Sexual differences in exploration behavior in Xenopus tropicalis?
The two sexes of a species often differ in many ways. How sexes differ depends on the selective context, with females often investing more in reproductive output and males in territory defense and resource acquisition. This also implies that behavioral strategies may differ between the two sexes, allowing them to optimize their fitness in a given ecological context. Here, we investigated whether males and females differ in their exploration behavior in an aquatic frog (Xenopus tropicalis). Moreover, we explored whether females show different behavioral strategies in the exploration of a novel environment as has been demonstrated previously for males of the same species. Our results show significant sex differences, with males exploring their environment more than females. Yet, similar to males, female exploratory behavior varied significantly among individuals and broadly fell into three categories: shy, intermediate and bold. Moreover, like in males, behavioral strategies are decoupled from morphology and performance. Our results suggest that females are more sedentary than males, with males engaging in greater risk taking by exploring novel environments more. Male and female behaviors could, however, be classified into similar groups, with some individuals being bolder than others and displaying more exploration behavior. The decoupling of morphology and performance from behavior appears to be a general feature in the species and may allow selection to act on both types of traits independently.


A pure enzyme catalyzing penicillin biosynthesis.
Isopenicillin N synthetase (cyclase) has been purified to homogeneity from Cephalosporium acremonium strain C-10. The enzyme has a molecular weight of 40,000 to 42,000 and yields a single band on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The enzyme was purified in 10 percent yield by a combination of protamine sulfate and ammonium sulfate precipitations, gel filtration, and ion-exchange high-performance liquid chromatography. The purified enzyme can be stabilized with sucrose and stored at -20 degrees C for several weeks without any loss in activity.


Globalization of medical services: antidote for rising costs.
The costs of medical services continue to rise despite a number of measures used to contain them. These costs, if not stemmed, will begin to compromise other priorities. Serious problems call for a bold step; and this bold step is to locate medical care facilities in low-cost overseas sites that are rich in high-quality health human resources and have stable and sound governments. Issues pertaining to quality, acceptability, and other factors are surmountable problems.


Molecular and physiological characterization of RV remodeling in a murine model of pulmonary stenosis.
Right ventricular (RV) dysfunction is a common long-term complication in patients after the repair of congenital heart disease. Previous investigators have examined the cellular and molecular mechanisms of left ventricular (LV) remodeling, but little is known about the stressed RV. Our purpose was to provide a detailed physiological characterization of a model of RV hypertrophy and failure, including RV-LV interaction, and to compare gene alterations between afterloaded RV versus LV. Pulmonary artery constriction was performed in 86 mice. Mice with mild and moderate pulmonary stenosis (PS) developed stable hypertrophy without decompensation. Mice with severe PS developed edema, decreased RV function, and high mortality. Tissue Doppler imaging demonstrated septal dyssynchrony and deleterious RV-LV interaction in the severe PS group. Microarray analysis showed 196 genes with increased expression and 1,114 with decreased expression. Several transcripts were differentially increased in the afterloaded RV but not in the afterloaded LV, including clusterin, neuroblastoma suppression of tumorigenicity 1, Dkk3, Sfrp2, formin binding protein, annexin A7, and lysyl oxidase. We have characterized a murine model of RV hypertrophy and failure, providing a platform for studying the physiological and molecular events of RV remodeling. Although the molecular responses of the RV and LV to afterload stress are mostly concordant, there are several key differences, which may represent targets for RV failure-specific therapy.


Description of 3,180 courses of chelation with dimercaptosuccinic acid in children ≤ 5 y with severe lead poisoning in Zamfara, Northern Nigeria: a retrospective analysis of programme data.
In 2010, Médecins Sans Frontières (MSF) discovered extensive lead poisoning impacting several thousand children in rural northern Nigeria. An estimated 400 fatalities had occurred over 3 mo. The US Centers for Disease Control and Prevention (CDC) confirmed widespread contamination from lead-rich ore being processed for gold, and environmental management was begun. MSF commenced a medical management programme that included treatment with the oral chelating agent 2,3-dimercaptosuccinic acid (DMSA, succimer). Here we describe and evaluate the changes in venous blood lead level (VBLL) associated with DMSA treatment in the largest cohort of children ≤ 5 y of age with severe paediatric lead intoxication reported to date to our knowledge. In a retrospective analysis of programme data, we describe change in VBLL after DMSA treatment courses in a cohort of 1,156 children ≤ 5 y of age who underwent between one and 15 courses of chelation treatment. Courses of DMSA of 19 or 28 d duration administered to children with VBLL ≥ 45 µg/dl were included. Impact of DMSA was calculated as end-course VBLL as a percentage of pre-course VBLL (ECP). Mixed model regression with nested random effects was used to evaluate the relative associations of covariates with ECP. Of 3,180 treatment courses administered, 36% and 6% of courses commenced with VBLL ≥ 80 µg/dl and ≥ 120 µg/dl, respectively. Overall mean ECP was 74.5% (95% CI 69.7%-79.7%); among 159 inpatient courses, ECP was 47.7% (95% CI 39.7%-57.3%). ECP after 19-d courses (n = 2,262) was lower in older children, first-ever courses, courses with a longer interval since a previous course, courses with more directly observed doses, and courses with higher pre-course VBLLs. Low haemoglobin was associated with higher ECP. Twenty children aged ≤ 5 y who commenced chelation died during the period studied, with lead poisoning a primary factor in six deaths. Monitoring of alanine transaminase (ALT), creatinine, and full blood count revealed moderate ALT elevation in <2.5% of courses. No clinically severe adverse drug effects were observed, and no laboratory findings required discontinuation of treatment. Limitations include that this was a retrospective analysis of clinical data, and unmeasured variables related to environmental exposures could not be accounted for. Oral DMSA was a pharmacodynamically effective chelating agent for the treatment of severe childhood lead poisoning in a resource-limited setting. Re-exposure to lead, despite efforts to remediate the environment, and non-adherence may have influenced the impact of outpatient treatment. Please see later in the article for the Editors' Summary.


Inhibition of tumor growth by intramuscular injection of cDNA encoding tumor necrosis factor alpha coupled to NGR and RGD tumor-homing peptides.
The antitumor properties of tumor necrosis factor alpha (TNF) and its efficacy in selective destruction of tumor-associated vessels are well known. Besides the TNF protein, the TNF gene has been used for gene therapy of cancer and shown to induce antitumor responses both in animal models and in patients. We show here that the therapeutic properties of the TNF gene are improved by fusing the TNF sequence with those of peptides able to target tumor vessels, such as CNGRCG or ACDCRGDCFCG. Intramuscular administration of plasmid DNA encoding CNGRCG-TNF and ACDCRGDCFCG-TNF (pNGR-TNF and pRGD-TNF, respectively), but not plasmids encoding TNF (pTNF) or empty vector (pMock), inhibited the growth of subcutaneous murine B16F1 melanomas and RMA-T lymphomas implanted at sites distant from the site of plasmid injection. The combination of pNGR-TNF or pRGD-TNF with doxorubicin or melphalan induced stronger effects than single agents. These treatments induced antitumor effects without activating toxic or negative feedback mechanisms. In addition, pRGD-TNF increased the uptake of an antibody directed to a tumor-associated antigen. These results suggest that the therapeutic properties of NGR-TNF and RGD-TNF cDNAs are greater than those of TNF cDNA and provide the rationale for developing new gene therapy approaches based on vascular targeting with TNF coupled to tumor-homing peptides.


Role of vascular channels as a novel mechanism for subchondral bone damage at cruciate ligament entheses in osteoarthritis and inflammatory arthritis.
The purpose of this work was to test whether normal peri-entheseal vascular anatomy at anterior and posterior cruciate ligaments (ACL and PCL) was associated with distribution of peri-entheseal bone erosion/bone marrow lesions (BMLs) in inflammatory arthritis (IA) and osteoarthritis (OA). Normal microanatomy was defined histologically in mice and by 3 T MRI and histology in 21 cadaveric knees. MRI of 89 patients from the Osteoarthritis Initiative and 27 patients with IA was evaluated for BMLs at ACL and PCL entheses. Antigen-induced arthritis (AIA) in mice was evaluated to ascertain whether putative peri-entheseal vascular regions influenced osteitis and bone erosion. Vascular channels penetrating cortical bone were identified in knees of non-arthritic mice adjacent to the cruciate ligaments. On MRI of normal cadavers, vascular channels adjacent to the ACL (64% of cases) and PCL (71%) entheses were observed. Histology of 10 macroscopically normal cadaveric specimens confirmed the location of vascular channels and associated subclinical changes including subchondral bone damage (80% of cases) and micro-cyst formation (50%). In the AIA model, vascular channels clearly provided a site for inflammatory tissue entry and osteoclast activation. MRI showed BMLs in the same topographic locations in both patients with early OA (41% ACL, 59% PCL) and IA (44%, 33%). The findings show that normal ACL and PCL entheses have immediately adjacent vascular channels which are common sites of subtle bone marrow pathology in non-arthritic joints. These channels appear to be key determinants in bone damage in inflammatory and degenerative arthritis.


Analytic density functional theory calculations of pure vibrational hyperpolarizabilities: the first dipole hyperpolarizability of retinal and related molecules.
We present a general approach for the analytic calculation of pure vibrational contributions to the molecular (hyper)polarizabilities at the density functional level of theory. The analytic approach allows us to study large molecules, and we apply the new code to the study of the first dipole hyperpolarizabilities of retinal and related molecules. We investigate the importance of electron correlation as described by the B3LYP exchange-correlation functional on the pure vibrational and electronic hyperpolarizabilities and compare the computed hyperpolarizabilities with available experimental data. The effects of electron correlation on the pure vibrational corrections vary signficantly even between these structurally very similar molecules, making it difficult to estimate these effects without explicit calculations at the density functional theory level. As expected, the frequency-dependent first hyperpolarizability, which determines the experimentally observed second-harmonic generation, is dominated by the electronic term, whereas for the static hyperpolarizability, the vibrational contribution is equally important. As a consequence, frequency extrapolation of the measured optical hyperpolarizabilities can only provide an estimate for the electronic contribution to the static hyperpolarizability, not its total value. The relative values of the hyperpolarizabilities for different molecules, obtained from the calculations, are in reasonable agreement with experimental data.


