Neopterin as a marker of C hepatitis in thalassaemia major.
The authors studied serum neopterin in 106 patients with beta thalassaemia major. A good correlation was found between neopterin values and glutamic pyruvic transaminase (GPT) mean values of the last 6 months, whereas no correlation was found between neopterin values and some siderosis indexes (iron/body weight, total accumulated iron). A statistically significant correlation was found between neopterin values (greater than 10 nM/L vs. less than 10 nM/L) and histological liver findings (chronic hepatitis vs. siderosis). Neopterin values were also statistically different between splenectomized and not splenectomized patients. Moreover serum neopterin was higher in HCV-Ab positive than in HCV-Ab negative patients, and 91.6% of the HCV-Ab positive group also showed histological signs of chronic hepatitis. These data suggest that increased serum neopterin might help to identify chronic C hepatitis in thalassaemic patients.


Development of a Risk Prediction Model for Carbapenem-resistant Enterobacteriaceae Infection After Liver Transplantation: A Multinational Cohort Study.
Patients colonized with carbapenem-resistant Enterobacteriaceae (CRE) are at higher risk of developing CRE infection after liver transplantation (LT), with associated high morbidity and mortality. Prediction model for CRE infection after LT among carriers could be useful to target preventive strategies. Multinational multicenter cohort study of consecutive adult patients underwent LT and colonized with CRE before or after LT, from January 2010 to December 2017. Risk factors for CRE infection were analyzed by univariate analysis and by Fine-Gray subdistribution hazard model, with death as competing event. A nomogram to predict 30- and 60-day CRE infection risk was created. A total of 840 LT recipients found to be colonized with CRE before (n = 203) or after (n = 637) LT were enrolled. CRE infection was diagnosed in 250 (29.7%) patients within 19 (interquartile range [IQR], 9-42) days after LT. Pre- and post-LT colonization, multisite post-LT colonization, prolonged mechanical ventilation, acute renal injury, and surgical reintervention were retained in the prediction model. Median 30- and 60-day predicted risk was 15% (IQR, 11-24) and 21% (IQR, 15-33), respectively. Discrimination and prediction accuracy for CRE infection was acceptable on derivation (area under the curve [AUC], 74.6; Brier index, 16.3) and bootstrapped validation dataset (AUC, 73.9; Brier index, 16.6). Decision-curve analysis suggested net benefit of model-directed intervention over default strategies (treat all, treat none) when CRE infection probability exceeded 10%. The risk prediction model is freely available as mobile application at https://idbologna.shinyapps.io/CREPostOLTPredictionModel/. Our clinical prediction tool could enable better targeting interventions for CRE infection after transplant.


Characteristics and Outcomes of Patients With Pregnancy-Related End-Stage Kidney Disease.
The incidence of pregnancy-related acute kidney injury is increasing and is associated with significant maternal morbidity including progression to end-stage kidney disease (ESKD). Little is known about characteristics and long-term outcomes of patients who develop pregnancy-related ESKD. To examine the characteristics and clinical outcomes of patients with pregnancy-related ESKD and to investigate associations between pre-ESKD nephrology care and outcomes. This was a cohort study of 183 640 reproductive-aged women with incident ESKD between January 1, 2000, and November 20, 2020, from the US Renal Data System and maternal data from births captured in the US Centers for Disease Control and Prevention publicly available natality data. Data were analyzed from December 2022 to June 2023. Pregnancy-related primary cause of ESKD, per International Classification of Diseases, Ninth Revision (ICD-9) and ICD-10 codes reported at ESKD onset by the primary nephrologist on Centers for Medicare and Medicaid Services form 2728. Multivariable Cox proportional hazards and competing risk models were constructed to examine time to (1) mortality, (2) access to kidney transplant (joining the waiting list or receiving a live donor transplant), and (3) receipt of transplant after joining the waitlist. A total of 341 patients with a pregnancy-related primary cause of ESKD were identified (mean [SD] age 30.2 [7.3]). Compared with the general US birthing population, Black patients were overrepresented among those with pregnancy-related ESKD (109 patients [31.9%] vs 585 268 patients [16.2%]). In adjusted analyses, patients with pregnancy-related ESKD had similar or lower hazards of mortality compared with those with glomerulonephritis or cystic kidney disease (adjusted hazard ratio [aHR], 0.96; 95% CI, 0.76-1.19), diabetes or hypertension (aHR, 0.49; 95% CI, 0.39-0.61), or other or unknown primary causes of ESKD (aHR, 0.60; 95% CI, 0.48-0.75). Despite this, patients with pregnancy-related ESKD had significantly lower access to kidney transplant compared with those with other causes of ESKD, including (1) glomerulonephritis or cystic kidney disease (adjusted subhazard ratio [aSHR], 0.51; 95% CI, 0.43-0.66), (2) diabetes or hypertension (aSHR, 0.81; 95% CI, 0.67-0.98), and (3) other or unkown cause (aSHR, 0.82; 95% CI, 0.67-0.99). Those with pregnancy-related ESKD were less likely to have nephrology care or have a graft or arteriovenous fistula placed before ESKD onset (nephrology care: adjusted relative risk [aRR], 0.47; 95% CI, 0.40-0.56; graft or arteriovenous fistula placed: aRR, 0.31; 95% CI, 0.17-0.57). In this study, those with pregnancy-related ESKD had reduced access to transplant and nephrology care, which could exacerbate existing disparities in a disproportionately Black population. Increased access to care could improve quality of life and health outcomes among these young adults with high potential for long-term survival.


Overcoming the Barriers to Diversity in Orthopaedic Surgery: A Global Perspective.
Diversity in orthopaedics continues to lag behind that in other surgical specialties. This pattern exists globally and is not unique to gender or race. This review offers a global perspective on overcoming the barriers to diversity in orthopaedics. A literature search of MEDLINE and Embase was conducted and a narrative review was undertaken. Publications that discussed any aspect of diversity or solutions to diversity within orthopaedics or academic orthopaedics were identified. A total of 62 studies were included. Studies showed that diversity in orthopaedic training is limited by structural barriers such as long hours, requirements to relocate during training, training inflexibility, and a lack of exposure to orthopaedics. Implicit bias during the selection process for training, discrimination, and a lack of role models are additional barriers that are experienced by both minority and female surgeons. The global lack of diversity suggests that there are also inherent "cultural barriers" that are unique to orthopaedics; however, these barriers are not uniformly experienced. Perceptions of orthopaedics as promoting an unhealthy work-life balance and the existence of a "boys' club" must be addressed. Strong, committed leaders can embed cultural norms, support trainees, and act as visible role models. Targeted efforts to increase diverse recruitment and to reduce bias in selection processes for medical school and specialty training will increase diversity in the "training pipeline." Diversity in orthopaedics continues to lag behind that in other specialties. Increasing diversity is important for providing a more inclusive training environment, improving patient care, and reducing health disparities. Structural and cultural barriers need to be addressed to improve diversity in orthopaedics. Promoting a culture supportive of all surgeons is essential to reframing perceptions that may prevent individuals from even considering a career as an orthopaedic surgeon. Changing attitudes require focused efforts from committed leadership in a "top-down" approach that prioritizes diversity. The efforts from national bodies seeking to tackle the lack of diversity, as well as the establishment of organizations committed to diversity, such as the International Orthopaedic Diversity Alliance, provide reasons to be optimistic for the future.


Overloaded Adeno-Associated Virus as a Novel Gene Therapeutic Tool for Otoferlin-Related Deafness.
Hearing impairment is the most common sensory disorder in humans. So far, rehabilitation of profoundly deaf subjects relies on direct stimulation of the auditory nerve through cochlear implants. However, in some forms of genetic hearing impairment, the organ of Corti is structurally intact and therapeutic replacement of the mutated gene could potentially restore near natural hearing. In the case of defects of the otoferlin gene (OTOF), such gene therapy is hindered by the size of the coding sequence (~6 kb) exceeding the cargo capacity (<5 kb) of the preferred viral vector, adeno-associated virus (AAV). Recently, a dual-AAV approach was used to partially restore hearing in deaf otoferlin knock-out (Otof-KO) mice. Here, we employed in vitro and in vivo approaches to assess the gene-therapeutic potential of naturally-occurring and newly-developed synthetic AAVs overloaded with the full-length Otof coding sequence. Upon early postnatal injection into the cochlea of Otof-KO mice, overloaded AAVs drove specific expression of otoferlin in ~30% of all IHCs, as demonstrated by immunofluorescence labeling and polymerase chain reaction. Recordings of auditory brainstem responses and a behavioral assay demonstrated partial restoration of hearing. Together, our results suggest that viral gene therapy of DFNB9-using a single overloaded AAV vector-is indeed feasible, reducing the complexity of gene transfer compared to dual-AAV approaches.


Tumescent power liposuction in the treatment of the enlarged male breast.
Tumescent power liposuction is widely used on various parts of the body for minimal-access lipectomy. The undesired fat deposits are injected with tumescence fluid containing saline, epinephrine, bicarbonate and lidocaine; the latter is used as the only source of pain control. The fat is then removed using vibrating microcannulas. To evaluate the value of tumescent power liposuction in the treatment of the enlarged male breast. 38 male patients aged 23-64 years (mean age 39.8 +/- 9.7 years) with enlarged breasts were enrolled in the study. In 32 patients, breasts were enlarged due to fat tissue, and the ductal glands were not palpable (pseudogynecomastia). In 6 patients, the ductal glands were enlarged (gynecomastia). All patients were treated with tumescent liposuction over a 2-year period using a single entry site from the axillary fossa. Both fat as well as ductal and stromal tissue were removed by microcannulas. None of the patients had early postoperative complications of infection, hematoma or seroma. There were no treatment-induced asymmetries, contour deformities or irregularities. No open excision or skin reduction procedures were required. Tumescent liposuction using a single entry site in the axillary fossa is a minimally invasive technique to treat enlarged male breasts. Both fat (pseudogynecomastia in adipose patients) as well as ductal and stromal tissue (in gynecomastia) can be removed with tumescent liposuction, resulting in a high level of patient satisfaction.


