Francisella tularensis is a gram-negative facultative intracellular bacterium and the causative agent of tularemia. Two subspecies (type A and B strains) of the pathogen exist, the former being much ...more virulent than the latter for humans and other higher mammals. In this study, we examined the effect of virulent strains of
F. tularensis infection on the thymus and thymocytes and the potential mechanisms involved. Low-dose aerosol exposure of C57BL/6 mice with type A, but not type B,
F. tularensis caused severe reduction in thymus weight and destruction of thymocytes, particularly CD4
+CD8
+ thymocytes, by day 4 after infection. The depletion of thymocytes was accompanied by a significant increase in circulating cortisone levels and could be partially prevented by adrenalectomy. Moreover, thymus atrophy and thymocyte depletion following infection were abolished in mice deficient in tumor necrosis factor receptors 1 and 2, but not in FasL-deficient mice. The severe destruction of the thymus and selective depletion of immature thymocytes during type A
F. tularensis infection may represent a key pathogenic mechanism in tularemia and could hinder the development of an effective primary immune response against this highly virulent pathogen.
The endogenous lipid agent N-arachidonoylethanolamine (anandamide), among other effects, has been shown to be involved in nociceptive processing both in the central and peripheral nervous systems. ...Anandamide is thought to be synthesised by several enzymatic pathways both in a Ca super(2+)-sensitive and Ca super(2+)-insensitive manner, and rat primary sensory neurons produce anandamide. Here, we show for the first time, that cultured rat primary sensory neurons express at least four of the five known Ca super(2+)-insensitive enzymes implicated in the synthesis of anandamide, and that application of 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-arachidonoy l, the common substrate of the anandamide-synthesising pathways, results in anandamide production which is not changed by the removal of extracellular Ca super(2+). We also show that anandamide, which has been synthesised in primary sensory neurons following the application of 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-arachidonoy l induces a transient receptor potential vanilloid type 1 ion channel-mediated excitatory effect that is not inhibited by concomitant activation of the cannabinoid type 1 receptor. Finally, we show that sub-populations of transient receptor potential vanilloid type 1 ion channel-expressing primary sensory neurons also express some of the putative Ca super(2+)-insensitive anandamide-synthesising enzymes. Together, these findings indicate that anandamide synthesised by primary sensory neuron via a Ca super(2+)-insensitive manner has an excitatory rather than an inhibitory role in primary sensory neurons and that excitation is mediated predominantly through autocrine signalling. Regulation of the activity of the Ca super(2+)-insensitive anandamide-synthesising enzymes in these neurons may be capable of regulating the activity of these cells, with potential relevance to controlling nociceptive processing.
The endogenous lipid agent N-arachidonoylethanolamine (anandamide), among other effects, has been shown to be involved in nociceptive processing both in the central and peripheral nervous systems. ...Anandamide is thought to be synthesised by several enzymatic pathways both in a Ca^sup 2+^-sensitive and Ca^sup 2+^-insensitive manner, and rat primary sensory neurons produce anandamide. Here, we show for the first time, that cultured rat primary sensory neurons express at least four of the five known Ca^sup 2+^-insensitive enzymes implicated in the synthesis of anandamide, and that application of 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-arachidonoyl, the common substrate of the anandamide-synthesising pathways, results in anandamide production which is not changed by the removal of extracellular Ca^sup 2+^. We also show that anandamide, which has been synthesised in primary sensory neurons following the application of 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-arachidonoyl induces a transient receptor potential vanilloid type 1 ion channel-mediated excitatory effect that is not inhibited by concomitant activation of the cannabinoid type 1 receptor. Finally, we show that sub-populations of transient receptor potential vanilloid type 1 ion channel-expressing primary sensory neurons also express some of the putative Ca^sup 2+^-insensitive anandamide-synthesising enzymes. Together, these findings indicate that anandamide synthesised by primary sensory neuron via a Ca^sup 2+^-insensitive manner has an excitatory rather than an inhibitory role in primary sensory neurons and that excitation is mediated predominantly through autocrine signalling. Regulation of the activity of the Ca^sup 2+^-insensitive anandamide-synthesising enzymes in these neurons may be capable of regulating the activity of these cells, with potential relevance to controlling nociceptive processing.PUBLICATION ABSTRACT
Abstract 186
Acute Myeloid Leukemia - Therapy, excluding Transplantation: Pediatric and Adult AML Therapy
F is a protein bound, cytotoxic, cyclin dependent kinase inhibitor. A prior Phase II trial of ...TST with FLAM, with F given by one hour bolus daily × 3 for adults with newly-diagnosed AML with poor-risk features demonstrated that the complete remission (CR) rate was 30/45 (67%) with median overall survival (OS) and disease-free survival (DFS) for CR patients being 12.6 and 13.3 months, respectively. We now compare FLAM using bolus F (50 mg/m2 daily × 3; Arm A) vs. FLAM using F given by pharmacologically-derived “hybrid” schedule (30 mg/m2 bolus over 30 min followed by 40 mg/m2 in a 4 hr infusion daily × 3; Arm B) in 70 newly-diagnosed AML patients (pts) with poor-risk features. Results: Pt demographics are presented below.