Deletion of the protein tyrosine phosphatase PTPN22 for adoptive T cell therapy facilitates CTL effector function but promotes T cell exhaustion.
Adoptive cell therapy (ACT) is a promising strategy for treating cancer, yet it faces several challenges such as lack of long-term protection due to T cell exhaustion induced by chronic TCR stimulation in the tumor microenvironment. One benefit of ACT, however, is that it allows for cellular manipulations, such as deletion of the phosphotyrosine phosphatase non-receptor type 22 (PTPN22), which improves CD8+ T cell antitumor efficacy in ACT. We tested whether Ptpn22KO cytolytic T cells (CTLs) were also more effective than Ptpn22WT CTL in controlling tumors in scenarios that favor T cell exhaustion. Tumor control by Ptpn22WT and Ptpn22KO CTL was assessed following adoptive transfer of low numbers of CTL to mice with subcutaneously implanted MC38 tumors. Tumor infiltrating lymphocytes were isolated for analysis of effector functions. An in vitro assay was established to compare CTL function in response to acute and chronic restimulation with antigen-pulsed tumor cells. The expression of effector and exhaustion-associated proteins by Ptpn22WT and Ptpn22KO T cells was followed over time in vitro and in vivo using the ID8 tumor model. Finally, the effect of PD-1 and TIM-3 blockade on Ptpn22KO CTL tumor control was assessed using monoclonal antibodies and CRISPR/Cas9-mediated knockout. Despite having improved effector function at the time of transfer, Ptpn22KO CTL became more exhausted than Ptpn22WT CTL, characterized by more rapid loss of effector functions, and earlier and higher expression of inhibitory receptors (IRs), particularly the terminal exhaustion marker TIM-3. TIM-3 expression, under the control of the transcription factor NFIL3, was induced by IL-2 signaling which was enhanced in Ptpn22KO cells. Antitumor responses of Ptpn22KO CTL were improved following PD-1 blockade in vivo, yet knockout or antibody-mediated blockade of TIM-3 did not improve but further impaired tumor control, indicating TIM-3 signaling itself did not drive the diminished function seen in Ptpn22KO CTL. This study questions whether TIM-3 plays a role as an IR and highlights that genetic manipulation of T cells for ACT needs to balance short-term augmented effector function against the risk of T cell exhaustion in order to achieve longer-term protection.


Short communication: Glucagon-like peptide-2 and coccidiosis alter tight junction gene expression in the gastrointestinal tract of dairy calves.
Tight junction (TJ) proteins are integral factors involved in gut barrier function, and therapy with glucagon-like peptide-2 (GLP-2) enhances gut integrity. Our aim was to assess effects of GLP-2 treatment on mRNA expression of 8 TJ complex proteins in the intestine of dairy calves not infected or infected with Eimeria bovis at 11±3d of age. Mucosal epithelium from jejunum, ileum, and cecum was collected at slaughter from Holstein bull calves assigned to 4 groups: noninfected, buffer-treated (n=5); noninfected, GLP-2 treated (n=4); E. bovis-infected, buffer-treated (n=5); and E. bovis-infected, GLP-2-treated (n=4). Infected calves were orally dosed with 100,000 to 200,000 sporulated E. bovis oocysts on d 0; GLP-2-treated calves received 50 µg of GLP-2/kg of body weight subcutaneously twice daily for 10d beginning on d 18; and buffer-treated calves received an equal injection volume of 0.01 M Na bicarbonate buffer. All calves were killed on d 28. The mRNA expression of coxsackie and adenovirus receptor (CXADR), claudins 1, 2, and 4 (CLDN1, CLDN2, and CLDN4), F11 receptor (F11R), junction adhesion molecule 2 (JAM2), occludin (OCLN), and tight junction protein ZO-1 (TJP1) was determined by real-time quantitative PCR. In jejunum and ileum, an interaction of E. bovis infection and GLP-2 treatment on gene expression was noted. In jejunum of noninfected calves, GLP-2 increased CXADR, CLDN2, OCLN, and TJP1 mRNA expression but had no effect on mRNA expression in infected calves. Treatment with GLP-2 also increased tight junction protein ZO-1 protein expression in jejunum of noninfected calves as determined by immunohistochemistry. In ileum, E. bovis decreased expression of JAM2, OCLN, and TJP1 in buffer-treated calves, and GLP-2 increased TJP1 expression in infected calves. In cecum, E. bovis infection reduced expression of CXADR, CLDN4, F11R, and OCLN, and GLP-2 therapy increased expression of CLDN4, F11R, OCLN, and TJP1. Results are consistent with studies in nonruminants showing decreased expression of TJ complex proteins in the intestinal tract during pathogen-induced diarrhea and increased TJ protein expression in intestinal tissues in response to GLP-2 treatment. In conclusion, E. bovis reduces gene expression of TJ proteins primarily in cecum of calves 28d postinfection, and GLP-2 increases expression of selected TJ genes in intestinal tissues. Use of GLP-2 to improve gut barrier function in ruminants during pathogen-induced diarrhea warrants additional study.


Breast cancers with compromised DNA repair exhibit selective sensitivity to elesclomol.
The basal-like subtype of breast cancers, including those that contain germline mutations in BRCA1, tend to be triple-negative (i.e. lack expression of estrogen and progesterone receptors and lack overexpression/amplification of the HER2/neu oncogene), which renders them relatively insensitive to existing "targeted" therapy. BRCA1-mutated and basal-like breast cancers harbor compromised ability for repairing oxidative DNA damage by the DNA base-excision repair pathway. We found that this defective repair mechanism predicts sensitivity to elesclomol, an experimental therapeutic that produces elevated levels of oxidative DNA damage. In conclusion, BRCA1-mutated and/or basal-like breast cancers may benefit from treatment regimens that include elesclomol.


Phase II preradiation R115777 (tipifarnib) in newly diagnosed GBM with residual enhancing disease.
Glioblastoma multiforme (GBM) is a lethal primary malignant brain tumor in adults. R115777 (tipifarnib) is an oral agent with antiproliferative effects, being a potent and selective inhibitor of farnesyltransferase. This multicenter, open-label phase II study was designed to evaluate the efficacy and safety of R115777 given after surgery and prior to radiation in patients with newly diagnosed and residual enhancing GBM. Following surgery, an MRI confirmed the presence of residual enhancing tumor. Patients on enzyme-inducing antiseizure drugs (EIASDs) received 600 mg twice per day, and those not on EIASDs received 300 mg twice per day. One to three monthly cycles of R115777 were administered, and radiation was initiated with progression or after three cycles. A cycle consisted of 3 weeks of continuous R115777 followed by a 1-week rest. MRI was done monthly. The primary end point was overall survival; secondary end points were tumor response rate and toxicity. A total of 28 confirmed GBM patients entered the study; 15 patients (54%) were on EIASDs. The overall median time of survival was 7.7 months. There were no tumor responses. Eight patients (29%) had stable disease as the best response. The study was stopped early due to progression of the disease in 12 patients (48%). A total of 24 patients (85%) were off study before the planned treatment schedule for radiation therapy. R115777 administered prior to radiation therapy in patients with newly diagnosed GBM and residual enhancing disease did not result in any measurable responses or improvement in survival. R115777 administered prior to radiation therapy is not recommended for patients with newly diagnosed GBM.


Cloning, expression and localization of human BM88 shows that it maps to chromosome 11p15.5, a region implicated in Beckwith-Wiedemann syndrome and tumorigenesis.
Porcine BM88 is a neuron-specific protein that enhances neuroblastoma cell differentiation in vitro and may be involved in neuronal differentiation in vivo. Here we report the identification, by Western blotting, of homologous proteins in human and mouse brain and the isolation of their respective cDNAs. Several human and mouse clones were identified in the EST database using porcine BM88 cDNA as a query. A human and a mouse EST clone were chosen for sequencing and were found both to predict a protein of 149 amino acids, with 79.9% reciprocal identity, and 76.4% and 70.7% identities to the porcine protein, respectively. This indicated that the clones corresponded to the human and mouse BM88 homologues. In vitro expression in a cell-free system as well as transient expression in COS7 cells yielded polypeptide products that were recognized by anti-BM88 antibodies and were identical in size to the native BM88 protein. Northern-blot analysis showed a wide distribution of the gene in human brain whereas immunohistochemistry on human brain sections demonstrated that the expression of BM88 is confined to neurons. The initial mapping assignment of human BM88 to chromosome 11p15.5, a region implicated in Beckwith-Wiedemann syndrome and tumorigenesis, was retrieved from the UniGene database maintained at the National Centre for Biotechnology Information (NCBI, Bethesda, MD, U.S.A.). We confirmed this localization by performing fluorescence in situ hybridization on BM88-positive cosmid clones isolated from a human genomic library. These results suggest that BM88 may be a candidate gene for genetic disorders associated with alterations at 11p15.5.


Elimination of hepatitis C. Positioning document of the Spanish Association for the Study of the Liver (AEEH).
The Spanish Association for the Study of the Liver (AEEH) is convinced that the elimination of hepatitisC virus (HCV) in Spain is possible as long as we are able to use the resources and tools necessary for it. This document reflects the position of the AEEH regarding the elimination of HCV, establishing a wide range of recommendations that can be grouped into five categories: 1)Screening of HCV according to age, of the existence of classic acquisition risk factors of infection, active search of previously diagnosed patients and development of micro-elimination strategies in vulnerable populations; 2)Simplification of HCV diagnosis (one-step diagnosis and diagnosis at the point of patient care); 3)Simplification of patient treatment and improvement of care circuits; 4)Health policy measures, and, finally, 5)Establishment of HCV elimination indicators.


Natural products and their derivatives as cholinesterase inhibitors in the treatment of neurodegenerative disorders: an update.
Alzheimer's disease (AD) is the most common form of neurodegenerative disorders. If more effective therapies than the ones currently available are not developed that either prevent AD or other neurodegenerative or block progression of the diseases in its very early stages, the economic and societal cost of caring for AD patients will be devastating. Besides the neuropathologic hallmarks of the diseases, namely neurofibrillary tangles and AD neuritic plaques, the disease is characterized neurochemically by a consistent deficit in cholinergic neurotransmission, particularly affecting cholinergic neurons in basal forebrain. AD and other forms of dementia could be treated by the use of agents which restore the level of acetylcholine through inhibition of both two major forms of cholinesterase: acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Moreover, the inhibition of AChE holds a key role not only to enhance cholinergic transmission in the brain but also to reduce the aggregation of beta-amyloid and the formation of the neurotoxic fibrils in AD. Following this view, in recent years, an increased interest has emerged directed to finding drugs able to inhibit both of these events. This review summarizes and highlights recent advances in current knowledge on natural products as cholinesterase inhibitors and how these compounds have also served as the starting points for semi-synthetic analogs with improved properties.


