Optimal long-term antithrombotic treatment of patients with stable coronary artery disease and atrial fibrillation: "OLTAT registry".

BACKGROUND: The optimal long-term antithrombotic treatment of patients with stable coronary artery disease (CAD) and atrial fibrillation (AF) is a challenge in daily practice. We sought to determine the prevalence of hemorrhagic complications and ischaemic events depending on antithrombotic strategy in patients with stable CAD and AF. METHODS: The primary outcome was major adverse cardiac and cerebrovascular events (MACCE) defined as a composite of cardiovascular mortality, myocardial infarction and ischaemic stroke. The subsequent risks of MACCE and clinically significant bleedings requiring hospitalisation (major safety outcome) were analyzed in a propensity score-matched analysis by adjusted Cox regression models. RESULTS: Six hundred and six patients with high thrombotic and bleeding risks (mean age 73.4 ±â€¯9.8 years, 25.2% female, CHA2DS2-VASc score:4.7 ±â€¯1.5, and HAS-BLED score:3.1 ±â€¯1.0) were included, and 127 propensity-matched pairs were analyzed. At inclusion, 172 patients (28.4%) were on oral anticoagulation (OAC) alone (75.6% on VKA and 24.4% on DOAC) and 434 patients (71.6%) on OAC + single antiplatelet therapy (SAPT) (71.9% on VKA and 28.1% on DOAC). At 5-year follow-up, MACCE rate did not significantly differ in both groups (30.9% in OAC + SAPT vs. 26.8% in OAC alone; adjusted HR 1.1 [0.8-1.5], p = 0.58), but clinically significant bleedings (28.3% vs. 18.5%; adjusted HR 1.8 [1.2-2.8], p = 0.005) and total deaths (29.5% vs. 20.8%; adjusted HR 1.4 [95% CI 1.0-2.2], p = 0.049) were higher in patients with OAC + SAPT than in patients with OAC alone. CONCLUSIONS: In patients with stable CAD and AF, the addition of antiplatelet therapy to VKA or DOAC therapy was independently associated with a higher risk of bleeding and overall mortality, without significant reduction in cardiac and cerebral ischaemic events.

Risk factors for Newcastle disease in broiler farms in Israel.

Following a large outbreak of Newcastle disease (ND) in Israel, a cross-sectional study was conducted in the broilers sector. The aim of the study was to find geographical and farm related risk factors for ND. Information was available on 96% of the broiler farms in Israel. Of these, farms diagnosed with ND in the years 2010-2012 were compared with the other farms. Risk factors for ND were analyzed, using Generalized Estimating Equation models. Six variables were found to be associated with the risk for ND outbreak: a distance of less than 300m from another farm (OR=1.77, 95% CI 1.07-2.93), a distance of less than 6000m from a national border (OR=2.00, 95% CI 1.22-3.30), farm location in the Ha'amakim district (OR=2.46, 95% CI 1.32-4.61), village type: a Moshav (village) vs. Kibbutz (Cooperative village) (OR=1.96, 95% CI 1.04-3.70), and carcass disposal in an uncovered bin (OR=1.96, 95% CI 1.18-3.26). A distance of less than 800m from an inter-city road was found to be a protective factor (OR=0.60, 95% CI 0.37-0.98). The results of this study provide information that may be used to improve surveillance and control of ND.

FoxO1-dependent induction of acute myeloid leukemia by osteoblasts in mice.

