture and muscle atrophy via inhibiting NF-κB/HIF-1α signaling pathway in rabbit.
We investigate the underlying biological effects and mechanisms of rESWT on myogenic contracture and muscle atrophy in a rabbit model of extending knee joint contracture. In group control, the knee joint was not fixed. In group I-4w, the knee joint was only fixed for 4 weeks. In groups SR-1 w, SR-2 w, and SR-4 w, the knee joint was fixed for 4 weeks before the rabbits underwent 1, 2, and 4 weeks of self-recovery, respectively. In groups rESWT-1 w, rESWT 2 w, and rESWT-4 w, the knee joint was fixed for 4 weeks before the rabbits underwent 1, 2, and 4 weeks of rESWT, respectively. The myogenic contracture was measured, the cross-sectional area and key protein levels for NF-κB/HIF-1α signaling pathway and myogenic regulatory factors were evaluated. During the recovery period, biological findings showed that the levels of myogenic contracture and muscle atrophy were milder in group rESWT by compared with group SR after 2 weeks. Molecular biological analysis showed that MyoD protein levels in the group rESWT was significantly higher than those in the group SR, and importantly, phospho-NF-κB p65 and HIF-1α protein levels in the group rESWT were significantly lower than those in the group SR at the same time point. This is the first study demonstrated that rESWT has the potential to reduce myogenic contracture and muscle atrophy after long-term immobilization in animal model. It is a possible mechanism that changing the low oxygen environment in skeletal muscle through rESWT may inhibit activation of NF-κB/HIF-1α signaling pathway.


Adaptation of intestinal nutrient transport in health and disease. Part II.
The first part of this review dealt with the physiology of glucose transport with specific emphasis on transporters of the brush border membrane (BBM) and the basolateral membrane (BLM). On the BBM, the sodium (Na)/glucose transporters (SGLT1 and SGLT2), the Na-independent transporter (GLUT5) and on the BLM the hexose transporter (GLUT2) are discussed. The molecular biology of these transporters is also reviewed. In the second part of the review, we discuss the manner in which intestinal adaptation may be modified by alterations in the diet, especially the lipid constituents, and two important examples of intestinal adaptation will be given: diabetes mellitus and inflammatory bowel disease.


Interfacial reaction of intermetallic compounds of ultrasonic-assisted brazed joints between dissimilar alloys of Ti6Al4V and Al4Cu1Mg.
Ultrasonic-assisted brazing of Al4Cu1Mg and Ti6Al4V using Zn-based filler metal (without and with Si) has been investigated. Before brazing, the Ti6Al4V samples were pre-treated by hot-dip aluminizing and ultrasonic dipping in a molten filler metal bath in order to control the formation of intermetallic compounds between the Ti6Al4V samples and the filler metal. The results show that the TiAl(3) phase was formed in the interface between the Ti6Al4V substrate and the aluminized coating. For the Zn-based filler metal without Si, the Ti6Al4V interfacial area of the brazed joint did not change under the effect of the ultrasonic wave, and only consisted of the TiAl(3) phase. For the Zn-based filler metal with Si, the TiAl(3) phase disappeared and a Ti(7)Al(5)Si(12) phase was formed at the interfacial area of the brazed joints under the effect of the ultrasonic wave. Due to the TiAl(3) phase completely changing to a Ti(7)Al(5)Si(12) phase, the morphology of the intermetallic compounds changed from a block-like shape into a lamellar-like structure. The highest shear strength of 138MPa was obtained from the brazed joint free of the block-like TiAl(3) phase.


Representations of stem cell clinics on Twitter.
The practice of travelling abroad to receive unproven and unregulated stem cell treatments has become an increasingly problematic global phenomenon known as 'stem cell tourism'. In this paper, we examine representations of nine major clinics and providers of such treatments on the microblogging network Twitter. We collected and conducted a content analysis of Twitter posts (n = 363) by these establishments and by other users mentioning them, focusing specifically on marketing claims about treatment procedures and outcomes, discussions of safety and efficacy of stem cell transplants, and specific representations of patients' experiences. Our analysis has shown that there were explicit claims or suggestions of benefits associated with unproven stem cell treatments in approximately one third of the tweets and that patients' experiences, whenever referenced, were presented as invariably positive and as testimonials about the efficacy of stem cell transplants. Furthermore, the results indicated that the tone of most tweets (60.2 %) was overwhelmingly positive and there were rarely critical discussions about significant health risks associated with unproven stem cell therapies. When placed in the context of past research on the problems associated with the marketing of unproven stem cell therapies, this analysis of representations on Twitter suggests that discussions in social media have also remained largely uncritical of the stem cell tourism phenomenon, with inaccurate representations of risks and benefits for patients.


Evaluation of efficacy and safety of intradermal delivery of vaccines through microneedle(s) in human beings: a protocol for a systematic review.
Microneedles are defined as micron-sized projections with an insertion length ranging from 20 to 1500 μm and an external diameter up to 300 μm. Medications administered through microneedles diffuse through the deeper layers of the skin, into the systemic circulation, with minimal stimulation of pain-sensitive nerve endings. The rich presence of dendritic cells in the dermis makes microneedle-based vaccine delivery an attractive option. This systematic review will evaluate the efficacy and safety of intradermal delivery of vaccines using microneedles, in human beings. We will search the following databases for studies reporting the efficacy and/or safety of intradermal delivery of vaccines using microneedles: Epistemonikos and the Cochrane Library for systematic reviews and MEDLINE (through PubMed), EMBASE, Cochrane CENTRAL, LIVIVO, Web of Science, Scopus and CINAHL databases for primary studies. We will also search grey literature databases and hand search reference lists of relevant studies. We will include randomised and quasi-randomised trials in human beings (any age), using microneedles (any material, length or bore) to deliver vaccines intradermally, wherein outcomes reflecting efficacy, safety, pain responses, participant satisfaction or cost are reported. We will additionally include non-randomised observational studies for long-term safety outcomes that are not reported in trials. Eligibility for inclusion will be independently determined by two reviewers. The risk of bias of the included studies will be assessed using the Cochrane RoB2 Tool (for randomised trials) and Newcastle-Ottawa Scale (for other study designs). Data on efficacy and safety will be pooled through meta-analysis (where feasible). We will explore the heterogeneity amongst randomised trials, using the Higgins and Thompson I2 method. We will undertake sensitivity analysis to explore the impact of study quality and subgroup analysis based on the age of participants, length of microneedle and vaccine dosage. The GRADE approach will be used to estimate the confidence in the evidence. This is a protocol for a systematic review; hence, there are no results at this stage. The proposed systematic review will provide evidence on efficacy, safety, pain responses, participant acceptability and cost in human beings (adults and children) for vaccines administered through the intradermal route using microneedles. Since intradermal injections using microneedles are associated with less pain due to their short lengths and narrow bores, we anticipate that delivery of vaccine antigens using this method could be a safe, efficacious and less painful alternative compared with conventional injections using hypodermic needles. The evidence in this review will be useful for policymakers, vaccine manufacturers and healthcare providers to consider this approach for the vaccination of infants and children in routine immunisation programmes. Therefore, we plan to disseminate the review through a peer-reviewed journal publication and will also provide data that cannot be included in the published version to anyone upon reasonable request. PROSPERO CRD42020213608.


Interactions between fecal gut microbiome, enteric pathogens, and energy regulating hormones among acutely malnourished rural Gambian children.
The specific roles that gut microbiota, known pathogens, and host energy-regulating hormones play in the pathogenesis of non-edematous severe acute malnutrition (marasmus SAM) and moderate acute malnutrition (MAM) during outpatient nutritional rehabilitation are yet to be explored. We applied an ensemble of sample-specific (intra- and inter-modality) association networks to gain deeper insights into the pathogenesis of acute malnutrition and its severity among children under 5 years of age in rural Gambia, where marasmus SAM is most prevalent. Children with marasmus SAM have distinct microbiome characteristics and biologically-relevant multimodal biomarkers not observed among children with moderate acute malnutrition. Marasmus SAM was characterized by lower microbial richness and biomass, significant enrichments in Enterobacteriaceae, altered interactions between specific Enterobacteriaceae and key energy regulating hormones and their receptors. Our findings suggest that marasmus SAM is characterized by the collapse of a complex system with nested interactions and key associations between the gut microbiome, enteric pathogens, and energy regulating hormones. Further exploration of these systems will help inform innovative preventive and therapeutic interventions. The work was supported by the UK Medical Research Council (MRC; MC-A760-5QX00) and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreement; Bill and Melinda Gates Foundation (OPP 1066932) and the National Institute of Medical Research (NIMR), UK. This network analysis was supported by NIH U54GH009824 [CLD] and NSF OCE-1558453 [CLD].