Emergency medicine in India: why are we unable to 'walk the talk'?
The largest democracy on earth, the second most populous country and one of the most progressive countries in the globe, India, has advanced tremendously in most conventional fields of Medicine. However, emergency medicine (EM) is a nascent specialty and is yet to receive an identity. Today, it is mostly practised by inadequately trained clinicians in poorly equipped emergency departments (EDs), with no networking. Multiple factors such as the size of the population, variation in standards of medical education, lack of pre-hospital medical systems and non-availability of health insurance schemes are some of the salient causes for this tardy response. The Indian medical system is governed by a central, regulatory body which is responsible for the introduction and monitoring of all specialties--the Medical Council of India (MCI). This organisation has not recognized EM as a distinct specialty, despite a decade of dogged attempts. Bright young clinicians who once demonstrated a keen interest in EM have eventually migrated to other conventional branches of medicine, due to the lack of MCI recognition and the lack of specialty status. The Government of India has launched a nationwide network of transport vehicles and first aid stations along the national highways to expedite the transfer of patients from a crash site. However, this system cannot be expected to decrease morbidity and mortality, unless there is a concurrent development of EDs. The present article intends to highlight factors that continue to challenge the handful of dedicated, full time emergency physicians who have tenaciously pursued the cause for the past decade. A three-pronged synchronous development strategy is recommended: (i) recognise the specialty of EM as a distinct and independent basic specialty; (ii) initiate postgraduate training in EM, thus enabling EDs in all hospitals to be staffed by trained Emergency physicians; and (iii) ensure that EMs are staffed by trained ambulance officers. The time is ripe for a paradigm shift, since the country is aware that emergency care is the felt need of the hour and it is the right of the citizen.


Models of long-distance transport: how is carrier-dependent auxin transport regulated in the stem?
• This paper presents two models of carrier-dependent long-distance auxin transport in stems that represent the process at different scales. • A simple compartment model using a single constant auxin transfer rate produced similar data to those observed in biological experiments. The effects of different underlying biological assumptions were tested in a more detailed model representing cellular and intracellular processes that enabled discussion of different patterns of carrier-dependent auxin transport and signalling. • The output that best fits the biological data is produced by a model where polar auxin transport is not limited by the number of transporters/carriers and hence supports biological data showing that stems have considerable excess capacity to transport auxin. • All results support the conclusion that auxin depletion following apical decapitation in pea (Pisum sativum) occurs too slowly to be the initial cause of bud outgrowth. Consequently, changes in auxin content in the main stem and changes in polar auxin transport/carrier abundance in the main stem are not correlated with axillary bud outgrowth.


The human vasoactive intestinal peptide/pituitary adenylate cyclase-activating peptide receptor 1 (VPAC1) promoter: characterization and role in receptor expression during enterocytic differentiation of the colon cancer cell line Caco-2Cl.20.
The basic organization of the human vasoactive intestinal peptide/pituitary adenylate cyclase-activating peptide receptor (VPAC) 1 promoter was investigated after cloning the 5'-flanking region (1.4 kb) of the VPAC1 gene from a human genomic library. Subsequent functional analysis of various deletions of the 5'-flanking sequence, subcloned upstream of a luciferase reporter gene, was carried out in HT-29 cells. The minimal promoter region identified encompasses the -205/+76 sequence and contains a crucial CCAAT box (-182/-178) and a GC-rich sequence. Moreover a region (-1348/-933) containing a silencer element was identified. We previously showed that the expression of the VPAC1 receptor binding site is strictly dependent upon the enterocytic differentiation of human colon cancer Caco-2 cells [Laburthe, Rousset, Rouyer-Fessard, Couvineau, Chantret, Chevalier and Zweibaum (1987) J. Biol. Chem. 262, 10180-10184]. In the present study we show that VPAC1 mRNA increases dramatically when Caco-2Cl.20 cells differentiate, as measured by RNase protection assays and reverse transcriptase-PCR. A single transcript species of 3 kb is detected in differentiated cells by Northern-blot analysis. Accumulation of VPAC1 receptor mRNA is due to a 5-fold increase of transcription rate (run-on assay) without a change in mRNA half-life (9 h). Stable transfections of various constructs in Caco-2Cl.20 cells and subsequent analysis of reporter gene expression, during the enterocytic differentiation process over 25 days of culture, further indicated that the -254/+76 5'-flanking sequence is endowed with the regulatory element(s) necessary for transcriptional regulation of VPAC1 during differentiation. Altogether, these observations provide the first characterization of the basic organization of the human VPAC1 gene promoter and unravel the crucial role of a short promoter sequence in the strict transcriptional control of VPAC1 expression during differentiation of human colon cancer Caco-2 cells.


[ANALYSIS AND COMPARISON OF SERUM LIPID PROFILE IN PATIENTS WITH DIABETIC MELLITUS AND HYPERTENSION IN A TERTIARY HEALTH CENTRE IN NORTH WEST NIGERIA].
Serum Lipid profile is an important biochemical parameter that can be used as a marker of adverse cardiovascular events. This study aim to analyze and compare serum lipid profile among hypertensive and diabetic patients. Serum lipid profile of 172 and 142 patients with diagnosis of hypertension and diabetes mellitus respectively seen over a 4year period were retrieved from the electronic data base of chemical pathology department of Barau Dikko Teaching Hopital, Kaduna. Percentages of patients with abnormal lipid values were calculated for the various lipids in the two groups of hypertension and diabetes and comparison of the mean was carried out in between the groups. Among hypertensives; 16.0%, 25.6%, 31.8% and 14.0% had abnormal HDL, LDL, total cholesterol and triglycerides respectively with 5.8% having both elevated cholesterol and triglyceride. In the diabetic group; 22.4%, 16.9%, 30.1% and 13.8% had abnormal HDL, LDL, total cholesterol and triglyceride respectively with 7.3% having both elevated total cholesterol and triglyceride. Comparison of mean of the various lipids among hypertensive and diabetic patients respectively is as follows: HDL (mean value 1.3±0.8 vs 1.2±0.3, t 1.737, p 0.08), LDL(mean value 3.3±1.0 vs 3.1±1.1, t 2.170, p 0.03), total cholesterol(mean value 5.3±1.2 vs 5.2±1.7, t 0.598, p 0.55) and triglyceride (mean value 1.6±1.0 vs 1.6±0.6, t 0.389, p 0.70). In this study, the predominant abnormality of lipids among the patients in the two groups was total hypercholesterolaemia and hypertensive patients had significantly higher LDL levels when compared to that of diabetic patients.


Evaluation of detailed training data to identify risk factors for retirement because of tendon injuries in Thoroughbred racehorses.
To identify the risk factors for premature retirement because of tendon injury in a Thoroughbred racehorse population. 175 Thoroughbred racehorses (cases) at the Hong Kong Jockey Club that were retired from racing because of tendon injury between 1997 and 2004 and for which the last preretirement exercise was at a fast pace were each matched with 3 control horses that were randomly selected from all uninjured horses that had galloped on the same date as that last exercise episode. Training data for all horses were examined. Conditional logistic regression analyses were performed to identify risk factors for retirement from racing attributable to tendon injury. Two multivariable conditional logistic regression models were created; each contained 8 explanatory variables. Compared with control horses, case horses were older at the time of import, accumulated more race distance soon after import, were more likely to have had previous official veterinary or ultrasonographic examinations, raced fewer times during their career, and were in training for a longer period and had exercised at a reduced intensity during the 180-day period preceding the last fast-paced work date. In addition to identification of risk factors for tendon injury among racing Thoroughbreds, results have suggested that resources focused on obtaining accurate training data may be misdirected in the absence of internationally agreed criteria for incident tendon injury among racehorses. Nevertheless, changes in training intensity and findings of previous clinical examinations could be used to identify horses at risk of tendon injury-associated retirement.


Behavioral health at-risk contracting--a rate development and financial reporting guide.
The process of developing rates for behavioral capitation contracts can seem mysterious and intimidating. The following article explains several key features of the method used to develop capitation rates. These include: (1) a basic understanding of the mechanics of rate calculation; (2) awareness of the variables to be considered and assumptions to be made; (3) a source of information to use as a basis for these assumptions; and (4) a system to collect detailed actual experience data.


What's in an EEM? Molecular signatures associated with dissolved organic fluorescence in boreal Canada.
Dissolved organic matter (DOM) is a master variable in aquatic systems. Modern fluorescence techniques couple measurements of excitation emission matrix (EEM) spectra and parallel factor analysis (PARAFAC) to determine fluorescent DOM (FDOM) components and DOM quality. However, the molecular signatures associated with PARAFAC components are poorly defined. In the current study we characterized river water samples from boreal Québec, Canada, using EEM/PARAFAC analysis and ultrahigh resolution mass spectrometry (FTICR-MS). Spearman's correlation of FTICR-MS peak and PARAFAC component relative intensities determined the molecular families associated with 6 PARAFAC components. Molecular families associated with PARAFAC components numbered from 39 to 572 FTICR-MS derived elemental formulas. Detailed molecular properties for each of the classical humic- and protein-like FDOM components are presented. FTICR-MS formulas assigned to PARAFAC components represented 39% of the total number of formulas identified and 59% of total FTICR-MS peak intensities, and included significant numbers compounds that are highly unlikely to fluoresce. Thus, fluorescence measurements offer insight into the biogeochemical cycling of a large proportion of the DOM pool, including a broad suite of unseen molecules that apparently follow the same gradients as FDOM in the environment.


Failure to CAPTCHA Attention: Null Results from an Honesty Priming Experiment in Guatemala.
We report results from a large online randomised tax experiment in Guatemala. The trial involves short messages and choices presented to taxpayers as part of a CAPTCHA pop-up window immediately before they file a tax return, with the aim of priming honest declarations. In total our sample includes 627,242 taxpayers and 3,232,430 tax declarations made over four months. Treatments include: honesty declaration; information about public goods; information about penalties for dishonesty, questions allowing a taxpayer to choose which public good they think tax money should be spent on; or questions allowing a taxpayer to state a view on the penalty for not declaring honestly. We find no impact of any of these treatments on the average amount of tax declared. We discuss potential causes for this null effect and implications for 'online nudges' around honesty priming.