Preterm Delivery Phenotypes in Systemic Lupus Erythematosus Pregnancies.
Women with systemic lupus erythematosus (SLE) are at a greater risk of preterm delivery, many of which may be medically indicated (iatrogenic). We investigated preterm delivery phenotypes in SLE and general population comparators and assessed the role of preeclampsia. We used population-based Swedish Register data (2001-2013) and defined maternal SLE as ≥2 SLE-coded discharge diagnoses from the Patient Register with ≥1 coded by an appropriate specialist. Women from the general population were identified using the Total Population Register. Preterm delivery was defined as <37 weeks and separated into spontaneous and iatrogenic, as well as later versus extremely preterm (32 to <37 weeks vs. <32 weeks). Maternal comorbidity was assessed, and the proportion mediated by preeclampsia was calculated examining first, subsequent, and all pregnancies. Preterm delivery was more common in SLE for the first (22 vs. 6%) and subsequent (15 vs. 4%) pregnancies among 781 SLE-exposed pregnancies and 11,271 non-SLE pregnancies. Of SLE-exposed first births, 27% delivered before 32 weeks, and 90% were iatrogenic (compared with 47% of non-SLE first births). Preterm delivery complicates a greater proportion of SLE pregnancies than general population pregnancies, and a considerable proportion of risk is mediated through preeclampsia.


Cross-Cultural Adaptation, Validity, and Reliability Testing of the Tilburg Frailty Indicator (TFI) Amharic Version for Screening Frailty in Community-Dwelling Ethiopian Older People.
Frailty is a global health problem, including in African countries. Despite this, no reliable or valid frailty instruments incorporate any African language, and no research exists to cross-culturally adapt and test the validity and reliability of instruments commonly used in other countries for use within African countries. The Tilburg Frailty Indicator (TFI) is a reliable and validated instrument with the potential to be relevant for older populations living in Africa. This study aimed to develop the TFI Amharic (TFI-AM) version for use within Ethiopia. This study employed psychometric testing and the evaluation of a translated and adapted instrument. The original English language version of the TFI was translated and culturally adapted into Amharic using the World Health Organization process of translation and adaptation of an instrument. A convenience sample of ninety-six community-dwelling older people 60 years and over was recruited. Cronbach's alpha was used for the analysis of the internal consistency of the TFI Amharic (TFI-AM) version using IBM SPSS 26.0 (IBM Corp., Armonk, NY, USA). Face and content validities of the TFI-AM were determined. The TFI-AM total mean score was 5.76 (±2.89). The internal consistency of the TFI-AM was very good with an overall Cronbach alpha value of 0.82. The physical domain showed the highest reliability with a 0.75 Cronbach's alpha value while the social domain was the lowest with a 0.68 Cronbach's alpha value. The Cronbach's alpha reliability coefficients of the instrument ranged from 0.68 to 0.75. The item content validity index value ranged from 0.83 to 1.0 and the total content validity index average for the instrument was 0.91. The TFI-AM is reliable, valid, and reproducible for the assessment of frailty among community-dwelling older populations in Ethiopia. TFI-AM proved an easy-to-administer, applicable and fast instrument for assessing frailty in community-dwelling older populations.


Calibration belt for quality-of-care assessment based on dichotomous outcomes.
Prognostic models applied in medicine must be validated on independent samples, before their use can be recommended. The assessment of calibration, i.e., the model's ability to provide reliable predictions, is crucial in external validation studies. Besides having several shortcomings, statistical techniques such as the computation of the standardized mortality ratio (SMR) and its confidence intervals, the Hosmer-Lemeshow statistics, and the Cox calibration test, are all non-informative with respect to calibration across risk classes. Accordingly, calibration plots reporting expected versus observed outcomes across risk subsets have been used for many years. Erroneously, the points in the plot (frequently representing deciles of risk) have been connected with lines, generating false calibration curves. Here we propose a methodology to create a confidence band for the calibration curve based on a function that relates expected to observed probabilities across classes of risk. The calibration belt allows the ranges of risk to be spotted where there is a significant deviation from the ideal calibration, and the direction of the deviation to be indicated. This method thus offers a more analytical view in the assessment of quality of care, compared to other approaches.


The Humeral Implant in Shoulder Arthroplasty.
Humeral hemiarthroplasty, anatomic total shoulder arthroplasty, and reverse total shoulder arthroplasty all rely on a prosthetic articular surface fixed to the proximal humerus. Humeral implant designs have changed considerably as a result of improved understanding of proximal humeral anatomy and prosthetic biomechanics. Fixed, monoblock implants have been superseded by modular implants with variable inclination, offset, version, and stem length. Press-fit designs now commonly have surface coatings that allow bony ingrowth. Metaphyseal fixation is often favored over diaphyseal fixation. Both cemented and noncemented fixation continue to be used, and each of these techniques has advantages and disadvantages. Although aseptic loosening rarely requires revision, complications, such as osteolysis, stress shielding, radiolucent lines, and proximal humeral bone loss, can occur. Humeral periprosthetic fractures continue to be a disabling complication and are difficult to manage. Innovations such as short-stemmed implants, stemless implants, and platform stems are currently under clinical investigation.


The Legal Doctrine on 'Limitation of Liability' in the Precedent Analysis on Plastic Surgery Medical Malpractice Lawsuits.
This study intended to review the precedents on plastic surgery medical malpractice lawsuits in lower-court trials, classify the reasons of 'limitation of liability' by type, and suggest a standard in the acknowledgement of limitation of liability ratio. The 30 lower-court's rulings on the cases bearing the medical negligence of the defendants acknowledged the liability ratio of the defendants between 30% and 100%. Ten cases ruled that the defendants were wholly responsible for the negligence or malpractice, while 20 cases acknowledged the limitation of liability principle. In the determination of damage compensation amount, the court considered the cause of the victim side, which contributed in the occurrence of the damage. The court also believed that it is against the idea of fairness to have the assailant pay the whole compensation, even there is no victim-side cause such as previous illness or physical constitution of the patient, and applies the legal doctrine on limitation of liability, which is an independent damage compensation adjustment system. Most of the rulings also limited the ratio of responsibility to certain extent. When considering that the legal doctrine on limitation of liability which supports concrete validity for the fair sharing of damage, the tangible classification of causes of limitation of liability suggested in this study would be a useful tool in forecasting the ruling of a plastic surgery medical malpractice lawsuit.


Gastrointestinal blood flow in the red Irish lord, Hemilepidotus hemilepidotus: long-term effects of feeding and adrenergic control.
Cardiac output, blood flow to the coeliac and mesenteric arteries, dorsal aortic blood pressure and heart rate were recorded simultaneously at rest and postprandial for 6 days in a teleost, the red Irish lord (Hemilepidotus hemilepidotus). We anticipated that gastrointestinal blood flow would increase postprandially, supported by an increase in cardiac output. However, we had no predictions for either the exact time-course of this response, or for the regional distribution of blood flow between to the two major arteries comprising the splanchnic circulation. In resting, unfed animals, blood flow to the coeliac artery and mesenteric artery was 4.1 +/- 0.6 ml min(-1) kg(-1) and 4.9 +/-1.3 ml min(-1) kg(-1), respectively (mean +/- SEM, n = 7), which together represented 34% of cardiac output. Feeding increased blood flow to the coeliac and mesenteric arteries in a time-dependent manner. The increase in coeliac artery blood flow preceded that in the mesenteric artery, a finding that is consistent with the coeliac artery supplying blood to the liver and stomach, while the mesenteric artery supplies blood to the stomach and intestine. Coeliac blood flow had increased by 84 +/- 18% after 1 day and had a peak increase of 112 +/- 40% at day 4 postprandial. Mesenteric blood flow was not significantly elevated at day 1, but had increased by 94 +/- 19% at day 4 postprandial. Cardiac output also increased progressively, increasing by a maximum of 90 +/- 30% at day 4. Because the increase in cardiac output was adequate to meet the postprandial increase in gut blood flow, the postprandial decreases in vascular resistance for the coeliac and mesenteric circulations mirrored the increases in blood flow. Intra-arterial injections of adrenaline and noradrenaline into resting fish more than doubled coeliac and mesenteric vascular resistances, and blood flow decreased proportionately. This adrenergic vasoconstriction was totally abolished by pretreatment with the alpha-adrenoceptor antagonist phentolamine, which in itself approximately halved coeliac and mesenteric vascular resistances. These observations indicate a significant alpha-adrenergic tone in the gastrointestinal circulation of the red Irish lord, the loss of which could not entirely account for the post-prandial increase in gastrointestinal blood flow. Other control mechanisms are suggested.


Factors influencing self-care behaviours of patients with type 2 diabetes in China based on the health belief model: a cross-sectional study.
The study aimed to explore the status and predictors of self-care behaviours in patients with type 2 diabetes in China based on the health belief model. The cross-sectional study included 1140 patients aged ≥36 years with type 2 diabetes who had established health records in community health service institutions. A questionnaire was designed based on the health belief model, which mainly included perceived susceptibility, severity, benefits, barriers, effectiveness, sociodemographic characteristics and self-care behaviours. Using a multistage sampling method, 36 villages and communities were randomly selected in China. A total of 1260 patients with type 2 diabetes were contacted, but 118 refused to participate in the study. Of the 1142 participants, two were subsequently excluded, and the final number of participants included in the study was 1140 (90.5% response rate). The average score of health beliefs was 0.71 (SD=0.08). The logistic regression analysis showed that sex, region, perceived severity, perceived barriers and perceived benefits were related to self-care behaviours. Perceived severity, benefits and barriers were key factors affecting self-care behaviours in patients with type 2 diabetes; health education for patients should be strengthened to improve the self-care level of patients with diabetes.


[Neurogenic bladder caused by spinal cord traction].
A neurogenic bladder was the presenting syndrome in three cases of spinal cord traction. Of the typical symptomatic triad: neuro-orthopedic, cutaneous and urologic, the latter was of primary importance. Symptoms in the first case were incomplete bladder retention with distention of upper urinary tract, right-sided vesicorenal reflux and renal insufficiency. Six months after excision of a sacral lipoma and freeing of the filum terminale, micturition had become normal without residue, and renal function normalized. Right-sided reflux was corrected by submucosal advancement surgery with good results. The clinical history was more suggestive in the second case. Although inaugural symptoms were mictional, there was foot paralysis and a retrosacral lipoma above an abnormal hairy tuft in the upper part of the gluteal cleft. Operation revealed the presence of a dermoid cyst and a lipoma. Their excision combined with section of the filum terminale allowing ascension of the medullary cone. Marked clinical and urodynamic improvement was obtained with normal micturition and disappearance of incontinence. An anti-reflux operation suppressed residual reflux with good urographic results. Marked improvement in mictional disorders was obtained also in the 3rd case after excision of a sacral extradural lipoma and section of the filum terminale, allowing objective ascension of the medullary cone by 4 cm. A very detailed analysis was conducted of similar cases reported in the literature, about 2% of neurogenic bladders in children being affected. The importance of early diagnosis is emphasized as well as the essential need to establish a precise diagnosis of the lipoma of cauda equina and of medullary fixation. Early neurosurgery is justified by the high frequency of improvement in cases treated in this way.


