Lower or Higher Oxygenation Targets for Acute Hypoxemic Respiratory Failure.
Patients with acute hypoxemic respiratory failure in the intensive care unit (ICU) are treated with supplemental oxygen, but the benefits and harms of different oxygenation targets are unclear. We hypothesized that using a lower target for partial pressure of arterial oxygen (Pao2) would result in lower mortality than using a higher target. In this multicenter trial, we randomly assigned 2928 adult patients who had recently been admitted to the ICU (≤12 hours before randomization) and who were receiving at least 10 liters of oxygen per minute in an open system or had a fraction of inspired oxygen of at least 0.50 in a closed system to receive oxygen therapy targeting a Pao2 of either 60 mm Hg (lower-oxygenation group) or 90 mm Hg (higher-oxygenation group) for a maximum of 90 days. The primary outcome was death within 90 days. At 90 days, 618 of 1441 patients (42.9%) in the lower-oxygenation group and 613 of 1447 patients (42.4%) in the higher-oxygenation group had died (adjusted risk ratio, 1.02; 95% confidence interval, 0.94 to 1.11; P = 0.64). At 90 days, there was no significant between-group difference in the percentage of days that patients were alive without life support or in the percentage of days they were alive after hospital discharge. The percentages of patients who had new episodes of shock, myocardial ischemia, ischemic stroke, or intestinal ischemia were similar in the two groups (P = 0.24). Among adult patients with acute hypoxemic respiratory failure in the ICU, a lower oxygenation target did not result in lower mortality than a higher target at 90 days. (Funded by the Innovation Fund Denmark and others; HOT-ICU ClinicalTrials.gov number, NCT03174002.).


The Use of Prosodic Cues in Sentence Processing by Prelingually Deaf Users of Cochlear Implants.
The purpose of this study is to assess the use of prosodic and contextual cues to focus by prelingually deaf adolescent users of cochlear implants (CIs) when identifying target phonemes. We predict that CI users will have slower reaction times to target phonemes compared with a group of normally-hearing (NH) peers. We also predict that reaction times will be faster when both prosodic and contextual (semantic) cues are provided. Eight prelingually deaf adolescent users of CIs and 8 adolescents with NH completed 2 phoneme-monitoring experiments. Participants were aged between 13 and 18 years. The mean age at implantation for the CI group was 1.8 years (SD: 1.0). In the prosodic condition, reaction times to a target phoneme in a linguistically focused (i.e., stressed) word were compared between the two groups. The semantic condition compared reaction time with target phonemes when contextual cues to focus were provided in addition to prosodic cues. Reaction times of the CI group were slower than those of the NH group in both the prosodic and semantic conditions. A linear mixed model was used to compare reaction times using Group as a fixed factor and Phoneme and Subject as random factors. When only prosodic cues (prosodic condition) to focus location were provided, the mean reaction time of the CI group was 512 msec compared with 317 msec for the NH group, and this difference was significant (p < 0.001). The provision of contextual cues speeded reaction times for both groups (semantic condition), indicating that top-down processing aided both groups in their search for a focused item. However, even with both prosodic and contextual cues, the CI users' processing times remained slower, compared with the NH group, with mean reaction times of 385 msec for the CI users but 232 msec for the NH listeners (p < 0.001). Prelingually deaf CI users' processing of prosodic cues is less efficient than that of their NH peers, as evidenced by slower reaction times to targets in phoneme monitoring. The provision of contextual cues speeded reaction times for both NH and CI groups, although the CI users were slower in responding than the NH group. These findings contribute to our understanding of how CI users employ/integrate prosodic and semantic cues in speech processing.


Molecular aspects of mammalian ovulation.
Ovulation, recurring every reproductive cycle of the mammalian female and triggered by a surge of luteinizing hormone (LH) released from the pituitary is an essential prerequisite for fertilization and subsequent embryonic development. Here we shall review two of the biological responses leading to follicle rupture -- vascular changes and proteolysis. Naturally, our present knowledge is based mainly on work in a few species, such as the rat, the mouse and, to lesser extent the pig and monkeys and observations in the human. Therefore any generalizations to other mammals, should be considered as a working hypothesis yet to be confirmed. The LH surge stimulates, in the preovulatory follicles, a cascade of proteolytic enzymes, including plasminogen activator (PA), plasmin and matrix metalloproteinases (MMPs). These enzymes bring about the degradation of perifollicular matrix and, most notably, the decomposition of the meshwork of collagen fibers which provides the strength to follicular wall. Pharmacological blockage of any of these enzymes resulted in the reduction of ovulation rate. The increased ovarian proteolytic activity associated with ovulation is controlled by locally produced specific inhibitors, plasminogen activator inhibitor-1 (PAI-1) and tissue inhibitor of metalloproteases-1 (TIMP-1). The increased synthesis of these two specific proteinase inhibitors in the theca of growing follicles ensures their development by protecting them from enzymes diffusing from ovulatory follicles. The stimulation of ovulation by the gonadotropin results in an increase in follicular blood flow, hyperemia, increase in vascular permeability and a marked increase in follicular volume. These vascular changes and the proteolytic activity are triggered either directly by LH or by local mediators and factors produced in response to the gonadotropic stimulus. These mediators allow the tight coordination of these two cascades culminating in the rupture of follicle wall. We shall review here, briefly, the various mediatory systems that have been implicated in follicle rupture. These include steroids, vascular endothelial growth factor (VEGF), cytokines, eicosanoids, platelet activating factor (PAF), nitric oxide and nitric oxide synthase (NO/NOS), kinins and oxygen radicals.


Membrane environment imposes unique selection pressures on transmembrane domains of G protein-coupled receptors.
We have investigated the influence of the plasma membrane environment on the molecular evolution of G protein-coupled receptors (GPCRs), the largest receptor family in Metazoa. In particular, we have analyzed the site-specific rate variation across the two primary structural partitions, transmembrane (TM) and extramembrane (EM), of these membrane proteins. We find that TM domains evolve more slowly than do EM domains, though TM domains display increased rate heterogeneity relative to their EM counterparts. Although the majority of residues across GPCRs experience strong to weak purifying selection, many GPCRs experience positive selection at both TM and EM residues, albeit with a slight bias towards the EM. Further, a subset of GPCRs, chemosensory receptors (including olfactory and taste receptors), exhibit increased rates of evolution relative to other GPCRs, an effect which is more pronounced in their TM spans. Although it has been previously suggested that the TM's low evolutionary rate is caused by their high percentage of buried residues, we show that their attenuated rate seems to stem from the strong biophysical constraints of the membrane itself, or by functional requirements. In spite of the strong evolutionary constraints acting on the TM spans of GPCRs, positive selection and high levels of evolutionary rate variability are common. Thus, biophysical constraints should not be presumed to preclude a protein's ability to evolve.


Substituting polyunsaturated fat for saturated fat: A health impact assessment of a fat tax in seven European countries.
There is evidence that replacing saturated fat (SFA) with polyunsaturated fat (PUFA) lowers ischemic heart disease (IHD). In order to improve the population's diet, the World Health Organization has called for the taxation of foods that are high in SFA. We aimed to assess the potential health gains of a European fat tax by applying the SFA intake reduction that has been observed under the Danish fat tax to six other European countries. For each country, we created a fat tax scenario with a decreased SFA intake and a corresponding increase in PUFA. We compared this fat tax scenario to a reference scenario with no change in SFA intake, and to a guideline scenario with a population-wide SFA intake in line with dietary recommendations. We used DYNAMO-HIA to dynamically project the policy-attributable IHD cases of these three scenarios 10 years into the future. A fat tax would reduce prevalent IHD cases by a minimum of 500 and 300 among males and females in Denmark, respectively, up to a maximum of 5,600 and 4,000 among males and females in the UK. Thereby, the prevented IHD cases under a fat tax scenario would correspond to between 11.0% (in females in the Netherlands) and 29.5% (in females in Italy) of the prevented IHD cases under a guideline scenario, which represents the maximum preventable disease burden. Henceforth, our quantification of beneficial health impacts makes the case for the policy debate on fat taxes.


Deranged calcium signaling in Purkinje cells and pathogenesis in spinocerebellar ataxia 2 (SCA2) and other ataxias.
Spinocerebellar ataxias (SCAs) constitute a heterogeneous group of more than 30 autosomal-dominant genetic and neurodegenerative disorders. SCAs are generally characterized by progressive ataxia and cerebellar atrophy. Although all SCA patients present with the phenotypic overlap of cerebellar atrophy and ataxia, 17 different gene loci have so far been implicated as culprits in these SCAs. It is not currently understood how mutations in these 17 proteins lead to the cerebellar atrophy and ataxia. Several pathogenic mechanisms have been studied in SCAs but there is yet to be a promising target for successful treatment of SCAs. Emerging research suggests that a fundamental cellular signaling pathway is disrupted by a majority of these mutated genes, which could explain the characteristic death of Purkinje cells, cerebellar atrophy, and ataxia that occur in many SCAs. We propose that mutations in SCA genes cause disruptions in multiple cellular pathways but the characteristic SCA pathogenesis does not begin until calcium signaling pathways are disrupted in cerebellar Purkinje cells either as a result of an excitotoxic increase or a compensatory suppression of calcium signaling. We argue that disruptions in Purkinje cell calcium signaling lead to initial cerebellar dysfunction and ataxic sympoms and eventually proceed to Purkinje cell death. Here, we discuss a calcium hypothesis of Purkinje cell neurodegeneration in SCAs by primarily focusing on an example of spinocerebellar ataxia 2 (SCA2). We will also present evidence linking deranged calcium signaling to the pathogenesis of other SCAs (SCA1, 3, 5, 6, 14, 15/16) that lead to significant Purkinje cell dysfunction and loss in patients.