Correlation between brain glycogen and convulsive state in mice submitted to methionine sulfoximine.
It is now well established that in epileptic patients, hypometabolic foci appear during interictal periods. The meaning and the mechanism of such an hypometabolism are as yet unclear. The aim of the present investigation was to look for a putative relationship between glucose metabolism in the brain and the genesis of seizures in mice using administration of the convulsant, methionine sulfoximine. Besides its epileptic action, methionine sulfoximine is a powerful glycogenic agent. We analyzed the epileptogenic and glycogenic effects of methionine sulfoximine in two inbred mouse strains with different susceptibility towards the convulsant. CBA/J mice displayed high response to methionine sulfoximine. The tonic convulsions appeared 5-6 h after MSO administration, without brain glycogen content variations during the preconvulsive period. These mice died of status epilepticus during the first seizure(s). Conversely, C57BL/6J mice displayed low response to MSO. The tonic and clonic seizures appeared 8 to 14 h after MSO administration with only 2% mortality. The seizures were preceded by an increase in brain glycogen content during the preconvulsive period. Moreover, during seizures, C57BL/6J mice were able to mobilize this accumulated brain glycogen, that returned to high value after seizures. The epileptic and glycogenic responses of the parental strains were also observed in mice of the F2 generation. The F2 mice that convulsed early (16%) did not utilize their small increase in brain glycogen content, and resembled CBA/J mice; while the F2 mice that seized tardily (24%) increased their brain glycogen content before convulsion, utilized it during convulsions, and resembled C57BL/6J mice. Sixty percent of the F2 mice presented an intermediate pattern in epileptogenic responses to the convulsant. These data suggest a possible genetic link between the two MSO effects, epileptiform seizures and increase in brain glycogen content. The increase in brain glycogen content and the capability of its mobilization during seizures could delay the seizure's onset and could be considered a "resistance factor" against the seizures.


Role of security guards in Code Black events in medical and surgical settings: A retrospective chart audit.
The prevalence of security guards in health care settings is growing worldwide. There is a need to explore and understand their role and actions to inform policy and training and support least restrictive practices in health care. The aim of this study was to conduct a retrospective chart audit of security guard logs to investigate security guard involvement in Code Blacks, called in emergency situations of personal threats including patient and/or visitor violence, in medical and surgical wards in a large metropolitan health network in South Australia. Security guards attended 1664 Code Blacks (0.63% of admissions) over the 2.5-year study period. Events were more frequently reported in medical than surgical wards. The most common reasons for security guard attendance were patients threatening/harming staff and patients threatening/harming themselves. The most frequent security guard actions were "Attend only/standby," "Physical restraint," and "Patient located and returned to the ward." The most frequent outcomes were physical restraint, chemical restraint, and de-escalation respectively. Results highlight the imperative that health services maintain and increase efforts to support least restrictive practice through policy directives and staff training.


Endovascular suture occlusion of the middle cerebral artery in rats: effect of suture insertion distance on cerebral blood flow, infarct distribution and infarct volume.
Sprague-Dawley rats anesthetized with isoflurane, underwent MCA occlusion by intraluminal 3-0 suture insertion, either 22 mm (n = 8) or 18 mm (n = 6) beyond the CCA bifurcation or were sham-operated as controls (n = 3) for autoradiographic analysis of cerebral blood flow. Infarct volume was measured 24 hours after the onset of ischemia (22 mm, n = 11; 18 mm, n = 10); neurological examinations were performed at 6 and 24 hours. Cerebral blood flow in the MCA distribution was significantly lower in the 22 mm suture insertion group than in the 18 mm group (p < 0.05). The total infarct volume was significantly larger (197 +/- 15 versus 135 +/- 19 mm3, p < 0.05) and the coefficient of variance was significantly smaller (23.8% versus 43.9%, p < 0.05) in the 22 mm group. Border zone regions of medial caudoputamen and dorsolateral cortex were often spared in the 18 mm group but never in the 22 mm group. The neurological deficit was more severe in the 22 mm group at 24 hours (p < 0.05), but not at 6 hours. The greater blood flow reduction and the less variable histological damage in dorsolateral cortex (a watershed area between the middle and anterior cerebral arteries) and the greater histological damage in medial caudate in the 22 mm group further characterizes this focal ischemia model for two potential applications: 22 mm insertion for studies requiring extensive and reproducible infarcts; 18 mm insertion for studies requiring less severe and more variable lesions after permanent MCA occlusion.


Telehealth Mindfulness-Oriented Recovery Enhancement vs Usual Care in Individuals With Opioid Use Disorder and Pain: A Randomized Clinical Trial.
Methadone treatment (MT) fails to address the emotion dysregulation, pain, and reward processing deficits that often drive opioid use disorder (OUD). New interventions are needed to address these factors. To evaluate the efficacy of MT as usual (usual care) vs telehealth Mindfulness-Oriented Recovery Enhancement (MORE) plus usual care among people with an OUD and pain. This study was a randomized clinical trial conducted from August 2020 to June 2022. Participants receiving MT for OUD and experiencing chronic pain were recruited at 5 clinics in New Jersey. In usual care, participants received MT, including medication and counseling. Participants receiving MORE plus usual care attended 8 weekly, 2-hour telehealth groups that provided training in mindfulness, reappraisal, and savoring in addition to usual care. Primary outcomes were return to drug use and MT dropout over 16 weeks. Secondary outcomes were days of drug use, methadone adherence, pain, depression, and anxiety. Analyses were based on an intention-to-treat approach. A total of 154 participants (mean [SD] age, 48.5 [11.8] years; 88 female [57%]) were included in the study. Participants receiving MORE plus usual care had significantly less return to drug use (hazard ratio [HR], 0.58; 95% CI, 0.37-0.90; P = .02) and MT dropout (HR, 0.41; 95% CI, 0.18-0.96; P = .04) than those receiving usual care only after adjusting for a priori-specified covariates (eg, methadone dose and recent drug use, at baseline). A total of 44 participants (57.1%) in usual care and 39 participants (50.6%) in MORE plus usual care returned to drug use. A total of 17 participants (22.1%) in usual care and 20 participants (13.0%) in MORE plus usual care dropped out of MT. In zero-inflated models, participants receiving MORE plus usual care had significantly fewer days of any drug use (ratio of means = 0.58; 95% CI, 0.53-0.63; P < .001) than those receiving usual care only through 16 weeks. A significantly greater percentage of participants receiving MORE plus usual care maintained methadone adherence (64 of 67 [95.5%]) at the 16-week follow-up than those receiving usual care only (56 of 67 [83.6%]; χ2 = 4.49; P = .04). MORE reduced depression scores and ecological momentary assessments of pain through the 16-week follow-up to a significantly greater extent than usual care (group × time F2,272 = 3.13; P = .05 and group × time F16,13000 = 6.44; P < .001, respectively). Within the MORE plus usual care group, EMA pain ratings decreased from a mean (SD) of 5.79 (0.29) at baseline to 5.17 (0.30) at week 16; for usual care only, pain decreased from 5.19 (0.28) at baseline to 4.96 (0.29) at week 16. Within the MORE plus usual care group, mean (SD) depression scores were 22.52 (1.32) at baseline and 18.98 (1.38) at 16 weeks. In the usual care-only group, mean (SD) depression scores were 22.65 (1.25) at baseline and 20.03 (1.27) at 16 weeks. Although anxiety scores increased in the usual care-only group and decreased in the MORE group, this difference between groups did not reach significance (group × time unadjusted F2,272 = 2.10; P= .12; Cohen d = .44; adjusted F2,268 = 2.33; P = .09). Within the MORE plus usual care group, mean (SD) anxiety scores were 25.5 (1.60) at baseline and 23.45 (1.73) at 16 weeks. In the usual care-only group, mean (SD) anxiety scores were 23.27 (1.75) at baseline and 24.07 (1.73) at 16 weeks. This randomized clinical trial demonstrated that telehealth MORE was a feasible adjunct to MT with significant effects on drug use, pain, depression, treatment retention, and adherence. ClinicalTrials.gov Identifier: NCT04491968.


Assay of lapatinib in murine models of cigarette smoke carcinogenesis.
Lapatinib, a dual tyrosine kinase inhibitor targeting the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER-2), is prescribed for the treatment of patients with metastatic breast cancer overexpressing HER-2. Involvement of this drug in pulmonary carcinogenesis has been poorly investigated. We used murine models suitable to evaluate cigarette smoke-related molecular and histopathological alterations. A total of 481 Swiss H mice were used. The mice were exposed to mainstream cigarette smoke (MCS) during the first four months of life. After 10 weeks, MCS caused an elevation of bulky DNA adducts, oxidative DNA damage and an extensive downregulation of microRNAs in lung. After four months, an increase in micronucleus frequency was observed in peripheral blood erythrocytes. After 7.5 months, histopathological alterations were detected in the lung, also including benign tumors and malignant tumors, and in the urinary tract. A subchronic toxicity study assessed the non-toxic doses of lapatinib, administered daily with the diet after weaning. After 10 weeks, lapatinib significantly attenuated the MCS-related nucleotide changes and upregulated several low-intensity microRNAs in lung. The drug poorly affected the MCS systemic genotoxicity and had modest protective effects on MCS-induced preneoplastic lesions in lung and kidney, when administered under conditions that temporarily mimicked interventions either in current smokers or ex-smokers. On the other hand, it caused some toxicity to the liver. Thus, on the whole, lapatinib appears to have a low impact in the smoke-related lung carcinogenesis models used, especially in terms of tumorigenic response.


Sustainable and recyclable heterogenous palladium catalysts from rice husk-derived biosilicates for Suzuki-Miyaura cross-couplings, aerobic oxidations and stereoselective cascade carbocyclizations.
A new eco-friendly approach for the preparation of sustainable heterogeneous palladium catalysts from rice husk-derived biogenic silica (RHP-Si and RHU-Si). The designed heterogeneously supported palladium species (RHP-Si-NH2-Pd and RHU-Si-NH2-Pd) were fully characterized and successfully employed as catalysts for various chemical transformations (C-C bond-forming reactions, aerobic oxidations and carbocyclizations). Suzuki-Miyaura transformations were highly efficient in a green solvent system (H2O:EtOH (1:1) with excellent recyclability, providing the cross-coupling products with a wide range of functionalities in high isolated yields (up to 99%). Palladium species (Pd(0)-nanoparticles or Pd(II)) were also efficient catalysts in the green aerobic oxidation of an allylic alcohol and a co-catalytic stereoselective cascade carbocyclization transformation. In the latter case, a quaternary stereocenter was formed with excellent stereoselectivity (up to 27:1 dr).