Minding the osmol gap: a sentinel event and subsequent laboratory investigation.
Many hospitals are unable to determine toxic alcohol concentrations in a clinically meaningful time frame. Thus, clinicians use surrogate markers when evaluating potentially poisoned patients. A patient presented after an intentional antifreeze (ethylene glycol) ingestion with an osmol gap of -10.6 that remained stable one hour later. Further investigation revealed that the serum osmolality was calculated and not measured. The true osmol gap was 16.4, which correlated to a measured ethylene glycol concentration of 808 mg/L (80.8 mg/dL, 13.0 mmol/L). A telephone survey of hospital laboratories in our catchment area was performed to investigate the potential for similar events. Thirty-eight (47 percent) hospitals responded. No laboratories were able to test for toxic alcohols. One hospital (2.6 percent) reported routinely calculating osmolality based on chemistries, while two hospitals (5.3 percent) reported scenarios in which this might occur. Thirty-five (92.1 percent) hospitals could directly measure osmolality. Two hospitals (5.3 percent) were reliant on outside laboratories for osmolality measurement. The 47 percent response rate and one geographic area are significant limitations. Over 10 percent of hospitals that responded could have significant difficulty assessing patients with toxic alcohol ingestion. Until the standard of rapidly obtaining toxic alcohol concentrations is broadly implemented, we recommend that policies and procedures be put in place to minimize errors associated with the determination of the osmol gap.


Take away body parts! An investigation into the use of 3D-printed anatomical models in undergraduate anatomy education.
Understanding the three-dimensional (3D) nature of the human form is imperative for effective medical practice and the emergence of 3D printing creates numerous opportunities to enhance aspects of medical and healthcare training. A recently deceased, un-embalmed donor was scanned through high-resolution computed tomography. The scan data underwent segmentation and post-processing and a range of 3D-printed anatomical models were produced. A four-stage mixed-methods study was conducted to evaluate the educational value of the models in a medical program. (1) A quantitative pre/post-test to assess change in learner knowledge following 3D-printed model usage in a small group tutorial; (2) student focus group (3) a qualitative student questionnaire regarding personal student model usage (4) teaching faculty evaluation. The use of 3D-printed models in small-group anatomy teaching session resulted in a significant increase in knowledge (P = 0.0001) when compared to didactic 2D-image based teaching methods. Student focus groups yielded six key themes regarding the use of 3D-printed anatomical models: model properties, teaching integration, resource integration, assessment, clinical imaging, and pathology and anatomical variation. Questionnaires detailed how students used the models in the home environment and integrated them with anatomical learning resources such as textbooks and anatomy lectures. In conclusion, 3D-printed anatomical models can be successfully produced from the CT data set of a recently deceased donor. These models can be used in anatomy education as a teaching tool in their own right, as well as a method for augmenting the curriculum and complementing established learning modalities, such as dissection-based teaching. Anat Sci Educ 11: 44-53. © 2017 American Association of Anatomists.


[Malignant neoplasm in burn scar: Marjolin's ulcer. Report of two cases and review of the literature].
Marjolin's ulcer forms part of a group of neoplasms that originate in a burn scar, a phenomenon associated with superficial tissue trauma. The frequency of Marjolin's ulcer is low and represents between 2 and 5% of all squamous cell carcinomas of the skin. This condition is found three times more frequently in men than in women and is thought to be more aggressive than conventional squamous cell carcinoma of the skin. We present two cases of squamous cell carcinoma that originated on a burn scar. 41 year old woman with gasoline burn on the left foot, 3 months old, in whom an exofitic ulcerated lesion on the right calcaneum region has evolved since she was 32 years old. Left transtibial amputation was decided. Another woman who started its suffering 9 years after a thorax burn with a progressive fungus lesion on the scar area. For its size and as it was a high degree neoplasia, surgical resection and radiotherapy to the zone of the primary with 50 Gy in 25 fractions was decided. Marjolin's ulcer usually occurs in old burn sites that were not skin grafted and were left to heal secondarily. Although it is believed that there is a latency period of 25-40 years after burn injury before the occurrence of malignancy, this may occur in a period as short as 3 months. Recurrence after radical surgery is 14.7%. Nonetheless, because of the aggressive behavior of this type of cancer, appropriate radical treatment allows an adequate control of the disease. Early grafting of the burn site can prevent the formation a malignant neoplasm. This condition should be suspected in a non-healing chronic ulcer on a burn scar.


Toxin and subunit specificity of blocking affinity of three peptide toxins for heteromultimeric, voltage-gated potassium channels expressed in Xenopus oocytes.
The ability of voltage-gated potassium channel alpha-subunits to form heteromultimers has complicated efforts to use toxins to characterize potassium channels in native cells. Here I investigate the effects of subunit composition on toxin blocking affinity, using three members of the Shaker subfamily of potassium channel alpha-subunits (Kv1.1, Kv1.2 and Kv1.4), which are known to form heteromultimers in vivo, in the Xenopus oocyte expression system. These subunits were coexpressed as pairs in which one member was toxin-sensitive and the other relatively insensitive. The blocking affinity of two dendrotoxins (DTX-I and delta-DTX) and a scorpion toxin (tityustoxin-Kalpha) on the resulting mixed population of channels was measured to evaluate three models of toxin block. The single subunit model, in which a single toxin-sensitive subunit renders the channel toxin sensitive, best described all of the data for the two dendrotoxins and the block of tityustoxin-Kalpha for a mixed population of channels composed of Kv1.1 and Kv1.2 subunits. However, with tityustoxin-Kalpha, the data for a mixed population of Kv1.2 and Kv1.4 subunits was fit best by a model in which the toxin interacts with all four subunits for high-affinity block. The data suggest that subunit composition of potassium channels can have a large effect on toxin block and that different toxins yield strikingly diverse results with the same pair of subunits, even when they are nearly identical in blocking affinity for the toxin-sensitive subunit.


Detection and quantification of male-specific fetal DNA in the serum of pregnant cynomolgus monkeys (Macaca fascicularis).
Because of their developmental similarities to humans, nonhuman primates are often used as a model to study fetal development for potential clinical applications in humans. The detection of fetal DNA in maternal plasma or serum offers a source of fetal genetic material for prenatal diagnosis. However, no such data have been reported for cynomolgus monkeys (Macaca fascicularis), an important model in biomedical research. We have developed a specific, highly sensitive PCR system for detecting and quantifying male-specific fetal DNA in pregnant cynomolgus monkeys. We used multiplex quantitative real-time PCR to analyze cell-free DNA in maternal blood serum obtained from 46 pregnant monkeys at gestational weeks 5, 12, and 22. The presence of SRY gene and DYS14 Y chromosomal sequences was determined in 28 monkeys with male-bearing pregnancies. According to confirmation of fetal sex at birth, the probe and primers for detecting the Y chromosomal regions at each time point revealed 100% specificity of the PCR test and no false-positive or false-negative results. Increased levels of the SRY-specific sequences (mean, 4706 copies/mL serum DNA; range, 1731 to 12,625) and DYS14-specific sequences (mean, 54,814 copies/mL serum DNA; range, 4175-131,250 copies) were detected at week 22. The SRY- and DYS14-specific probes appear to be an effective combination of markers in a multiplex PCR system. To our knowledge, this report is the first to describe the detection of cell-free DNA in cynomolgus monkeys.


Organ donation. 3. Brain stem death.
Following an exploration of nurses' perceptions of organ donation, and of consent and patient's rights in the preceding articles, this series concludes with an examination of brain stem death, and in particular the literature which challenges popular assumptions about it. This makes challenging and sometimes disturbing reading, but as the author reminds us, these are issues which theatre nurses cannot ignore.


Construction and characterization of a bispecific anti-CD20 antibody with potent antitumor activity against B-cell lymphoma.
To develop more effective anti-CD20 reagents for B-cell lymphoma, we designed and constructed a bispecific tetravalent anti-CD20 antibody, 11B8/2F2(ScFvHL)(4)-Fc, derived from two fully human monoclonal antibodies (mAb), 2F2 and 11B8. 2F2 is a type I CD20 mAb, which is potent in complement-dependent cytotoxicity (CDC) assays but poor at inducing apoptosis, whereas 11B8 is a type II CD20 mAb, which is effective in induction of apoptosis but ineffective in CDC. Our results showed that 11B8/2F2(ScFvHL)(4)-Fc possessed apoptosis-inducing activity markedly superior to that of 2F2, and even 11B8, 11B8 plus 2F2, and 2F2(ScFvHL)(4)-Fc, a 2F2-derived monospecific tetravalent antibody developed previously. Interestingly, 11B8/2F2(ScFvHL)(4)-Fc displayed a similar ability to mediate CDC as 2F2(ScFvHL)(4)-Fc, although two of its four antigen-binding arms originated from 11B8. To explore why 11B8/2F2(ScFvHL)(4)-Fc was so potent in both CDC and apoptotic activity, a bispecific divalent antibody composed of 2F2 and 11B8, denoted as 11B8/2F2-ScFvFc, was constructed and characterized. Our results partially explained the reason for the potent CDC and apoptosis-inducing activity of 11B8/2F2(ScFvHL)(4)-Fc. Further in vivo therapy studies showed that 11B8/2F2(ScFvHL)(4)-Fc had a significantly more potent antitumor activity compared with 2F2, 11B8, 2F2 plus 11B8, and 2F2(ScFvHL)(4)-Fc. These data suggest that 11B8/2F2(ScFvHL)(4)-Fc may serve as a potential therapeutic agent for B-cell lymphoma.