Oscillations in daily pain prediction accuracy.
Dynamical systems modeling was used to analyze fluctuations in the pain prediction process of people with rheumatoid arthritis. 170 people diagnosed with rheumatoid arthritis completed 29 consecutive days of diaries. Difference scores between pain predictions and next-day pain experience ratings provided a time series of pain prediction accuracy. Pain prediction accuracy oscillated over time. The oscillation amplitude was larger at the start of the diary than at the end, which indicates damping toward more accurate predictions. State-level psychological characteristics moderated the damping pattern such that the oscillations for patients with lower negative affect and higher pain control damped more quickly than the oscillations for their counterparts. Those findings suggest that low negative affect and high pain control generally contributed to a more accurate pain prediction process in the chronically ill. Positive affect did not differentiate the damping pattern but, within each oscillation cycle, patients with higher positive affect spent more time making inaccurate predictions than their counterparts. The current analyses highlight the need to account for change in data through dynamical modeling, which cannot be fully observed through traditional statistical techniques.


Binding of Escherichia coli heat-stable enterotoxin to receptors on rat intestinal cells.
This study was performed to determine whether receptors for Escherichia coli heat-stable enterotoxin (ST) exist on intestinal epithelial cells. Binding sites for 125I-ST were found on rat jejunal and ileal villus cells. Binding was rapid, reversible, linear with cell number, saturable, and temperature dependent. Significant degradation of 125I-ST occurred when incubated with cells at 37 degrees C but not at 25 degrees C. Binding was specific to ST since binding of 125I-ST was competitively inhibited by increasing concentrations of human or porcine ST but not by E. coli heat-labile, cholera, or staphylococcal enterotoxins. Addition of excess unlabeled ST to cells preincubated with 125I-ST resulted in dissociation of much but not all of the bound 125I-ST. Binding of 125I-ST to jejunal and ileal cells occurs with two affinities, and this is due to the phenomenon of negative cooperativity. The potency of ST for inhibiting the binding of 125I-ST was identical to the potency of ST in stimulating cGMP production. These data support the existence of receptors for ST on intestinal cells, and these receptors may be involved in the action of ST.


A study for characterization of IgE-mediated cutaneous immediate and late-phase reactions in non-allergic domestic cats.
Immunoglobulin-E (IgE) mediated reactions can be induced by intradermal injection of anti-IgE antibodies in both humans and dogs. These reactions grossly and histologically mimic changes seen in naturally occurring allergic dermatitis in these species. Similar studies have not been conducted in the cat. Purified polyclonal rabbit-origin IgG specific for canine IgE (anti-IgE) and rabbit immunoglobulin G (IgG) were injected intradermally in 7 non-allergic laboratory colony cats. Wheal measurements were obtained and biopsies collected before injection and at injection sites after 20 min, 6, 24, and 48 h. Injection of anti-IgE induced an immediate wheal response which was significantly larger than that seen after injection of rabbit IgG. Anti-IgE injected skin was also significantly thicker than IgG-injected skin. This corresponded with a significant increase in number of visibly degranulated mast cells in anti-IgE samples when compared to IgG samples. Injection of anti-IgE was associated with the rapid recruitment of inflammatory cells to the injected dermis. The number of inflammatory cells and mononuclear cells were significantly elevated after the injection of anti-IgE when compared to IgG-injected skin. Both eosinophils and neutrophils were significantly increased in anti-IgE samples relative to IgG, although neutrophils were only transiently increased. The high eosinophil and relatively low neutrophil cell counts in these samples were consistent with previously documented histologic features of naturally occurring feline allergic skin disease. Immunohistochemistry identified a significantly overall increased CD1a(+) cells after the intradermal injection of anti-IgE when compared to IgG and non-injected skin. CD3(+), CD8(+) and CD4(+) were also significantly increased overall in anti-IgE injected skin relative to IgG injected skin. These data document the gross and cellular response to injection of anti-IgE in the skin of healthy, non-allergic cats and support a possible role for IgE in the development of feline allergic dermatitis.


Assessing mental imagery in clinical psychology: a review of imagery measures and a guiding framework.
Mental imagery is an under-explored field in clinical psychology research but presents a topic of potential interest and relevance across many clinical disorders, including social phobia, schizophrenia, depression, and post-traumatic stress disorder. There is currently a lack of a guiding framework from which clinicians may select the domains or associated measures most likely to be of appropriate use in mental imagery research. We adopt an interdisciplinary approach and present a review of studies across experimental psychology and clinical psychology in order to highlight the key domains and measures most likely to be of relevance. This includes a consideration of methods for experimentally assessing the generation, maintenance, inspection and transformation of mental images; as well as subjective measures of characteristics such as image vividness and clarity. We present a guiding framework in which we propose that cognitive, subjective and clinical aspects of imagery should be explored in future research. The guiding framework aims to assist researchers in the selection of measures for assessing those aspects of mental imagery that are of most relevance to clinical psychology. We propose that a greater understanding of the role of mental imagery in clinical disorders will help drive forward advances in both theory and treatment.


Gomisin N isolated from Schisandra chinensis significantly induces anti-proliferative and pro-apoptotic effects in hepatic carcinoma.
Lignans isolated from Schisandria chinensis have been prescribed as anti-cancer and anti-hepatitis treatments in Chinese medicine. To investigate the applications of lignans isolated from Schisandria chinensis in hepatic carcinoma therapy, their apoptotic ability was screened using a cell proliferation assay. Compared to the other lignans, gomisin N induced high apoptotic levels in hepatic carcinoma. Cell morphology and flow cytometric analysis demonstrated that this lignan induced cell death at high concentrations, but did not induce any changes at low concentrations. In addition, the expression levels of Bcl-2 and Bax proteins, which are involved in the apoptotic pathway, were markedly increased in only the 320 µM-treated group compared to the vehicle and other concentration groups, while the expression level of p53 protein remained unchanged in this group. These results suggest that gomisin N is an anti-cancer drug candidate capable of inhibiting the proliferation and inducing the apoptosis of human hepatic carcinomas.


The emergence of lncRNAs in cancer biology.
The discovery of numerous noncoding RNA (ncRNA) transcripts in species from yeast to mammals has dramatically altered our understanding of cell biology, especially the biology of diseases such as cancer. In humans, the identification of abundant long ncRNA (lncRNA) >200 bp has catalyzed their characterization as critical components of cancer biology. Recently, roles for lncRNAs as drivers of tumor suppressive and oncogenic functions have appeared in prevalent cancer types, such as breast and prostate cancer. In this review, we highlight the emerging impact of ncRNAs in cancer research, with a particular focus on the mechanisms and functions of lncRNAs.


Comparison of five-year clinical outcomes of 524 cemented and cementless medial unicompartmental knee replacements.
To compare the outcomes of cemented and cementless Unicompartmental Knee Replacements (UKR) at 5 years after surgery. 262 cemented and 262 cementless medial mobile-bearing UKR, implanted by four high-volume surgeons using identical indications and surgical techniques, were reviewed by independent physiotherapists at 5 years. Survival, Oxford Knee Score (OKS), American Knee Society Score (AKSS), and EQ-5D-5L were assessed. The cementless cohort was mainly implanted after the cemented. Each cohort was divided into early and late sub-groups and compared, to assess if any differences were due to progressive improvement in surgical practice over time. There were no significant differences between the cohorts for demographics, pre-operative scores, and 5-year revision (0.8%), re-operation (1.5%), and complication rates (5%). The cementless cohort had significantly better 5-year OKS (43v41, p = 0.008), AKSS-Objective (94v90, p = 0.049) and EQ-5D-5L (0.81v0.87, p = 0.0001). Pain sub-scores within OKS, AKSS, and EQ-5D-5L were also significantly better in the cementless cohort, and the differences were proportionally much greater and more significant than differences in their respective overall scores. There was no significant improvement in scores between the early and late subgroups of the cohorts, whereas the 'early-cementless' cohort had significantly better scores than the contemporaneously implanted 'late-cemented' cohort. This suggests that differences found were due to implant type, instead of improved surgical practice over time. Cementless UKR is associated with better clinical outcomes than cemented UKR, which is primarily due to improved pain relief. Both cemented and cementless UKR are safe with low reoperation and complication rates, and a 5-year survival of 99%.


Characteristics of sexual abuse in childhood and adolescence influence sexual risk behavior in adulthood.
Childhood and adolescent sexual abuse has been associated with subsequent (adult) sexual risk behavior, but the effects of force and type of sexual abuse on sexual behavior outcomes have been less well-studied. The present study investigated the associations between sexual abuse characteristics and later sexual risk behavior, and explored whether gender of the child/adolescent moderated these relations. Patients attending an STD clinic completed a computerized survey that assessed history of sexual abuse as well as lifetime and current sexual behavior. Participants were considered sexually abused if they reported a sexual experience (1) before age 13 with someone 5 or more years older, (2) between the ages of 13 and 16 with someone 10 or more years older, or (3) before the age of 17 involving force or coercion. Participants who were sexually abused were further categorized based on two abuse characteristics, namely, use of penetration and force. Analyses included 1177 participants (n=534 women; n=643 men). Those who reported sexual abuse involving penetration and/or force reported more adult sexual risk behavior, including the number of lifetime partners and number of previous STD diagnoses, than those who were not sexually abused and those who were abused without force or penetration. There were no significant differences in sexual risk behavior between nonabused participants and those who reported sexual abuse without force and without penetration. Gender of the child/adolescent moderated the association between sexual abuse characteristics and adult sexual risk behavior; for men, sexual abuse with force and penetration was associated with the greatest number of episodes of sex trading, whereas for women, those who were abused with penetration, regardless of whether the abuse involved force, reported the most episodes of sex trading. These findings indicate that more severe sexual abuse is associated with riskier adult sexual behavior.


Dendritic cells in oral tolerance in the gut.
Oral tolerance is a process that allows generation of systemic unresponsiveness to food antigens. Hence if the same antigen is introduced systemically even under immunogenic conditions it does not induce immune responsiveness. Dendritic cells (DCs) have been identified as essential players in this process. DCs in the gut are located in a strategic position as they can interact directly with luminal antigens or indirectly after their transcytosis across epithelial cells. DCs can then migrate to associated lymphoid tissues to induce tolerance. Antigen presenting cells in the gut are specialized in function and have divided their labour so that there are cells capable to migrate to the draining mesenteric lymph node for induction of T regulatory cells, while other subsets are resident and are required to enforce tolerance locally in the gut after food antigen exposure. In this review, I shall summarize the characteristics of antigen presenting cells in the gut and their involvement in oral tolerance induction. In addition, I will also emphasize that tolerance to food allergens may be contributed by plasmacytoid DCs in the liver that participate to the elimination or anergy of allergen-specific CD8 T cells. Hence specialized functions are associated to different subsets of antigen presenting cells and different organs.