In vitro stimulation of penetration gland emptying by Trichobilharzia szidati and T. regenti (Schistosomatidae) cercariae. Quantitative collection and partial characterization of the products.
Induction of penetration gland emptying by cercariae of the bird schistosomes Trichobilharzia szidati and T. regenti employing linoleic acid, linolenic acid, praziquantel and calcium ionophore A23187 showed that both postacetabular and circumacetabular cells released their content at chosen stimulant concentrations. The gland secretions consisted of soluble and insoluble parts. The former one adhering to the ground seemed to have different saccharide composition from the glands of Schistosoma mansoni. It bound labelled saccharides, thus exhibiting lectin-like activity. Protein profiles of the latter one were identical after stimulation by all four stimulants in T. szidati. The soluble secretions contained several proteolytic enzymes; 31 kDa and 33 kDa cysteine proteases were identified in E/S products of T. szidati and T. regenti, respectively. The circumacetabular glands contained a significant amount of calcium. Immunohistochemistry revealed that the origin of E/S products after in vitro stimulation is in both penetration glands and tegumental structures. No crossreactivity was observed between the bird schistosomes and a serum raised against S. mansoni elastase.


Fosphenytoin Alleviates Herpes Simplex Virus Infection-Induced Provoked and Spontaneous Pain-Like Behaviors in Mice.
In this study, we investigated the effects of fosphenytoin (fPHT), a water-soluble prodrug of phenytoin, on the pain responses of a mouse herpes zoster (HZ) pain model. Transdermal herpes simplex virus type 1 (HSV-1) inoculation induced mechanical allodynia and hyperalgesia of the hind paw and spontaneous pain-like behaviors, such as licking the affected skin. Intravenous injection of fPHT (15 and 30 mg/kg) alleviated HSV-1-induced provoked pain (allodynia and hyperalgesia). The suppressive effects of fPHT on provoked pain were weaker than those of diclofenac and pregabalin which were used as positive controls. fPHT, diclofenac, and pregabalin significantly suppressed HSV-1-induced spontaneous pain-like behaviors. Among them, high-dose fPHT (30 mg/kg) showed the strongest suppression. Intravenous fPHT may become a viable option for an acute HZ pain, especially for spontaneous pain.


Sucrosomial Iron Supplementation in Anemic Patients with Celiac Disease Not Tolerating Oral Ferrous Sulfate: A Prospective Study.
Patients with celiac disease (CD) frequently suffer from iron deficiency anemia (IDA) and may benefit from iron supplementation. However, intolerance to iron sulfate and duodenal atrophy could reduce the efficacy of this supplementation. This study evaluated the efficacy of a new sucrosomial iron formulation in patients with CD. Consecutive patients with CD and IDA were divided into two groups: patients with a known intolerance to iron sulfate were treated with sucrosomial iron (30 mg of iron/day), while those receiving iron supplementation for the first time were assigned to iron sulfate (105 mg of iron/day). Forty-three patients were enrolled (38 females, mean age 49 ± 9 years). After a follow-up of 90 days both groups showed an increase in Hb levels compared to baseline (+10.1% and +16.2% for sucrosomial and sulfate groups, respectively), and a significant improvement in all iron parameters, with no statistical difference between the two groups. Patients treated with sucrosomial iron reported a lower severity of abdominal symptoms, such as abdominal and epigastric pain, abdominal bloating, and constipation, and a higher increase in general well-being (+33% vs. +21%) compared to the iron sulfate group. Sucrosomial iron can be effective in providing iron supplementation in difficult-to-treat populations, such as patients with CD, IDA, and known intolerance to iron sulfate.


[Standardization and automation of HLA B27 typing by flow cytometry: validation and comparison with microlymphocytotoxicity].
One of the strongest known association between human leukocyte antigen (HLA) phenotype and disease is that of ankylosing spondylitis and HLA-B27. Thus, the determination of HLA-B27 status is an useful tool in the diagnosis of ankylosing spondylitis. To date, the 2 reference methods for HLA typing (microlymphocytotoxicity and molecular biology techniques), are costly in terms of both technician time and materials, and require a great deal of experience. In total, these techniques are not well-suited for routine application in clinical immunology laboratories. Use of flow cytometry has recently been applied for HLA-B27 typing. Nevertheless, it requires an extensive validation protocol. We developed a flow cytometry technique as standardized as possible (whole blood, automated lysing system, automated photomultiplier voltage calibration, definition of thresholds stable with time) and validated our results by comparison with microlymphocytotoxicity. In total, 326 samples were analyzed. We found 99% of concordant results between the 2 techniques, and neither false positive results nor false negative results with flow cytometry could be observed. These results illustrate the reliability of the protocol. It should be remembered that reference technique remains necessary to confirm the few results (< 1%) found in "grey zone" by flow cytometry. Standardization of flow cytometry techniques, as described in this work for HLA B27, seems to be a reasonable goal for the next decade in clinical immunology laboratories.


Saturated amplification of a collisionally pumped optical-field-ionization soft X-ray laser at 41.8 nm.
We report the first saturated amplification of an optical-field-ionization soft x-ray laser. The amplifying medium is generated by focusing a circularly polarized 330-mJ, 35-fs, 10-Hz Ti:sapphire laser system in a few-mm cell filled with xenon. A gain of 67 cm(-1) on the 4d(9)5p-4d(9)5d transition at 41.8 nm in Pd-like xenon and a gain-length product of 15 have been inferred at saturation. This source delivers about 5 x 10(9) photons per pulse. The influence of the pumping energy and the laser polarization on the lasing output are also presented.


Ontologies Applied in Clinical Decision Support System Rules: Systematic Review.
Clinical decision support systems (CDSSs) are important for the quality and safety of health care delivery. Although CDSS rules guide CDSS behavior, they are not routinely shared and reused. Ontologies have the potential to promote the reuse of CDSS rules. Therefore, we systematically screened the literature to elaborate on the current status of ontologies applied in CDSS rules, such as rule management, which uses captured CDSS rule usage data and user feedback data to tailor CDSS services to be more accurate, and maintenance, which updates CDSS rules. Through this systematic literature review, we aim to identify the frontiers of ontologies used in CDSS rules. The literature search was focused on the intersection of ontologies; clinical decision support; and rules in PubMed, the Association for Computing Machinery (ACM) Digital Library, and the Nursing & Allied Health Database. Grounded theory and PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 guidelines were followed. One author initiated the screening and literature review, while 2 authors validated the processes and results independently. The inclusion and exclusion criteria were developed and refined iteratively. CDSSs were primarily used to manage chronic conditions, alerts for medication prescriptions, reminders for immunizations and preventive services, diagnoses, and treatment recommendations among 81 included publications. The CDSS rules were presented in Semantic Web Rule Language, Jess, or Jena formats. Despite the fact that ontologies have been used to provide medical knowledge, CDSS rules, and terminologies, they have not been used in CDSS rule management or to facilitate the reuse of CDSS rules. Ontologies have been used to organize and represent medical knowledge, controlled vocabularies, and the content of CDSS rules. So far, there has been little reuse of CDSS rules. More work is needed to improve the reusability and interoperability of CDSS rules. This review identified and described the ontologies that, despite their limitations, enable Semantic Web technologies and their applications in CDSS rules.


Two ribosome recruitment sites direct multiple translation events within HIV1 Gag open reading frame.
In the late phase of the HIV virus cycle, the unspliced genomic RNA is exported to the cytoplasm for the necessary translation of the Gag and Gag-pol polyproteins. Three distinct translation initiation mechanisms ensuring Gag production have been described with little rationale for their multiplicity. The Gag-IRES has the singularity to be located within Gag ORF and to directly interact with ribosomal 40S. Aiming at elucidating the specificity and the relevance of this interaction, we probed HIV-1 Gag-IRES structure and developed an innovative integrative modelling strategy to take into account all the gathered information. We propose a novel Gag-IRES secondary structure strongly supported by all experimental data. We further demonstrate the presence of two regions within Gag-IRES that independently and directly interact with the ribosome. Importantly, these binding sites are functionally relevant to Gag translation both in vitro and ex vivo. This work provides insight into the Gag-IRES molecular mechanism and gives compelling evidence for its physiological importance. It allows us to propose original hypotheses about the IRES physiological role and conservation among primate lentiviruses.


Prevalence of Theileria equi and Babesia caballi infections in horses belonging to resource-poor farmers in the north-eastern Free State Province, South Africa.
The prevalence of Theileria equi and Babesia caballi infections in the north-eastern Free State Province of South Africa was determined by examination of thin and thick Giemsa-stained blood smears, IFAT and PCR. No parasites were detected by microscopy from any blood samples collected at five study sites, Qwaqwa, Kestell, Harrismith, Vrede and Warden. Of the tested serum samples, 28/29 (96.5%), 20/21 (95.2%) and 42/42 (100%) were positive by IFAT for T. equi infections in Harrismith, Kestell and Qwaqwa, respectively, and 5/29 (17.2%), 13/21 (61.9%) and 30/42 (71.4%) were sero-positive for B. caballi infections in Harrismith, Kestell and Qwaqwa, respectively. All DNA samples from the study sites were negative for B. caballi infections by PCR, but five samples, two from each of Kestell and Warden and one from Vrede, were PCR positive for T. equi infections. The high prevalence of antibodies against T. equi and B. caballi in the sampled horses indicates that the animals had been exposed to T. equi and B. caballi infections but the absence of parasitaemia and very low number of positive PCR samples, however, imply that T. equi and B. caballi are endemically stable in the north-eastern Free State Province.


Neuroinflammation in inflammatory bowel disease.
Inflammatory bowel disease is a chronic intestinal inflammatory condition, the pathology of which is incompletely understood. Gut inflammation causes significant changes in neurally controlled gut functions including cramping, abdominal pain, fecal urgency, and explosive diarrhea. These symptoms are caused, at least in part, by prolonged hyperexcitability of enteric neurons that can occur following the resolution of colitis. Mast, enterochromaffin and other immune cells are increased in the colonic mucosa in inflammatory bowel disease and signal the presence of inflammation to the enteric nervous system. Inflammatory mediators include 5-hydroxytryptamine and cytokines, as well as reactive oxygen species and the production of oxidative stress. This review will discuss the effects of inflammation on enteric neural activity and potential therapeutic strategies that target neuroinflammation in the enteric nervous system.