Transport of amino acid amide sarcosinamide and sarcosinamide chloroethylnitrosourea in human glioma SK-MG-1 cells.
The transport of the amino acid amide N-[3H]sarcosinamide (methyl glycinamide) was investigated in human glioma SK-MG-1 cells. Sarcosinamide uptake was found to be temperature dependent, sodium independent, and linear up to 1 min at 22 degrees C. Equilibrium was reached after 10 min at 22 degrees C with accumulation slightly above unity. Sarcosinamide was not metabolized in the cells as shown by thin layer chromatography. The uptake of sarcosinamide was significantly decreased when the extracellular pH was lowered from 7.5 to 6.0 and significantly enhanced at pH values above 7.5. The latter effect may be due mainly to increased cell permeability at high pH. The uptake of the labeled sarcosinamide was trans-stimulated by excess cold sarcosinamide. Sarcosinamide uptake over a 200-fold range of concentrations followed Michaelis-Menten kinetics with a Km of 0.284 +/- 0.041 mM and a Vmax of 0.154 +/- 0.024 nmol/10(6) cells/min. The uptake of sarcosinamide was significantly reduced by iodoacetate but not by the metabolic poisons NaF, ouabain, or dinitrophenyl, suggesting that the uptake is not dependent on energy, rather it proceeds by facilitated diffusion. Several naturally occurring substrates were unable to inhibit the uptake of sarcosinamide. Leucine significantly reduced the uptake of sarcosinamide, while sarcosinamide was a weak inhibitor of leucine transport. 2-Aminobicyclo[2,2,1]heptane-2-carboxylic acid a specific substrate for the sodium-independent, 2-aminobicyclo[2,2,1]heptane-2-carboxylic acid-sensitive amino acid system L failed to inhibit the uptake of sarcosinamide. Epinephrine reduced the uptake of sarcosinamide and sarcosinamide was equally potent as an inhibitor of epinephrine transport. Dixon plot analysis demonstrated that epinephrine (Km = 0.270 mM) inhibits the uptake of sarcosinamide competitively (Ki = 0.260 mM). These results indicate that sarcosinamide is a substrate for the catecholamine transporter. The alkylating agent, sarcosinamide chloroethylnitrosourea, was tested for its ability to inhibit the uptake of sarcosinamide. The results of Dixon plot analysis were consistent with competitive inhibition of sarcosinamide uptake and the inhibition constant Ki for SarCNU was found to be 3.26 +/- 0.57 mM. The steady-state intracellular concentration of SarCNU was found to be significantly higher (cell:medium ratio of 1.03 +/- 0.01) than that of BCNU cell:medium ratio of 0.52 +/- 0.12). These findings indicate that SarCNU and sarcosinamide share the same carrier for uptake in SK-MG-1 cells. This transport mechanism may be responsible for the increased accumulation of SarCNU as compared to BCNU, a nitrosourea which enters cells by passive diffusion.


Proliferation and significance of clinically relevant β-lactamases.
Inactivation of β-lactam antibiotics by β-lactamases in bacterial infections is associated with some of the most serious infectious disease issues that are currently encountered. The evolution of unique β-lactamases has resulted in more than 1,300 distinct enzymes that have been identified in natural clinical isolates. Of these enzymes, the most deleterious β-lactamases are the extended-spectrum β-lactamases, or ESBLs, that hydrolyze most penicillins and cephalosporins, and the carbapenemases that may inactivate all β-lactam classes of drugs. The most prominent ESBLs worldwide are the CTX-M-14 and CTX-M-15 enzymes. Among enzyme families, the TEM and OXA β-lactamases exhibit the greatest number of variants. The broad groups of carbapenemases are particularly treacherous, especially the KPC serine carbapenemases and the NDM family of metallo-β-lactamases, both of which appear in multidrug-resistant Gram-negative pathogens that are often resistant to most classes of antibiotics. Although new β-lactamase inhibitor combinations are being investigated as a means of controlling infections caused by these organisms, additional approaches are sorely needed.


Risk of Ischemic Stroke After a Facial Bone Fracture in Elderly Patients.
Ischemic stroke is a major disease in our aging society, and the incidence of facial bone fractures among the elderly has increased. However, there have been few studies evaluating stroke after facial bone fractures. The purpose of this study was to investigate the frequency and risk of stroke after facial bone fractures. This study included patients 65 years or older with a diagnosis of facial bone fracture (study group) and patients who had previously undergone plastic surgery procedures such as mass excisions or cosmetic surgery (control group) from 2006 to 2015. We evaluated the incidence of new-onset ischemic stroke and its associated risk factors during a 1-year follow-up period. Patients were excluded if they had a history of stroke or if they were lost to follow-up during the course of the study period. There were no demographic differences between the 2 groups except in age. According to the hazard ratio, the study group had a significantly higher risk of ischemic stroke than did the control group during the follow-up period. There was an identified interaction between the sexes. Only the women in our study group had an increased risk of ischemic stroke that was statistically significant. After adjusting for the risk factors, the increased stroke risk in patients in the study group persisted at about the same level as in the unadjusted analysis. Regarding the stroke-free survival rates, the curve also showed that the study group had a significantly lower 1-year stroke-free survival rate. Facial bone fractures are associated with increased risk of stroke at 1-year follow-up among elderly patients, particularly women.


[Videofluoroscopy study of swallowing in neurogenic dysphagia].
Videofluoroscopy (VFS) was for the first time used for examining swallowing in 49 patients with nervous diseases. Disturbances in each phase of swallowing act are analyzed with evaluation of the time parameters and defects, causes of aspiration in neurogenic dysphagia are discussed, and cricopharyngeal insufficiency is described. Neurogenic dysphagia is characterized by a combination of disorders which determine the degree of dysphagia. The most severe swallowing disorders were observed in patients with multiple foci in the brain stem and in diphtheritic polyneuropathies. The authors conclude that VFS is the optimal method for the diagnosis of neurogenic dysphagia.


Human endometrial DNA methylome is cycle-dependent and is associated with gene expression regulation.
Human endometrium undergoes major gene expression changes, resulting in altered cellular functions in response to cyclic variations in circulating estradiol and progesterone, largely mediated by transcription factors and nuclear receptors. In addition to classic modulators, epigenetic mechanisms regulate gene expression during development in response to environmental factors and in some diseases and have roles in steroid hormone action. Herein, we tested the hypothesis that DNA methylation plays a role in gene expression regulation in human endometrium in different hormonal milieux. High throughput, genome-wide DNA methylation profiling of endometrial samples in proliferative, early secretory, and midsecretory phases revealed dynamic DNA methylation patterns with segregation of proliferative from secretory phase samples by unsupervised cluster analysis of differentially methylated genes. Changes involved different frequencies of gain and loss of methylation within or outside CpG islands. Comparison of changes in transcriptomes and corresponding DNA methylomes from the same samples revealed association of DNA methylation and gene expression in a number of loci, some important in endometrial biology. Human endometrial stromal fibroblasts treated in vitro with estradiol and progesterone exhibited DNA methylation changes in several genes observed in proliferative and secretory phase tissues, respectively. Taken together, the data support the observation that epigenetic mechanisms are involved in gene expression regulation in human endometrium in different hormonal milieux, adding endometrium to a small number of normal adult tissues exhibiting dynamic DNA methylation. The data also raise the possibility that the interplay between steroid hormone and methylome dynamics regulates normal endometrial functions and, if abnormal, may result in endometrial dysfunction and associated disorders.


Polysubstance use classes and health outcomes among women attending specialist substance use treatment services.
Substance use is increasingly prevalent among women. Little research examines subgroups of women with substance use issues to identify their characteristics and thus enable treatment recommendations. The present study used latent class analysis to identify subgroups of substance use among women in substance-use treatment based on use in the 30 days prior to intake and examined changes in mental health and treatment outcomes following 60 days of treatment. Participants were women (N = 493) attending specialist non-government substance use treatment services in New South Wales, Australia. Four distinct classes of substance users were identified: (i) Amphetamine Type Stimulants (ATS) Polysubstance (40.6%, n = 200); (ii) Alcohol Only (33.1%, n = 163); (iii) Cannabis and Alcohol (17.0%, n = 84) and (iv) Other Polysubstance (9.3%, n = 46). Women in the ATS Polysubstance class were the youngest and those in the Alcohol Only class were the oldest. Findings show that classes with high polysubstance use (ATS Polysubstance) differed from the single-substance use class (Alcohol Only). The ATS Polysubstance class had significantly greater improvements in health outcomes after 60 days compared to the Alcohol Only class. These findings suggest that although women with polysubstance use can benefit from substance use treatment, younger women (ATS Polysubstance) may benefit even more than older women (Alcohol Only). Future research should utilise a longitudinal design and examine additional psychosocial characteristics to extend on current findings.


Frequent and unexplained gonadal abnormalities in whitefish (central alpine Coregonus sp.) from an alpine oligotrophic lake in Switzerland.
The occurrence of a large number of whitefish with morphologically altered gonads in Lake Thun (Switzerland) has been reported by commercial fishermen since the year 2000. Macroscopic and microscopic examination of gonads revealed that 35% (281 out of 808) of whitefish from Lake Thun were affected. Frequency of gonadal abnormalities varied significantly with sex, age and ecotype of whitefish. Apparent females (26% [106/408]) showed significantly less gonadal alterations than apparent males (40% [151/225]). Fish with deformed gonads were observed in all age classes from 1 to 6 yr, but were most frequent in the year classes 3+ to 5+. The gonadal alterations showed different frequencies among the 3 ecotypes of whitefish living in the lake: 1 ecotype was less affected (26%) than the other 2 forms (41% and 32%, respectively). The gonadal alterations included adhesions/fusions to the peritoneal wall and the lateral trunk musculature (overall: 5%; in females: 5%; in males: 5%), asymmetry (4%; 6%; 4%), atrophy (4%; 6%; 1%), compartmentations (11%; 4%; 18%), constrictions (3%; 1%; 7%) and hermaphroditism (1.1% of sampled fish, and 10 additional specimens collected by fishermen during the filleting process). In some cases, more than one alteration was observed in the same fish. Hermaphroditism manifested as 3 different types: (1) the lobular type, in which a consecutive sequence of testicular and ovarian lobes are found on the same gonad strand; (2) discrete gonads within one fish, with one gonad strand being ovarian tissue and the other being testicular tissue; and (3) the mosaic type, in which oocytes lie in tissue with normal testicular morphology, or spermatids or sperm are present in ovarian tissue. Several features of the gonadal alterations described in this study of whitefish from Lake Thun have also been reported for whitefish from other areas. However, the Lake Thun situation appears to be unique because of the high prevalence of fish affected and the broad variation of abnormal features. The causes of the frequent appearance of these gonadal alterations in whitefish from Lake Thun remain unclear.