Silver nanoparticles in denture adhesive: An antimicrobial approach against Candida albicans.
To evaluate the antimicrobial potential of silver nanoparticles (Ag NPs) synthesized using three different routes (ultraviolet light, Turkevich, and green chemistry method using Glycine max extract) associated with COREGA® denture powder adhesive. Heat-cured acrylic resin specimens were treated with different Ag NPs associated with the adhesive (AD + Ag UV, AD + Ag Turk, and AD + Ag Gm groups). As controls, the specimens were treated with a combination of adhesive and nystatin (AD + Nyst group), only adhesive (AD group), or submerged on the surface of the specimens (PBS group). After the treatments, biofilms of C. albicans developed for 3, 6, and 12 h on the specimen surfaces. The biofilm was quantified using colony-forming units per milliliter, colorimetric assay, and confocal laser scanning microscopy. Regardless of the period, we observed an inhibition of fungal load and a reduction in metabolic activity and biofilm mass in the resin specimens treated with the combinations AD/Ag NPs, compared to AD and PBS. The antimicrobial action of the AD + Turk and AD + Ag Gm groups was similar than that for the AD + Nyst group in all periods and viability tests, except for the biofilm mass (12 h). The COREGA® adhesive with Ag NPs, mainly those synthesized using the Turkevich and Glycine max methods, showed excellent antimicrobial activity against C. albicans biofilms, maintained for up to 12 h. The association of Ag NPs to the adhesive can add preventive or therapeutic effects against denture stomatitis, to this prosthetic material.


Impact of COVID-19 Pandemic on Training and Well-Being in Radiology Residency: A National Survey of Diagnostic Radiology Trainees in Saudi Arabia.
To understand and report the perceived impact of the COVID-19 pandemic on radiology residents in Saudi Arabia with respect to their education, clinical activities, and personal well-being. The survey questionnaire was designed by a team of experts based on a review of the literature and was distributed electronically through the Saudi Commission for Health Specialties to residents registered in all radiology residency training programs in Saudi Arabia during the academic year 2019 to 2020. Categorical variables were presented as counts and percentage. Numerical variables were presented as mean and standard deviation if normally distributed. Chi-square testing was used to compare categorical variables with the perceived impact of the COVID-19 pandemic. Spearman correlation was used to correlate numerical variables at the level of significance p-value < 0.05. A total of 109 residents completed the online survey during the study period, with a response rate of 32.2% (109/337). The mean age was 27.3 years (standard deviation, 1.86). The majority of respondents (71.5%, 78/109) reported either a severe or moderate negative impact on educational activities. Also, the majority (73.4%, 80/109) reported either a minimal or moderate negative impact on clinical activities. Residents training in the western province perceived a statistically higher negative impact on educational activities compared to their peers in other regions (p = 0.01). Residents in their second year of residency training perceived a statistically higher negative impact on their participation in clinical activities (p = 0.014). Less than half of the respondents (45.9%, 50/109) reported that they were redeployed to work in another department. The majority (80%, 40/50) reported a negative impact on their well-being. The majority of radiology residents in Saudi Arabia reported a negative impact of the COVID-19 pandemic on their education, clinical activities, and personal well-being. Our study also identified and explored some of the innovative solutions and strategies implemented by the training programs and the SCFHS to mitigate the negative effects on trainees.


Geographic Targeting and Normative Frames: Revisiting the Equity of Conditional Cash Transfer Program Distribution in Bolivia, Colombia, Ecuador, and Peru.
Four Andean countries of Bolivia, Colombia, Ecuador, and Peru introduced national health-focused conditional cash transfer (CCT) programs in the 2000s. This study probes whether policymakers in these countries targeted CCT programs to subregions with the highest prevalence of ill-health or those with the lowest socioeconomic status (SES) to evaluate the equity of geographic targeting and means-testing, as well as the potential role of normative frames, bounded rationality, and clientelism as explanatory mechanisms for inequities in social spending. The distribution of vaccination coverage, underweight, stunting, and child deaths is established both within and between subnational regions and SES quintiles from 1998 to 2012 using every available nationally representative household survey. The equity of CCT program targeting and strength of association with subregional SES and health outcomes are measured using generalized entropy index decomposition and meta-regression. Finally, simple predictive models for CCT targeting are created using lagged subregional SES, health outcomes, and concentration indices. Bolivia and Peru both effectively targeted at-risk subregions, but subregions in Peru with no CCT program coverage result in higher mistargeting rates for the country as a whole. Only Bolivia failed to attain CCT coverage concentration indices that are at least as large as the health inequalities they are targeting. Despite this insufficient progressivity, Bolivia has the most efficient subregional targeting, while the lowest rates of mistargeting for child deaths are found in Colombia and Ecuador. Finally, the simple predictive model performs as well or better than observed CCT coverage distribution for every country, year, and outcome. Both Peru and Ecuador have targeted programs to their poorest populations effectively, demonstrating that this is possible with both universal and geographic targeting. No clear evidence of clientelism was found, while the dominant normative frame underlying CCT program targeting decisions appears to be the relative SES of subregions, rather than absolute SES, prevalence of health outcomes, or health inequalities. To reduce the inequitable impacts of bounded rationality, policymakers can use simple predictive models to target CCT coverage effectively and without leaving behind the most vulnerable populations that happen to live in more affluent subregions.


Ankle and Pantalar Arthrodesis: End-Stage Salvage in Cavus Foot.
Bony alignment is the primary goal in foot and ankle reconstruction of the cavovarus foot. This condition presents as a malalignment causing a medial overload of the ankle articular surface and lateral overload of the hindfoot, midfoot, and forefoot. A painful gait associated with articular degeneration of the numerous joints can lead to a chronic and rigid arthrosis of joints, warranting arthrodesis of the affected joints accordingly.


A screen for regulators of survival of motor neuron protein levels.
The motor neuron disease spinal muscular atrophy (SMA) results from mutations that lead to low levels of the ubiquitously expressed protein survival of motor neuron (SMN). An ever-increasing collection of data suggests that therapeutics that elevate SMN may be effective in treating SMA. We executed an image-based screen of annotated chemical libraries and discovered several classes of compounds that were able to increase cellular SMN. Among the most important was the RTK-PI3K-AKT-GSK-3 signaling cascade. Chemical inhibitors of glycogen synthase kinase 3 (GSK-3) and short hairpin RNAs (shRNAs) directed against this target elevated SMN levels primarily by stabilizing the protein. It was particularly notable that GSK-3 chemical inhibitors were also effective in motor neurons, not only in elevating SMN levels, but also in blocking the death that was produced when SMN was acutely reduced by an SMN-specific shRNA. Thus, we have established a screen capable of detecting drug-like compounds that correct the main phenotypic change underlying SMA.


Animal models of human genetic diseases: do they need to be faithful to be useful?
With the advances in molecular genetics, animal models of human diseases are becoming more numerous and more refined every year. Despite this, one must recognize that they generally do not faithfully and comprehensively mimic the homologous human disease. Faced with these imperfections, some geneticists believe that these models are of little value, while for others, on the contrary, they are important tools. We agree with this second statement, and in this review, we examine the reasons that may explain the observed differences and suggest means to circumvent or even exploit them. Our opinion is that animal models should be regarded more as tools capable of answering specific questions rather than mere replicas, at a smaller scale, of a given human disease. Far from disappointing they are probably called for a promising future.


Acute toxicity evaluation of the plant molluscicide, Apodytes dimidiata (Icacinaceae), to Eisenia fetida (Oligochaeta) and Oreochromis mossambicus (Cichlidae) in South Africa.
The crude aqueous leaf extract of a South African tree, Apodytes dimidiata, has been identified as a potential molluscicide for snail control in anti-schistosomiasis programmes in rural communities. Before preliminary field trials could be implemented its acute toxic effects on two non-target organisms were examined in accordance with the OECD guidelines to identify any potential hazards that might arise from the plant's use. Laboratory results showed that working molluscicidal concentrations of the plant extract were non-toxic to earthworms suggesting that it is non-hazardous to soil-dwelling fauna. The plant extract proved toxic to fish and was assigned the risk phrase 'harmful to the aquatic environment' according to the EEC classification scheme. Based on these toxicity evaluations, aqueous extracts of A. dimidiata are considered safe for use in preliminary field trials.


Risk factors for osteoporosis after renal transplantation and effect of vitamin D receptor Bsm I polymorphism.
Rapid loss of vertebral or hip mineral density after renal transplantation is a major complication which occurs within 6-12 months. The aim of this study was to evaluate risk factors contributing to bone disease in the early stage after renal transplantation and the effect of vitamin D receptor (VDR) gene polymorphisms. We prospectively followed for up to 12 months 44 patients (29 men and 15 women) with end-stage renal disease who underwent kidney transplantation. All patients received prednisone with either cyclosporine (CsA)/mycophenolate mofetil (MMF) or tacrolimus (Tac)/MMF therapy. Spine, hip, and whole body bone mineral density (BMD) was measured at 12 months after transplantation. According to World Health Organization recommendations, our patients were categorized as normal, osteopenic, or osteoporotic BMD levels. VDR alleles were genotyped as BB, Bb, or bb by polymerase chain reactions based on polymorphism at the Bsm I restriction site. Forty-six percent of patients were normal, 43% osteopenic, and 11% osteoporotic. Significant risk factors for osteoporosis among renal transplant recipients were younger age and pretransplant high intact parathyroid hormone (iPTH) levels. (P values .045 and .027, respectively). According to polymorphic group categorization, posttransplant serum Ca was significantly higher in patients with BB or Bb genotype than in those with bb genotype (P = .012). Although there was no statistical significance regarding iPTH levels, it was higher among Bb+BB than the bb genotype group. Also, first-year BMD analysis after transplantation according to Bsm I polymorphism showed significant differences in femur BMD levels according to the dual classification of polymorphism (P < .05). The BMD levels in the bb group was higher than in the Bb+BB group. Although high pretransplant iPTH levels and younger age enhanced posttransplant bone loss, functionally different alleles of the VDR gene may modulate bone turnover during the first year after renal transplantation.