Concise review: hematopoietic stem cell transplantation: targeting the thymus.
Allogeneic hematopoietic stem cell (HSC) transplantation can cure patients suffering from diverse genetic and acquired diseases as well as cancers. Nevertheless, under conditions where T-cell reconstitution is critical, the entry of donor progenitors into the thymus remains a major bottleneck. It is assumed that following the intravenous injection of HSC, they first home to the BM. More committed progenitors can then be exported to the thymus in response to a myriad of signals regulating thymus seeding. Notably although, the thymus is not continually receptive to the import of hematopoietic progenitors. Furthermore, as stem cells with self-renewing capacity do not take up residence in the thymus under physiological conditions, the periodic colonization of the thymus is essential for the sustained differentiation of T lymphocytes. As such, we and others have invested significant efforts into exploring avenues that might foster a long-term thymus-autonomous differentiation. Here, we review strategic approaches that have resulted in long-term T-cell differentiation in immunodeficient (SCID) mice, even across histocompatibility barriers. These include the forced thymic entry of BM precursors by their direct intrathymic injection as well as the transplantation of neonatal thymi. The capacity of the thymus to support hematopoietic progenitors with renewal potential will hopefully promote the development of new therapeutic strategies aimed at enhancing T-cell differentiation in patients undergoing HSC transplantation.


[An experience of cyberknife treatment in patients with advanced pancreaticobilliary malignancy].
CyberKnifeTM stereotactic body radiotherapy (SBRT) has been thought as a promising treatment modality for inoperable or recurred pancreaticobiliary malignancies. But, clinical course of CyberKnifeTM treatment have not been established yet, so we report the experience of CyberKnifeTM treatment in 19 patients with recurred or advanced pancreaticobilliary malignancies. Between July 2008 and May 2009, 19 patients (gallbladder cancer 4, common bile duct cancer 5, and pancreatic cancer 10) with recurred (12) and advanced pancreaticobiliary cancer (7) underwent CyberKnifeTM treatment in Soonchunhyang University Hospital. Tumor size was evaluated at 1, 3, 6, 8 and every 3 months after SBRT. The mean age was 60.2 years, and the mean size of target lesions was 28.1±1.30 mm. After CyberKnifeTM treatment, the average size of target lesions was decreased; 2.53±4.18 mm from months 0-1 in 19 patients, 2.47±4.7 mm from months 1-3 in 15 patients, 0.08±5.11 mm from months 3-6 in 12 patients. However, the average size of target lesions was increased 3.67±8.98 mm from months 6-8 in 6 patients. There were 2 cases of massive duodenal ulcer bleeding after CyberKnifeTM treatment, one of them expired due to ulcer bleeding. Also, other minor complications appeared such as 1 case of abdominal pain and 1 case of diarrhea. CyberKnifeTM treatment seems to be effective in local control of pancreaticobiliary cancer, but we experienced serious complications. Further prospective studies will be needed for the proper evaluation of role of CyberknifeTM treatment in patients with advanced pancreaticobiliary malignancies.


Keratoacanthoma. A clinical study.
Keratoacanthoma (KA) is a relatively common tumor believed to be a benign epidermal neoplasm. Ninety patients with one or more KAs were observed in regard to clinical, therapeutic, and prognostic implications. In particular, we were able to analyze the relationship of KA to internal malignant neoplasms in 78 patients. Keratoacanthoma is a disease of the elderly (mean patient age, 64.1 years). It is associated with other nonmelanoma cutaneous neoplasias in 21% of cases, a figure lower than that seen with squamous cell carcinomas. When solitary, KA is not associated with concurrent or subsequent internal malignant neoplasms more often than would be predicted by population statistics. Therapy is generally curative, but about 8% of the patients had recurrences. These patients may be successfully treated with several existing modalities.


Distractors Selectively Modulate Electrophysiological Markers of Perceptual Decisions.
Current models of perceptual decision-making assume that choices are made after evidence in favor of an alternative accumulates to a given threshold. This process has recently been revealed in human EEG recordings, but an unresolved issue is how these neural mechanisms are modulated by competing, yet task-irrelevant, stimuli. In this study, we tested 20 healthy participants on a motion direction discrimination task. Participants monitored two patches of random dot motion simultaneously presented on either side of fixation for periodic changes in an upward or downward motion, which could occur equiprobably in either patch. On a random 50% of trials, these periods of coherent vertical motion were accompanied by simultaneous task-irrelevant, horizontal motion in the contralateral patch. Our data showed that these distractors selectively increased the amplitude of early target selection responses over scalp sites contralateral to the distractor stimulus, without impacting on responses ipsilateral to the distractor. Importantly, this modulation mediated a decrement in the subsequent buildup rate of a neural signature of evidence accumulation and accounted for a slowing of RTs. These data offer new insights into the functional interactions between target selection and evidence accumulation signals, and their susceptibility to task-irrelevant distractors. More broadly, these data neurally inform future models of perceptual decision-making by highlighting the influence of early processing of competing stimuli on the accumulation of perceptual evidence.


A new model of an arteriovenous fistula in chronic kidney disease in the mouse: beneficial effects of upregulated heme oxygenase-1.
The arteriovenous fistula (AVF) is the preferred hemodialysis vascular access, but it is complicated by high failure rates and attendant morbidity. This study provides the first description of a murine AVF model that recapitulates two salient features of hemodialysis AVFs, namely, anastomosis of end-vein to side-artery to create the AVF and the presence of chronic kidney disease (CKD). CKD reduced AVF blood flow, observed as early as 3 days after AVF creation, and increased neointimal hyperplasia, venous wall thickness, thrombus formation, and vasculopathic gene expression in the AVF. These adverse effects of CKD could not be ascribed to preexisting alterations in blood pressure or vascular reactivity in this CKD model. In addition to vasculopathic genes, CKD induced potentially vasoprotective genes in the AVF such as heme oxygenase-1 (HO-1) and HO-2. To determine whether prior HO-1 upregulation may protect in this model, we upregulated HO-1 by adeno-associated viral gene delivery, achieving marked venous induction of the HO-1 protein and HO activity. Such HO-1 upregulation improved AVF blood flow and decreased venous wall thickness in the AVF. Finally, we demonstrate that the administration of carbon monoxide, a product of HO, acutely increased AVF blood flow. This study thus demonstrates: 1) the feasibility of a clinically relevant murine AVF model created in the presence of CKD and involving an end-vein to side-artery anastomosis; 2) the exacerbatory effect of CKD on clinically relevant features of this model; and 3) the beneficial effects in this model conferred by HO-1 upregulation by adeno-associated viral gene delivery.


Rethinking the carcinogenesis of breast cancer: The theory of breast cancer as a child deficiency disease or a pseudo semi-allograft.
The theory of breast cancer as a child deficiency disease is an inversion of the current paradigm, which considers full-term pregnancies to be a protective factor and uses nulliparous women as the reference group. Instead, the theory of breast cancer as a child deficiency disease says that women with the highest parity (about 20, which is the limit of human fertility) are those with the lowest risk and should be used as the reference group in risk estimations. This theory is explained biologically by converting parity from the simple value of number of children into an understanding of the long-lasting biological and immunological effects of pregnancy. These effects can be reflected, as measured by functional genomics, in gene expression of the immune cells in the blood. Each pregnancy represents a unique fetus or semi-allograft, which provokes the creation and deposit of memory cell clones in the mother. Gene expression levels have been found to change linearly with number of full-term pregnancies in healthy women, but not in breast cancer patients. High hormone levels are necessary for a successful pregnancy, as they modulate the immune response from adaptive to innate in order to protect the fetus (considered as a semi-allograft) from rejection. At the end of the pregnancy, hormone levels drop, and the immune system recognizes the semi-allograft, but not in time for rejection to occur before birth. High hormones levels are also classified as carcinogens illustrating that carcinogenesis in the breast could be viewed as a war or balance between later exposures to hormonal carcinogens and the protection of the immune system. We propose that breast tumors are pseudo semi-allografts made up of transformed breast tissue cells. Assuming that the sensitivity to the exposure to increased levels of endogenous or exogenous hormones in women with breast cancer mimic those that occur in pregnancy, these breast tumor cells are protected against the body's immune reaction, just as the fetus is during pregnancy. However, with more pregnancies, the potential to eradicate the pseudo semi-allograft might increase due to enhanced immune surveillance. The theory of breast cancer as a child deficiency disease proposes that the protective effect of pregnancy on breast cancer incidence via the immune system is independent of other risk factors.


Prognostic significance of lymphocyte morphology in patients with advanced chronic lymphocytic leukemia treated with first line therapy of fludarabine + prednisone.
Chronic lymphocytic leukemia (CLL) is characterized by clinical, immunophenotypic and morphologic heterogeneity. The morphologic pattern of CLL lymphocytes at diagnosis has been associated with likelihood of different prognoses, while its prognostic significance at the time of disease progression is uncertain. In 69 previously untreated patients with advanced CLL the morphology of peripheral blood (PB) lymphocytes was retrospectively analyzed prior to therapy with fludarabine (FD: 25 mg/m(2) x 5 consecutive days every 4 weeks) and prednisone (P: 40 mg/m(2) x 5 consecutive days every 4 weeks). Two groups of patients were identified: the first one characterized by typical CLL morphology (T) and < or =11% of atypical lymphocytes, and the second one characterized by >11% of atypical lymphocytes (A). The second group was further subdivided into a group characterized by prolymphocyte prevalence (Ap) and into a group characterized by mixed cell morphology (Amc), with a prevalence of large-sized lymphocytes and/or small, cleaved lymphocytes and/or lymphoplasmocytoid cells with or without shaped nucleus. Forty-two patients (61%) showed a T morphology and 27 (39%) an A morphology. The latter group included 14 patients with an Ap morphology and 13 with an Amc morphology. Two thirds of patients with A morphology showed an immunophenotypic score of 3-4. No significant differences in the distribution of clinical features prior to therapy were observed within the three morphologic groups (T, Ap, Amc), except for a higher lymphocyte count in the Ap group (p<0.05). The morphologic pattern did not have a significant impact on the response rate or on the duration of response. Patients with A morphology did, nonetheless, have a significantly shorter survival than patients with T morphology (p=0.05). However, in multivariate analysis we failed to demonstrate an independent prognostic effect of the lymphocyte morphology observed prior to therapy, while age (< or =55 vs >55 years) and CLL duration (< or =12 vs >12 months) emerged as significant and independent prognostic factors of survival probability. The results of this study indicate that about one third of CLL patients with advanced disease have an atypical morphology and that about two thirds of patients with A morphology also show a low immunophenotypic score. The morphologic pattern at the time of progression does not allow identification of prognostic subgroups of patients with different response rates to first line therapy with FD + P.