Variability in the incidence of renal replacement therapy over time in Western industrialized countries: A retrospective registry analysis.
A growing number of patients started renal replacement therapy (RRT) in Western industrialized countries between 1980 an early 2000s. Thereafter reports from national and international registries suggest a trend towards stabilization and sometimes a decrease in the incidence rate. To investigate the differences in overall and age-specific incidence rates between industrialized countries from 1998 until 2013. Secondly, to investigate changes in incidence rates over time and their association with specific age categories. We extracted the unadjusted overall incidence of RRT and age-specific incidence rates from renal registry reports in Europe, the United States, Canada, Australia and New Zealand. Time trends in the incidence rate by country and age categories were analyzed by Joinpoint regression analysis. The incidence rate in 2013 ranged from 89 per million population (pmp) in Finland to 363 pmp in the US. Incidence rates in the lower age categories (20-64 year) were similar between countries and remained stable over time. Higher incidence countries were characterized by higher numbers of patients in both the 65-74 and ≥75 year categories starting RRT. Joinpoint analysis confirmed that most countries had significant reductions in the incidence rate at the end of the study period. These reductions were explained by lower numbers of older patients starting RRT and were observed also in countries with lower overall incidence rates. This study confirmed different incidence rates of RRT between industrialized countries worldwide. Countries with the highest overall incidence rates also had the highest incidence rates in the oldest age categories. Since the early 2000's the number of older patients starting RRT is either stabilizing or even decreasing in most countries. This reduction is universal and is also observed in countries with previously low incidence rates.


Size-Exclusion Chromatography-based isolation minimally alters Extracellular Vesicles' characteristics compared to precipitating agents.
Extracellular vesicles (EVs) have become an attractive field among the scientific community. Yet, a major challenge is to define a consensus method for EVs isolation. Ultracentrifugation has been the most widely used methodology but rapid methods, including Size Exclusion Chromatography (SEC) and/or precipitating agents such as Polyethylene glycol (PEG) or PRotein Organic Solvent PRecipitation (PROSPR) have emerged. To evaluate the impact of these different methods on the resulting EV preparations, plasma EVs were isolated using SEC, PEG and PROSPR, and their total protein content, NTA and Cryo-electron microscopy profiles, and EV-markers were compared. Also, their effect on recipient cells was tested. Low protein content and Cryo-EM analysis showed that SEC removed most of the overabundant soluble plasma proteins, which were not removed using PEG and partially by PROSPR. Moreover, only SEC allowed the detection of the EV-markers CD9, CD63 and CD81, LGALS3BP and CD5L, suggesting a putative interference of the precipitating agents in the structure/composition of the EVs. Furthermore, PEG and PROSPR-based EV isolation resulted in reduced cell viability in vitro. These results stress that appropriate EV-isolation method should be considered depending on the forthcoming application of the purified EVs.


Effects of grape seed extract on periodontal disease: an experimental study in rats.
This study aimed to demonstrate the effect of grape seed extract (GSE) on periodontitis. Ligature induced periodontitis was created in 40 rats and they were assigned to four equal groups. One group was fed laboratory diet (group A) while three groups received GSE additionally. Silk ligatures were placed around the cervical area of the mandibular first molars for four weeks to induce periodontitis. The GSE groups were reallocated regarding GSE consumption as: for two weeks before ligation (group B; totally eight weeks), from ligation to two weeks after removal of the ligature (group C; totally six weeks), and for two weeks from ligature removal (group D; totally two weeks). Sections were assessed histologically and immunohistochemically. Inflammatory cell number (ICN), connective tissue attachment level (CAL), osteoclast density (OD), IL-10 and TGF-β stainings in gingival epithelium (GE), connective tissue (GC), and periodontal ligament (PL) were used as the study parameters. Lower ICN, higher CAL, and lower OD were observed in the GSE groups (p<0.05). IL-10 was more intensive in the GSE groups and in the GEs (p<0.05). Group B showed the highest IL-10 for PL (p<0.05). TGF-ß was higher in the GEs of all groups (p<0.017). The results suggest anti-inflammatory activities of GSE, but further investigations are needed for clarification of these activities.


Simple behavioural and physical interventions for nocturnal enuresis in children.
Nocturnal enuresis (bedwetting) is a socially disruptive and stressful condition which affects around 15-20% of five year olds, and up to 2% of young adults. Although there is a high rate of spontaneous remission, the social, emotional and psychological costs can be great. Simple behavioural methods of treating bedwetting include reward systems such as star charts given for dry nights, lifting or waking the children at night to urinate, retention control training to enlarge bladder capacity (bladder training) and fluid restriction. To assess the effects of simple behavioural interventions on nocturnal enuresis in children, and to compare these with other interventions. We searched the Cochrane Incontinence Group trials register. The reference list of a previous version of this review was also searched. Date of the most recent search: December 2001. All randomised or quasi-randomised trials of simple behavioural interventions for nocturnal enuresis in children up to the age of 16. Trials focused solely on daytime wetting were excluded. In a previous version of this review, trials up to 1997 were independently assessed by two reviewers. Previous trials were re-assessed, and further trials were assessed for quality, and data were extracted by another reviewer. Twelve reliable trials met the inclusion criteria, involving 748 children of whom 365 received a simple behavioural intervention. However, within each comparison each outcome was addressed by single trials only, precluding meta-analysis. In single small trials, reward systems (e.g. star charts), lifting and waking were each associated with significantly fewer wet nights, higher cure rates and lower relapse rates compared to controls. There was not enough evidence to evaluate retention control training (bladder training), whether compared with controls or dry bed training, or used as a supplement to alarms, or versus desmopressin. Cognitive therapy may have lower failure and relapse rates than star charts, but this finding was based on one small trial only. One small trial of poor quality suggested that star charts were initially less successful than amitriptyline but this difference did not persist after the treatments stopped. Simple behavioural methods may be effective for some children, but further trials are needed, in particular in comparison with treatments known to be effective, such as desmopressin, tricyclic drugs and alarms. However, simple methods could be tried as first line therapy before considering alarms or drugs, because these alternative treatments may be more demanding and may have adverse effects.


Precursor peptide progastrin(1-80) reduces apoptosis of intestinal epithelial cells and upregulates cytochrome c oxidase Vb levels and synthesis of ATP.
We recently reported that downregulation of gastrin gene expression in colon cancer cells significantly suppresses relative levels of mitochondrial cytochrome c (cyt c) oxidase Vb (Cox Vb) RNA and protein. These unexpected findings suggested the possibility that gastrin gene products [mainly progastrin (PG)] may be directly or indirectly mediating the observed effects in colon cancer cells. Because colon cancer cells do not respond to exogenous PG, we examined the possibility of whether PG regulates Cox Vb expression in gastrin-responsive intestinal epithelial cells (IECs) in vitro. Levels of Cox Vb RNA and protein were significantly increased in a dose-dependent manner in response to PG. Mitochondrial synthesis of ATP was also increased by approximately three- to fivefold in response to optimal concentrations (0.1-1.0 nm) of PG. Possible antiapoptotic effects of PG were additionally examined, because activation of caspases 9 and 3 had been noted in colon cancer cells downregulated for gastrin gene expression. We measured a significant loss in the levels of cyt c in the cytosol of PG-treated vs. control IEC cells, which correlated with a significant loss in the activation of caspases 9 and 3, resulting in a significant loss in DNA fragmentation on PG treatment of the cells. Our results thus suggest the novel possibility that the precursor PG peptide exerts direct antiapoptotic effects on IECs, which may contribute to the observed growth effects of PG on these cells. Additionally, Cox Vb gene appears to be an important intracellular target of PG, resulting in an increase in ATP levels, which may also contribute to the observed increase in the growth of target cells in response to PG.


Harnessing Secondary Coordination Sphere Interactions That Enable the Selective Amidation of Benzylic C-H Bonds.
Engineering site-selectivity is highly desirable especially in C-H functionalization reactions. We report a new catalyst platform that is highly selective for the amidation of benzylic C-H bonds controlled by π-π interactions in the secondary coordination sphere. Mechanistic understanding of the previously developed iridium catalysts that showed poor regioselectivity gave rise to the recognition that the π-cloud of an aromatic fragment on the substrate can act as a formal directing group through an attractive noncovalent interaction with the bidentate ligand of the catalyst. On the basis of this mechanism-driven strategy, we developed a cationic (η5-C5H5)Ru(II) catalyst with a neutral polypyridyl ligand to obtain record-setting benzylic selectivity in an intramolecular C-H lactamization in the presence of tertiary C-H bonds at the same distance. Experimental and computational techniques were integrated to identify the origin of this unprecedented benzylic selectivity, and robust linear free energy relationship between solvent polarity index and the measured site-selectivity was found to clearly corroborate that the solvophobic effect drives the selectivity. Generality of the reaction scope and applicability toward versatile γ-lactam synthesis were demonstrated.


Radiofluorination of an Anionic, Azide-Functionalized Teroligomer by Copper-Catalyzed Azide-Alkyne Cycloaddition.
This study describes the synthesis, radiofluorination and purification of an anionic amphiphilic teroligomer developed as a stabilizer for siRNA-loaded calcium phosphate nanoparticles (CaP-NPs). As the stabilizing amphiphile accumulates on nanoparticle surfaces, the fluorine-18-labeled polymer should enable to track the distribution of the CaP-NPs in brain tumors by positron emission tomography after application by convection-enhanced delivery. At first, an unmodified teroligomer was synthesized with a number average molecular weight of 4550 ± 20 Da by free radical polymerization of a defined composition of methoxy-PEG-monomethacrylate, tetradecyl acrylate and maleic anhydride. Subsequent derivatization of anhydrides with azido-TEG-amine provided an azido-functionalized polymer precursor (o14PEGMA-N3) for radiofluorination. The 18F-labeling was accomplished through the copper-catalyzed cycloaddition of o14PEGMA-N3 with diethylene glycol-alkyne-substituted heteroaromatic prosthetic group [18F]2, which was synthesized with a radiochemical yield (RCY) of about 38% within 60 min using a radiosynthesis module. The 18F-labeled polymer [18F]fluoro-o14PEGMA was obtained after a short reaction time of 2-3 min by using CuSO4/sodium ascorbate at 90 °C. Purification was performed by solid-phase extraction on an anion-exchange cartridge followed by size-exclusion chromatography to obtain [18F]fluoro-o14PEGMA with a high radiochemical purity and an RCY of about 15%.


The emergence of local wrinkling or global buckling in thin freestanding bilayer films.
Periodic wrinkling of a rigid capping layer on a deformable substrate provides a useful method for templating surface topography for a variety of novel applications. Many experiments have studied wrinkle formation during the compression of a rigid film on a relatively soft pre-strained elastic substrate, and most have focused on the regime where the substrate thickness can be considered semi-infinite relative to that of the film. As the relative thickness of the substrate is decreased, the bending stiffness of the film dominates, causing the bilayer to transition to either local wrinkling or a global buckling instability. In this work optical microscopy was used to study the critical parameters that determine the emergence of local wrinkling or global buckling of freestanding bilayer films consisting of a thin rigid polymer capping layer on a pre-strained elastomeric substrate. The thickness ratio of the film and substrate as well as the pre-strain were controlled and used to create a buckling phase diagram which describes the behaviour of the system as the ratio of the thickness of the substrate is decreased. A simple force balance model was developed to understand the thickness and strain dependences of the wrinkling and buckling modes, with excellent quantitative agreement being obtained with experiments using only independently measured material parameters.