A socio-economic optimization model for blood supply chain network design during the COVID-19 pandemic: An interactive possibilistic programming approach for a real case study.
In uncertain circumstances like the COVID-19 pandemic, designing an efficient Blood Supply Chain Network (BSCN) is crucial. This study tries to optimally configure a multi-echelon BSCN under uncertainty of demand, capacity, and blood disposal rates. The supply chain comprises blood donors, collection facilities, blood banks, regional hospitals, and consumption points. A novel bi-objective Mixed-Integer Linear Programming (MILP) model is suggested to formulate the problem which aims to minimize network costs and maximize job opportunities while considering the adverse effects of the pandemic. Interactive possibilistic programming is then utilized to optimally treat the problem with respect to the special conditions of the pandemic. In contrast to previous studies, we incorporated socio-economic factors and COVID-19 impact into the BSCN design. To validate the developed methodology, a real case study of a Blood Supply Chain (BSC) is analyzed, along with sensitivity analyses of the main parameters. According to the obtained results, the suggested approach can simultaneously handle the bi-objectiveness and uncertainty of the model while finding the optimal number of facilities to satisfy the uncertain demand, blood flow between supply chain echelons, network cost, and the number of jobs created.


Corticosteroids suppress ectopic neural discharge originating in experimental neuromas.
Some injured sensory fibers ending in an experimental neuroma in the rat sciatic nerve discharge spontaneously. Furthermore, many become sensitive to a range of physical and chemical stimuli. The resulting afferent barrage is thought to contribute to paresthesias and pain associated with peripheral nerve injury. We report that the development of such ectopic neuroma discharge is largely prevented when the freshly cut nerve end is treated with any of 3 commercially available corticosteroid preparations including two in depot form, triamcinolone hexacetonide (Lederspan) and triamcinolone diacetate (Ledercort), and one in soluble form, dexamethasone (Dexacort). These corticosteroids also produce a rapid and prolonged suppression of ongoing discharge in chronic neuromas that have already become active. The kinetics of corticosteroid suppression of neuroma discharge suggest a direct membrane action rather than an anti-inflammatory action.


Effect of Schneiderian membrane integrity on bone formation in sinus augmentation: An experimental study in rabbits.
To assess the effect of Schneiderian membrane (SM) perforation on bone formation by applying a particulate deproteinized bovine bone mineral (PBBM). Bilateral sinus augmentation was performed in eight rabbits. The same amount of PBBM was placed at a sinus where the SM was intentionally perforated for the perforation group (standardized to 3 mm diameter) and the other sinus with an intact SM that served as the intact group. At 12 weeks, all animals were euthanized for radiographic and histomorphometric analyses. The area of the newly formed bone in the perforation group was significantly less than that in the intact group (18.7% and 25.5%, respectively, p = .028). The newly formed bone in the area close to the perforated SM was significantly less than that in the intact group (18.7% and 26.1%, respectively, p < .05). However, there was no significant difference in the total augmented area (p = .234) and the total augmented volume (p = .382) between the two groups. SM perforation had an adverse effect on new bone formation, predominantly close to the area of membrane perforation. However, no significant difference was found in the total augmented volume between the SM perforation and the intact groups.


Persisting impairment following Rocky Mountain Spotted Fever: a case report.
A patient initially presented in the emergency room with fever, confusion, and a petechial rash. Rocky Mountain Spotted Fever (RMSF) was diagnosed and appropriate treatment was initiated. He subsequently became obtunded and required mechanical ventilation and temporary cardiac pacing. Four weeks later, he presented to our rehabilitation unit with ataxia, hyperreflexia and upper motor neuron signs, dysesthesias, sensorimotor axonopathy demonstrated by electrodiagnostic studies, and a global decrement in cognitive capability. Although he significantly improved in functional mobility and self-care, he exhibited little improvement in his cognitive impairment at 6-month follow-up. An understanding of the natural history of, and long-term impairments associated with, RMSF will be helpful to physiatrists in developing rehabilitation care plans and in assisting such patients with community re-entry.


Influence of adjacent teeth on the accuracy of intraoral scanning systems for class II inlay preparation.
This study aimed to evaluate the influence of the presence of adjacent teeth on the accuracy of intraoral scanning (IOS) systems for class II inlay preparation. The mesio-occlusal inlay preparation was prepared in an anatomical model of the maxillary molar. The prepared tooth was secured to a typodont with the mesial adjacent tooth removed or in situ. Ten digital impressions of the inlay preparation were acquired using three IOS systems (CEREC Primescan, 3Shape TRIOS 3, and Medit i500). A laboratory scanner (3Shape E3) was used to obtain the reference scan data. The mean absolute deviation values were calculated to evaluate the accuracy of the digital models. The group with the adjacent teeth present showed lower trueness and precision compared to that without the adjacent tooth (p < .05). Significant differences were observed among the IOS systems (p < .05). Primescan showed the highest accuracy, irrespective of the presence of adjacent teeth. The presence of the adjacent tooth negatively affected the accuracy of all the IOSs tested. Although the performance of Primescan was superior to that of TRIOS 3 and i500, each IOS system showed clinically acceptable levels of accuracy for class II inlay preparation. The adjacent tooth can be a confounding factor for accurate digital impressions of class II inlay preparation.


Requirements for veterinary research and the recruitment of veterinary surgeons into research.
Veterinary science plays a crucial role in society and it is important that veterinarians are involved. However, there are concerns about a growing gap in the quality of veterinary science compared with other biomedical sciences, and about falling recruitment of veterinarians into research. Andrea Nolan and Massimo Palmarini, on behalf of the rcvs Research Subcommittee, discuss these concerns and the steps being taken to encourage more veterinary graduates into a career in research.


Determinism, well-posedness, and applications of the ultrahyperbolic wave equation in spacekime.
Spatiotemporal dynamics of many natural processes, such as elasticity, heat propagation, sound waves, and fluid flows are often modeled using partial differential equations (PDEs). Certain types of PDEs have closed-form analytical solutions, some permit only numerical solutions, some require appropriate initial and boundary conditions, and others may not have stable, global, or even well-posed solutions. In this paper, we focus on one-specific type of second-order PDE - the ultrahyperbolic wave equation in multiple time dimensions. We demonstrate the wave equation solutions in complex time (kime) and show examples of the Cauchy initial value problem in space-kime. We extend the classical formulation of the dynamics of the wave equation with respect to positive real longitudinal time. The solutions to the Cauchy boundary value problem in multiple time dimensions are derived in Cartesian, polar, and spherical coordinates. These include both bounded and unbounded spatial domains. Some example solutions are shown in the main text with additional web-based dynamic illustrations of the wave equation solutions in space-kime shown in the appendix. Solving PDEs in complex time has direct connections to data science, where solving under-determined linear modeling problems or specifying the initial conditions on limited spatial dimensions may be insufficient to forecast, classify, or predict a prospective value of a parameter or a statistical model. This approach extends the notion of data observations, anchored at ordered longitudinal events, to complex time, where observables need not follow a strict positive-real structural arrangement, but instead could traverse the entire kime plane.


Periarticular calcifications.
Periarticular calcification and ossification is a frequent finding on imaging and may sometimes pose a diagnostic challenge. The differential diagnoses for this radiological finding are wide and can be classified into broad groups such as idiopathic, developmental, trauma, burns, infection, tumor, connective tissue disease, crystalline, metabolic, vascular, and foreign bodies. With careful consideration of the clinical and imaging findings as well as awareness of mimickers of periarticular mineralization, the list of differential diagnoses can be narrowed down. This article aims to review the clinical-radiologic findings of periarticular calcified or ossified lesions with relevant imaging illustrations.


Adolescent and young adult brain tumors: current topics and review.
The management of brain tumors developed in adolescents and young adults (AYAs) is challenging because of their histological heterogeneity and low incidence. The brain tumor and its treatment interventions can negatively affect neurological, neurocognitive, and endocrinological function, and dramatically affect the circumstances of AYA patients progressing to further education, employment, and marriage. Specific support is thus necessary to maintain the quality of life (QOL) of AYA brain tumor patients. AYA patients and survivors require active intervention and support for returning to school or work, progressing to further education, finding employment, and preserving fertility. Recent cancer genome profiling revealed that AYA gliomas include pediatric- and adult-type genetic alteration. Insights into the biology underlying the distribution of tumors in AYAs may influence the development of prospective trials. A more individualized view of brain tumors may influence stratification of patients' in future clinical studies as well as selection for molecular targeted therapy. Here I review strategies for achieving a better outcome to decrease late effects and improve QOL.