Exposure Perception as a Key Indicator of Risk Perception and Acceptance of Sources of Radio Frequency Electromagnetic Fields.
The presented survey was conducted in six European countries as an online study. A total of 2454 subjects participated. Two main research questions were investigated: firstly, how does the cognitive, moral, and affective framing of radio frequency electromagnetic field (RF EMF) exposure perception influence RF EMF risk perception? Secondly, can the deployment of mobile phone base stations have greater acceptance with RF EMF exposure reduction? The findings with respect to the first question clearly indicated that the cognitive framed exposure perception is the main determinant of RF EMF risk perception. The concomitant sensitivity to exposure strength offers an opportunity to improve the acceptance of base stations by exposure reduction. A linear regression analysis supported this assumption: in a fictional test situation, exposure reduction improved the acceptance of base stations, operationalized as the requested distance of the base station from one's own home. Furthermore, subjects with high RF EMF risk perception were most sensitive to exposure reduction. On average, a 70% exposure reduction reduced the requested distance from about 2000 meters to 1000 meters. The consequences for risk communication are discussed.


Comparison between a β-tricalcium phosphate and an absorbable collagen sponge carrier technology for rhGDF-5-stimulated periodontal wound healing/regeneration.
The objective of this study is to compare a candidate β-tricalcium phosphate (β-TCP) carrier technology with the absorbable collagen sponge (ACS) benchmark to support recombinant human growth/differentiation factor-5 (rhGDF-5)-stimulated periodontal wound healing/regeneration. Routine, bilateral, critical-size (5-mm), 1-wall, intrabony periodontal defects were surgically created in the mandibular premolar region in 10 beagle dogs. Five animals received rhGDF-5/β-TCP and five animals received rhGDF-5/ACS, with a total of 20 μg rhGDF-5 per defect. The animals were euthanized for histologic and histometric analyses at 8 weeks postsurgery. Both rhGDF-5/ACS and rhGDF-5/β-TCP stimulated the formation of functionally oriented periodontal ligament, cellular mixed fiber cementum, and woven/lamellar bone. Bone regeneration (height and area) was significantly greater for the rhGDF-5/β-TCP construct than for the rhGDF-5/ACS (3.26 ± 0.30 mm versus 2.22 ± 0.82 mm, P <0.01; and 10.45 ± 2.26 mm(2) versus 5.62 ± 2.39 mm(2), P <0.01, respectively). Cementum formation ranged from 3.83 ± 0.73 mm to 3.03 ± 1.18 mm without significant differences between groups. Root resorption/ankylosis was not observed. The β-TCP carrier technology significantly enhanced rhGDF-5-stimulated bone formation compared with the ACS benchmark in this discriminating periodontal defect model. The structural integrity of the β-TCP carrier, preventing compression while providing a framework for bone ingrowth, may account for the observed results.


Rat synapsin 1 promoter mediated transgene expression in testicular cell types.
Previous reports described the rat synapsin 1 promoter as primarily neuron selective. However, ectopic expression of a transgene under the rat synapsin 1 promoter was also detected in testis from some transgenic mouse lines. Here we investigate which cells within the testis express a transgene consisting of the rat synapsin 1 promoter fused with luciferase. Synapsin 1-luciferase expression vectors were introduced into HeLa cells, into TM3 cells derived from mouse testicular Leydig cells, and into one-cell embryos to make transgenic mice. Indirect immunofluorescence suggests that nontransfected TM3 cells do not express endogenous synapsin 1. TM3 stable transfectants, however, expressed luciferase under the direction of the synapsin 1 promoter, in both promoter orientations. HeLa cells displayed only low levels of activity. Transgenic mice carrying the synapsin 1-luciferase construct displayed high levels of luciferase activity in the brain, spinal cord, and testis. Enriched populations of prepuberal types A and B spermatogonia and adult Leydig cells, pachytene spermatocytes, and round spermatids prepared from transgenic mice all displayed substantial luciferase activity. Thus, the rat synapsin 1 promoter can mediate reporter gene expression in neurons and testicular cell types.


The first center for evidence-based medicine in Lithuania: an opportunity to change culture and improve clinical practice.
In post-Soviet countries, where medical practice largely relies on experience alone, the incorporation of the best research evidence in clinical practice is limited. In order to promote the awareness and utilization of evidence-based medicine (EBM) among Lithuanian doctors, we organized EBM conferences in each of the two Lithuanian medical schools. More than 500 medical professionals and students attended the conferences in Vilnius (2013) and Kaunas (2014) demonstrating that there is a high demand for formal EBM teaching. Building on the success of these seminal conferences, and to start addressing the lack of EBM practice in the country, the first Lithuanian Centre for Evidence-Based Medicine was established at Vilnius University Medical Faculty in 2014. The Centre will focus on the implementation of EBM teaching in medical school curriculum, formulating management guidelines, writing systematic reviews and supporting Lithuanian authors in doing so.


Dialysis arthropathy: amyloid or iron?
The clinical, biochemical, radiological, and pathological features in five cases of dialysis arthropathy were analysed. All patients were receiving long term haemodialysis and had had multiple blood transfusions. The arthropathy affected both large and small joints, was predominantly bilateral, and in all cases was associated with the carpal tunnel syndrome. In some instances joint pain was exacerbated during dialysis. In four cases the serum ferritin concentration was raised. Radiological examination showed a few juxta-articular cysts and erosions but most affected joints looked normal. All synovial tissue examined showed amyloid, which stained immunohistochemically for beta 2 microglobulin. Large amounts of iron were present in synovial tissue from affected joints. It is suggested that the deposits of iron, rather than amyloid, in synovial tissue may be the cause of the arthropathy. Iron may be derived locally as a result of haemarthrosis or it may be a manifestation of systemic iron overload.


Efficacy of ChAdOx1 vaccines against SARS-CoV-2 Variants of Concern Beta, Delta and Omicron in the Syrian hamster model.
ChAdOx1 nCoV-19 (AZD1222) is a replication-deficient simian adenovirusâ€"vectored vaccine encoding the spike (S) protein of SARS-CoV-2, based on the first published full-length sequence (Wuhan-1). AZD1222 was shown to have 74% vaccine efficacy (VE) against symptomatic disease in clinical trials and over 2.5 billion doses of vaccine have been released for worldwide use. However, SARS-CoV-2 continues to circulate and consequently, variants of concern (VoCs) have been detected, with substitutions in the S protein that are associated with a reduction in virus neutralizing antibody titer. Updating vaccines to include S proteins of VoCs may be beneficial over boosting with vaccines encoding the ancestral S protein, even though current real-world data is suggesting good efficacy against hospitalization and death following boosting with vaccines encoding the ancestral S protein. Using the Syrian hamster model, we evaluated the effect of a single dose of AZD2816, encoding the S protein of the Beta VoC, and efficacy of AZD1222/AZD2816 as a heterologous primary series against challenge with the Beta or Delta variant. We then investigated the efficacy of a single dose of AZD2816 or AZD1222 against the Omicron VoC. As seen previously, minimal to no viral sgRNA could be detected in lungs of vaccinated animals obtained at 5 days post inoculation, in contrast to lungs of control animals. Thus, these vaccination regimens are protective against the Beta, Delta, and Omicron VoCs in the hamster model.


Effect of antenatal dexamethasone on the expression of endothelial nitric oxide synthase in the lungs of postnatal pups.
Activities of endothelial nitric oxide synthase (eNOS) are developmentally regulated and its presence at birth may play a role in the transition of cardiopulmonary circulation. Antenatal dexamethasone (Dex) therapy accelerates fetal lung maturation. We speculate that Dex therapy may enhance pulmonary eNOS protein expression in the newborn. This article examines whether antenatal Dex therapy affected the expression of eNOS in the lungs of rat pups in the postnatal period. Time-dated pregnant Wistar rats were subjected to 2 doses of Dex (0.8 mg/kg, intramuscularly, daily) or equivalent volume of normal saline at the 18th and 19th gestational day and delivered naturally. The newborn pups were randomly assigned to 4 groups by age: days 1, 3, 5, and 7. After homogenization, abundance of eNOS protein in lungs was determined by Western blot analysis. There were 7 dams in each group. Mean body weights of the pups in the Dex group were lighter than those in the control at birth and remained stunted up to day 7 (5.68+/-0.47 g v 6.34+/-0.47 g, P <.01). However, there were no differences in wet lung weights and lung/body weight ratios between both groups in the study period. Abundance of eNOS protein expression decreased in both the control and Dex groups (P < .01). Pups that received antenatal Dex had 39% more in abundance of eNOS protein expression in lungs when compared to the control on day 1 (P < .05) but there were no differences between both groups from day 3 to 7. We conclude that antenatal Dex therapy enhances the abundance of eNOS protein expression in the lung at birth and could be a factor in improving respiratory functions in infants who received antenatal steroid therapy.


Demystifying ethnic/sex differences in kidney function: is the difference in (estimating) glomerular filtration rate or in serum creatinine concentration?
The recent evaluation of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation for estimating the glomerular filtration rate (GFR) in multiple ethnicities has raised the question on how well this equation performs for African-American and Asian subjects. There is no doubt that serum creatinine (Scr) concentration differs between ethnicities and sexes. We show that creatinine-based equations for white populations may be inaccurate for estimating GFR in other ethnic/gender groups, especially in populations from Asia. This study presents a mathematical analysis of the CKD-EPI-equation complemented with a literature review of median and reference values for IDMS-standardized Scr-concentrations for multiple ethnicities. The study shows that at equal eGFR-CKD-EPI-values, the ratio of Scr between females and males equals 0.79 and between other ethnicities/sexes and white males is constant too. From this information, it is possible to calculate mean Scr-values that correspond very well with literature values directly obtained from Scr-distributions in healthy white males and females and in black males, but the discrepancy is larger for other populations. Our results confirm the criticism that has been raised for using the CKD-EPI-equation for these ethnicities. An alternative eGFR-model is proposed based on a population-normalized Scr that needs further validation.