High Filamin a Expression in Adrenocortical Carcinomas Is Associated with a Favourable Tumour Behaviour: A European Multicentric Study.
The insulin-like growth factor 2 (IGF2) promotes cell growth by overactivating the IGF system in an autocrine loop in adrenocortical carcinomas (ACCs). The cytoskeleton protein filamin A (FLNA) acts as a repressor of IGF2 mitogenic signalling in ACC cells. The aims of this study were to test FLNA expression by immunohistochemistry in 119 ACCs and 26 adrenocortical adenomas (ACAs) and to evaluate its relationship with clinicopathological features and outcome in ACCs. We found that 71.4% of ACCs did not express FLNA, whereas FLNA absence was a rare event in ACAs (15.4%, p < 0.001 vs. ACCs). In addition, the expression of FLNA was associated with a less aggressive tumour behaviour in ACCs. Indeed, the subgroup of ACCs with high FLNA showed a lower ENSAT stage, Weiss score, and S-GRAS score compared to ACCs with low FLNA expression (p < 0.05). Moreover, patients with high FLNA had a longer overall survival than those with low FLNA (p < 0.05). In conclusion, our data suggest that FLNA may represent a "protective" factor in ACCs, and the integration of FLNA immunohistochemical expression in ACC tissues along with other clinical and molecular markers could be helpful to improve diagnostic accuracy and prognosis prediction in ACCs.


Effects of high dietary levels of soybean meal and its constituents (potassium, oligosaccharides) on foot pad dermatitis in growing turkeys housed on dry and wet litter.
Soybean meal (SBM) is the main protein source in diets for turkeys. High dietary levels of SBM are thought to increase the incidence of foot pad dermatitis (FPD). Therefore, this study was conducted to test potential effects of high SBM and to elucidate which constituents in SBM might be associated with the development of FPD. Two week-old female turkeys were allotted to four groups of 29 birds each, and housed on dry wood shavings in floor pens over a period of three weeks. Four different diets were fed: control, high SBM, high potassium (K) or high oligosaccharide (OL) diet. Additionally, for only 8 h/d half of the animals in each group were exposed to wet litter (27% DM) in adjacent separate boxes. The foot pads of all birds were assessed on days 0, 7, 14 and 21 for external lesions. For the histopathology of the foot pads, on day 0 three birds from each group, and on days 7 and 14 six birds per feeding group were selected. The remaining birds in each group were sacrificed on day 21 and their pads were evaluated histologically. High dietary levels of SBM, potassium or oligosaccharides did not influence the severity of FPD on dry litter, but slightly increased the severity on wet litter. However, there were no histopathological differences in FPD severity between these dietary treatments within each litter form compared to the control. Nevertheless, the FPD severity was in general higher on wet litter. Thus, litter moisture appears to be one of the most important factors involved in FPD in turkeys. In addition, all nutritional factors which increase water intake and excreta or litter moisture may contribute to an increased development and severity of FPD in turkeys.


A scoping review of the reasons for and approaches to non-uptake of pertussis and influenza vaccinations in pregnant women in the United Kingdom and Ireland.
Pertussis and influenza cause significant morbidity and mortality in pregnancy and the neonatal period. Maternal vaccination in pregnancy would reduce harm, but low vaccine uptake is a concern. This scoping review aimed to understand the reasons for, and approaches, to non-uptake of pertussis and influenza vaccinations in pregnant women in the UK and Ireland. The inclusion criteria of this scoping review consist of pregnant women who avail of pertussis and influenza vaccines in the UK and Ireland. MEDLINE, EMBASE, Web of Science and CINAHL databases were searched in June 2021 and updated in October 2022. Searches were limited to English language reports published after 2011. We followed the Joanna Briggs Institute guidance on scoping reviews. Data were extracted and charted. Five themes emerged from the literature. Acceptability, as well as organisational and awareness issues, were overarching themes regarding reasons for and approaches to non-uptake of the vaccines respectively. Other themes included healthcare professional factors, information interpretation and pregnancy-related factors. Women need clear, comprehensible information, ideally provided by their healthcare professionals, in a way that is meaningful and addresses their circumstances and risk perceptions. This research will serve as a base for future work that aims behaviour science interventions at the wider pregnant population as well as the target groups that have been identified in this review.


Reduced nicotinamide adenine dinucleotide phosphate oxidase-independent resistance to Aspergillus fumigatus in alveolar macrophages.
The fungal pathogen Aspergillus fumigatus is responsible for increasing numbers of fatal infections in immune-compromised humans. Alveolar macrophages (AM) are important in the innate defense against aspergillosis, but little is known about their molecular responses to fungal conidia in vivo. We examined transcriptional changes and superoxide release by AM from C57BL/6 and gp91(phox)(-/-) mice in response to conidia. Following introduction of conidia into the lung, microarray analysis of AM showed the transcripts most strongly up-regulated in vivo to encode chemokines and additional genes that play a critical role in neutrophil and monocyte recruitment, indicating that activation of phagocytes represents a critical early response of AM to fungal conidia. Of the 73 AM genes showing > or = 2-fold changes, 8 were also increased in gp91(phox)(-/-) mice by conidia and in C57BL/6 mice by polystyrene beads, suggesting a common innate response to particulate matter. Ingenuity analysis of the microarray data from C57BL/6 mice revealed immune cell signaling and gene expression as primary mechanisms of this response. Despite the well-established importance of phagocyte NADPH oxidase in resisting aspergillosis, we found no evidence of this mechanism in AM following introduction of conidia into the mouse lung using transcriptional, luminometry, or NBT staining analysis. In support of these findings, we observed that AM from C57BL/6 and gp91(phox)(-/-) mice inhibit conidial germination equally in vitro. Our results indicate that early transcription in mouse AM exposed to conidia in vivo targets neutrophil recruitment, and that NADPH oxidase-independent mechanisms in AM contribute to inhibition of conidial germination.


Nursing research-the road ahead.
In a summary of NURSING RESEARCH anniversary year articles, implications from and highlights of the articles are discussed and future needs of and directions for research in nursing are outlined.


Rac GTPase isoforms Rac1 and Rac2 play a redundant and crucial role in T-cell development.
Rac GTPases have been implicated in the regulation of diverse functions in various blood cell lineages, but their role in T-cell development is not well understood. We have carried out conditional gene targeting to achieve hematopoietic stem cell (HSC)- or T-cell lineage-specific deletion of Rac1 or Rac1/Rac2 by crossbreeding the Mx-Cre or Lck-Cre transgenic mice with Rac1(loxp/loxp) or Rac1(loxp/loxp);Rac2(-/-) mice. We found that (1) HSC deletion of both Rac1 and Rac2 inhibited production of common lymphoid progenitors (CLPs) in bone marrow and suppressed T-cell development in thymus and peripheral organs, whereas deletion of Rac1 moderately affected CLP production and T-cell development. (2) T cell-specific deletion of Rac1 did not affect T-cell development, whereas deletion of both Rac1 and Rac2 reduced immature CD4(+)CD8(+) and mature CD4(+) populations in thymus as well as CD4(+) and CD8(+) populations in spleen. (3) The developmental defects of Rac1/Rac2 knockout T cells were associated with proliferation, survival, adhesion, and migration defects. (4) Rac1/Rac2 deletion suppressed T-cell receptor-mediated proliferation, IL-2 production, and Akt activation in thymocytes. Thus, Rac1 and Rac2 have unique roles in CLP production and share a redundant but essential role in later stages of T-cell development by regulating survival and proliferation signals.


Dignity and respect during pregnancy and childbirth: a survey of the experience of disabled women.
Despite the increasing number of women with disability globally becoming pregnant, there is currently limited research about their experiences. A national survey of women's experience of dignity and respect during pregnancy and childbirth raised concerns about the possibility of women with disability having unequal care with overall less choice and control. To address this further we conducted a study to explore the experiences of dignity and respect in childbirth of women with disability. The study involved a self-selecting, convenience sample of 37 women who had given birth in the United Kingdom and Ireland and had completed an internet-based survey. Women were identified through online networks and groups of and for disabled parents and for people with specific medical conditions. Data were collected using an online survey tool. Survey data were analysed using descriptive statistics. Thematic analysis was used for open questions. Despite generally positive responses, just over half of the group of women expressed dissatisfaction with care provision. Only 19% thought that reasonable adjustments or accommodations had been made for them (7/37). When reasonable adjustments were not in place, participants' independence and dignity were undermined. More than a quarter of women felt they were treated less favourably because of their disability (10/37, 27%). At all points in the pregnancy continuum more than a quarter of women felt their rights were either poorly or very poorly respected; however this was greatest in the postnatal period (11/35, 31%). In addition, more than half of the women (20/36, 56%) felt that maternity care providers did not have appropriate awareness of or attitudes to disability. Women's experiences of dignity and respect in childbirth revealed that a significant proportion of women felt their rights were poorly respected and that they were treated less favourably because of their disability. This suggests that there is a need to look more closely at individualised care. It was also evident that more consideration is required to improve attitudes of maternity care providers to disability and services need to adapt to provide reasonable adjustments to accommodate disability, including improving continuity of carer.


Commitment of C3H10T1/2 pluripotent stem cells to the adipocyte lineage.
The increase of adipose tissue mass associated with obesity is due in part to an increase in the number of adipocytes. This hyperplasia results from recruitment of pluripotent stem cells present in the vascular stroma of adipose tissue. A model cell culture system has been developed that recapitulates this process both ex vivo and in vivo. After treatment of pluripotent C3H10T1/2 stem cells with bone morphogenic protein 4 (BMP4) during proliferation followed by differentiation inducers at growth arrest, the cells synchronously enter S phase and undergo mitotic clonal expansion, a hallmark of preadipocyte differentiation. Upon exiting the cell cycle, these cells express adipocyte markers and acquire adipocyte characteristics at high frequency. C3H10T1/2 cells treated with BMP4 in cell culture and implanted s.c. into athymic mice develop into tissue indistinguishable from adipose tissue in normal fat depots. We interpret the findings as evidence that BMP4 is capable of triggering commitment of pluripotent C3H10T1/2 stem cells to the adipocyte lineage.


Head and neck manifestations of dermatomyositis-polymyositis.
Dermatomyositis and polymyositis are rare disorders of connective tissue that manifest themselves primarily as muscular weakness. Fifty-five percent of 45 patients with this diagnosis at Thomas Jefferson University Hospital had symptoms referable to the head and neck. While dysphagia and the cutaneous manifestation predominate, such symptoms as facial swelling and oral mucosal disorders may require the treating physician to seek the advice of an otolaryngologist before the patient suffers any muscular changes. A thorough knowledge of this disease entity is essential to specialists in head and neck diseases.