Patients with chronic kidney disease are at an elevated risk of dementia: a population-based cohort study in Taiwan.
Chronic kidney disease (CKD) is more prevalent in Taiwan than in most countries. This population-based cohort study evaluated the dementia risk associated with CKD. Using claims data of 1,000,000 insured residents covered in the universal health insurance of Taiwan, we selected 37049 adults with CKD newly diagnosed from 2000-2006 as the CKD cohort. We also randomly selected 74098 persons free from CKD and other kidney diseases, frequency matched with age, sex and the date of CKD diagnosed. Incidence and hazard ratios (HRs) of dementia were evaluated by the end of 2009. Subjects in the CKD cohort were more prevalent with comorbidities than those in the non-CKD cohort (p <0.0001). The dementia incidence was higher in the CKD cohort than in the non-CKD cohort (9.30 vs. 5.55 per 1,000 person-years), with an overall HR of 1.41 (95% confidence interval (CI), 1.32-1.50), controlling for sex, age, comorbidities and medicaitions. The risk was similar in men and women but increased sharply with age to an HR of 133 (95% CI, 68.9-256) for the elderly. However, the age-specific CKD cohort to non-CKD cohort incidence rate ratio decreased with age, with the highest ratio of 16.0 (95% CI, 2.00-128) in the youngest group. Among comorbidities and medications, alcoholism and taking benzodiazepines were also associated with dementia with elevated adjusted HRs of 3.05 (95% CI 2.17-4.28) and 1.23 (95% CI 1.14-1.32), respectively. Patients with CKD could have an elevated dementia risk. CKD patients with comorbidity deserve attention to prevent dementia.


Prenatal diagnosis of the megacystis-megaureter association.
A total of 11 male neonates with hydronephrosis and a large bladder in utero had the megacystis-megaureter association. Prenatal ultrasound findings included bilateral hydroureteronephrosis; a large, smooth, thin-walled bladder, and normal volume of amniotic fluid. Postnatal studies demonstrated grades 4 to 5 bilateral reflux, a large bladder without obstruction and in 2 infants nonfunction of a kidney or renal moiety. Of 7 infants initially managed nonoperatively 5 have undergone surgery due to persistent reflux or breakthrough urinary infections. The prenatal diagnosis of the megacystis-megaureter association can be suspected with reasonable accuracy. Prompt postnatal continuous antibiotic prophylaxis and uroradiological confirmation allow for nonemergency management of this condition with excellent results.


An alternative method for purifying and detoxifying diphtheria toxin.
Infections caused by Corynebacterium diphtheriae frequently induce situations in which very small doses of antigens injected intradermally can cause strong inflammatory reactions. This bacterium secretes the diphtheria toxin (DT), a virulence factor that can be lethal to the human organism at doses below 0.1 μg/kg of body weight. The present work proposes alternative methods of DT purification using affinity chromatography and of DT detoxification through conjugating with the polymer methoxypolyethylene glycol activated (mPEG). Tests were performed to evaluate: the formation of edemas and the presence of dermonecrotic activity, in vitro cytotoxicity to Vero cells, the neutralizing activity of serum from guinea pigs immunized with the diphtheria toxoid inactivated with mPEG, and the immunogenic activity of the purified and modified toxin. The results indicated that purification with Blue Sepharose was an efficient method, yielding antigen purity equivalent to 2600 Lf/mg of protein nitrogen. The modification of the Purified Toxin with mPEG did not result in the formation of edema or necrosis although it was immunogenic and stimulated the formation of antibodies that could neutralize the Purified Toxin. The toxoid obtained from the purified toxin maintained its immunogenic characteristics, inducing antibodies with neutralizing activity; edema and necrosis were still observed, however.


Heterotopic gastrointestinal cyst of the oral cavity.
A case of an oral heterotopic gastrointestinal cyst of the tongue is described and a review of the literature is presented. The oral gastrointestinal cyst is a developmental lesion found more commonly in males, with a wide age range, but mostly occurring in the young. It presents as an asymptomatic swelling and most likely arises from misplaced embryonal tissue. Conservative surgical excision is the treatment of choice and no recurrence is expected.


Transmanubrial osteomuscular sparing approach for lung cancer invading the anterior part of the thoracic inlet.
Standard treatment for lung cancer presenting as a superior sulcus tumor is induction chemoradiotherapy followed by surgery, which yields rates of about 70% complete resection and 50% 5-year survival rate. However, the surgical technique to achieve complete resection for superior sulcus tumor invading major anatomical sites including the subclavian artery is challenging. The anterior transcervical thoracic approach applied by Dartevelle and colleagues provides excellent exposure of the subclavian vessels. Grunenwald and associates have improved on this approach to preserve the clavicle and sternoclavicular joint. We applied the transmanubrial osteomuscular-sparing approach in two patients. In both cases, exposure of the subclavian vessels was excellent. In one case, the subclavian artery was resected and reconstructed with a polytetrafl uoroethylene graft. This patient has continued to show recurrence-free survival for more than 5 years. We outline our experience and review the literature on the surgical approach for superior sulcus tumor invading the anterior part of the thoracic inlet.


Pain relief in infants after major surgery: a descriptive study.
Twenty subjects (nurses or parents) were interviewed concerning postoperative pain and pain relief in infants. Details of postoperative analgesics given were obtained from hospital records of 32 infants, aged 0 to 12 months, who had undergone major surgery, and routines for postoperative pain relief in infants were investigated at four Swedish hospitals where major surgery is performed on infants. Although both nurses and parents were found to be able to recognize postoperative pain reactions in infants, attitudes to pain relief were not uniform. In principle, postoperative pain relief is given "as required," although both dosage and intervals between doses are arbitrary.


Data sparks new care model.
Nurses at Hennepin County Medical Center (HCMC), a public teaching hospital in Minneapolis, Minn., combined clinical data and critical thinking savvy to create positive change.


Effective tetracycline removal from liquid streams of dairy manure via hierarchical poly (vinyl alcohol-co-ethylene)/polyaniline metal complex nanofibrous membranes.
Antibiotic residues from animal wastes enter underground and surface water streams, posing high risks to public health. Novel technologies capable of removing the residues from the matrix of concern such as animal waste should be developed. This research investigates the development of nanofiber absorbent for removing tetracycline (TC) antibiotic residues from liquid streams of dairy manure produced in a typical dairy farm. Hierarchically structured nanofibrous adsorbent was developed through growing a uniform polyaniline (PAni) nanodots on poly (vinyl alcohol-co-ethylene) (EVOH) nanofiber membrane (NFM). Moreover, Cu2+ ions were chelated on the developed EVOH/PAni-Cl NFM to improve TC adsorption efficiency and selectivity. The TC adsorption capacities of EVOH/PAni-Cl-Cu2+ and EVOH/PAni-Cl) NFM were 1100 mg g-1 and 600 mg g-1 within 120 min., respectively. The NFMs adsorption efficiency was investigated using dairy wastewater. Initial TC concentrations in dairy wastewater sample varied between 20 and 50 ppm. The EVOH/PAni-Cl-Cu2+ NFM showed TC removal of 86% from dairy manure samples at 25 ppm initial TC concentration within 60 min. during batch mode treatment. Results showed that the dynamic binding efficiency of 450 mg g-1 can be achieved at an initial TC concentration of 50 ppm. Furthermore, the NFM displayed efficient chemical and physical stability even after 8 cycles of reusing without significant changes in its performance or hazardous Cu2+ leaching.


Structural MRI in Idiopathic Parkinson's Disease.
Among modern neuroimaging modalities, magnetic resonance imaging (MRI) is a widely available, non-invasive, and cost-effective method to detect structural and functional abnormalities related to neurodegenerative disorders. In the last decades, MRI have been widely implemented to support PD diagnosis as well as to provide further insights into motor and non-motor symptoms pathophysiology, complications and treatment-related effects. Different aspects of the brain morphology and function may be derived from a single scan, by applying different analytic approaches. Biomarkers of neurodegeneration as well as tissue microstructural changes may be extracted from structural MRI techniques. In this chapter, we analyze the role of structural imaging to differentiate PD patients from controls and to define neural substrates of motor and non-motor PD symptoms. Evidence collected in the premotor PD phase will be also critically discussed. White matter as well as gray matter integrity imaging studies has been reviewed, aiming to highlight points of strength and limits to their potential application in clinical settings.