Osteoblasts, the bone forming cells, affect self-renewal and expansion of hematopoietic stem cells (HSCs), as well as homing of healthy hematopoietic cells and tumor cells into the bone marrow. Constitutive activation of ß-catenin in osteoblasts is sufficient to alter the differentiation potential of myeloid and lymphoid progenitors and to initiate the development of acute myeloid leukemia (AML) in mice. We show here that Notch1 is the receptor mediating the leukemogenic properties of osteoblast-activated ß-catenin in HSCs. Moreover, using cell-specific gene inactivation mouse models, we show that FoxO1 expression in osteoblasts is required for and mediates the leukemogenic properties of ß-catenin. At the molecular level, FoxO1 interacts with ß-catenin in osteoblasts to induce expression of the Notch ligand, Jagged-1. Subsequent activation of Notch signaling in long-term repopulating HSC progenitors induces the leukemogenic transformation of HSCs and ultimately leads to the development of AML. These findings identify FoxO1 expressed in osteoblasts as a factor affecting hematopoiesis and provide a molecular mechanism whereby the FoxO1/activated ß-catenin interaction results in AML. These observations support the notion that the bone marrow niche is an instigator of leukemia and raise the prospect that FoxO1 oncogenic properties may occur in other tissues.

Inter- and intraindividual correlations of background abundances of (2)H, (18)O and (17)O in human urine and implications for DLW measurements.

BACKGROUND/OBJECTIVES: The method of choice for measuring total energy expenditure in free-living individuals is the doubly labeled water (DLW) method. This experiment examined the behavior of natural background isotope abundance fluctuations within and between individuals over time to assess possible methods of accounting for variations in the background isotope abundances to potentially improve the precision of the DLW measurement. SUBJECTS/METHODS: In this work, we measured natural background variations in (2)H, (18)O and (17)O in water from urine samples collected from 40 human subjects who resided in the same geographical area. Each subject provided a urine sample for 30 consecutive days. Isotopic abundances in the samples were measured using Off-Axis Integrated Cavity Output Spectroscopy. RESULTS: Autocorrelation analyses demonstrated that the background isotopes in a given individual were not temporally correlated over the time scales of typical DLW studies. Using samples obtained from different individuals on the same calendar day, cross-correlation analyses demonstrated that the background variations of different individuals were not correlated in time. However, the measured ratios of the three isotopes (2)H, (18)O and (17)O were highly correlated (R(2)=0.89-0.96). CONCLUSIONS: Although neither specific timing of DLW water studies nor intraindividual comparisons were found to be avenues for reducing the impact of background isotope abundance fluctuations on DLW studies, strong inter-isotope correlations within an individual confirm that use of a dosing ratio of 8‰:1‰ (0.6 p.p.m.: p.p.m.) optimizes DLW precision. Theoretical implications for the possible use of (17)O measurements within a DLW study require further study.

Integrating animal health and foodborne disease surveillance.

The control of foodborne diseases from an animal source has become an important part of public health policy. Since the agents that cause these diseases originate in animals, Veterinary Services, as well as Public Health Services, must be involved in their control. Control programmes should be established either through cooperation between the two Services or by the consolidation of all those involved into a single food control agency. Surveillance is an important part of these control programmes. The following questions must be addressed when planning an effective surveillance programme. What is the relative incidence, morbidity, mortality and economic cost of the foodborne disease in humans? Is the animal population the exclusive or a significant source of the human foodborne infection? What kind of surveillance is needed to identify the disease-causing agent in the animal population? Are we interested in identifying all cases of a disease in order to eradicate it or is our aim to reduce its incidence in the animal population? Do we have the ability to control the disease in the animal population? What disease detection tests are available? What are the sensitivity, specificity and cost of these diagnostic tests? Finally, does the country, region or agency involved have the legal, financial and educational resources to carry out this surveillance and follow it up with appropriate action? After these questions have been resolved,the veterinary and public health sectors must jointly decide if surveillance and control are feasible. If so, they can then begin to develop an appropriate programme.

Recent trends in the epidemiology of non-typhoidal Salmonella in Israel, 1999-2009.