Postpartum psychosis: A proposed treatment algorithm.
Postpartum psychosis (PPP) is a psychiatric emergency that generally warrants acute inpatient care. PPP is marked by the sudden onset of affective and psychotic symptoms with a rapid deterioration in mental state. Evidence suggests that PPP is a discrete disorder on the bipolar disorder spectrum with a distinct treatment profile and prognosis. We conducted a PubMed database search for various terms involving PPP and its treatment and included peer-reviewed articles published in English. To provide a treatment algorithm for the management of PPP based on available evidence. Pharmacological therapy is the mainstay of PPP management in the acute phase. Evidence points to a combination of antipsychotics and lithium in the acute treatment of PPP. Electroconvulsive therapy can offer a rapid treatment response where required. Lithium appears to have the best evidence for relapse prevention and prophylaxis in PPP. Psychoeducation is essential and psychosocial interventions used in bipolar disorder may be effective in PPP. Early detection and prompt treatment with antipsychotics and lithium, followed by maintenance treatment with lithium, is associated with a favourable prognosis in PPP.


Abnormal crypts of Morgagni: the cause of perianal abscess and fistula-in-ano.
Fistula-in-ano in infants is thought to begin with a cryptitis that proceeds to a perianal abscess. Of 52 patients in 15 years, 51 were male, 45 were under 12 months, 7 had multiple tracts, and 2 recurred in 6 years; all of which points to a developmental anomaly. We believe the anomaly to be a markedly irregular thickened dentate line that harbors from 3 to 13 deep (3 to 10 mm) abnormal crypts (AC), which foster cryptitis. There have been no recurrences since we started doing cryptotomies on these AC in addition to the fistulotomy. The cause may be a defect in the dorsal portion of the cloacal membrane which fuses with the hindgut during the seventh week.


Identification of diagnostic serum protein profiles of glioblastoma patients.
Diagnosis of a glioblastoma (GBM) is triggered by the onset of symptoms and is based on cerebral imaging and histological examination. Serum-based biomarkers may support detection of GBM. Here, we explored serum protein concentrations of GBM patients and used data mining to explore profiles of biomarkers and determine whether these are associated with the clinical status of the patients. Gene and protein expression data for astrocytoma and GBM were used to identify secreted proteins differently expressed in tumors and in normal brain tissues. Tumor expression and serum concentrations of 14 candidate proteins were analyzed for 23 GBM patients and nine healthy subjects. Data-mining methods involving all 14 proteins were used as an initial evaluation step to find clinically informative profiles. Data mining identified a serum protein profile formed by BMP2, HSP70, and CXCL10 that enabled correct assignment to the GBM group with specificity and sensitivity of 89 and 96%, respectively (p < 0.0001, Fischer's exact test). Survival for more than 15 months after tumor resection was associated with a profile formed by TSP1, HSP70, and IGFBP3, enabling correct assignment in all cases (p < 0.0001, Fischer's exact test). No correlation was found with tumor size or age of the patient. This study shows that robust serum profiles for GBM may be identified by data mining on the basis of a relatively small study cohort. Profiles of more than one biomarker enable more specific assignment to the GBM and survival group than those based on single proteins, confirming earlier attempts to correlate single markers with cancer. These conceptual findings will be a basis for validation in a larger sample size.


Predicting base editing outcomes with an attention-based deep learning algorithm trained on high-throughput target library screens.
Base editors are chimeric ribonucleoprotein complexes consisting of a DNA-targeting CRISPR-Cas module and a single-stranded DNA deaminase. They enable transition of C•G into T•A base pairs and vice versa on genomic DNA. While base editors have great potential as genome editing tools for basic research and gene therapy, their application has been hampered by a broad variation in editing efficiencies on different genomic loci. Here we perform an extensive analysis of adenine- and cytosine base editors on a library of 28,294 lentivirally integrated genetic sequences and establish BE-DICT, an attention-based deep learning algorithm capable of predicting base editing outcomes with high accuracy. BE-DICT is a versatile tool that in principle can be trained on any novel base editor variant, facilitating the application of base editing for research and therapy.


Regulation of BRCC, a holoenzyme complex containing BRCA1 and BRCA2, by a signalosome-like subunit and its role in DNA repair.
We have isolated a holoenzyme complex termed BRCC containing BRCA1, BRCA2, and RAD51. BRCC not only displays increased association with p53 following DNA damage but also ubiquitinates p53 in vitro. BRCC36 and BRCC45 are novel components of the complex with sequence homology to a subunit of the signalosome and proteasome complexes. Reconstitution of a recombinant four-subunit complex containing BRCA1/BARD1/BRCC45/BRCC36 revealed an enhanced E3 ligase activity compared to that of BRCA1/BARD1 heterodimer. In vivo, depletion of BRCC36 and BRCC45 by the small interfering RNAs (siRNAs) resulted in increased sensitivity to ionizing radiation and defects in G2/M checkpoint. BRCC36 shows aberrant expression in sporadic breast tumors. These findings identify BRCC as a ubiquitin E3 ligase complex that enhances cellular survival following DNA damage.


M2B10O14F6 (M = Ca, Sr): Two Noncentrosymmetric Alkaline Earth Fluorooxoborates as Promising Next-Generation Deep-Ultraviolet Nonlinear Optical Materials.
Two novel noncentrosymmetric alkaline earth fluorooxoborates, M2B10O14F6 (M = Ca, Sr), were synthesized and characterized. Both of these two isostructural compounds had layered [B5O7F3]∞ structures with large second harmonic generation (SHG) responses ranging from 2.3 to 2.5 × KH2PO4 (KDP) and short UV absorption edges (<200 nm). The first-principles calculation demonstrated that their nonlinear optical (NLO) properties were superior to those of KBe2BO3F2 (KBBF). In contrast to the alkali fluorooxoborates, these two fluorooxoborates showed not only remarkable stability against air and moisture but also high thermal stability. Therefore, M2B10O14F6 (M = Ca, Sr) should be promising deep-ultraviolet (DUV) NLO materials.


Computed tomography of benign ovarian masses.
Although ultrasound is the primary imaging modality for evaluating benign gynecologic pelvic masses, CT may provide diagnostic information regarding ovarian masses that are discovered fortuitously. The relatively infrequent use of CT in evaluating the adnexa has resulted in a paucity of literature regarding the CT characteristics of benign ovarian masses. The CT appearances of 24 benign ovarian masses are presented. Pathologic diagnoses were ovarian cyst (nine), endometrioma (five), teratoma (three), serous cystadenoma (two), mucinous cystadenoma (two), thecoma (one), cystadenofibroma (one), and Brenner tumor (one). Benign ovarian cysts have characteristic homogeneous water density and smooth walls on CT. Single internal septations and slight wall irregularity are also common features, but soft-tissue mural or septal nodules are uncommon. Computed tomography can be diagnostic in evaluating cystic teratomas. Other benign ovarian masses exhibit a spectrum of CT appearances that is often nonspecific, and surgical or biopsy proof may be necessary to exclude malignancy.


Sex-specific effects of a high fat diet on aortic inflammation and dysfunction.
Obesity and vascular dysfunction are independent and sexually dimorphic risk factors for cardiovascular disease. A high fat diet (HFD) is often used to model obesity in mice, but the sex-specific effects of this diet on aortic inflammation and function are unclear. Therefore, we characterized the aortic immune cell profile and function in 6-week-old male and female C57BL/6 mice fed a normal chow diet (NCD) or HFD for 10 weeks. Metabolic parameters were measured weekly and fortnightly. At end point, aortic immune cell populations and endothelial function were characterized using flow cytometry and wire myography. HFD-male mice had higher bodyweight, blood cholesterol, fasting blood glucose and plasma insulin levels than NCD mice (P < 0.05). HFD did not alter systolic blood pressure (SBP), glycated hemoglobin or blood triglycerides in either sex. HFD-females had delayed increases in bodyweight with a transient increase in fasting blood glucose at week 8 (P < 0.05). Flow cytometry revealed fewer proinflammatory aortic monocytes in females fed a HFD compared to NCD. HFD did not affect aortic leukocyte populations in males. Conversely, HFD impaired endothelium-dependent vasorelaxation, but only in males. Overall, this highlights biological sex as a key factor determining vascular disease severity in HFD-fed mice.


[The effects of a physical activity reinforcement program on exercise compliance, depression, and anxiety in continuous ambulatory peritoneal dialysis patients].
This study was to evaluate the effects of a physical activity reinforcement program on exercise compliance, depression, and anxiety in continuous ambulatory peritoneal dialysis(CAPD) patients. A nonequivalent control group with a pre-post test was designed. Data collection was done from December, 2002 to June, 2003 at a hospital. The degree of depression and anxiety of the patients was assessed by the score of SCL-90-R, and exercise compliance was measured by exercise period, frequency, time and intensity. The experimental group was composed of 19 participants who were educated based on an exercise education protocol and carried out walking exercises two to four times a week after hearing verbal persuasion biweekly through the telephone or a face-to-face interview for 12 weeks, while 17 participants in control group received no intervention. 1. The experimental group showed significant improvement in self-efficacy of exercise compliance (U=79.00, p=.01), exercise period (chi2=20.84, p=.00), exercise frequency (chi2=9.03, p=.01), exercise time (chi2=9.03, p=.01) and exercise intensity (chi2=11.09, p=.00) compared to those of the control group. 2. The experimental group showed a lower depression score (U=84.50, p=.01) than the results of the control group. 3. However, there were no changes in anxiety level compared to the control group. The physical activity reinforcement program was found to have an effect on exercise compliance and the depression score of CAPD patients. The results provided evidence for the importance of physical activity and verbal persuasion in CAPD patients.