Effect of vaccination on severity and dissemination of whooping cough.
A study was undertaken in general practice to clarify those factors, especially vaccinations, that influence the clinical picture and infectivity of whooping cough in the community. Although the range of the disease encountered was fairly mild, its duration was notable (mean +/- SD 50.9 +/- 32.1 days). By using multiway contingency table analysis it was found that in the more severe cases of whooping cough vaccination significantly shortened the illness (p less than 0.005) and reduced the number of coughing spasms (p less than 0.025). The protective effect of the vaccine was most notable in modifying infectivity within the family: 19% of vaccinated family contacts of index patients in whom the disease had been confirmed bacteriologically developed the disease when exposed to it compared with 72% of non-vaccinated contacts (p less than 0.001). These results show that whooping cough vaccination modifies the clinical illness and offers a worthwhile degree of protection to children exposed to the disease.


Lyme Borreliosis: Is there a preexisting (natural) variation in antimicrobial susceptibility among Borrelia burgdorferi strains?
The development of antibiotics changed the world of medicine and has saved countless human and animal lives. Bacterial resistance/tolerance to antibiotics have spread silently across the world and has emerged as a major public health concern. The recent emergence of pan-resistant bacteria can overcome virtually any antibiotic and poses a major problem for their successful control. Selection for antibiotic resistance may take place where an antibiotic is present: in the skin, gut, and other tissues of humans and animals and in the environment. Borrelia burgdorferi, the etiological agents of Lyme borreliosis, evades host immunity and establishes persistent infections in its mammalian hosts. The persistent infection poses a challenge to the effective antibiotic treatment, as demonstrated in various animal models. An increasingly heterogeneous subpopulation of replicatively attenuated spirochetes arises following treatment, and these persistent antimicrobial tolerant/resistant spirochetes are non-cultivable. The non-cultivable spirochetes resurge in multiple tissues at 12 months after treatment, with B. burgdorferi-specific DNA copy levels nearly equivalent to those found in shame-treated experimental animals. These attenuated spirochetes remain viable, but divide slowly, thereby being tolerant to antibiotics. Despite the continued non-cultivable state, RNA transcription of multiple B. burgdorferi genes was detected in host tissues, spirochetes were acquired by xenodiagnostic ticks, and spirochetal forms could be visualized within ticks and mouse tissues. A number of host cytokines were up- or down-regulated in tissues of both shame- and antibiotic-treated mice in the absence of histopathology, indicating a lack of host response to the presence of antimicrobial tolerant/resistant spirochetes.


Adolescent illicit drug use and subsequent academic and psychosocial adjustment: an examination of socially-mediated pathways.
Questions remain regarding the consequences of illicit drug use on adolescent adjustment and the nature of mechanisms that may explain these consequences. In this study, we examined whether early-onset illicit drug use predicts subsequent academic and psychosocial adjustment and whether associations are socially-mediated by decreased school engagement and increased peer deviancy. 4885 adolescents were followed throughout secondary school. We used regressions to determine whether illicit drug use in grade 7 predicted academic achievement, school dropout, depressive symptoms, and conduct problems in grades 10-11, adjusting for potential confounders. We used path analysis to test whether significant associations were mediated by school engagement and peer deviancy in grade 8. Illicit drug use predicted conduct problems and school dropout, but not academic achievement and depressive symptoms. The association between illicit drug use and conduct problems was fully mediated by increased peer deviancy. The association between illicit drug use and school dropout was partially mediated by increased peer deviancy, but remained mostly direct. No indirect association via decreased school engagement was found. Examination of reverse pathways revealed that conduct problems and academic achievement in grade 7 predicted drug use in grades 10-11. These associations were mediated by peer deviancy and school engagement (conduct problems only). Adolescent illicit drug use influences the risk of school dropout and conduct problems in part by contributing to deviant peer affiliation. Reciprocal social mediation characterizes the association between drug use and conduct problems. A reverse mechanism best explains the association with academic achievement.


Integrated function of a kinetic proofreading mechanism: dynamic analysis separating the effects of speed and substrate competition on accuracy.
All of the data relating to isoleucyl-tRNA synthetase and its proofreading of valyl-tRNAIle have been integrated into a single model whose dynamic behavior has been determined by numerical solution of the relevant kinetic equations. The results indicate that (1) the system normally operates in vivo with amino acid concentrations slightly above the apparent Km of the system, (2) increases in the displacement of reactants from thermodynamic equilibrium increase the net reaction velocity when the appropriate nominal parameter values are selected, (3) the cost of proofreading decreases with an increase in displacement of reactants from equilibrium, (4) accuracy and reaction velocity tend to be inversely related when substrate competition is unchanged but directly related or unrelated when substrate competition is altered, (5) changes in substrate competition are about twice as effective as changes in reaction velocity in altering the overall accuracy of aminoacylation, and (6) simultaneous changes in substrate competition and reaction velocity have a cumulative but not additive effect upon accuracy. With regard to the temporal development of errors and proofreading costs, we have seen two different patterns. In one, errors or costs gradually change with time following an abrupt alteration; in the other, errors or costs change dramatically in one direction and then more slowly reverse themselves. In all cases, the system responds to change quickly (less than 0.02-0.2 s) but shows no tendency to oscillate.


Hepatitis C virus-induced vasculitis: therapeutic options.
Hepatitis C virus (HCV) is now well recognised as the main etiologic agent of mixed cryoglobulinaemia vasculitis (cryovas). New opportunities and problems in developing therapy have therefore emerged. Antiviral therapy with pegylated interferon-α and ribavirin (plus protease inhibitor in the case of HCV genotype 1 infection) should be considered as induction therapy for HCV-cryovas with mild to moderate disease severity and activity. An early virologic response to antiviral therapy is correlated with a complete clinical response of HCV-cryovas. In patients presenting with more severe disease (ie, worsening of renal function, mononeuritis multiplex, extensive skin disease including ulcers and distal necrosis), an immunosuppression induction phase is often necessary while awaiting the generally slow response to antiviral treatments. Combination therapy with rituximab plus an optimal antiviral agent is recommended, as it may target the downstream B cell arm of autoimmunity and the viral trigger. Careful monitoring for adverse effects is mandatory, since some manifestations of HCV-cryovas, such as peripheral neuropathy or skin ulcers, may worsen with interferon-based therapy. Clinicians should be aware of the possibility of malignant lymphoma when patients develop a relapse of cryovas without virological relapse. Room for other treatment strategies is very limited. Low-dose corticosteroids may help to control minor intermittent inflammatory signs such arthralgia but do not succeed in case of major organ involvement. Other immunosuppressants should be given only in case of refractory forms of HCV-cryovas, which are frequently associated with an underlying B cell lymphoma.


Overt colon ischemia after endovascular aneurysm repair: the importance of microembolization as an etiology.
The purpose of this study was to analyze the incidence, severity, and etiologic factors of the development of colon ischemia after endovascular aortoiliac aneurysm repair (EVAR). During the last 9 years we performed 278 elective EVARs using a variety of grafts. To facilitate these repairs, one hypogastric artery (HA) was coil embolized in 109 patients and both HAs were coil embolized in 13 patients. The preprocedural status of the inferior mesenteric, hypogastric, and iliac arteries as well as anatomical characteristics of the abdominal aortic aneurysm were determined arteriographically and by computerized tomographic scans. Postoperative colon ischemia was documented by colonoscopy or operative findings. Colon ischemia occurred in eight patients (2.9%). Three patients with colon ischemia died and had evidence of widespread (cutaneous, renal, small bowel, and/or lower extremity) microembolization. One of these three had a colectomy and microscopic emboli were present. One other patient who required a colectomy also had pathologic evidence of colonic microembolization but survived. Four other patients with colon ischemia were treated conservatively and survived. In one patient, previous colectomy with interruption of mesenteric collaterals may have been a contributory cause of colon ischemia. Of the eight patients with colon ischemia, only one had unilateral HA occlusion, and none had bilateral HA occlusion. The other 121 patients with unilateral and bilateral HA occlusion had no evidence of colon ischemia. Colon ischemia occurs after EVAR with an incidence approximating that of open repair. Colon ischemia was unrelated to HA interruption. Embolization appears to be a major cause of colon ischemia, although inadequate mesenteric collateral circulation may also play an etiologic role. Mortality with colon ischemia accompanied by widespread embolization was high, whereas colon ischemia without it was often mild and amenable to nonoperative management.


Effect of a participatory organizational-level occupational health intervention on job satisfaction, exhaustion and sleep disturbances: results of a cluster randomized controlled trial.
We examined whether the implementation of a participatory organizational-level intervention aiming to improve the working environment with a focus on the core task at work, increased job satisfaction and reduced exhaustion and sleep disturbances among pre-school employees. The study sample consisted of 41 intervention group pre-schools with 423 employees and 30 control group pre-schools with 241 employees. The intervention lasted 25 months and consisted of seminars, workshops, and workplace specific intervention activities that were developed by focusing on the core task at work. We analyzed within-group changes in the three outcome variables from baseline to follow-up with t-tests for paired samples, separately for intervention and control group. Between-group differences in changes in the three outcome variables were analyzed using a mixed model with a repeated statement to account for the clustering effect of workplaces. Within-group analyses showed that exhaustion decreased statistically significantly in both the intervention and the control group. There were no statistically significantly changes in job satisfaction and sleep disturbances. Between-group analyses showed that there was no statistically significant difference between the two groups for changes in any of the outcome variables, neither in the unadjusted or in the adjusted analyses. We found no evidence that participating in an organizational-level occupational health intervention aiming to improve the working environment with a focus on the core task at work has an effect on pre-school employees' job satisfaction, exhaustion and sleep disturbances. ISRCTN16271504 , November 15, 2016.