The aim of the present study was to assess the recent trends in the epidemiology of non-typhoid Salmonella in Israel using a sentinel laboratory-based surveillance network. Between 1999 and 2009, 8758 Salmonella stool isolates were reported by five sentinel laboratories. There was a significant decrease in the incidence rate of Salmonella isolates from 70·5/100,000 in 1999 to 21·6/100,000 in 2005 followed by a slight increase to 30·3/100,000 in 2009. Of all Salmonella, 64·3% were isolated from children in the 0-4 years age group. Up to 2008, S. Enteritidis was the most prevalent serotype and in 2009 S. Infantis emerged as the most common Salmonella serotype. The decrease in the incidence of S. Enteritidis and S. Typhimurium and increase in S. Infantis among humans were associated with a similar trend among breeding flocks, which followed significant preventive interventions conducted against S. Enteritidis and S. Typhimurium infections in poultry. Tight surveillance and education of food handlers and consumers should be enhanced to reduce the foodborne transmission of Salmonella in Israel.

The bioethics and utility of selling kidneys for renal transplantation.

In the 53 years since kidney transplantation was first performed, this procedure has evolved from a highly speculative biomedical endeavor to a medically viable and often standard course of therapy. Long-term survival is markedly improved among patients who receive a kidney compared with patients who remain on the waiting list for such an organ. As outcomes have improved and more clinical indications have emerged, the number of people awaiting transplantation has grown significantly. In stark contrast to the robust expansion of the waiting list, the number of available deceased donors has remained relatively constant over the last several years. The current mechanism for procuring kidneys relies on voluntary donations by the general public, with the primary motivation being altruism. However, in light of the ever-increasing waiting list, it is the researchers' belief that the current system needs to be revised if supply is ever going to meet demand. In response to this critical organ shortage, different programs have been developed in an attempt to increase organ donation. At present, however, no solution to the problem has emerged. This report begins by outlining the scope of the problem and current legislation governing the procurement of transplantable organs/tissues in the United States. It continues with an overview of different proposals to increase supply. It concludes by exploring some of the controversy surrounding the proposal to increase donation using financial incentives. Though the following discussion certainly has implications for other transplantable organs, this report focuses on kidney transplantation because the waiting list for kidneys is by far the longest of all waiting lists for solid organs; and, as kidney transplant carries the smallest risk to living donors, it is the least ethically problematic.

Use of broadband, continuous-wave diode lasers in cavity ring-down spectroscopy for liquid samples.

Cavity ring-down spectroscopy (CRDS) is an extremely sensitive absorption technique that has been applied primarily to gas samples, which are characterized by having narrow absorption features. Recently, CRDS has also been applied to liquid samples, which have broad absorption features. The use of small inexpensive diode lasers as light sources for liquid samples is demonstrated. The low cost coupled with the ease and technical straightforwardness of application gives this technique wide appeal.

Clinical presentation of inhalational anthrax following bioterrorism exposure: report of 2 surviving patients.

The use of anthrax as a weapon of biological terrorism has moved from theory to reality in recent weeks. Following processing of a letter containing anthrax spores that had been mailed to a US senator, 5 cases of inhalational anthrax have occurred among postal workers employed at a major postal facility in Washington, DC. This report details the clinical presentation, diagnostic workup, and initial therapy of 2 of these patients. The clinical course is in some ways different from what has been described as the classic pattern for inhalational anthrax. One patient developed low-grade fever, chills, cough, and malaise 3 days prior to admission, and then progressive dyspnea and cough productive of blood-tinged sputum on the day of admission. The other patient developed progressively worsening headache of 3 days' duration, along with nausea, chills, and night sweats, but no respiratory symptoms, on the day of admission. Both patients had abnormal findings on chest radiographs. Non-contrast-enhanced computed tomography of the chest showing mediastinal adenopathy led to a presumptive diagnosis of inhalational anthrax in both cases. The diagnoses were confirmed by blood cultures and polymerase chain reaction testing. Treatment with antibiotics, including intravenous ciprofloxacin, rifampin, and clindamycin, and supportive therapy appears to have slowed the progression of inhalational anthrax and has resulted to date in survival.

Levels of phospholipid metabolites in breast cancer cells treated with antimitotic drugs: a 31P-magnetic resonance spectroscopy study.

