On Sep 27, 2012, the NYC Department of Health and Mental Hygiene (DOHMH) alerted health-care providers and the public about 12 cases of invasive serogroup C Neisseria meningitidis disease occurring ...in NYC since Aug 2010 among men who have sex with men. Cases were identified through existing mandatory notifiable disease reporting and classified according to the Council of State and Territorial Epidemiologists case definitions. Among other things Weiss shares that DOHMH publicized this outbreak among the population at risk through advertising, mass e-mail messages on MSM websites, posters distributed at MSM bars and clubs, and outreach to community leaders and physician's groups.
E X E C U T I V E S U M M A R Y
According to the 2008 revision of the World Health Organization (WHO) classification of myeloid malignancies, philadelphia chromosome (Ph)-negative myeloproliferative ...neoplasms (MPNs) include clonal, hematologic disorders such as polycythemia vera, primary myelofibrosis, and essential thrombocythemia. Recent years have witnessed major advances in the understanding of the molecular pathophysiology of these rare subgroups of chronic, myeloproliferative disorders. Identification of somatic mutations in genes associated with pathogenesis and evolution of these myeloproliferative conditions (Janus Kinase 2; myeloproliferative leukemia virus gene; calreticulin) led to substantial changes in the international guidelines for diagnosis and treatment of Ph-negative MPN during the last few years. The MPN-Working Group (MPN-WG), a panel of hematologists with expertise in MPN diagnosis and treatment from various parts of India, examined applicability of this latest clinical and scientific evidence in the context of hematology practice in India. This manuscript summarizes the consensus recommendations formulated by the MPN-WG that can be followed as a guideline for management of patients with Ph-negative MPN in the context of clinical practice in India.
A significant proportion of implantable cardioverter-defibrillators (ICDs) have been subject to Food and Drug Administration (FDA) advisories. The impact of device advisories on mortality or patient ...care is poorly understood. Although estimated risks of ICD generators under advisory are low, dependency on ICD therapies to prevent sudden death justifies the assessment of long-term mortality.
To test the association of FDA advisory status with long-term mortality.
The study was a retrospective, single-center review of clinical outcomes, including device malfunctions, in patients from implantation to either explant or death. Patients with ICDs first implanted at Cleveland Clinic between August 1996 and May 2004 who became subject to FDA advisories on ICD generators were identified. Mortality was determined by using the Social Security Death Index.
In 1644 consecutive patients receiving first ICD implants, 704 (43%) became subject to an FDA advisory, of which 172 (10.5%) were class I and 532 (32.3%) were class II. ICDs were explanted before advisory notifications in 14.0% of class I and 10.1% of class II advisories. Among ICDs under advisory, 28 (4.0%) advisory-related and 15 non-advisory- related malfunctions were documented. Over a median follow-up of 70 months, 814 patients died. Kaplan-Meier 5-year survival rate was 65.6% overall, and 64.2, 61.1, and 69.3% in patients with no, class I, and class II advisories, respectively (P = .17).
ICD advisories impacted 43% of the patients. Advisory-related malfunctions affected 4% within the combined advisory group. Based on a conservative management strategy, ICDs under advisory were not associated with increased mortality over a background of significant disease-related mortality.
Electrographic seizures in critically ill patients are often equivocal. In this study, we sought to determine the diagnostic accuracy of electrographic seizure annotation in adult intensive care ...units (ICUs) and to identify affecting factors.
To investigate diagnostic accuracy, interreader agreement (IRA) measures were derived from 5,769 unequivocal and 6,263 equivocal seizure annotations by five experienced electroencephalogram (EEG) readers after reviewing 74 days of EEGs from 50 adult ICU patients. Factors including seizure equivocality (unequivocal vs. equivocal) and laterality (generalized, partial, or bilaterally independent), cyclicity (cyclic vs. noncyclic), persistency (occurrence of status epilepticus), and patient consciousness level (coma vs. noncoma) were further investigated for their influence on IRA measures.