Realistic distractions and interruptions that impair simulated surgical performance by novice surgeons.
HYPOTHESIS Although the risks for operating room distractions and interruptions (ORDIs) are acknowledged, most research on this topic is unrealistic, inconclusive, or methodologically unsound. We hypothesized that realistic ORDIs induce errors in a simulated surgical procedure performed by novice surgeons. DESIGN, SETTING, AND PARTICIPANTS Eighteen second-year, third-year, and research-year surgical residents completed a within-subjects experiment on a laparoscopic virtual reality simulator. Based on 9 months of operating room observations, 4 distractions and 2 interruptions were designed and timed to occur during critical stages in simulated laparoscopic cholecystectomy. The control factor was the absence or presence of ORDIs, with order randomly counterbalanced across the subjects. MAIN OUTCOME MEASURES The primary outcome measure was surgical errors measured by the simulator as damage to arteries, bile duct, or other organs. The second outcome measure was whether the participants remembered a prospective memory task assigned prior to the procedure and important to operative conduct. RESULTS Major surgical errors were committed in 8 of 18 simulated procedures (44%) with ORDIs vs only 1 of 18 (6%) without ORDIs (P = .02). Interrupting questions caused the most errors. Sidebar conversations were the next most likely distraction to lead to errors. Ten of 18 participants (56%) forgot the prospective memory task with ORDIs, while 4 of 18 (22%) forgot the task without ORDI (P = .04). All 8 surgical errors with ORDIs occurred after 1 PM (P = .001). CONCLUSIONS Typical ORDIs have the potential to cause operative errors in surgical trainees. This performance deficit was prevalent in the afternoon.


Arachidonic acid and docosahexaenoic acid supplemented to an essential fatty acid-deficient diet alters the response to endotoxin in rats.
This study examined fatty acid profiles, triene-tetraene ratios (20:3n9/20:4n6), and nutritional and inflammatory markers in rats fed an essential fatty acid-deficient (EFAD) diet provided as 2% hydrogenated coconut oil (HCO) alone for 2 weeks or with 1.3 mg of arachidonic acid (AA) and 3.3 mg of docosahexaenoic acid (DHA) (AA + DHA) added to achieve 2% fat. Healthy controls were fed an AIN 93M diet (AIN) with 2% soybean oil. The HCO and AA + DHA diets led to significant reductions of linoleic acid, α-linolenic acid, and AA (20:4n6) and increases in Mead acid (20:3n9) in plasma and liver compared with the AIN diet; but the triene-tetraene levels remained well within normal. However, levels of 20:3n9 and 20:4n6 were lower in liver phospholipids in the AA + DHA than in HCO group, suggesting reduced elongation and desaturation in ω-9 and -6 pathways. The AA + DHA group also had significantly lower levels of 18:1n9 and 16:1n7 as well as 18:1n9/18:0 and 16:1n7/16:0 than the HCO group, suggesting inhibition of stearyl-Co A desaturase-1 activity. In response to lipopolysaccharide, the levels of tumor necrosis factor and interleukin-6 were significantly lower with HCO, reflecting reduced inflammation. The AA + DHA group had higher levels of IL-6 and C-reactive protein than the HCO group but significantly lower than the AIN group. However, in response to endotoxin, interleukin-6 was higher with AA + DHA than with AIN. Feeding an EFAD diet reduces baseline inflammation and inflammatory response to endotoxin long before the development of EFAD, and added AA + DHA modifies this response.


Serum vitamin A and E concentrations in acute falciparum malaria: modulators or markers of severity?
1. To assess the association between vitamin A, vitamin E and the clinical course of severe malaria, serial morning blood samples were taken from 24 Vietnamese patients, aged 18-62 years, receiving intensive treatment for complicated Plasmodium falciparum infections. A single fasting blood sample was also taken from 10 control subjects aged 22-45 years. Serum retinol, carotene and vitamin E concentrations were measured by h.p.l.c. 2. Admission serum retinol concentration was depressed relative to that of the control subjects (0.69 +/- 0.35 versus 1.86 +/- 0.41 mumol/l mean +/- SD, P < 0.001) and correlated inversely with indices of hepatic function, but positively with the simultaneous serum creatinine concentration (P < 0.05). During the first week of treatment, serum retinol concentration increased in parallel with improving liver function, whereas serum creatinine concentration remained elevated in the majority of patients. Serum alpha- and beta-carotene concentrations remained depressed throughout. 3. Serum vitamin E concentration, corrected for total serum cholesterol concentration in the form of a ratio, was also depressed at presentation (3.1 +/- 1.8 x 10(3) versus 4.2 +/- 0.8 x 10(3) in control subjects; P < 0.05), but tended to be higher than the control value at the time of discharge (0.1 > P > 0.05); there was a significant correlation between admission ratio and parasite clearance time (P = 0.04). 4. On the basis of this and previous studies, vitamin A replacement could be considered in selected severely ill patients without renal impairment. As found previously in animal models, depressed vitamin E levels may have a beneficial effect on the course of malarial infection.


Assessing the effects of pharmacological agents on respiratory dynamics using time-series modeling.
Developing quantitative descriptions of how stimulant and depressant drugs affect the respiratory system is an important focus in medical research. Respiratory variables-respiratory rate, tidal volume, and end tidal carbon dioxide-have prominent temporal dynamics that make it inappropriate to use standard hypothesis-testing methods that assume independent observations to assess the effects of these pharmacological agents. We present a polynomial signal plus autoregressive noise model for analysis of continuously recorded respiratory variables. We use a cyclic descent algorithm to maximize the conditional log likelihood of the parameters and the corrected Akaike's information criterion to choose simultaneously the orders of the polynomial and the autoregressive models. In an analysis of respiratory rates recorded from anesthetized rats before and after administration of the respiratory stimulant methylphenidate, we use the model to construct within-animal z-tests of the drug effect that take account of the time-varying nature of the mean respiratory rate and the serial dependence in rate measurements. We correct for the effect of model lack-of-fit on our inferences by also computing bootstrap confidence intervals for the average difference in respiratory rate pre- and postmethylphenidate treatment. Our time-series modeling quantifies within each animal the substantial increase in mean respiratory rate and respiratory dynamics following methylphenidate administration. This paradigm can be readily adapted to analyze the dynamics of other respiratory variables before and after pharmacologic treatments.


Expression of adhesion and extracellular matrix molecules in the developing human brain.
Cell adhesion molecules and extracellular matrix molecules have important roles in cell migration and connection. Their developmental expression has not been fully described in humans. In this report, these molecules were examined by immunohistochemistry in frontal tissue samples from 14- to 28-week-old fetuses aborted for obstetric reasons (n = 20) and four fetuses with nervous system abnormalities. Neural cell adhesion molecule (NCAM), tenascin, and laminin were expressed after 17 weeks. Neural cell adhesion molecule was observed in the neuropil, whereas tenascin and laminin also had cellular and vascular expression. Thrombospondin and fibronectin, apparent after 14 weeks, showed a redistribution from periventricular to outer cortical layers after midgestation. N-cadherin and integrin were observed in mid- and late gestation. Maternal or environmental conditions seemed to influence the pattern of expression. Fetuses with nervous system abnormalities had altered expression of several molecules. The descriptive data obtained in this study might constitute a basis for further studies investigating the role of these molecules in developmental abnormalities of the brain.


Manifestations and implications of uncertainty for improving healthcare systems: an analysis of observational and interventional studies grounded in complexity science.
The application of complexity science to understanding healthcare system improvement highlights the need to consider interdependencies within the system. One important aspect of the interdependencies in healthcare delivery systems is how individuals relate to each other. However, results from our observational and interventional studies focusing on relationships to understand and improve outcomes in a variety of healthcare settings have been inconsistent. We sought to better understand and explain these inconsistencies by analyzing our findings across studies and building new theory. We analyzed eight observational and interventional studies in which our author team was involved as the basis of our analysis, using a set theoretical qualitative comparative analytic approach. Over 16 investigative meetings spanning 11 months, we iteratively analyzed our studies, identifying patterns of characteristics that could explain our set of results. Our initial focus on differences in setting did not explain our mixed results. We then turned to differences in patient care activities and tasks being studied and the attributes of the disease being treated. Finally, we examined the interdependence between task and disease. We identified system-level uncertainty as a defining characteristic of complex systems through which we interpreted our results. We identified several characteristics of healthcare tasks and diseases that impact the ways uncertainty is manifest across diverse care delivery activities. These include disease-related uncertainty (pace of evolution of disease and patient control over outcomes) and task-related uncertainty (standardized versus customized, routine versus non-routine, and interdependencies required for task completion). Uncertainty is an important aspect of clinical systems that must be considered in designing approaches to improve healthcare system function. The uncertainty inherent in tasks and diseases, and how they come together in specific clinical settings, will influence the type of improvement strategies that are most likely to be successful. Process-based efforts appear best-suited for low-uncertainty contexts, while relationship-based approaches may be most effective for high-uncertainty situations.


Ozone depletion and climate change: impacts on UV radiation.
We assess the importance of factors that determine the intensity of UV radiation at the Earth's surface. Among these, atmospheric ozone, which absorbs UV radiation, is of considerable importance, but other constituents of the atmosphere, as well as certain consequences of climate change, can also be major influences. Further, we assess the variations of UV radiation observed in the past and present, and provide projections for the future. Of particular interest are methods to measure or estimate UV radiation at the Earth's surface. These are needed for scientific understanding and, when they are sufficiently sensitive, they can serve as monitors of the effectiveness of the Montreal Protocol and its amendments. Also assessed are several aspects of UV radiation related to biological effects and health. The implications for ozone and UV radiation from two types of geoengineering methods that have been proposed to combat climate change are also discussed. In addition to ozone effects, the UV changes in the last two decades, derived from measurements, have been influenced by changes in aerosols, clouds, surface reflectivity, and, possibly, by solar activity. The positive trends of UV radiation observed after the mid-1990s over northern mid-latitudes are mainly due to decreases in clouds and aerosols. Despite some indications from measurements at a few stations, no statistically significant decreases in UV-B radiation attributable to the beginning of the ozone recovery have yet been detected. Projections for erythemal irradiance (UVery) suggest the following changes by the end of the 21(st) century (2090-2100) relative to the present time (2010-2020): (1) Ozone recovery (due to decreasing ozone-depleting substances and increasing greenhouse gases) would cause decreases in UVery, which will be highest (up to 40%) over Antarctica. Decreases would be small (less than 10%) outside the southern Polar Regions. A possible decline of solar activity during the 21(st) century might affect UV-B radiation at the surface indirectly through changes induced in stratospheric ozone. (2) The projected changes in cloud cover would lead to relatively small effects (less than 3%), except at northern high latitudes where increases in cloud cover could lead to decreases in UVery by up to 7%. (3) Reductions in reflectivity due to the melting of sea-ice in the Arctic would lead to decreases of UVery by up to 10%, while at the margins of the Antarctic the decreases would be smaller (2-3%). The melting of the sea-ice would expose the ocean surface formerly covered by ice to UV-B radiation up to 10 times stronger than before. (4) The expected improvement of air-quality and reductions of aerosols over the most populated areas of the northern hemisphere may result in 10-20% increases in UVery, except over China where even larger increases are projected. The projected aerosol effect for the southern hemisphere is generally very small. Aerosols are possibly the most important factor for future UV levels over heavily populated areas, but their projected effects are the most uncertain.


