Nonresponse to clozapine and ultrarapid CYP1A2 activity: clinical data and analysis of CYP1A2 gene.

Clozapine (CLO), an atypical antipsychotic, depends mainly on cytochrome P450 1A2 (CYP1A2) for its metabolic clearance. Four patients treated with CLO, who were smokers, were nonresponders and had low plasma levels while receiving usual doses. Their plasma levels to dose ratios of CLO (median; range, 0.34; 0.22 to 0.40 ng x day/mL x mg) were significantly lower than ratios calculated from another study with 29 patients (0.75; 0.22 to 2.83 ng x day/mL x mg; P < 0.01). These patients were confirmed as being CYP1A2 ultrarapid metabolizers by the caffeine phenotyping test (median systemic caffeine plasma clearance; range, 3.85; 3.33 to 4.17 mL/min/kg) when compared with previous studies (0.3 to 3.33 mL/min/kg). The sequencing of the entire CYP1A2 gene from genomic DNA of these patients suggests that the -164C > A mutation (CYP1A2*1F) in intron 1, which confers a high inducibility of CYP1A2 in smokers, is the most likely explanation for their ultrarapid CYP1A2 activity. A marked (2 patients) or a moderate (2 patients) improvement of the clinical state of the patients occurred after the increase of CLO blood levels above the therapeutic threshold by the increase of CLO doses to very high values (ie, up to 1400 mg/d) or by the introduction of fluvoxamine, a potent CYP1A2 inhibitor, at low dosage (50 to 100 mg/d). Due to the high frequency of smokers among patients with schizophrenia and to the high frequency of the -164C > A polymorphism, CYP1A2 genotyping could have important clinical implications for the treatment of patients with CLO.

Systemic in vivo lentiviral delivery of miR-15a/16 reduces malignancy in the NZB de novo mouse model of chronic lymphocytic leukemia.

Similar to human chronic lymphocytic leukemia (CLL), the de novo New Zealand Black (NZB) mouse model has a genetically determined age-associated increase in malignant B-1 clones and decreased expression of microRNAs miR-15a and miR-16 in B-1 cells. In the present study, lentiviral vectors were employed in vivo to restore miR-15a/16, and both the short-term single injection and long-term multiple injection effects of this delivery were observed in NZB. Control lentivirus without the mir-15a/16 sequence was used for comparison. We found that in vivo lentiviral delivery of mir-15a/16 increased miR-15a/16 expression in cells that were transduced (detected by GFP expression) and in sera when compared with control lentivirus treatment. More importantly, mice treated with the miR-expressing lentivirus had decreased disease. The lentivirus had little systemic toxicity while preferentially targeting B-1 cells. Short-term effects on B-1 cells were direct effects, and only malignant B-1 cells transduced with miR-15a/16 lentivirus had decreased viability. In contrast, long-term studies suggested both direct and indirect effects resulting from miR-15a/16 lentivirus treatment. A decrease in B-1 cells was found in both the transduced and non-transduced populations. Our data support the potential use of systemic lentiviral delivery of miR-15a/16 to ameliorate disease manifestations of CLL.

Systemic antibodies can inhibit mouse mammary tumor virus-driven superantigen response in mucosa-associated lymphoid tissues.

Many mucosal pathogens invade the host by initially infecting the organized mucosa-associated lymphoid tissue (o-MALT) such as Peyer's patches or nasal cavity-associated lymphoid tissue (NALT) before spreading systemically. There is no clear demonstration that serum antibodies can prevent infections in o-MALT. We have tested this possibility by using the mouse mammary tumor virus (MMTV) as a model system. In peripheral lymph nodes or in Peyer's patches or NALT, MMTV initially infects B lymphocytes, which as a consequence express a superantigen (SAg) activity. The SAg molecule induces the local activation of a subset of T cells within 6 days after MMTV infection. We report that similar levels of anti-SAg antibody (immunoglobulin G) in serum were potent inhibitors of the SAg-induced T-cell response both in peripheral lymph nodes and in Peyer's patches or NALT. This result clearly demonstrates that systemic antibodies can gain access to Peyer's patches or NALT.

Vascularite rhumatoïde et autres complications systémiques: aspects diagnostique et thérapeutique [Diagnosis and treatment of rheumatoid vasculitis and other systemic complications of rheumatoid arthritis]

Rheumatoid arthritis is a systemic disease that can potentially affect any organ. If the articular manifestations are central to the disease; skin, ophthalmic, neurological, cardiac, pulmonary as well as renal manifestations are well recognized, the latter particularly in the context of a secondary amyloidosis. Although incidence of extraarticular manifestations appears to decrease, likely a result from our more aggressive and early management of rheumatoid arthritis, their consequences remain severe in terms of morbidity and mortality, and their treatments complicated. The new biological therapies seem to be a promising alternative to current therapies, such as cyclophosphamide and high dose prednisone, even if evidences are still limited.