On average, 70% of seizures marked by a reference reader overlapped, at least in part, with those marked by a test reader (any-overlap sensitivity, AO-Sn). Agreed seizure duration between reader pairs (overlap-integral sensitivity, OI-Sn) was 62%, while agreed nonseizure duration (overlap-integral specificity, OI-Sp) was 99%. A test reader would annotate one additional seizure not overlapping with a reference reader's annotation in every 11.7 h of EEG, that is, the false-positive rate (FPR) was 0.0854/h. Classifying seizure patterns into unequivocal and equivocal improved specificity and FPR (unequivocal patterns) but compromised sensitivity only for equivocal patterns. Sensitivity of all and unequivocal annotations was higher for patients with status epilepticus. Specificity was higher for partial than for bilaterally independent unequivocal seizure patterns, and lower for cyclic all seizure patterns.
Diagnosing electrographic seizures in critically ill adults is highly specific and moderately sensitive. Improved criteria for diagnosing electrographic seizures in the ICU are needed.
The endothelial cell (EC) urokinase receptor plays an important role in the localization and receptor-mediated activation of EC-bound plasminogen and hence surface-localized fibrinolysis. Thrombin ...induced a rapid (< 5 minute), time- (0 to 30 minutes) and dose- (0.1 to 8 U/mL) dependent decrease in the specific binding of Iodine-labeled two-chain urokinase-type plasminogen activator (tcu-PA) or diisopropylfluorophosphate-tcu-PA to urokinase-type plasminogen activator receptor (u-PAR) in cultured ECs from various sources (range, 21% to 50%). The thrombin receptor activation peptide but not control peptide showed a similar but reduced decrease in the specific binding of sup 125 Iodine-labeled tcu-PA to u-PAR. Incubation of thrombin-treated cultures (10 to 12 hours) in complete medium restored Iodine-labeled tcu-PA ligand binding to normal levels. u-PAR mRNA levels rapidly (1 hour) increased and peaked 10 to 12 hours after thrombin treatment as analyzed by reverse transcriptase-polymerase chain reaction. Decreased thrombin-induced Iodine-labeled tcu-PA binding correlated with the time-dependent decrease in surface-localized plasmin generation, as measured by the direct activation of Iodine-labeled Glu-plasminogen and quantification of the 20-kD light chains of Iodine-labeled plasmin. After incubation with thrombin, plasmin generation was decreased 50% to 56% (125 to 152 fmol/3 to 3.5 x 10 cells). Isolation of metabolically labeled Sulfur-labeled u-PAR from the media of thrombin and phospholipase C-treated human aortic cultures yielded nearly equal 10- and nearly equal 12-fold more 55-kD Mr and nearly equal 6-fold more 35-kD M sub r Sulfur-labeled u-PAR forms than control cultures, respectively. The u-PAR antigen forms (Mr, 54 kD) and the glycosyl-phosphatidylinositol-anchored protein CD59 (Mr, 20 kD) were also simultaneously identified by immunoprecipitation in the media of thrombin-treated cultures. This suggests that thrombin may release u-PAR and decrease u-PA ligand binding through a common pathway involving phospholipase C. These results establish a novel interrelation between thrombin and EC fibrinolysis and suggest that thrombin may also have an additional regulatory role in the net expression of surface-localized EC fibrinolytic activity. (Arterioscler Thromb Vasc Biol. 1995;15:410-419.)