Design, synthesis, and biological evaluation of new thiazolo[5,4-d]pyrimidine derivatives as potent antiproliferative agents.
A series of thiazolo[5,4-d]pyrimidine derivatives were synthesized and evaluated for their antiproliferative activities against several human cancer cell lines. Structure-activity relationship studies were carried out, showing that most of the target compounds had good inhibition against the tested cell lines. Among them, compound 7i exhibited potent inhibition against human gastric cancer cells MGC-803 and HGC-27 with IC50 values of 4.64 and 5.07 μM, respectively and around 12-fold selectivity between MGC-803 and GES-1, indicating a relatively low toxicity to normal cells. The potency and low toxicity of compound 7i make the thiazolo[5,4-d]pyrimidine an attractive scaffold for designing new derivatives selectively targeting MGC-803 cells.


UV sensitive mutations in histone H3 in Saccharomyces cerevisiae that alter specific K79 methylation states genetically act through distinct DNA repair pathways.
Chromatin serves as a regulator of various nuclear processes, with post-translational modifications of histone proteins serving as modulators to influence chromatin function. We have previously shown that histone H3 K79 methylation is important for repair of UV-induced DNA damage in Saccharomyces cerevisiae, acting through multiple repair pathways. To evaluate the potential role of distinct K79 methylation states in DNA repair, we identified four mutations in histone H3 that confer sensitivity to UV, each of which also has a distinct effect on specific K79 methylation states. Epistasis analyses indicate that each mutation exerts its phenotypic effects through distinct subsets of the various DNA damage response pathways, suggesting the existence of discrete roles for histone H3 in DNA damage checkpoint and repair pathways. Furthermore, we find that the distribution of K79 methylation states is altered by mutation of the acetylatable N terminal lysines in histone H4. The combined results suggest that K79 methylation states may be modulated in response to UV damage via a trans-histone regulatory pathway, and that distinct methylation states may provide a means of coordinating specific DNA repair and damage checkpoint pathways.


Bromocriptine does not alter speed-accuracy tradeoff.
Being quick often comes at the expense of being accurate. This speed-accuracy tradeoff is a central feature of many types of decision making. It has been proposed that dopamine plays an important role in adjusting responses between fast and accurate behavior. In the current study we investigated the role of dopamine in perceptual decision making in humans, focusing on speed-accuracy tradeoff. Using a cued version of the random dot motion task, we instructed subjects to either make a fast or an accurate decision. We investigated decision making behavior in subjects who were given bromocriptine (a dopamine receptor agonist) or placebo. We analyzed the behavioral data using two accumulator models, the drift diffusion model, and the linear ballistic accumulator model. On a behavioral level, there were clear differences in decision threshold between speed and accuracy focus, but decision threshold did not differ between the drug and placebo sessions. Bayesian analyses support the null hypothesis that there is no effect of bromocriptine on decision threshold. On the neural level, we replicate previous findings that the striatum and pre-supplementary motor area are active when preparing for speed, compared with accurate decisions. We do not find an effect of bromocriptine on this activation. Therefore, we conclude that bromocriptine does not alter speed-accuracy tradeoff.


Reward activates stimulus-specific and task-dependent representations in visual association cortices.
Humans reliably learn which actions lead to rewards. One prominent question is how credit is assigned to environmental stimuli that are acted upon. Recent functional magnetic resonance imaging (fMRI) studies have provided evidence that representations of rewarded stimuli are activated upon reward delivery, providing possible eligibility traces for credit assignment. Our study sought evidence of postreward activation in sensory cortices satisfying two conditions of instrumental learning: postreward activity should reflect the stimulus category that preceded reward (stimulus specificity), and should occur only if the stimulus was acted on to obtain reward (task dependency). Our experiment implemented two tasks in the fMRI scanner. The first was a perceptual decision-making task on degraded face and house stimuli. Stimulus specificity was evident as rewards activated the sensory cortices associated with face versus house perception more strongly after face versus house decisions, respectively, particularly in the fusiform face area. Stimulus specificity was further evident in a psychophysiological interaction analysis wherein face-sensitive areas correlated with nucleus accumbens activity after face-decision rewards, whereas house-sensitive areas correlated with nucleus accumbens activity after house-decision rewards. The second task required participants to make an instructed response. The criterion of task dependency was fulfilled as rewards after face versus house responses activated the respective association cortices to a larger degree when faces and houses were relevant to the performed task. Our study is the first to show that postreward sensory cortex activity meets these two key criteria of credit assignment, and does so independently from bottom-up perceptual processing.


Microfibrils provide non-linear elastic behaviour in the abdominal artery of the lobster Homarus americanus.
1. Microfibrils are becoming increasingly recognized as an important component of the extra-cellular matrix. However, almost nothing is known about their mechanical role in the diversity of tissues in which they are found. 2. Microfibrils form the principal structural component in the wall of the abdominal artery of the lobster Homarus americanus. We have used previous estimates of the mechanical properties of these microfibrils, estimates of the fraction of the aorta wall volume occupied by the microfibrils, and their angular distribution as a function of strain in a numerical model that predicts the macroscopic mechanical properties of the whole tissue. 3. Microfibrils alone, when their reorientation and deformation are accounted for, characterize the stress-strain behaviour of the vessel. Evidence of the evolutionary conservation of fibrillin between medusans, echinoderms and vertebrates implies that the mechanical properties of lobster microfibrils may apply to microfibrillar function in other taxa. This will have profound implications on the perceived roles of microfibrils in development, physiology and disease.


Action-outcome relationships are represented differently by medial prefrontal and orbitofrontal cortex neurons during action execution.
Internal representations of action-outcome relationships are necessary for flexible adaptation of motivated behavior in dynamic environments. Prefrontal cortex (PFC) is implicated in flexible planning and execution of goal-directed actions, but little is known about how information about action-outcome relationships is represented across functionally distinct regions of PFC. Here, we observe distinct patterns of action-evoked single unit activity in the medial prefrontal cortex (mPFC) and orbitofrontal cortex (OFC) during a task in which the relationship between outcomes and actions was independently manipulated. The mPFC encoded changes in the number of actions required to earn a reward, but not fluctuations in outcome magnitude. In contrast, OFC neurons decreased firing rates as outcome magnitude was increased, but were insensitive to changes in action requirement. A subset of OFC neurons also tracked outcome availability. Pre-outcome anticipatory activity in both mPFC and OFC was altered when reward expectation was reduced, but did not differ with outcome magnitude. These data provide novel evidence that PFC regions encode distinct information about the relationship between actions and impending outcomes during action execution.


Site- and subunit-specific incorporation of unnatural amino acids into HIV-1 reverse transcriptase.
A highly efficient cell-free translation system has been combined with suppressor tRNA technology to substitute nor-Tyr and 3-fluoro-Tyr in place of Tyr183 at the DNA polymerase active site of p66 of human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT). Supplementing the wild-type HIV-1 p51 RT subunit into this translation system permitted reconstitution of the biologically relevant p66/p51 heterodimer harboring Tyr analogs exclusively on the catalytically competent p66 subunit. Addition of an affinity tag at the p66 C-terminus allowed rapid, one-step purification of reconstituted and selectively mutated heterodimer HIV-1 RT via strep-Tactin-agarose affinity chromatography. The purified enzyme was demonstrated to be free of contaminating nucleases, allowing characterization of the DNA polymerase and ribonuclease H activities associated with HIV-1 RT. Preliminary characterization of HIV-1 RT(nor-Tyr) and HIV-1 RT(m-fluoro-Tyr) is presented. The success of this strategy will facilitate detailed molecular analysis of structurally and catalytically critical amino acids via their replacement with closely related, unnatural analogs.


Protein kinase d as a potential chemotherapeutic target for colorectal cancer.
Protein kinase D (PKD) signaling plays a critical role in the regulation of DNA synthesis, proliferation, cell survival, adhesion, invasion/migration, motility, and angiogenesis. To date, relatively little is known about the potential role of PKD in the development and/or progression of human colorectal cancer. We evaluated the expression of different PKD isoforms in colorectal cancer and investigated the antitumor activity of PKD inhibitors against human colorectal cancer. PKD2 was the dominant isoform expressed in human colon cancer cells. PKD3 expression was also observed but PKD1 expression, at both the RNA and protein levels, was not detected. Suppression of PKD using the small molecule inhibitors CRT0066101 and kb-NB142-70 resulted in low micromolar in vitro antiproliferative activity against multiple human colorectal cancer cell lines. Drug treatment was associated with dose-dependent suppression of PKD2 activation. Incubation with CRT0066101 resulted in G(2)-M phase arrest and induction of apoptosis in human colorectal cancer cells. Further studies showed that CRT0066101 treatment gave rise to a dose-dependent increase in expression of cleaved PARP and activated caspase-3, in addition to inhibition of AKT and ERK signaling, and suppression of NF-κB activity. Transfection of PKD2-targeted siRNAs resulted in similar effects on downstream pathways as observed with small molecule inhibitors. Daily administration of CRT0066101 resulted in significant inhibition of tumor growth in HCT116 xenograft nude mice. Taken together, our studies show that PKD plays a significant role in mediating growth signaling in colorectal cancer and may represent a novel chemotherapeutic target for the treatment of colorectal cancer.