Age# < 50Secondary AMLAdverse GeneticsMDS/MPDt-AMLSingleComplexFlt3ARM A (n = 36)59ü(24–78)31956133Total 24/36 = 67%Total 22/36 = 61%ARM B (n = 34)58ü(20–73)51698105Total 25/34 = 74%Total 23/34 = 68%
Grade > 3 tumor lysis occurred in 4/70 (6%) with 1 death (A), 1 transient hemodialysis (A), 1 transient hyperkalemia (B), and 1 discontinuation of therapy (B). Four pts (6%) died from regimen toxicity before day 60 (1 A, 3 B). Median time for ANC >500/uL was Day 33 (range 22–71), and platelets > 50,000/uL Day 30 (21-80) for both arms. CR rate in Arm A is 23/36 (64%) including 16/24 (67%) with prior MDS and 13/19 (68%) with adverse cytogenetics and 3/3 (100%) with FLT3-ITD. CR rate in Arm B is 24/34 (71%) including 16/24 (67%) with prior MDS, 12/18 (67%) with adverse cytogenetics, and 4/5 (80%) with FLT3-ITD. As of 7/1/10, 20/23 Arm A CR pts have received chemotherapy and/or allogeneic hematopoietic stem cell transplantation (HCT) in CR: 15/23 (65%) of these pts remain alive and in continuous CR for up to 14+ months, 2 relapsed 4 months post-HCT, and 2 died (1 FLAM consolidation, 1 HCT). Similarly, 20/24 Arm B CR pts have received chemotherapy and/or HCT in CR: 12/20 (60%) remain alive and in continuous CR for up to 18+ months. Of Arm B pts receiving FLAM consolidation, 1 relapsed at 2 months, 1 died at 8 months of cardiac failure, and 2 died during therapy. Three were unable to receive a second cycle and 1 refused. Overall, 51/70 (73%) of all pts and 40/47 (85%) of CR pts are alive 2+ - 19+ months after FLAM. Conclusions: TST with FLAM induces CR in >60% of newly diagnosed, poor-risk AML pts, including those with prior MDS and adverse genetics. There does not appear to be major difference in toxicity or responses between the two F schedules (bolus vs. “hybrid” bolus-infusion). Thus far, allogeneic HCT has been successfully undertaken in 21/47 (45%) of first CR patients, median age 57 (20-64), with 2 early relapses and 1 death from GVHD. Bolus F may be easier to administer than hybrid F and is therefore recommended for further study in newly diagnosed AML pts. These salutary results of FLAM in poor-risk pts will now be evaluated broadly in adults with AML and compared to traditional cytotoxic chemotherapy induction regimens.
No relevant conflicts of interest to declare.
The "Diagnosis and Treatment of Sleep Apnea in Cerebrovascular Disease" (GoToSleep) study is evaluating a strategy to improve the diagnosis and treatment of sleep apnea among veterans with stroke or ...transient ischemic attack (TIA) who also have hypertension. Specifically, the GoToSleep study was designed to overcome some of the barriers that exist within the Veterans Health Administration (VHA) to the timely diagnosis and treatment of sleep apnea by using ambulatory home-based polysomnography and auto-titrating continuous positive airway pressure (CPAP) to reduce the reliance on laboratory-based sleep studies.
The GoToSleep study is a prospective, multi-site, randomized, controlled strategy trial among an expected 318 veterans with cerebrovascular disease and hypertension who are assigned to an intervention group or a control group. Patients in the intervention group receive unattended polysomnography at baseline, and those with sleep apnea receive auto-titrating CPAP therapy for up to one year. Patients in the control group receive usual care and unattended polysomnography at the end of the study to identify the rate of undiagnosed sleep apnea. The primary objectives of the GoToSleep study are to determine whether a diagnostic and therapeutic intervention strategy among veterans with cerebrovascular disease and hypertension improves: (1) detection of sleep apnea; (2) appropriate treatment for sleep apnea; and (3) control of hypertension. Twenty-four-hour blood pressure assessments are made at baseline and at the end of the one-year study period for both groups. Antihypertensive medications and their doses are recorded at the time of the 24-hour blood pressure measurements.
This manuscript provides the rationale for 4 key components of the design of the GoToSleep trial: the inclusion of patients with cerebrovascular disease and hypertension without the use of a measure of daytime sleepiness as an eligibility criterion; the use of portable polysomnography and auto-titrating CPAP in patients' homes rather than using sleep laboratory polysomnography with fixed pressure CPAP; the analytic approach to evaluating change in blood pressure in the context of change in antihypertensive medications; and the use of a usual care control group.
We retrospectively studied the evolution of histopathologic features in successive renal biopsies in patients with lupus nephritis, to evaluate the effects of various treatment regimens. Repeat renal ...biopsies had been performed in 62 patients after more than 18 months of observation (median interval, 44 months) in randomized therapeutic trials comparing prednisone with cytotoxic drugs. Renal histopathologic features were graded individually, and a composite score reflecting the number and severity of irreversible lesions was defined as a chronicity index. The chronicity index for patients treated with conventional high-dose prednisone increased linearly with the interval between biopsies, whereas the index in the group receiving cytotoxic-drug treatments did not increase over time. After statistical adjustment for important prognostic factors (age and initial chronicity index) identified by multiple linear regression, the difference in the slopes between the group receiving prednisone and the group receiving cytotoxic drugs was significant (P less than 0.0001). We conclude that cytotoxic-drug treatment reduces the likelihood of progressive renal scarring in lupus nephritis.
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