Magnetic resonance spectroscopy (MRS) methods have provided valuable information on cancer cell metabolism. In this study, we characterized the 31P-MR spectra of breast cancer cell lines exhibiting differences in hormonal response, estrogen receptors (positive/negative), and metastatic potential. A correlation was made between the cytotoxic effect of antimitotic drugs and changes in cell metabolism pattern. Because most anticancer drugs are more effective on proliferating cells, our study attempted to elucidate the metabolic profile and specific metabolic changes associated with the effect of anticancer drugs on proliferating breast cancer cell lines. Accordingly, for the 31P-MRS experiments, cells were embedded in Matrigel to preserve their proliferation profile and ability to absorb drugs. The MRS studies of untreated cells indicated that the levels of phosphodiesters and uridine diphosphosugar metabolites were significantly higher in estrogen receptor-positive and low metastatic potential cell lines. 31P-MRS observations revealed a correlation between the mode of action of anticancer drugs and the observed changes in cell metabolic profiles. When cells were treated with antimicrotubule drugs (paclitaxel, vincristine, colchicine, nocodazole), but not with methotrexate and doxorubicin, a profound elevation of intracellular glycerophosphorylcholine (GPC) was recorded that was not associated with changes in phospholipid composition of cell membrane. Remarkably, the rate of elevation of intracellular GPC was much faster in cell population synchronized at G2-M compared with the unsynchronized cells. The steady-state level of GPC for paclitaxel-treated cells was reached after approximately 4 h for synchronized cells and after approximately 24 h (approximate duration of one cell cycle) for the unsynchronized ones. These observations may indicate a correlation between microtubule status and cellular phospholipid metabolism. This study demonstrates that 31P-MRS may have diagnostic value for treatment decisions of breast cancer and reveals new aspects of the mechanism of action of antimicrotubule drugs.

Psychoanalytic supervision: the intersubjective development.

The author argues that an intersubjective perspective on the analytic process makes the notion of purely didactic supervision, avoiding countertransference issues, untenable and that countertransference is both a clue to the analysand's psychic reality and a factor in its evolution. Supervision is seen as a highly personal learning process for both supervisor and supervisee and its emotional climate as a crucial factor in its evolution into a transitional space, generating new meanings. Supervision is portrayed as the crossroads of a matrix of object relations of three persons, of a complex network of transference/countertransference patterns. The avoidance or denial of the supervisor's subjective role in it, maintaining 'a myth of the supervisory situation', may make supervision stilted or even oppressive and stand in the way of resolving supervisory crises and stalemates. It is argued that several factors contribute to the conflictuality of supervision for all partners (often including the analysand): the continuous process of mutual evaluation, the reciprocal fears of exposing one's weaknesses, the impact of the institute as a setting and the transferences it arouses and the inherent conflicts of loyalty for each participant in the analytic/supervisory triad. The resulting dynamics and relational patterns could become a legitimate and freeing topic in supervisory discourse.

Recent advances in the treatment of acute leukemia: 1999.

This review briefly summarizes literature noteworthy in the field of adult acute leukemia published during 1999. The relationship between specific cytogenetic abnormalities and response to treatment was explored within a clinical framework. In particular, detailed analyses of the abnormalities seen in acute promyelocytic leukemia were examined. Two case reports of special interest were published: one shed light on the role of histone deacetylase inhibitors in combination with all-trans retinoic acid, and the other, on the role of granulocyte colony-stimulating factor in this disease. The clinical activity of arsenic was also reported and its mechanism of action explored. In acute lymphoblastic leukemia, attention was focused on occult translocations, and the importance of minimal residual disease was again emphasized. Lastly, results of early clinical trials using an anti-CD19 antibody were reported, with provocative results.

Anisocoria associated with the medical treatment of irritable bowel syndrome.