Accessibility of alpha 2-repressed promoters to the activator Gal4.
It has been proposed that eukaryotic repressors of transcription can act by organizing chromatin, thereby preventing the accessibility of nearby DNA to activator proteins required for transcription initiation. In this study, we test this idea for the yeast alpha 2 repressor using a simple, artificial promoter that contains a single binding site for the activator protein Gal4 and a single binding site for the repressor alpha 2. When both the repressor and the activator are expressed in the same cell, the artificial promoter is efficiently repressed. In vivo footprinting experiments demonstrate that Gal4 can occupy its binding site even when the promoter is repressed. This result indicates that alpha 2-directed repression must result from interference with some stage in transcription initiation other than activator binding to DNA.


Biomechanical Comparison of 3 Glenoid-Side Fixation Techniques for Superior Capsular Reconstruction.
Superior capsular reconstruction (SCR) was recently introduced as a treatment for irreparable superior rotator cuff tears in younger patients. Purpose/Hypothesis: The purpose was to assess the biomechanical strength of 3 methods for fixation of the graft to the glenoid for SCR. It was hypothesized that a 4-anchor technique would provide greater load to failure than 3-anchor techniques. Controlled laboratory study. Thirty-six cadaveric specimens were randomized into 3 groups of previously established glenoid-side graft fixation techniques: (1) three 3.5-mm knotless screw-in anchors, (2) three 3.0-mm knotless push-in anchors, and (3) a 4-anchor hybrid construct with two 3.0-mm knotted push-in anchors and two 2.9-mm knotless push-in anchors. The repairs were cyclically loaded at 0.5 Hz from 10 to 200 N, then pulled to failure. Elongation, stiffness, maximum load at failure, and mode of failure were recorded and calculated. There were no significant differences in graft elongation or stiffness among the 3 techniques ( P > .37 and P > .26, respectively). Maximum load to failure was significantly greater in technique 1 (mean ± SD, 427.85 ± 119.70 N) than technique 3 (319.5 ± 57.60 N) ( P = 0.024). There were no significant differences in load to failure between techniques 1 and 2 or between techniques 2 and 3. Glenoid-side graft fixation with 3 threaded 3.5-mm suture anchors showed a significant superior pull-out strength when compared with a 4-anchor hybrid technique and thus might be recommended in SCR for patients with irreparable superior rotator cuff tears to achieve maximum stability. SCR presents a novel alternative for treatment of irreparable superior rotator cuff tears in younger patients. Glenoid fixation is essential to provide adequate fixation of the graft to prevent the humeral head from rising and to restore normal biomechanics.


Bone augmentation using a synthetic hydroxyapatite/silica oxide-based and a xenogenic hydroxyapatite-based bone substitute materials with and without recombinant human bone morphogenetic protein-2.
To test whether or not bone regeneration using deproteinized bovine bone mineral (DBBM) is comparable to hydroxyapatite/silica oxide (HA/SiO) and to test the effect of recombinant human bone morphogenetic protein-2 (rhBMP-2) as an adjunct to DBBM for localized bone regeneration. In each of the 10 rabbits, 4 titanium cylinders were placed on the external cortical plates of their calvaria. Four treatment modalities were randomly allocated: (i) empty, (ii) HA/SiO, (iii) DBBM, and (iv) DBBM plus rhBMP-2 (DBBM/BMP). The animals were sacrificed at week 8. Descriptive histology and histomorphometric assessment using a superimposed test grid of points and cycloids were performed. The mean number of points of the test grid coinciding with bone within the cylinder reached 124 ± 35 bone points for empty controls, 92 ± 40 bone points for DBBM, 98 ± 44 bone points for synthetic HA/SiO, and 146 ± 34 bone points DBBM/BMP. The P-value for DBBM with and without BMP reached a borderline statistical significance of 0.051. However, the area of bone regeneration within the cylinders peaked for DBBM/BMP and was statistically significantly higher compared with empty cylinders (P < 0.05). The bone-to-bone substitute contact ranged between 32.9% ± 21.7 for DBBM, 39.6 ± 18.4% for HA/SiO, and 57.8% ± 10.2 for DBBM/BMP. The differences between DBBM/BMP and controls (DBBM, HA/SiO) were statistically significant (P < 0.05). DBBM and HA/SiO rendered comparable amounts of bone regeneration. The addition of rhBMP-2 to DBBM resulted in more favorable outcomes with respect to the area of bone regeneration and to bone-to-implant contact, thereby indicating the potential of this growth factor to enhance bone regeneration within this animal model.


Paragangliomas of the neck.
Between 1967 and 1990 inclusive, 28 patients with paragangliomas of the neck were diagnosed at the University of Alabama at Birmingham Affiliated Hospitals. There were 11 men and 17 women, whose ages ranged from 12 to 76 years (mean, 47 years). Tumor locations included the carotid bodies (19 cases), the vagus nerves (three), supraglottic larynx (two), the left lateral pharyngeal wall (one), posterior to the right jugular vein (not otherwise defined) (one), subcutaneous neck tissue (one), and a cervical lymph node with unknown primary (one). Diagnostic workup included angiography (23 cases) with preoperative embolization (three), computed tomography (one), magnetic resonance imaging (two), and urinary catecholamine assay (four). All 28 patients underwent resection of the lesions. Cranial nerve damage occurred in 11 patients (39%). There were no perioperative deaths or cerebrovascular accidents, although one of two saphenous vein grafts became thrombotic after carotid body tumor resection.


An open, randomized, comparative study of oral finasteride and 5% topical minoxidil in male androgenetic alopecia.
Androgenetic alopecia (AGA) is undoubtedly the most common form of hair loss in males. It is a condition which may cause cosmetic and psychosocial problems in androgen-dependent cases. In this open, randomized and comparative study we evaluated the efficacy of oral finasteride and 5% topical minoxidil treatment for 12 months in 65 male patients with mild to severe AGA. We randomly assigned 40 (61.53%) patients to receive 1 mg/day oral finasteride for 12 months, and 25 (38.47%) patients applied 5% topical minoxidil solution twice daily for 12 months. There were no significant differences between the 2 groups considering age, age of onset of hair loss, family history and type of hair loss (p > 0.05). In the clinical evaluation at the endpoint of treatment, the clinical cure rates (i.e. increased intensity of hair) were 80% (32/40) for the oral finasteride group and 52% (13/25) for the 5% topical minoxidil group. Encountered side effects were all mild, and there was no need to stop the treatment. In the group given oral finasteride, side effects were noted in 7 patients: 6 patients suffered from loss of libido, and 1 patient had an increase in other body hairs; irritation of the scalp was seen in 1 patient in the group administered 5% minoxidil. These adverse events disappeared as soon as the treatment was stopped. The laboratory data on both drug groups did not show any statistically or clinically significant intragroup changes from baseline values to the endpoint (p > 0.05), except the level of serum total testosterone which was increased, and free testosterone and serum prostate-specific antigen in the finasteride group which were statistically decreased from baseline values to the endpoint (p < 0.05). In this comparative study of systemic finasteride and topical minoxidil, it was concluded that both drugs were effective and safe in the treatment of mild to severe AGA, although oral finasteride treatment was more effective (p < 0.05). Adverse events were not considered important either, and these side effects disappeared as soon as the treatment was stopped.


Pharmacoeconomics of amifostine in ovarian cancer.
Physicians are frequently pressured to make therapeutic decisions within a cost-effective framework to demonstrate value to managed care. Because cancer is a chronic disease, health care costs are known to be expensive and physicians must use their resources as efficiently as possible. Historically, economic analyses in oncology have emphasized survival as their clinical end point. Today, both government groups and professional organizations are moving toward making quality of life the clinical end point in determining the economics of chemotherapy. This report evaluates the cost and efficacy of amifostine (Ethyol; Alza Pharmaceuticals, Palo Alto, CA/US Bioscience, West Conshohocken, PA) use in the treatment of advanced ovarian cancer using two pharmacoeconomic analyses. A cost-utility analysis performed in the United States indicated that inclusion of amifostine therapy had both a favorable clinical and cost-utility profile compared with other medical therapies. A second cost-benefit analysis, conducted in Canada, suggested that use of amifostine in patients with advanced ovarian cancer would be cost saving. Amifostine is a novel agent that protects against both chemotherapy- and radiotherapy-induced toxicities, such as nephrotoxicity, neutropenia, thrombocytopenia, peripheral neuropathy, mucositis, and xerostomia. These toxicities are disturbing to both patients and physicians alike. The results of these studies support the use of amifostine as a valuable resource both economically and clinically.


Using clinical guidelines to assess the potential value of laboratory medicine in clinical decision-making.
It is often quoted that 70% of clinical decisions are based on laboratory results, but the evidence to substantiate this claim is lacking. Since clinical guidelines aim to document best-practice decision making for specific disease conditions, inclusion of any laboratory test means that the best available evidence is recommending clinicians use it. Cardiovascular disease (CVD) is the world's most common cause of mortality, so this study reviewed all CVD guidelines published by five national/international authorities to determine what proportion of them recommended laboratory testing. Five leading CVD guidelines were examined, namely the European Society of Cardiology (ESC), the UK National Institute for Health and Clinical Excellence (NICE), the American College of Cardiology (ACC), the Australian Heart Foundation (AHF) and the Cardiac Society of Australia and New Zealand (CSANZ). A total of 101 guidelines were reviewed. Of the 33 individual ESC guidelines relating to CVD, 24/33 made a direct reference to the use of clinical laboratory tests in either diagnosis or follow-up treatment. The same applied to 15/20 of NICE guidelines, 24/32 from the ACC and 15/16 from the AHF/CSANZ. Renal function and blood count testing were the most recommended (39 and 26 times), with lipid, troponin and natriuretic peptide measurement advocated 25, 19 and 19 times respectively. This study has shown that laboratory testing is advocated by between 73% and 94% of individual CVD guideline recommendations from five national/international authorities. This provides an index to assess the potential value of laboratory medicine to healthcare.