The effect of normo (NTG)- and hypertriglyceridemic (HTG)-VLDL on cultured human umbilical vein endothelial cell (HUVEC) surface-localized fibrinolysis was examined following pre-incubation with ...NTG-, HTG-VLDL, LDL (1−20 μg/mL) or buffer (control). Ligand binding assays, using 125I-labeled tcu-PA, t-PA, or Glu-plasminogen (Glu-Pmg) were carried out in the absence/presence of lipoproteins. Scatchard analyses showed that HTG-VLDL decreased the B max for 125I-labeled Glu-Pmg ligand binding ∼35% (2.11 ± 0.39)−(1.40 ± 0.32) × 106 sites/cell, p < 0.05 and increased the K d,app ∼5-fold (0.32 ± 0.03 to 1.74 ± 0.08 μM, p < 0.01), while NTG-VLDL, LDL, and buffer had no effect. 125I-labeled PA ligand binding was unaffected by these lipoproteins. Receptor-bound PA activation of cell-bound 125I-labeled Glu-Pmg was measured by quantitation of either the M r 20 kDa light- or M r 60 kDa heavy-chain of 125I-labeled plasmin, following SDS−PAGE. Kinetic analysis of these data (HTG-VLDL vs controls) indicated that HTG-VLDL decreased the V max of tcu-PA- and t-PA-mediated activation of plasminogen ∼2.7-fold (0.317 ± 0.023 vs 0.869 ± 0.068 nM s-1, p < 0.01) and ∼2.9-fold (0.391 ± 0.098 vs 1.152 ± 0.265 nM s-1, p < 0.01), respectively. Increasing concentrations of the HTG-VLDL increased 1/V max, yielding a series of parallel plots, typical for uncompetitive inhibition with a K i for inhibition of ∼10 μg/mL. The combined ligand binding and kinetic data best fit an uncompetitive inhibition model in which the binding of the large HTG-VLDL particle to the EC surface may directly affect Glu-Pmg binding and activation, thus contributing to early fibrin deposition and the increased thrombotic risk associated with HTG.
beta 2 microglobulin knockout (beta2M-/-) mice lack CD8+ T and natural killer T cells. We hypothesized that beta 2M-/- mice are resistant to lethal intraabdominal sepsis. To test this hypothesis, ...mortality, cytokine production, and physiologic function were assessed in beta 2M-/- mice during sepsis caused by cecal ligation and puncture (CLP). beta 2M-/- mice survived significantly longer than wild-type mice after CLP but ultimately exhibited 100% mortality. Treatment of beta 2M-/- mice with anti-asialoGM1 to deplete natural killer cells conferred greater than 70% long-term survival. Compared with wild-type mice, beta 2M-/- mice treated with anti-asialoGM1 produced decreased amounts of proinflammatory cytokines and did not exhibit hypothermia or metabolic acidosis after CLP. Adoptive transfer of CD8+ T and natural killer cells into beta 2M-/- mice treated with anti-asialoGM1 re-established CLP-induced mortality. CD8 knockout mice treated with anti-asialoGM1, which are specifically deficient in CD8+ T and natural killer cells, exhibited 40% long-term survival after CLP. Furthermore, treatment of wild-type mice with antibodies to CD8 and asialoGM1 conferred a significant survival benefit compared with wild-type mice treated with nonspecific IgG. These findings demonstrate that beta 2M-/- mice treated with anti-asialoGM1 are resistant to CLP-induced mortality and that depletion of CD8+ T and natural killer cells largely accounts for the survival benefit observed in these mice.
beta 2 microglobulin knockout (beta2M-/-) mice lack CD8+ T and natural killer T cells. We hypothesized that beta 2M-/- mice are resistant to lethal intraabdominal sepsis. To test this hypothesis, ...mortality, cytokine production, and physiologic function were assessed in beta 2M-/- mice during sepsis caused by cecal ligation and puncture (CLP). beta 2M-/- mice survived significantly longer than wild-type mice after CLP but ultimately exhibited 100% mortality. Treatment of beta 2M-/- mice with anti-asialoGM1 to deplete natural killer cells conferred greater than 70% long-term survival. Compared with wild-type mice, beta 2M-/- mice treated with anti-asialoGM1 produced decreased amounts of proinflammatory cytokines and did not exhibit hypothermia or metabolic acidosis after CLP. Adoptive transfer of CD8+ T and natural killer cells into beta 2M-/- mice treated with anti-asialoGM1 re-established CLP-induced mortality. CD8 knockout mice treated with anti-asialoGM1, which are specifically deficient in CD8+ T and natural killer cells, exhibited 40% long-term survival after CLP. Furthermore, treatment of wild-type mice with antibodies to CD8 and asialoGM1 conferred a significant survival benefit compared with wild-type mice treated with nonspecific IgG. These findings demonstrate that beta 2M-/- mice treated with anti-asialoGM1 are resistant to CLP-induced mortality and that depletion of CD8+ T and natural killer cells largely accounts for the survival benefit observed in these mice.
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