A case of anisocoria associated with oral pharmacologic treatment of irritable bowel syndrome is reported. A 26-year-old woman developed sudden onset of anisocoria and compromised accommodation that lasted 2 days after the use of oral scopolamine methylbromide for treatment of irritable bowel syndrome. The anisocoria and compromised accommodation occurred after contamination of the ocular surface after administration of scopolamine methylbromide and resolved within 1 week without further contamination. Oral preparations used for the pharmacologic treatment of irritable bowel syndrome can cause anisocoria due to anticholinergic pharmacologic blockade of the iris sphincter muscle.

Enhancement of 5-fluorouracil anabolism by methotrexate and trimetrexate in two rat solid tumor models, Walker 256 carcinosarcoma and Novikoff hepatoma, as evaluated by 19F-magnetic resonance spectroscopy.

Although 5-fluorouracil (5-FU) is one of the most effective single agents in treating solid tumors, its low effectiveness as a single agent has led to development of a number of modulators intended to enhance its therapeutic effectiveness. Of these, methotrexate (MTX) and trimetrexate (TMTX) have been shown to have synergistic anticancer activity with 5-FU. The effect of these two drugs on the uptake and the intratumoral metabolism of 5-FU was studied in two rat tumor models using 19F-nuclear magnetic resonance spectroscopy: on excised samples of Walker 256 carcinosarcoma and noninvasively (in vivo) in Novikoff hepatoma. In the rats bearing the Walker 256 tumor, a 4-hr pretreatment with MTX showed the maximal increase in the rate of conversion from 5-FU to its fluorinated nucleotides/nucleosides. In the rats bearing the Novikoff hepatoma, both modulators increased the amounts of cyctotoxic anabolites of 5-FU, but at the doses administered, the cumulative amounts of 5-FU anabolites formed after MTX were significantly higher than those formed after TMTX or after saline control. On the other hand, the increase in the levels of the fluorinated nucleotides/nucleosides after TMTX peaked at a later time. The possible significance of these findings is that timing of administration of a modulator is important because it affects both transport and metabolism of 5-FU. The two modulators studied, both antifolates, act differently on transport and on metabolism: MTX affects both, whereas TMTX, at the level studied, appears to affect predominantly the metabolic process. In addition, significant differences exist between tumor models. These data suggest possible mechanisms and processes that should be studied further in humans, using these noninvasive pharmacokinetic imaging methods for monitoring 5-FU targeting and metabolism.

Characterization of two novel sublines established from a human megakaryoblastic leukemia cell line transfected with p210(BCR-ABL).

Disease progression in chronic myelogenous leukemia (CML) is usually accompanied by chromosomal abnormalities such as an additional Ph chromosome, trisomies of chromosome 8 or 19, or i(17) in addition to the standard translocation t(9;22) (q34;q11). However, detailed studies of the various steps involved during this evolution are difficult to perform, thereby making the study of cell lines that contain the transposed genes BCR-ABL, especially those of human origin, an important focus. In this analysis we investigated the human megakaryoblastic cell line MO7e and its subline transfected with BCR-ABL, MO7e/p210. Initial studies demonstrated that the phenotype of the MO7e line was consistent with a megakaryocytic lineage as originally described and was growth factor dependent in liquid culture. The MO7e/p210 subline, however, was growth factor independent and could be further separated into two distinct sublines based on expression of glycophorin A using the monoclonal antibody R10. The subline R10 negative (R10-) was similar to the parent line MO7e but R10 positive (R10+) cells had a distinct erythroid phenotype. In addition, the R10- and R10+ sublines demonstrated strikingly different colony morphology when cultured in semisolid medium. Furthermore, R10+ cells had additional chromosomal abnormalities not detected in the R10- population. These results demonstrate that the insertion of the BCR-ABL in this human leukemia cell line resulted in two distinct subpopulations of cells, each now growth factor independent, but one with a phenotype and karyotype identical to the parent cell line and the other with a different phenotype and additional chromosomal abnormalities. These two subpopulations derived from the MO7e/p210 transfected cell line may prove useful in further understanding the multistep events that occur in the progression of this disease.