[Computed tomography of the normal male and female lesser pelvis].
The paper is concerned with an analysis of transverse slices of male and female small pelvis in CT-images. A high CT resolution in the characteristics of topical interrelationships of the pelvic organs was shown. A variability of the interrelationships of the pelvic organs with respect to their condition and the value of this factor for correct interpretation of tomograms were shown. A thorough preparation of patients for examination of the pelvic organs is very important for establishing diagnosis, topical characteristics and determination of a degree of dissemination of a pathological process.


The Relations Between Physical Activity Level, Executive Function, and White Matter Microstructure in Older Adults.
The population of older adults is increasing, indicating a need to examine factors that may prevent or mitigate age-related cognitive decline. The current study examined whether microstructural white matter characteristics mediated the relation between physical activity and executive function in older adults without any self-reported psychiatric and neurological disorders or cognitive impairment (N = 43, mean age = 73 y). Physical activity was measured by average intensity and number of steps via accelerometry. Diffusion tensor imaging was used to examine microstructural white matter characteristics, and neuropsychological testing was used to examine executive functioning. Parallel mediation models were analyzed using microstructural white matter regions of interest as mediators of the association between physical activity and executive function. Results indicated that average steps was significantly related to executive function (β = 0.0003, t = 2.829, P = .007), while moderate to vigorous physical activity was not (β = 0.0007, t = 1.772, P = .08). White matter metrics did not mediate any associations. This suggests that microstructural white matter characteristics alone may not be the mechanism by which physical activity impacts executive function in aging.


Whole blood tissue factor procoagulant activity remains detectable during severe aplasia following bone marrow and peripheral blood stem cell transplantation.
Using a novel whole blood assay, we recently demonstrated that tissue factor procoagulant activity (TF PCA) is present in normal individuals. Preliminary experiments suggested that this activity is localized in the mononuclear cell fraction. Postulating that whole blood TF PCA would therefore be undetectable when monocytes and neutrophils are absent from peripheral blood, we assayed TF PCA during the peri-transplant period in 15 consecutive patients undergoing allogeneic (n = 12) or autologous (n = 3) bone marrow transplantation (BMT) or peripheral blood stem cell transplantation (PBSCT). Baseline (pre-transplant) mean TF PCA was higher in patients compared to normal controls (P <0.005). Unexpectedly, although TF PCA during the period of profound aplasia was significantly reduced compared to baseline (p <0.05), fully 55% of the initial activity remained detectable. During the engraftment phase, TF PCA returned to pre-transplant levels, with a linear correlation between monocyte counts and TF PCA (r = 0.63). In contrast to normal whole blood, incubation of aplastic samples with E. Coli lipopolysaccharide ex vivo failed to induce TF PCA. Throughout the period of study--but especially during the aplastic phase--the absolute number of circulating endothelial cells (CECs) that were TF antigen-positive was increased compared to normals (P <0.001). However, removal of these cells from whole blood samples failed to significantly diminish total TF PCA indicating that CECs alone could not account for the detectable TF PCA during aplasia. We conclude that neither circulating mature myelo-monocytic cells nor endothelial cells can account for all the functionally intact TF in peripheral blood. Further studies are needed to identify the other source(s) of TF PCA.


Predictors of humeral head ischemia after intracapsular fracture of the proximal humerus.
The purpose of this study was to evaluate predictors of fracture-induced humeral head ischemia. Between February 1998 and December 2001, 100 intracapsular fractures of the proximal humerus, treated by open surgery, were included in a prospective surgical evaluation protocol (mean age, 60 years; minimum, 21 years; maximum, 88 years; 45 men; 57 right shoulders). Fracture morphology was assessed following a structured questionnaire and based on radiographic and intraoperative findings. Perfusion was assessed intraoperatively by observation of backflow after a borehole was drilled into the central part of the head in all shoulders and by intraosseous laser Doppler flowmetry in 46. Good predictors of ischemia were the length of the metaphyseal head extension (accuracy, 0.84 for calcar segments <8 mm), the integrity of the medial hinge (accuracy, 0.79 for disrupted hinge), and the basic fracture pattern (accuracy, 0.7 for combined types 2, 9, 10, 11, and 12). Moderate and poor predictors of ischemia were fractures consisting of four fragments (accuracy, 0.67), angular displacement of the head (accuracy, 0.62 for angulations over 45 degrees ), the amount of displacement of the tuberosities (accuracy, 0.61 for displacement over 10 mm), glenohumeral dislocation (accuracy, 0.49), head-split components (accuracy, 0.49), and fractures consisting of three fragments (accuracy, 0.38). When the above criteria (anatomic neck, short calcar, disrupted hinge) were combined, positive predictive values of up to 97% could be obtained. The most relevant predictors of ischemia were the length of the dorsomedial metaphyseal extension, the integrity of the medial hinge, and the basic fracture type determined with the binary description system.


Insulin receptor binding to monocytes, insulin secretion, and glucose tolerance following metformin treatment. Results of a double-blind cross-over study in type II diabetics.
We studied the effect of metformin therapy (1700 mg daily) on glucose tolerance, insulin secretion, and insulin binding to monocytes in 10 non-insulin-dependent diabetics (mean duration of disease 2.6 yr) who were treated for 4 wk with either metformin or placebo in a double-blind cross-over study. Metformin induced a significant decrease of glucose levels during an oral glucose load compared with placebo treatment (P less than 0.001). All patients studied showed normal or elevated basal insulin and C-peptide levels; their responses to an oral glucose load, however, were relatively hypoinsulinemic without any significant difference between metformin and placebo. Insulin binding to monocytes was nearly identical at all insulin concentrations tested in the placebo or metformin therapy phase. These data indicate that the glucose-lowering potency of metformin in non-insulin-dependent diabetics cannot be associated with changes in receptor number or affinity. It is suggested that metformin might have a positive influence on postreceptor defects in non-insulin-dependent diabetics.


Effects of biomechanical forces on signaling in the cortical collecting duct (CCD).
An increase in tubular fluid flow rate (TFF) stimulates Na reabsorption and K secretion in the cortical collecting duct (CCD) and subjects cells therein to biomechanical forces including fluid shear stress (FSS) and circumferential stretch (CS). Intracellular MAPK and extracellular autocrine/paracrine PGE2 signaling regulate cation transport in the CCD and, at least in other systems, are affected by biomechanical forces. We hypothesized that FSS and CS differentially affect MAPK signaling and PGE2 release to modulate cation transport in the CCD. To validate that CS is a physiological force in vivo, we applied the intravital microscopic approach to rodent kidneys in vivo to show that saline or furosemide injection led to a 46.5 ± 2.0 or 170 ± 32% increase, respectively, in distal tubular diameter. Next, murine CCD (mpkCCD) cells were grown on glass or silicone coated with collagen type IV and subjected to 0 or 0.4 dyne/cm(2) of FSS or 10% CS, respectively, forces chosen based on prior biomechanical modeling of ex vivo microperfused CCDs. Cells exposed to FSS expressed an approximately twofold greater abundance of phospho(p)-ERK and p-p38 vs. static cells, while CS did not alter p-p38 and p-ERK expression compared with unstretched controls. FSS induced whereas CS reduced PGE2 release by ∼40%. In conclusion, FSS and CS differentially affect ERK and p38 activation and PGE2 release in a cell culture model of the CD. We speculate that TFF differentially regulates biomechanical signaling and, in turn, cation transport in the CCD.


The reliability of the functional independence measure: a quantitative review.
The reliability of the Functional Independence Measure (FIMSM) for adults was examined using procedures of meta-analysis. Eleven published studies reporting estimates of reliability for the FIM were located using computer searches of Index Medicus, Psychological Abstracts, the Functional Assessment Information Service, and citation tracking. Studies were identified and coded based on type of reliability (interrater, test-retest, or equivalence), method of data analysis, size of sample, and training or experience of raters. Information from the articles was coded by two independent raters. Interrater reliability for coding all elements included in the analysis ranged from .89 to 1.00. The 11 investigations included a total of 1,568 patients and produced 221 reliability coefficients. The majority of the reliability values (81%) were from interrater reliability studies, and the intraclass correlation coefficient (ICC) was the most commonly used statistical procedure to compute reliability. The reported reliability values were converted to a common correlation metric and aggregated across the 11 studies. The results revealed a median interrater reliability for the total FIM of .95 and median test-retest and equivalence reliability values of .95 and .92, respectively. The median reliability values for the six FIM subscales ranged from .95 for Self-Care to .78 for Social Cognition. For the individual FIM items, median reliability values varied from .90 for Toilet Transfer to .61 for Comprehension. Median and mean reliability coefficients for FIM motor items were generally higher than for items in the cognitive or communication subscales. Based on the 11 studies examined in this review the FIM demonstrated acceptable reliability across a wide variety of settings, raters, and patients.


Gender-specific relationship between alcohol consumption and injury in the South Korean adults: A nationwide cross-sectional study.
Alcohol-related injuries have been concerned worldwide. However, there have been no large cross-sectional epidemiologic studies. The aim of this study was to investigate the association between alcohol and the prevalence of injury according to gender in a representative sample of the South Korean population. This cross-sectional study was based on data obtained in the Korea National Health and Nutrition Examination Survey from 2010 to 2012. In total, 15,249 Korean adults (7128 men and 8112 women) aged 19 years or older were enrolled. Injury was defined as the incidence of an injury or intoxication within the year before completing the survey questionnaire. Univariate and multiple logistic regression analyses were conducted to analyze the relationship between alcohol consumption and the prevalence of injury. Heavy alcohol consumption and high-risk drinking were associated with a higher prevalence of injury in women (adjusted odds ratio [aOR] and corresponding 95% confidence interval [CI]: 2.48 [1.321, 4.656], 1.816 [1.136, 2.929], respectively), and Alcohol Use Disorders Identification Test (AUDIT) scores ≥20 were associated with a higher prevalence of injury in both men and women (aOR and 95% CI: 1.425 [1.004, 2.024] and 3.71 [2.067, 6.66], respectively). According to the AUDIT scores results, women who were injured reported significantly more high-risk drinking behaviors per month compared with those who were not injured. Gender disparities in the relationship between alcohol and the prevalence of injury were found. Indeed, future research using a prospective design should examine the causal relationship between alcohol consumption and the prevalence injury according to gender to confirm that alcohol is a risk factor for injury and to identify the possible mechanisms underlying this phenomenon.