DNA diagnosis for the practicing obstetrician.
Laboratory advances in molecular genetics have resulted in numerous clinical applications for DNA analysis. Currently, because of cost, complexity, and resource limitations, DNA analysis is not used routinely for prenatal screening, but rather is targeted towards families at risk for an inherited condition. This article discusses the types of DNA analyses that are currently performed, the possible tissue sources of DNA for prenatal diagnosis, and the indications for DNA testing in obstetric practice. Internet addresses for the most up-to-date genetic information on a specific condition are given in this article.


env genes of avian retroviruses: nucleotide sequence and molecular recombinants define host range determinants.
The env gene of avian sarcoma and leukosis retroviruses is allelic in the virus population permitting the virus to use different host cell receptors. This polymorphism has allowed the classification of these viruses into different subgroups. In order to understand further the role of viral sequences involved in determining this host range phenomenon, we constructed molecular recombinants between subgroup A, B, and E viruses and showed that the host range determinant defining subgroup specificity was located within a 1.1-kb region of the genome that included most of the coding region for the env gene product gp85. We also determined the nucleotide sequence of the region of the env gene encoding gp85 for virus isolates representing subgroup A and B viruses. We compared the predicted amino acid sequences of gp85 to themselves and to the previously published sequences of subgroup B, C, and E env genes. Based on these comparisons, we draw the following conclusions: Within the gp85 coding domain, there are four variable regions (VR-1 to VR-4) ranging in size from 9 to 52 amino acids. The variable regions are located in the same relative positions for each of the env gene alleles compared. The variable regions range in homology from 42% (A compared to B) to 57% (C compared to E) in pairwise comparisons; the flanking conserved domains are on average 95% homologous. The sequences of three different subgroup B virus isolates are highly homologous in both the conserved and variable regions. Secondary structure predictions suggest that gp85 is composed mostly of beta sheet topology. Hydrophilic loops within the variable regions may define sites of receptor interaction and binding sites for subgroup specific neutralizing antibodies.


Visualization of the morphological changes in the median nerve after carpal tunnel release using three-dimensional magnetic resonance imaging.
This study aimed to compare the pre- and postoperative morphology of the median nerve using three-dimensional (3-D) MRI in patients with carpal tunnel syndrome (CTS). We assessed 31 patients with CTS who underwent open carpal tunnel release and T2*-weighted MRI of the wrist preoperatively and at 6 months postoperatively. The median nerve morphology was evaluated on the basis of the cross-sectional areas (CSAs) and cross-sectional volumes (CSVs). The association between these MRI findings and nerve conduction studies was also evaluated. The mean preoperative CSA and CSV values at the proximal carpal tunnel level significantly decreased from 22.2 mm2 and 24.4 mm3 to 16.5 mm2 and 18.1 mm3, respectively, postoperatively. Median nerve swelling at the proximal carpal tunnel level was observed in 29 (94%) and 23 (74%) patients before and after surgery, respectively. The mean preoperative CSA and CSV values at the hamate level significantly increased from 9.9 to 12.3 mm2 and from 10.9 to 13.5 mm3 after surgery, respectively. Nerve narrowing at the hamate bone level was preoperatively observed in 28 (90%) patients and postoperatively in 21 (68%) patients. Preoperative CSA and CSV values at the proximal carpal tunnel were significantly associated with preoperative distal motor and sensory latency. Visual confirmation of the median nerve morphology using 3-D MRI is useful when considering postoperative recovery and explaining the nerve condition to the patients. • The 3-D morphology of the median nerve after carpal tunnel release can be delineated using 3-D MRI. • Preoperative swelling of the median nerve in the 2-D and 3-D planes reflects the severity of carpal tunnel syndrome. • Visual confirmation of the median nerve morphology is useful when considering median nerve recovery after carpal tunnel release and for explaining the condition of the nerve to patients.


Marginal mandibular nerve injury during neck dissection and its impact on patient perception of appearance.
Neck dissection to remove cervical lymph nodes is common practice in head and neck cancer management. The marginal mandibular nerve may be injured during neck dissection, particularly of level 1. The rate of injury to this nerve is underreported in the literature and its impact on patients is not well defined. An observational study was undertaken on patients who had undergone neck dissection over a 5-year period. The patients were examined for weakness and given a questionnaire related their perception of their appearance and their function. Sixty-six patients were identified who had undergone 85 neck dissections. The rate of House Brackmann injury was 18% when analyzed by patient and 23% by neck. There were moderate correlations between observed injury and subjective responses to questions relating to ability to smile and weakness of the lower lip. The rate of smile asymmetry following neck dissection is relatively high; however, severe injuries to the marginal mandibular nerve are uncommon.


Nephrin, a transmembrane protein, is involved in pancreatic beta-cell survival signaling.
Nephrin, a cell surface signaling receptor, regulates podocyte function in health and disease. We study the role of nephrin in β-cell survival signaling. We report that in mouse islet β-cells and the mouse pancreatic beta-cell line (βTC-6 cells) nephrin is associated and partly co-localized with PI3-kinase. Incubation of cells with functional anti-nephrin antibodies induced nephrin clustering at the plasma membrane, nephrin phosphorylation and recruitment of PI3-kinase to nephrin thus resulting in increased PI3K-dependent Akt phosphorylation and augmented phosphorylation/inhibition of pro-apoptotic Bad and FoxO. Nephrin silencing abolished Akt activation and increased susceptibility of cells to apoptosis. High glucose impaired nephrin signaling, increased nephrin internalization and up-regulated PKCα expression. Interestingly, a marked decrease in nephrin expression and phosphorylated Akt was observed in pancreatic islets of db/db lepr-/- diabetic mice. Our findings revealed that nephrin is involved in β-cell survival and suggest that glucose-induced changes in nephrin signaling may contribute to gradual pancreatic β-cell loss in type 2 diabetes.


Prospective study of the potentiation of acenocoumarol by amiodarone.
The influence of oral amiodarone on the anticoagulant effect of the coumarin derivative acenocoumarol has been investigated prospectively in 10 patients with normal renal, hepatic and haematological function and who were not in cardiac failure. The daily dose of acenocoumarol was sufficient to produce a prothrombin activity of 25 to 35%. When the prothrombin time had become stable amiodarone 600 mg/d was administered for 1 week followed by 400 mg/d for the next 3 weeks. A decrease in prothrombin activity from 30.5 to 20.2% was observed, associated with a decrease in vitamin K coagulation factors, after a mean of 4 days following commencement of amiodarone. In 6 patients a prothrombin activity less than 20% required a 60% reduction in the dose of acenocoumarol after 1 week of amiodarone 600 mg, and a 33% reduction after 3 weeks of amiodarone 400 mg. There was no correlation between the plasma amiodarone and the decrease in prothrombin activity. Inhibition of acenocoumarol metabolism by amiodarone is the most likely explanation of these findings.


Inhibition of bovine dihydrofolate reductase and enhancement of methotrexate sensitivity by N4-(2-acetoxyethoxymethyl)-2-acetylpyridine thiosemicarbazone.
N4-(2-Acetoxyethoxymethyl)-2-acetylpyridine thiosemicarbazone (AATSC) belongs to a series of molecules known to have broad antimicrobial inhibitory activity. These molecules contain the 2-acetoxyethoxy moiety which could conceivably take up a conformation analogous to that of the ribosyl group. Moreover, the thiosemicarbazone moiety, when in the presence of a suitable enzymatic site, could mimic the triazine group, which is found in a number of antifolate drugs. AATSC, which has both bacterial inhibitory activity and water solubility, was accordingly evaluated for its antifolate activity against the bovine liver dihydrofolate reductase. AATSC is shown to be a fully uncompetitive inhibitor of that enzyme. Furthermore, AATSC enhances the activity of methotrexate. Such a potentiation could be useful for therapeutic purposes.


Detection of ligand-selective interactions of the human androgen receptor by SELDI-MS-TOF.
The human androgen receptor (AR) is expressed in nearly all prostate cancers (PCa) and is known to participate in tumor progression through the expression of genes involved in the proliferation and differentiation of PCa. It is suggested that different types of ligands induce a distinct AR conformation that would lead to a specific set of interacting partners for the AR, such as coactivators (CoA) and corepressors (CoR), heat shock proteins (HSP), remodeling factors, kinases, phosphatases, and transcription factors resulting in various degrees of AR activity and stability. The natural ligand of the AR, dihydrotestosterone (DHT), induces a transcriptionally active conformation of the AR while the steroidal antiandrogen cyproterone acetate (CPA) and the nonsteroidal compounds hydroxyflutamide (OHF), bicalutamide (Cas), and atraric acid (AA) prevent acquisition of a transcriptionally active conformation. The AR has, in addition to transactivation, other functional properties. However, the current known interaction partners of AR cannot explain the multitude of AR-mediated functions. Thus, many of the ligand-specific AR-interacting proteins still remain unidentified. Here we provide an assay system to assess AR interactions in LNCaP PCa cells. LNCaP cells were treated with the AR-agonist R1881 or AR-antagonists Cas or AA to induce ligand-specific cofactor (CoF) binding to the AR in vivo. Here we describe a method for the identification of ligand-selective interaction partners of AR combining immunological methods with surface-enhanced laser desorption/ionization (SELDI)--time of flight (TOF)--mass spectrometry (MS). Exemplified here is the interaction of a novel AR-CoF, the cell-cycle regulating protein cell division cycle-associated protein 2 (CDCA2) with AR in the presence of antagonist which is verified by a protein-protein interaction assay in vivo. This scheme can provide further insights into the molecular mechanisms of AR ligand selectivity.