Carcinogenic HPV infection in the cervical squamo-columnar junction.
Recent studies have suggested the involvement of a unique population of cells at the cervical squamo-columnar junction (SCJ) in the pathogenesis of early (squamous intraepithelial lesion or SIL) and advanced (squamous cell and adeno-carcinomas) cervical neoplasia. However, there is little evidence to date showing that SCJ cells harbour carcinogenic HPV or are instrumental in the initial phases of neoplasia. This study was designed to (1) determine if normal-appearing SCJ cells contained evidence of carcinogenic HPV infection and (2) trace their transition to early SIL. Sections of cervix from high-risk reproductive age women were selected and SCJ cells were analysed by using several techniques which increasingly implicated HPV infection: HPV DNA (genotyping and in situ hybridization)/RNA (PCR), immunostaining for HPV16 E2 (an early marker of HPV infection), p16(ink4), Ki67, and HPV L1 protein. In 22 cases with a history of SIL and no evidence of preneoplastic lesion in the excision specimen, HPV DNA was isolated from eight of ten with visible SCJ cells, six of which were HPV16/18 DNA-positive. In five of these latter cases, the SCJ cells were positive for p16(ink4) and/or HPV E2. Transcriptionally active HPV infection (E6/E7 mRNAs) was also detected in microdissected SCJ cells. Early squamous atypia associated with the SCJ cells demonstrated in addition diffuse p16(ink4) immunoreactivity, elevated proliferative index, and rare L1 antigen positivity. We present for the first time direct evidence that normal-appearing SCJ cells can be infected by carcinogenic HPV. They initially express HPV E2 and their progression to SIL is heralded by an expanding metaplastic progeny with increased proliferation and p16(ink4) expression. Whether certain SCJs are more vulnerable than others to carcinogenic HPV genotypes and what variables determine transition to high-grade SIL remain unresolved, but the common event appears to be a vulnerable cell at the SCJ.


D-dimer for the exclusion of acute venous thrombosis and pulmonary embolism: a systematic review.
Despite extensive literature, the diagnostic role of d-dimer for deep venous thrombosis (DVT) or pulmonary embolism (PE) remains unclear, reflecting multiple d-dimer assays and concerns about differing sensitivities and variability. To systematically review trials that assessed sensitivity, specificity, likelihood ratios, and variability among d-dimer assays. Studies in all languages were identified by searching PubMed from 1983 to January 2003 and EMBASE from 1988 to January 2003. The researchers selected prospective studies that compared d-dimer with a reference standard. Studies of high methodologic quality were included in the primary analyses; sensitivity analysis included additional weaker studies. Two authors collected data on study-level factors: d-dimer assay used, cutoff value, and whether patients had suspected DVT or PE. For DVT, the enzyme-linked immunosorbent assay (ELISA) and quantitative rapid ELISA dominate the rank order for these values: sensitivity, 0.96 (95% confidence limit [CL], 0.91 to 1.00), and negative likelihood ratio, 0.12 (CL, 0.04 to 0.33); and sensitivity, 0.96 (CL, 0.90 to 1.00), and negative likelihood ratio, 0.09 (CL, 0.02 to 0.41), respectively. For PE, the ELISA and quantitative rapid ELISA also dominate the rank order for these values: sensitivity, 0.95 (CL, 0.85 to 1.00), and negative likelihood ratio, 0.13 (CL, 0.03 to 0.58); and sensitivity, 0.95 (CL, 0.83 to 1.00), and negative likelihood ratio, 0.13 (CL, 0.02 to 0.84), respectively. The ELISA and quantitative rapid ELISA have negative likelihood ratios that yield a high certainty for excluding DVT or PE. The positive likelihood values, which are in the general range of 1.5 to 2.5, do not greatly increase the certainty of diagnosis. Sensitivity analyses do not affect these findings. Although many studies evaluated multiple d-dimer assays, findings are based largely on indirect comparisons of test performance characteristics across studies. The ELISAs in general dominate the comparative ranking among the d-dimer assays for sensitivity and negative likelihood ratio. For excluding PE or DVT, a negative result on quantitative rapid ELISA is as diagnostically useful as a normal lung scan or negative duplex ultrasonography finding.


Osteoporosis in men.
Osteoporotic fractures are the leading cause of morbidity and mortality among aging men. 30% of all hip fractures occur in men, and mortality resulting from not only the hip fracture, but also the spine and other major osteoporotic fractures, is significantly higher in men than in women. As in women, hypogonadism is the best documented risk factor for developing osteoporosis in men. In older men, testosterone levels are negatively correlated with the risk of fractures, and it seems that this age-related testosterone deficiency should not be considered as one of the many causes of secondary osteoporosis, rather one of the major and most important mechanisms of senile osteoporosis. Acute hypogonadism induced by ablation treatment for prostate cancer (surgical or pharmacological castration, antiandrogen therapy) is associated with an extremely high risk of fracture. Other documented causes of bone loss in men are cigarette smoking and alcohol abuse, and a number of diseases that require corticosteroid treatment. Pharmacotherapy of osteoporosis should be recommended to all men with a diagnosed osteoporotic fracture and all men with a high 10-year absolute fracture risk (FRAXTM). Not all drugs registered for the treatment of postmenopausal osteoporosis have been registered for the treatment of osteoporosis in men, and others have not been the subject of long-term and costly clinical trials required for such registration. The risk reduction of new fractures was documented only for treatment with zoledronic acid. Risedronate, strontium ranelate, teriparatide, and denosumab in men increase in bone mineral density comparable to that seen in postmenopausal women.


Drug utilization review in a teaching hospital: experience with vancomycin.
A prospective, two-phase, drug utilization review (DUR) was performed at the Royal Adelaide Hospital (RAH) to determine the extent and pattern of vancomycin use. For all patients commencing oral or parenteral vancomycin, treatment indication, route of administration, duration of therapy, results of culture and sensitivity tests, adverse drug reactions and results of therapeutic drug level monitoring were recorded. Vancomycin courses were classified as being for therapy or prophylaxis and compared with predetermined audit criteria to assess appropriateness of use. During the 8 week initial phase, data on 62 treatment courses in 59 patients were recorded, 50% for therapy and 50% for prophylaxis. Sixty four percent were classified as inappropriate, occurring in 32% of therapeutic courses and 97% of those for prophylaxis. During the 10 week re-evaluation, conducted 10 months later, data for 43 treatment courses in 43 patients were reviewed, 42% for therapy and 58% for prophylaxis. Sixty five percent were inappropriate occurring in 17% of therapeutic courses and 100% of the prophylactic courses. When compared with the initial phase, the re-evaluation demonstrated a decrease in the empirical use of vancomycin in the combination treatment of neutropaenic fever and also in the duration of vancomycin use for surgical prophylaxis. During both study phases, criteria contraventions were mostly due to inappropriate indication or duration of therapy. The cost of inappropriate vancomycin use was reduced by over 50% between survey phases, from $Aus11,500 or 55% of total vancomycin cost during the initial phase to $Aus3,600 or 25.7% during the re-evaluation. The most effective of the remedial strategies implemented after the initial phase was direct consultation with prescriber groups.(ABSTRACT TRUNCATED AT 250 WORDS)


Patterns and predictors of proton pump inhibitor overuse among academic and non-academic hospitalists.
In the hospital setting, several studies have reported proton pump inhibitor (PPI) overuse, a majority of which is continued after discharge. In addition to being expensive, PPIs are associated with an increased risk of infections, osteoporosis and serious drug interactions. We examined the trends and predictors of PPI guidelines non-compliance among academic and non-academic hospitalists in USA. Oral PPI prescriptions initiated by 2 academic and 2 non-academic hospitalist groups were reviewed. Prescription indications were recorded when explicitly stated in the chart. Otherwise, qualified physicians reviewed the chart to make such determination. Indications were then compared to the published guidelines. Several variables were tested to determine independent predictors of initiation and post discharge continuation of guideline non-compliant prescriptions. Of the 400 PPI prescriptions 39% were guideline compliant. Academic hospitalists were significantly more compliant with PPI prescription guidelines (50 vs 29%). Gastrointestinal ulcer bleeding prophylaxis (GIP) for low risk patients was the most common indication for non-compliant prescriptions, while that of guideline compliant prescriptions was dyspepsia treatment. Independent predictors of the initiation of guideline non-compliant prescriptions were non-academic hospitalist group, PPI indication not documented in the chart, and GIP as part of the admission orderset. The latter was an independent predictor of those prescriptions continuation post-discharge (protective) in addition to non-academic hospitalists group. Hospitalists overprescribe PPI to a level comparable to that of the non-hospitalist providers in the literature. Understanding the determinants of increased compliance among academic groups is instrumental to design interventions aimed at increasing PPI prescription compliance.


Poison center outreach to hospitals through area conferences.
The Massachusetts Poison Control System (MPCS) conducted professional education conferences in 4 areas of its region as outreach to 31 targeted hospitals which have greater than 60 poisoned inpatients/year and consult with MPCS on less than 36% of Emergency Department (ED) patients. A hospital survey had indicated that area conferences were preferred to regionwide symposia. Preconference planning meetings with area ED MD's and RN's identified patient management issues to cover. Besides lectures, conferences included interactive sessions such as toxathons, skill stations, case presentations, panel discussions. The conferences reached 190 people from 38 acute care hospitals including 88% of targeted hospitals and the MD or RN in charge of the ED or greater than or equal to 2 staff members from 62% of targeted hospitals. Participants (74%) increased their knowledge by 53% based on a pre/post test and gave the conferences a 4.4 rating for improved knowledge gain (1 = no, 5 = much new knowledge). They rated skill stations 1st, toxathons 2nd, case presentations 3rd and lectures as a whole 4th in the amount of knowledge gained. Calls from targeted hospitals to MPCS increased but not significantly. Area education conferences with interactive formats effectively reach and educate hospital staff.


Similarities and differences in design considerations for cell therapy and pharmacologic cardiovascular clinical trials.
Cell therapies hold the potential for suppression, modification, or cure of disease. Several unique challenges have been recognized as this field has developed. Many of these involve considerations of trial design. This paper summarizes the discussion and suggestions constructed during the 8th Cardiovascular Clinical Trialists Workshop, a meeting involving cardiovascular clinical trialists, biostatisticians, National Institutes of Health scientists, European and United States regulators, and pharmaceutical industry scientists. Investigators must adapt research methods to accommodate the scientific advances associated with cell therapy. Safety and efficacy of cell therapy for cardiovascular indications should be evaluated with the same degree of scientific rigor required of pharmacologic agents, and the same fundamental regulatory requirements and scientific processes apply to both. Clinical trials for these indications should also meet standards similar to those set for drug therapies. Safety should be determined throughout development, dose responsiveness should be established and, while surrogate endpoints are important development tools, the ultimate demonstration of efficacy must rely on clinical benefit. The establishment of a global safety database for cell therapy would significantly advance the field. Efforts to discover innovative therapies must be balanced by a commitment to comprehensively evaluate the safety and efficacy of the new treatments.