Structure of Vps75 and implications for histone chaperone function.
The vacuolar protein sorting 75 (Vps75) histone chaperone participates in chromatin assembly and disassembly at both active and inactive genes through the preferential binding to histone H3-H4. Vps75 is also one of two histone chaperones, along with antisilencing factor 1, that promotes histone H3-Lys-56 acetylation by the regulation of Ty1 transposition protein 109 (Rtt109) histone acetyltransferase. Here, we report the x-ray crystal structure of Vps75 and carry out biochemical studies to characterize its interaction with Rtt109. We find that the Vps75 structure forms a homodimeric "headphone" architecture that includes an extended helical dimerization domain and earmuff domains at opposite ends and sides of the dimerization domain. Despite the similar overall architecture with the yeast nucleosome assembly protein 1 and human SET/TAF-1beta/INHAT histone chaperones, Vps75 shows several unique features including the relative disposition of the earmuff domains to the dimerization domain, characteristics of the earmuff domains, and a pronounced cleft at the center of the Vps75 dimer. These differences appear to correlate with the unique function of Vps75 to interact with Rtt109 for histone acetylation. Our biochemical studies reveal that two surfaces on the earmuff domain of Vps75 participate in Rtt109 interaction with a stoichiometry of 2:1, thus leaving the pronounced central cleft of the Vps75 dimer largely accessible for histone binding. Taken together, our data provide a structural framework for understanding how Vps75 mediates both nucleosome assembly and histone acetylation by Rtt109.


Duplication of the alimentary tract.
Duplications of the intestinal tract as can be seen from the embryologic and anatomic descriptions are varied and frequently complex. The great variety of presentation and pathology encountered requires almost individual treatment for each case. Certainly total surgical excision, or at the very least, good complete internal drainage should be carried out in these cases. Correct therapy should afford relief of the patients's symptoms and prevent future complications.


Overproduction, purification and characterization of FgaPT2, a dimethylallyltryptophan synthase from Aspergillus fumigatus.
A putative dimethylallyltryptophan synthase gene, fgaPT2, was identified in the genome sequence of Aspergillus fumigatus. fgaPT2 was cloned and overexpressed in Saccharomyces cerevisiae. The protein FgaPT2 was purified to near homogeneity and characterized biochemically. This enzyme was found to convert L-tryptophan to 4-dimethylallyltryptophan, a reaction known to be the first step in ergot alkaloid biosynthesis. FgaPT2 is a soluble, dimeric protein with a subunit size of 52 kDa, and contains no putative prenyl diphosphate binding site (N/D)DXXD. Km values for L-tryptophan and dimethylallyl diphosphate (DMAPP) were determined as 8 and 4 microM, respectively. Metal ions, such as Mg2+ and Ca2+, enhance the reaction velocity, but are not essential for the enzymic reaction. FgaPT2 showed a relatively strict substrate specificity for both tryptophan and DMAPP. FgaPT2 is the first enzyme in the biosynthesis of ergot alkaloids to be purified and characterized in homogeneous form after heterologous overproduction.


Antibodies in the pathogenesis of hypertension.
It has long been known that circulating levels of IgG and IgM antibodies are elevated in patients with essential and pregnancy-related hypertension. Recent studies indicate these antibodies target, and in many cases activate, G-protein coupled receptors and ion channels. Prominent among these protein targets are AT1 receptors, α1-adrenoceptors, β1-adrenoceptors, and L-type voltage operated Ca(2+) channels, all of which are known to play key roles in the regulation of blood pressure through modulation of vascular tone, cardiac output, and/or Na(+)/water reabsorption in the kidneys. This suggests that elevated antibody production may be a causal mechanism in at least some cases of hypertension. In this brief review, we will further describe the protein targets of the antibodies that are elevated in individuals with essential and pregnancy-related hypertension and the likely pathophysiological consequences of antibody binding to these targets. We will speculate on the potential mechanisms that underlie elevated antibody levels in hypertensive individuals and, finally, we will outline the therapeutic opportunities that could arise with a better understanding of how and why antibodies are produced in hypertension.


A virtual dissemination framework to inform and evaluate a neonatal project ECHO (NeoECHO).
To present the development, implementation and evaluation of a theoretically grounded novel virtual dissemination evaluation (VDE) framework. Care of intensive care unit patients requires access to the most up-to-date knowledge and best practices. To address this challenge, we present the development, implementation and evaluation of a theoretically grounded novel VDE framework. This framework is applied to a dissemination strategy, NeoECHO, in neonatal intensive care units. Evidence-based virtual education is implemented to prevent, detect and treat necrotizing enterocolitis in neonates. Research Methodology: Discussion Paper-Methodology. The virtual dissemination evaluation framework is a sequential combination of Integration of Integrated-Promoting Action on Research Implementation in Health Services and Moore's Expanded Outcomes frameworks. The framework's conceptual determinants, virtual facilitators and implementation evaluations were operationalized in the NeoECHO dissemination strategy and evaluated for feasibility. The virtual dissemination evaluation framework was conceptually mapped, and operational activities were examined including theoretical constructs drawing on insights of nursing theorists, especially Fawcett's criteria (2005) for frameworks with practical application (significance, internal consistency, parsimony, testability and design fit). The NeoECHO strategy was evaluated for virtual dissemination evaluation adherence, operationalization and feasibility of implementation evaluation. The virtual dissemination evaluation framework meets the criteria for a practical application and demonstrates feasibility for adherence and operationalization consistency. The implementation evaluation was usable in the virtual dissemination of best practices for neonatal care for necrotizing enterocolitis and healthcare providers were actively engaged in using NeoECHO as an implementation strategy. This examination of the foundational aspects of the framework underscores the rigour required for generalization of practical application. Effective virtual dissemination of evidence-based practices to hospital units requires structured delivery and evaluation, enabling engaged healthcare providers to actualize education rapidly. The virtual dissemination evaluation frameworks' potential for narrowing the evidence-based practice gap in neonatal care showcases its wider significance and applicability. Care of neonates in NICUs requires a multidisciplinary approach and necessitates access to the most up-to-date knowledge and best practices. More than traditional dissemination methods are required to bridge the implementation gap. The effective use of the VDE framework can enhance the design, implementation and evaluation of knowledge dissemination, ultimately elevating neonatal care quality. This paper introduces the VDE framework, a sequential combination of the iPARIHS and Moore's EO frameworks-as a methodological tool for designing, implementing and evaluating a neonatal strategy (NeoECHO) for virtual dissemination of education in NICUs. No patient or public contribution.


Cloning and sequencing of the cDNA species for mammalian dimeric dihydrodiol dehydrogenases.
Cynomolgus and Japanese monkey kidneys, dog and pig livers and rabbit lens contain dimeric dihydrodiol dehydrogenase (EC 22.214.171.124) associated with high carbonyl reductase activity. Here we have isolated cDNA species for the dimeric enzymes by reverse transcriptase-PCR from human intestine in addition to the above five animal tissues. The amino acid sequences deduced from the monkey, pig and dog cDNA species perfectly matched the partial sequences of peptides digested from the respective enzymes of these animal tissues, and active recombinant proteins were expressed in a bacterial system from the monkey and human cDNA species. Northern blot analysis revealed the existence of a single 1.3 kb mRNA species for the enzyme in these animal tissues. The human enzyme shared 94%, 85%, 84% and 82% amino acid identity with the enzymes of the two monkey strains (their sequences were identical), the dog, the pig and the rabbit respectively. The sequences of the primate enzymes consisted of 335 amino acid residues and lacked one amino acid compared with the other animal enzymes. In contrast with previous reports that other types of dihydrodiol dehydrogenase, carbonyl reductases and enzymes with either activity belong to the aldo-keto reductase family or the short-chain dehydrogenase/reductase family, dimeric dihydrodiol dehydrogenase showed no sequence similarity with the members of the two protein families. The dimeric enzyme aligned with low degrees of identity (14-25%) with several prokaryotic proteins, in which 47 residues are strictly or highly conserved. Thus dimeric dihydrodiol dehydrogenase has a primary structure distinct from the previously known mammalian enzymes and is suggested to constitute a novel protein family with the prokaryotic proteins.


Gastric mucosal density of Helicobacter pylori estimated by real-time PCR compared with results of urea breath test and histological grading.
The accuracy of the urea breath test (UBT) and histological grading for estimation of the density of Helicobacter pylori in gastric mucosa is not known. Real-time (TaqMan) PCR was used to estimate the total number of H. pylori genomes in biopsy samples. These values were compared with those obtained by the UBT and the histological grade obtained by the Sydney system. The UBT and endoscopy with antral and corporal biopsies were performed in 88 consecutive untreated patients with dyspepsia. Bacterial culture and the rapid urease test were done with fresh biopsy materials. TaqMan PCR and histological examination were done on serial paraffin sections of the biopsy samples. Of the five methods tested, TaqMan PCR had the highest sensitivity and specificity (both 100%) in the diagnosis of H. pylori infection. The mean density of H. pylori genomes for pairs of biopsy samples from individual patients was compared with the individual values obtained by the UBT; correlation between the results was significant. The density of H. pylori genomes was higher in histological grades 1, 2 and 3 than in grade 0, without significant differences between adjacent grades from 1 to 3. These results suggest that the severity of H. pylori infection of the stomach can be estimated by the UBT and that histopathologists might state whether the organism is present or absent, rather than making a quantitative statement as recommended in the Sydney system.


[Reinterventions for immediate obliterations in aorto-iliac and femoro-popliteal reconstructions].
The reasons for immediate failure in aorto-iliac and femoropopliteal surgery are examined in the light of personal experience. Technical errors are the most common cause of such failure. Ways in which the flow can be re-established during a second operation are also explained and the need for urgency is stressed.


Education status among orphans and non-orphans in communities affected by AIDS in Tanzania and Burkina Faso.
The AIDS pandemic has created an estimated 15 million orphans who may face elevated risk of poor health and social outcomes. This paper compares orphans and non-orphans regarding educational status and delay using data collected in three low-income communities affected by AIDS in Tanzania and Burkina Faso. Orphans were significantly more likely not to attend school than were non-orphans and also to be delayed when in school, though, after controlling for confounders, the risk was borderline and non-significant. Multivariate analysis indicates that variables such as age, religion, family of origin, the relation between the child and the head of household and the dependency ratio of the household better explain differences in education than does orphan status. This study suggests, therefore, that orphans' educational status is relatively equivalent to non-orphans perhaps as a result of family based or community program safety nets.