Analgesic efficacy and safety of intravenous paracetamol (acetaminophen) administered as a 2 g starting dose following third molar surgery.
The recommended dose for intravenous (IV) paracetamol injection in adults is 1g, however pharmacokinetic and pharmacodynamic findings suggest that a better analgesia could be obtained with a 2 g starting dose. A single-centre, randomised, double-blind, placebo-controlled, 3-parallel group study was performed to demonstrate the analgesic efficacy and safety of IV paracetamol 2 g. Following third molar surgery, patients reporting moderate to severe pain received a single 15-min infusion of either IV paracetamol 2 g, IV paracetamol 1g or placebo. Efficacy and safety were evaluated over 8 h. Laboratory tests were performed before and 48 h after drug administration. Two hundred and ninety seven patients (132 = IV paracetamol 2g; 132 = IV paracetamol 1g; 33 = placebo) were randomised and completed the study. The summed pain relief over 6h (TOTPAR6) was significantly superior with IV paracetamol 2 g as compared to IV paracetamol 1g and placebo (p < 0.0001). Pain relief scores of IV paracetamol 2g were significantly superior to IV paracetamol 1g and to placebo from T30' to T8h (p < 0.0001). Median duration of analgesia was significantly longer following IV paracetamol 2 g compared to IV paracetamol 1g and placebo (p < 0.0001). Adverse events occurred with the same frequency in the 3 treatment groups. No clinically significant changes from baseline were observed for vital signs or laboratory tests. The analgesic efficacy of a 2 g starting dose of IV paracetamol was superior over the recommended dose of 1g in terms of magnitude and duration of analgesic effect for postoperative pain following third molar surgery, with no significant difference between groups regarding safety.


Automated sample preparation for regulated bioanalysis: an integrated multiple assay extraction platform using robotic liquid handling.
A novel approach for regulated bioanalytical sample preparation has been developed to combine multiple types of extraction techniques into one integrated and automated sample-preparation suite that pairs a graphical user interface with the Hamilton Microlab(®) STAR robotic liquid handler. The multi-assay sample-preparation suite is composed of three bioanalytical extraction techniques: protein precipitation, solid-phase extraction and liquid-liquid extraction. Validation data provided highly reproducible and robust results for each respective automated extraction technique. The user-friendly graphical user interface and modular method design provide a flexible and versatile approach for routine bioanalytical sample-preparation and is the first fully integrated multiple assay sample-preparation suite for regulated bioanalysis.


Fast magnetic resonance imaging in steady-state precession (true FISP) in the prenatal diagnosis of a congenital brain teratoma.
Teratomas are the most common congenital intracranial tumor. Although fetal magnetic resonance (MR) imaging is becoming more popular for prenatal diagnosis, only 2 cases of congenital intracranial teratoma have been reported, and these cases relied on half-Fourier single-shot turbo spin echo (HASTE) imaging. We report the first known case of congenital intracranial teratoma diagnosed by means of a fast imaging in steady-state precession (true FISP) MR sequence. True FISP can be obtained in almost 20 seconds and provides superior contrast resolution compared with HASTE.


A facile synthesis of CuSe nanosheets for high-performance sodium-ion hybrid capacitors.
Due to the low price and abundant reserves of sodium resources, sodium-ion batteries have become the main candidate for the next generation of energy storage equipment, particularly for large-scale grid storage and low-speed electric vehicles. Transition metal selenides have attracted considerable attention because of their high reversible capacity, superior electrical conductivity and versatile structures. In this study, two-dimensional CuSe nanosheets are synthesized via a simple hydrothermal reaction. When acting as an electrode material for sodium-ion batteries, the CuSe electrode exhibits an initial coulombic efficiency of 96.7% at a current density of 0.1 A g-1 and a specific capacity of 330 mA h g-1 after 100 operation cycles, as well as retains a specific capacity of 211 mA h g-1 even at a high current density of 10 A g-1. Moreover, the anode delivers a specific capacity of 236 mA h g-1 after 3300 cycles at 5 A g-1 with a capacity retention of 91.2%. In sodium-ion hybrid capacitors (SHICs) with the two-dimensional CuSe nanosheets and Ti3C2T x MXene as the negative and positive materials, respectively, the nanosheets without any pre-sodiation present a lifespan of up to 2000 cycles at 2 A g-1 and a capacity retention of about 77.7%.


In vitro antifilarial activity of Azadirachta indica aqueous extract through reactive oxygen species enhancement.
To evaluate an aqueous preparation from the Azadirachta indica leaves (AEA) against Setaria cervi (S. cervi), a model filarial parasite. In vitro efficacy of AEA was evaluated against S. cervi through estimation of relative motility value, dye exclusion test and MTT assay. Visible morphological alterations were monitored using conventional microscopic techniques in microfilariae and haematoxylin-eosin stained sections of AEA-treated adults. Enhancement of reactive oxygen species in S. cervi treated with AEA was established through alteration in the activity of glutathione S-transferase, superoxide dismutase, catalase, peroxidase and level of superoxide anion and reduced glutathione. In vitro filaricidal activity of AEA is possibly through disturbing redox homeostasis by down-regulating and altering the level of some key antioxidants and regulatory enzymes like reduced glutathione, glutathione S-transferase, superoxide dismutase, catalase and glutathione peroxidase of S. cervi.


Culture of sheep Chlamydia in a sheep fibroblast cell culture.
Abortion and enteric isolates of Chlamydia psittaci from sheep differed in their growth in a fibroblastic cell culture derived from the small intestine of a lamb. Twenty abortion isolates, each from a different farm, produced large inclusions which could be passaged several times whereas 10 enteric isolates each from different farms (but from some of the farms of origin of the abortion isolates) produced sparse inclusions which could not be passaged. This appears to be a rapid method of distinguishing abortion and enteric isolates and may indicate different nutritional requirements or be related to the invasiveness of the isolates.


Urinary estrogen metabolites, prostate specific antigen, and body mass index among African-American men in South Carolina.
Estrogen metabolites have been linked to risk of breast cancer, and we were interested in whether they are associated with prostate specific antigen (PSA) and other factors associated with prostate cancer. African-American (AA) men in South Carolina have among the highest prostate cancer rates in the world, and thus provide an ideal population in which to investigate this hypothesis. We recruited AA men attending prostate cancer screenings in and around Columbia, South Carolina. Because very few men had elevated PSAs, we restricted our study to the 77 men whose PSA was below the cutpoint used by the screening program to indicate need for diagnostic workup. These men provided spot urine samples and answered demographic and lifestyle questions including self-reported body weight, height, exercise, tobacco use, medications, cancer history and age. Levels of urinary 2-hydroxyestrone (2-OHE1) and 16alpha-hydroxyestrone (16alpha-OHE1), and their ratio (2/16) and blood PSA levels were determined. After adjusting for a statistically significant interaction between age and BMI, we found a reduction of 14.2% in 2-OHE1 for each 1.0 ng/ml increase in PSA (p=0.05). For obese AA men only (BMI> or =30 kg/m2), 2-OHE1 increased by 36% for each decade of age (p=0.009). Estrogen metabolites may be related to PSA level in AA men. Older men with BMIs greater than 30 kg/m2 had an unexpected increase in 2-OHE1, suggesting a dysregulation of this estrogen metabolism pathway. Further studies of estrogen metabolites may provide insights into prostate cancer risk factors.


MOB control: reviewing a conserved family of kinase regulators.
The family of Mps One binder (MOB) co-activator proteins is highly conserved from yeast to man. At least two different MOB proteins have been identified in every eukaryote analysed to date. Initially, yeast genetics revealed essential roles for Mob1p and Mob2p in the regulation of mitotic exit and cell morphogenesis. Studies in flies then showed that dMOB1/MATS is a core component of Hippo signalling. Loss of dMOB1 resulted in increased cell proliferation and decreased cell death, suggesting that MOB1 acts as tumour suppressor protein. Recent work focused primarily on mammalian cells has shown how hMOB1 can regulate NDR/LATS kinases, a function that can to be counteracted by hMOB2. Here we summarise and discuss our current knowledge of this emerging protein family, with emphasis on subcellular localisation, protein-protein interactions and biological functions in apoptosis, mitosis, morphogenesis, cell proliferation and centrosome duplication.


Inflammasome-Derived Exosomes Isolation and Imaging by Transmission Electron Microscopy.
Exosomes are secreted small vesicles with diameters of 30-150 nm from cells. These vesicles transfer protein, mRNA, and miRNA to recipient cells to mediate many biological processes, including tumorigenesis, metastasis, drug resistance, immune response, etc. Here we describe the isolation and imaging of NLRP3 inflammasome-derived exosomes by transmission electron microscopy.