Covalent dye attachment influences the dynamics and conformational properties of flexible peptides.
Fluorescence spectroscopy techniques like Förster resonance energy transfer (FRET) and fluorescence correlation spectroscopy (FCS) have become important tools for the in vitro and in vivo investigation of conformational dynamics in biomolecules. These methods rely on the distance-dependent quenching of the fluorescence signal of a donor fluorophore either by a fluorescent acceptor fluorophore (FRET) or a non-fluorescent quencher, as used in FCS with photoinduced electron transfer (PET). The attachment of fluorophores to the molecule of interest can potentially alter the molecular properties and may affect the relevant conformational states and dynamics especially of flexible biomolecules like intrinsically disordered proteins (IDP). Using the intrinsically disordered S-peptide as a model system, we investigate the impact of terminal fluorescence labeling on the molecular properties. We perform extensive molecular dynamics simulations on the labeled and unlabeled peptide and compare the results with in vitro PET-FCS measurements. Experimental and simulated timescales of end-to-end fluctuations were found in excellent agreement. Comparison between simulations with and without labels reveal that the π-stacking interaction between the fluorophore labels traps the conformation of S-peptide in a single dominant state, while the unlabeled peptide undergoes continuous conformational rearrangements. Furthermore, we find that the open to closed transition rate of S-peptide is decreased by at least one order of magnitude by the fluorophore attachment. Our approach combining experimental and in silico methods provides a benchmark for the simulations and reveals the significant effect that fluorescence labeling can have on the conformational dynamics of small biomolecules, at least for inherently flexible short peptides. The presented protocol is not only useful for comparing PET-FCS experiments with simulation results but provides a strategy to minimize the influence on molecular properties when chosing labeling positions for fluorescence experiments.


Hirsutism and virilization.
In normal females, androstenedione from both the adrenal cortex and ovary, as a result of peripheral conversion, is the source of the majority of biologically active testosterone in the circulation. The control of the secretion of precursor steroid and androgenic hormone (testosterone) in females is not clear at this time. There are a number of possibilities to explain various types of hirsutism and virilization. The presence of true virilization indicates a significant disorder and requires complete investigation. The presence of increased amounts of 17-ketosteroids in the urine implicates the adrenal cortex as a source of the pathologic manifestations. The suppressibility of elevated 17-ketosteroids with cortisol analogues aids in distinguishing between adrenal hyperplasia and autonomous neoplasm of the adrenal cortex. By far the most common entity in this area is simple hirsutism without virilization. Although our knowledge of this disorder is quite incomplete, conservative management is indicated. Further progress in this field is rapidly occurring. An informed clinician can do an adequate job of diagnosis and treatment with the clinical and laboratory tools generally available.


The differential catalytic activity of ribosome-inactivating proteins saporin 5 and 6 is due to a single substitution at position 162.
Saporin, a type I ribosome-inactivating protein produced by the soapwort plant Saponaria officinalis belongs to a multigene family that encodes its several isoforms. The saporin seed isoform 6 has significantly higher N-glycosidase and cytotoxic activities compared with the seed isoform 5, although the two have identical active sites. In the present study, we have investigated the contribution of non-conservative amino acid changes outside the active sites of these isoforms towards their differential catalytic activity. The saporin 6 residues Lys134, Leu147, Phe149, Asn162, Thr188 and Asp196 were replaced by the corresponding saporin 5 residues, Gln134, Ser147, Ser149, Asp162, Ile188 and Asn196, to generate six variants of saporin 6, K134Q, L147S, F149S, N162D, T188I and D196N. By functional characterization, we show that the change in amino acid Asn162 in saporin 6 to aspartic acid residue of saporin 5 contributes mainly to the lower catalytic activity of saporin 5 compared with saporin 6. The non-involvement of other non-conservative amino acids in the differential catalytic activity of these isoforms was confirmed with the help of the double mutations N162D/K134Q, N162D/L147S, N162D/F149S, N162D/T188I and N162D/D196N.


Humoral aspects of the immune response to homografts. II. Relationship between the hemagglutinating and cytotoxic activities of certain isoimmune sera.
Isoimmune sera, prepared in BALB/c mice by immunization with living or lyophilized tissue from C57Bl/6 mice, were found to possess both hemagglutinating and cytotoxic activity for donor cells. Comparative titrations indicated a good correspondence between these two activities. Absorbtion with living or dead donor tissue caused removal or proportionate reduction of both activities. The results are consistent with the existence in isoimmune sera of a single class of isoantibodies, capable of agglutinating donor cells or of sensitizing them for complement lysis. Living and lyophilized tissue differ quantitatively, but not qualitatively, in their capacity to induce formation of these antibodies.


Influence of a Specialized Trigonella foenum-graecum Seed Extract (Libifem), on Testosterone, Estradiol and Sexual Function in Healthy Menstruating Women, a Randomised Placebo Controlled Study.
The aim of the study was to evaluate the effect of Trigonella foenum-graecum (fenugreek) seed extract on sex hormones and sexual function in healthy menstruating women who reported low sexual drive. This short term, single site, double blind, randomised, placebo-controlled study was conducted on 80 women, aged 20 to 49 years. Participants were randomised to either an oral dose of a standardised T. foenum-graecum seed extract (libifem) at a dose of 600 mg/day or placebo over two menstrual cycles. Dehydroepiandrosterone sulfate, progesterone, androstenedione, total and free testosterone, estradiol (E2), luteinizing hormone, follicle stimulating hormone, sex hormone binding globulin and cholesterol were measured at baseline and 8 weeks. The individual aspects of sexual function were measured using the Derogatis interview for sexual functioning and female sexual function index self-administered questionnaires. Stress, fatigue and quality of the relationship with partner were also measured using the PSS (Perceived Stress Scale), MFI-20 (Multidimensional Fatigue Inventory) and DAS (Dyadic Adjustment Scale) quality of life measures, respectively. There was a significant increase in free testosterone and E2 in the active group as well as sexual desire and arousal compared with the placebo group. The results indicate that this extract of T. foenum-graecum may be a useful treatment for increasing sexual arousal and desire in women.


Current dental concepts in antibiotic prophylaxis for total joint replacement patients.
The subject of antibiotic prophylaxis has evoked controversy and much debate over the validity of such practice. In July 1997, the American Dental Association and American Academy of Orthopedic Surgeons issued an advisory statement concerning the use of antibiotic prophylaxis for patients with total joint replacements. A historical perspective of the subject is presented, with a review of the recommendation for total joint replacement antibiotic prophylaxis, a discussion of the new decision-making responsibility for the dentist, and medicolegal ramifications of this change.


Glucocorticoids and the ageing hippocampus.
Approximately 30 % of human and mammalian populations develop cognitive impairments with ageing. Many of these impairments have been linked to dysfunction of the hippocampus, a well studied area of the medial-temporal lobe, which is involved in episodic memory and control of the hypothalamo-pituitary-adrenal stress axis and, thus, of glucocorticoid secretion. This paper reviews the growing body of studies which explore a possible relationship between lifetime exposure to glucocorticoids and hippocampal impairment. There is now strong evidence which associates hypercortisolemia in aged men with later cognitive dysfunction and this complements a wealth of rodent and other human data. We conclude with a discussion of possible pharmacological and behavioural interventions.


Systematic lymphadenectomy for survival in epithelial ovarian cancer: a meta-analysis.
The role of systematic lymphadenectomy (SL) remains unclear for improving overall survival (OS) in epithelial ovarian cancer (EOC). To evaluate the role of SL in EOC, we performed a meta-analysis for comparing the efficacy for OS between SL and unsystematic lymphadenectomy (USL). After the extensive literature search between January 1995 and December 2008, we analyzed 9 studies (2 randomized controlled trials [RCTs] and 7 observational studies) with 21,919 patients with EOC who underwent staging laparotomy including SL or USL. Although SL was a favorable factor for OS compared with USL (hazard ratio [HR], 0.72; 95% confidence interval [CI], 0.68-0.76), the efficacy of SL on increased OS could not be determined in all-stage and early-stage EOC owing to the lack of RCTs and the deviation of weight by large-scale observational studies, whereas SL improved OS in advanced-stage EOC (HR, 0.70; 95% CI, 0.67-0.75). Moreover, SL increased OS in patients with all-stage disease who underwent optimal debulking surgery (HR, 0.84; 95% CI, 0.69-0.99), whereas it could not improve OS statistically in early-stage and advanced-stage diseases. However, SL showed increased OS with marginal significance in advanced-stage EOC patients treated with optimal debulking surgery (HR, 0.82; 95% CI, 0.66-1.02). These findings suggest the possibility that SL can improve OS in advanced-stage EOC. However, the efficacy of SL on OS is still unknown because of the lack of RCTs, which requires more relevant studies for investigating the role of SL in EOC.


Pyramid of Discharge Needs: A Simple Framework on Discharge Planning for Medical Students and Residents.
Medical students and residents often have difficulty with discharge planning and determining appropriate post-hospitalization level of care. As the discharge planning process can be complex, physicians in-training often do not engage until late into the hospitalization or near day of discharge. This paper offers a simple pyramid construct that categorizes common discharge needs into 4 areas or tiers. As the topic of discharge planning is not formally taught in medical education, most trainees learn through experience and by trial and error. Using a simple pyramid and a basic flow chart to guide students and residents, the discharge planning process can be introduced as soon as possible during the hospitalization.


Action of an opiate receptor blocker on ovine cardiopulmonary responses to endotoxin.
The involvement of endorphins in the ovine cardiopulmonary response to endotoxin was evaluated by measuring blood levels of opiate receptor binding substances and administering the opiate receptor blocking agent naloxone prior to and after the administration of lipopolysaccharide. The animals were prepared for chronic study by placement of cardiovascular catheters and cannulation of the lung lymphatic at least 1 wk prior to study. The sheep were given endotoxin (0.75 micrograms/kg) and studied for 6 h. This was accomplished twice in the same animal. Naloxone (2 mg/kg bolus + 2 mg X kg-1 X h-1) was given with one of the two doses of the lipopolysaccharide. The response to endotoxin could be divided into two phases. In phase 1, there was an increase in protein-poor lung lymph and a marked increase in pulmonary artery pressure. In phase 2, the pulmonary lymph flow was elevated but the lymph protein level was higher than in phase 1. The pulmonary artery pressure, however, was near normal. During both phases leukocytes and cardiac output were reduced and the hematocrit was elevated. There was an increase in opiatelike materials in the plasma of these animals, and the response to endotoxin was partially blocked by naloxone. This suggested that endorphin-like materials were involved in the response to endotoxin.