Wetting and drying cycles drive variations in the stable carbon isotope ratio of respired carbon dioxide in semi-arid grassland.
In semi-arid regions, where plants using both C(3) and C(4) photosynthetic pathways are common, the stable C isotope ratio (delta(13)C) of ecosystem respiration (delta(13)C(R)) is strongly variable seasonally and inter-annually. Improved understanding of physiological and environmental controls over these variations will improve C cycle models that rely on the isotopic composition of atmospheric CO(2). We hypothesized that timing of precipitation events and antecedent moisture interact with activity of C(3) and C(4) grasses to determine net ecosystem CO(2) exchange (NEE) and delta(13)C(R). Field measurements included CO(2) and delta(13)C fluxes from the whole ecosystem and from patches of different plant communities, biomass and delta(13)C of plants and soils over the 2000 and 2001 growing seasons. NEE shifted from C source to sink in response to rainfall events, but this shift occurred after a time lag of up to 2 weeks if a dry period preceded the rainfall. The seasonal average of delta(13)C(R) was higher in 2000 (-16 per thousand) than 2001 (20 per thousand), probably due to drier conditions during the 2000 growing season (79.7 mm of precipitation from April up to and including July) than in 2001 (189 mm). During moist conditions, delta(13)C averaged -22 per thousand from C(3) patches, -16 per thousand from C(4) patches, and -19 per thousand from mixed C(3) and C(4) patches. However, during dry conditions the apparent spatial differences were not obvious, suggesting reduced autotrophic activity in C(4) grasses with shallow rooting depth, soon after the onset of dry conditions. Air and soil temperatures were negatively correlated with delta(13)C(R); vapor pressure deficit was a poor predictor of delta(13)C(R), in contrast to more mesic ecosystems. Responses of respiration components to precipitation pulses were explained by differences in soil moisture thresholds between C(3) and C(4) species. Stable isotopic composition of respiration in semi-arid ecosystems is more temporally and spatially variable than in mesic ecosystems owing to dynamic aspects of pulse precipitation episodes and biological drivers.


Dual-emissive carbon dots for dual-channel ratiometric fluorometric determination of pH and mercury ion and intracellular imaging.
Dual-emissive carbon dots (CDs) were fabricated for dual-channel ratiometric fluorometric determination of pH and mercury ion (Hg2+) and intracellular imaging. Dual-emissive CDs were synthesized by one-pot solvothermal treatment of cabbage. The CDs exhibited two distinctive fluorescence emissions at 500 and 678 nm under single excitation at 410 nm. The green emission (500 nm) had reversible linear response to pH (7.0-12.0) due to deprotonation and protonation of surface functional groups and their non-covalent interactions. On the other hand, the red emission (678 nm) had efficient and selective fluorescence response to Hg2+ by formation of non-emission complex between CDs and Hg2+. The limit of detection (LOD) and limit of quantification (LOQ) for Hg2+ were 6.25 and 20.63 nM, respectively. The CDs have been successfully applied for label-free ratiometric fluorometric determination of pH and Hg2+ in fish and human serum samples with good recoveries (92.0-108.3%). In addition, the CDs had excellent photostability, low cytotoxicity, and good biocompatibility for intracellular imaging. All in all, the system was multi-functional in determination, high in sensitivity, and excellent in selectivity, which demonstrated wide and promising applicability for biosensing and bioimaging in the future. Graphical abstract Schematic presentation of dual-emission carbon dots (CDs) synthesized by solvothermal treatment of cabbage for dual-channel determination of pH and Hg2+.


Primary biliary cirrhosis: does X mark the spot?
Primary biliary cirrhosis (PBC) is an autoimmune disease of unknown etiology leading to progressive destruction of intrahepatic bile duct, with cholestasis, cirrhosis, and eventually liver failure. Epidemiological data indicate that environmental factors trigger autoimmunity in genetically susceptible individuals, although no definitive association of PBC with specific genes has been found. Further, no convincing explanation has been provided for the strong female predominance observed in the prevalence of PBC. However, we recently suggested that the enhanced monosomy X in peripheral white blood cells, and particularly in lymphocytes, of affected women might play a role in the induction of PBC. Such observations appear independent from the degree of cholestasis and specific for PBC. In this review we discuss the implications of these findings and their immunological implications.


The role of cyclic AMP response element binding protein in transactivation of scavenger receptor class B type I promoter in transfected cells and in primary cultures of rat theca-interstitial cells.
In the ovary, lutropin (LH) stimulates the selective uptake and transport of cholesterol for steroid biosynthesis from HDL particles via the scavenger receptor class B type I (SR-BI). Furthermore the expression of SR-BI mRNA in the ovary is stimulated by LH and cyclic AMP (cAMP). Since the promoter of the rat SR-BI gene is devoid of consensus cyclic AMP response element (CRE) sequences, this study examined if cAMP response element binding protein (CREB) plays a role in the transactivation of SR-BI promoter (SR-BIpr). The transactivation of SR-BIpr was examined in transfected 293T cells and human granulosa SVOG-4o cells, and in primary cultures of rat theca-interstitial cells infected with adenoviral constructs containing the SR-BIpr and a luciferase reporter gene. Dose-related increases in SR-BRpr activity ranging from 2- to 4-fold was induces by 293T cells co-transfected with the catalytic subunit of protein kinase A (cPKA). Co-transfections with CREB and cPKA produced a concentration-dependent increase ranging from 6- to 32-fold. The cAMP-mediated transactivation was significantly attenuated by co-transfection with CREB M1, a non-phosphorylatable, dominant-negative form of CREB. An increase in transactivation of SR-BIpr activity was also seen in SVOG-4o cells co-transfected with CREB. In primary cultures of rat theca-interstitial (T-I) cells infected with an adenoviral construct of SR-BIpr, forskolin produced a marked increase in promoter activity. These data indicate that stimulation of the cAMP-PKA-CREB pathway enhances rat SR-BIpr activity and substantiate the role of CREB as an intermediary in this process. The absence of canonical CRE sequences in the rat SR-BIpr suggests that the activation of SR-BI by CREB may occur either through non-canonical CRE sequences or through additional transcription factors that cooperate with CREB in the activation of SR-BI promoter activity.


Incremental value of live/real time three-dimensional over two-dimensional transesophageal echocardiography in the evaluation of right coronary artery fistula.
We report an adult with a right coronary artery to right atrial fistula in whom live/real time three-dimensional transesophageal echocardiography with its ability to trace the entire course and obtain en face views of the fistula connections, was able to provide significant incremental information over two-dimensional transesophageal echocardiography.


Influence of the inducible nitric oxide synthase gene (NOS2A) on inflammatory bowel disease susceptibility.
The great amount of nitric oxide (NO) produced by the inducible isoform of NO synthase (iNOS) exerts deleterious effects, and iNOS expression is raised in the colonic mucosa of inflammatory bowel disease (IBD) patients. This is the first association analysis of polymorphisms within the NOS2A extended gene with IBD susceptibility. We analyzed 336 patients of Crohn's disease (CD), 355 of ulcerative colitis (UC), and 536 healthy controls from a Spanish population. We tested a (CCTTT)n microsatellite, a (-/TAAA) insertion, and two single nucleotide polymorphisms (SNPs) flanking them (rs2779251 and rs2779248) in the NOS2A promoter, together with two SNPs in the coding region: one within exon 10, D385D (rs1137933), and another mapping to exon 16, S608L (rs2297518). Analysis of these markers evidenced differences among IBD patients and healthy controls. Allele (CCTTT) 13 is related to higher UC risk (p = 0.001; odds ratio [OR] [95% confidence interval, CI] = 1.64 [1.20-2.23]). Carriers of minor alleles of the two promoter SNPs analyzed showed an association with UC predisposition, and common allele homozygotes of the two exonic SNPs were more frequent among CD patients than among controls. Concordantly, one out of the three haplotypes carrying both exonic risk alleles was found to increase CD susceptibility (p = 0.007; OR [95%CI] = 1.74 [1.13-2.67]). Therefore, the NOS2A gene seems to be involved in IBD aetiology.


Studies on two new vitamin D analogs, EB 1089 and KH 1060: effects on bone resorption and osteoclast recruitment in vitro.
We have investigated the effects on bone resorption of two new potent antiproliferative vitamin D3 analogs, EB 1089 and KH 1060, by studying recruitment of osteoclasts in murine bone marrow cultures and 45Ca release from prelabeled neonatal mouse calvarial bones. Binding studies to vitamin D receptor protein, from human osteosarcoma MG-63 cells, demonstrated kd values of 8.5 x 10(-11) for 1 alpha,25(OH)2D3, 6.5 x 10(-11) for KH 1060, and 2.7 x 10(-10) for EB 1089. 1 alpha,25(OH)2D3 and EB 1089 were equipotent stimulators of osteoclast recruitment in murine bone marrow cultures, with EC50 at 10(-10) mol/L, whereas KH 1060 was about tenfold more potent with an EC50 at 10(-11) mol/L. In serum-free media, 1 alpha,25(OH)2D3 enhanced 45Ca release from neonatal mouse calvarial bones with EC50 at 10(-11) mol/L, but in the presence of 10% fetal calf serum (FCS) the stimulatory effect was significantly diminished, with a threshold value at 10(-10) mol/L. EB 1089 stimulated bone resorption with an estimated EC50 at 3 x 10(-11) mol/L, whereas KH 1060 was about tenfold more potent than 1 alpha,25(OH)2D3, and stimulated bone resorption with an EC50 at 10(-12) mol/L. The effects of EB 1089 and KH 1060 on 45Ca release were not significantly affected by the addition of 10% FCS. Addition of vitamin D binding protein to serum-free incubations of neonatal mouse calvarial bones, significantly inhibited the bone resorbing effect of 1 alpha,25(OH)2D3, but did not affect EB 1089 and KH 1060 induced 45Ca release.(ABSTRACT TRUNCATED AT 250 WORDS)


Why can sensitization by an HLA-DR2 mismatch lead to antibodies that react also with HLA-DR1?
HLAMatchmaker is a matching algorithm that can be used to characterize antibodies specific for structurally defined epitopes. Under the auspices of the 15(th) International Histocompatibility Workshop, we are conducting a multilaboratory collaborative project to characterize these epitopes and also to determine how often they induce specific antibodies in patients with rejected kidney transplants. This report addresses the reactivity of post-allograft nephrectomy sera tested for DRB antibodies with Luminex assays using single alleles. This analysis was performed for 19 informative kidney transplant cases contributed by 13 laboratories worldwide. There were 11 cases with a single DR2 mismatch (DR15 or DR16), and nine of them (82%) showed antibodies with both DR2 and DR1. Although these antigens might share an epitope recognized by these antibodies, this interpretation is incorrect. The HLAMatchmaker analysis offers a clearly different explanation that involves antibodies induced by DR51, which commonly associates with DR2. DR51 has an epitope defined by the 96EV eplet, which is also present on DR1 but no other DR antigen. This means that the reactivity with DR51 and DR1 reflects the presence of 96EV-specific antibodies. Conversely, we analyzed eight patients sensitized by a single DR1 mismatch that has no associated DR51. All of these patients reacted also with DR51, and this could be explained only by antibodies against the shared 96EV eplet. These findings demonstrate that 96EV represents a highly immunogenic epitope that can induce cross-sensitization between antigens encoded by the different DRB loci, and also that DR51 is important in determining DRB mismatch acceptability of potential donors. This analysis has also demonstrated that antibody responses are restricted to a few epitopes on these immunizing DR antigens. For DR2 they are 142M3 (unique for DR2), 71QAA (shared with DB5*02), and 96QV (shared with DR10). DR51 mismatches appear to have three immunogenic eplets: 96EV (shared with DR1), 108T3 (unique for DR51), and 40HFD (shared with DR9). Immunogenic eplets on DR1 are 12LKF2 (unique for DR1), 14FEH (shared with DR9 and DR10), and 25HRL (shared with DR10).


Age-related changes in neuronal uptake of noradrenaline.
Age-related changes in the neuronal uptake of noradrenaline were studied in the vas deferens of 4-, 12- and 20-months old rats by determining the potentiating effect of cocaine on concentration-effect curves to noradrenaline and by evaluating the kinetic parameters (Vmax and apparent Km) of neuronal 3H-noradrenaline uptake. Since the neurotransmitters released by nerve terminals and the density of noradrenergic innervation are different in the epididymal and prostatic portion of the vas, the experiments were carried out in these two portions of the organ. In the epididymal portion, the ratio between EC50 for noradrenaline in the presence and in the absence of cocaine was reduced in tissues of middle-aged (12-months) and old (20-months) animals when compared with young (4-months) animals. The pD2 values for noradrenaline in the absence of cocaine and the kinetic parameters for neuronal 3H-noradrenaline uptake were not modified by ageing. Thus, in the epididymal portion there was no age-related change in neuronal uptake. The age-related decrease in the cocaine-induced supersensitivity to noradrenaline was due to an age-related decrease in the pD2 value for noradrenaline observed in the presence of cocaine, suggesting postsynaptic changes. In the prostatic portion, the ratio between EC50 for noradrenaline in the presence and in the absence of cocaine was also reduced in tissues of old animals (20-months) when compared with middle-aged and young animals. The pD2 value for noradrenaline in the absence of cocaine obtained in the prostatic portion of 20-months old rats was higher than that in the younger groups (4- and 12-months).(ABSTRACT TRUNCATED AT 250 WORDS)


Clinical Relevance of RUNX1 and CBFB Alterations in Acute Myeloid Leukemia and Other Hematological Disorders.
The translocation t(8;21), leading to a fusion between the RUNX1 gene and the RUNX1T1 locus, was the first chromosomal translocation identified in cancer. Since the first description of this balanced rearrangement in a patient with acute myeloid leukemia (AML) in 1973, RUNX1 translocations and point mutations have been found in various myeloid and lymphoid neoplasms. In this chapter, we summarize the currently available data on the clinical relevance of core binding factor gene alterations in hematological disorders. In the first section, we discuss the prognostic implications of the core binding factor translocations RUNX1-RUNX1T1 and CBFB-MYH11 in AML patients. We provide an overview of the cooperating genetic events in patients with CBF-rearranged AML and their clinical implications, and review current treatment approaches for CBF AML and the utility of minimal residual disease monitoring. In the next sections, we summarize the available data on rare RUNX1 rearrangements in various hematologic neoplasms and the role of RUNX1 translocations in therapy-related myeloid neoplasia. The final three sections of the chapter cover the spectrum and clinical significance of RUNX1 point mutations in AML and myelodysplastic syndromes, in familial platelet disorder with associated myeloid malignancy, and in acute lymphoblastic leukemia.


[Cytochemical study of different stages in the life cycle of Toxoplasma gondii. VII. Oxidation--reduction enzymes in the cyst forms].
Dehydrogenases of glycolysis, Kreb's cycle, and pentose-phosphate shunt were detected in cystozoites of Toxoplasma gondii strain SS-119 with various degrees of activity. A mixed oxidative metabolism may be postulated on this stage of the toxoplasma life cycle. Besides, the activity of cytochrome oxidase was detected in cystozoites; the addition of cytochrome c to the incubation medium significantly intensified the reaction intensity. Of interest seems the observation of a layer of higher enzymatic activity in the host brain tissue in the immediate neighbourhood with the cyst body. This may be regarded as the host cells' (or tissue') response to the presence of the parasite's alien body.


Involvement of PP2A in viral and cellular transformation.
Although the small DNA tumor virus SV40 (simian virus 40) fails to replicate in human cells, understanding how SV40 transforms human and murine cells has and continues to provide important insights into cancer initiation and maintenance. The early region of SV40 encodes two oncoproteins: the large T (LT) and small t (ST) antigens. SV40 LT contributes to murine and human cell transformation in part by inactivating the p53 and retinoblastoma protein tumor suppressor proteins. SV40 ST inhibits the activity of the protein phosphatase 2A (PP2A) family of serine-threonine phosphatases, and this interaction is required for SV40-mediated transformation of human cells. PP2A regulates multiple signaling pathways, suggesting many possible targets important for viral replication and cell transformation. Genetic manipulation of particular PP2A subunits has confirmed a role for specific complexes in transformation, and recent work implicates the perturbation of the phosphatidylinositol 3-kinase/Akt pathway and c-Myc stability in transformation by ST and PP2A. Mutations in PP2A subunits occur at low frequency in human tumors, suggesting that alterations of PP2A signaling play a role in both experimentally induced and spontaneously arising cancers. Unraveling the complexity of PP2A signaling will not only provide further insights into cancer development but may identify novel targets with promise for therapeutic manipulation.


Limited clinical utility of midtrimester fetal morphometric percentile rankings in screening for birth weight abnormalities.
Our purpose was to determine whether midtrimester fetal ultrasonographic morphometric percentile rankings are sensitive screening tests for preterm labor or birth weight abnormalities. Stepwise multiple regression and chi 2 analysis were used to identify midtrimester fetal measurements predicting birth weight and gestational age. Receiver-operator characteristics curves were used to evaluate abdominal circumference percentiles as a test for large-for-gestational-age and small-for-gestational-age infants. Extremes in abdominal circumference and head measurement percentiles were associated with large- and small-for gestational-age infants but not with preterm delivery. Abdominal circumference predicted birth weight in regression analysis; however, receiver-operator characteristic curves showed abdominal circumference percentiles to be poor screening tests for large- or small-for-gestational-age infants. The positive predictive value of 10th and 90th abdominal circumference percentiles for small- and large-for-gestational-age infants was < 20%. Midtrimester percentile rankings offer no clear benefit in targeting fetuses with potential birth weight abnormalities or risk of preterm delivery and may provide clinically misleading information.