Systemic mastocytosis with associated myeloproliferative disease and precursor B lymphoblastic leukaemia with t(13;13)(q12;q22) involving FLT3.

Systemic mastocytoses represent neoplastic proliferations of mast cells. In about 20% of cases systemic mastocytoses are accompanied by clonal haematopoietic non-mast cell-lineage disorders, most commonly myeloid neoplasms. A case of systemic mastocytosis carrying the characteristic mutation at codon 816 (D816V) in the KIT gene of mast cells, with two concurrent accompanying clonal haematopoietic non-mast cell-lineage disorders, chronic myeloproliferative disease, unclassifiable and precursor B lymphoblastic leukaemia is documented. Both accompanying clonal haematopoietic non-mast cell-lineage disorders carried the wild-type KIT gene, but had a novel t(13;13)(q12;q22) involving the FLT3 locus at 13q12. The chronic myeloproliferative disease, unclassifiable and the precursor B lymphoblastic leukaemia were cured by syngenous stem cell transplantation, but the systemic mastocytosis persisted for more than 10 years. The additional impact of molecular techniques on the correct diagnosis in haematological malignancies is highlighted, and evidence is provided that, apart from internal tandem duplications and mutations, FLT3 can be activated by translocations.

Agency Fact Sheet, Explanation of Fields, FY2005

This document produced by the Iowa Department of Administrative Services has been developed to provide a multitude of information about executive branch agencies/department on a single sheet of paper. The facts provides general information, contact information, workforce data, leave and benefits information and affirmative action data.

Pulmonary and systemic vascular dysfunction in young offspring of mothers with preeclampsia.

BACKGROUND: Adverse events in utero may predispose to cardiovascular disease in adulthood. The underlying mechanisms are unknown. During preeclampsia, vasculotoxic factors are released into the maternal circulation by the diseased placenta. We speculated that these factors pass the placental barrier and leave a defect in the circulation of the offspring that predisposes to a pathological response later in life. The hypoxia associated with high-altitude exposure is expected to facilitate the detection of this problem. METHODS AND RESULTS: We assessed pulmonary artery pressure (by Doppler echocardiography) and flow-mediated dilation of the brachial artery in 48 offspring of women with preeclampsia and 90 offspring of women with normal pregnancies born and permanently living at the same high-altitude location (3600 m). Pulmonary artery pressure was roughly 30% higher (mean+/-SD, 32.1+/-5.6 versus 25.3+/-4.7 mm Hg; P<0.001) and flow-mediated dilation was 30% smaller (6.3+/-1.2% versus 8.3+/-1.4%; P<0.0001) in offspring of mothers with preeclampsia than in control subjects. A strong inverse relationship existed between flow-mediated dilation and pulmonary artery pressure (r=-0.61, P<0.001). The vascular dysfunction was related to preeclampsia itself because siblings of offspring of mothers with preeclampsia who were born after a normal pregnancy had normal vascular function. Augmented oxidative stress may represent an underlying mechanism because thiobarbituric acid-reactive substances plasma concentration was increased in offspring of mothers with preeclampsia. CONCLUSIONS: Preeclampsia leaves a persistent defect in the systemic and the pulmonary circulation of the offspring. This defect predisposes to exaggerated hypoxic pulmonary hypertension already during childhood and may contribute to premature cardiovascular disease in the systemic circulation later in life.

Usefulness of heart rate to predict cardiac events in treated patients with high-risk systemic hypertension.

A high heart rate (HR) predicts future cardiovascular events. We explored the predictive value of HR in patients with high-risk hypertension and examined whether blood pressure reduction modifies this association. The participants were 15,193 patients with hypertension enrolled in the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial and followed up for 5 years. The HR was assessed from electrocardiographic recordings obtained annually throughout the study period. The primary end point was the interval to cardiac events. After adjustment for confounders, the hazard ratio of the composite cardiac primary end point for a 10-beats/min of the baseline HR increment was 1.16 (95% confidence interval 1.12 to 1.20). Compared to the lowest HR quintile, the adjusted hazard ratio in the highest quintile was 1.73 (95% confidence interval 1.46 to 2.04). Compared to the pooled lower quintiles of baseline HR, the annual incidence of primary end point in the top baseline quintile was greater in each of the 5 study years (all p <0.05). The adjusted hazard ratio for the primary end point in the highest in-trial HR heart rate quintile versus the lowest quintile was 1.53 (95% confidence interval 1.26 to 1.85). The incidence of primary end points in the highest in-trial HR group compared to the pooled 4 lower quintiles was 53% greater in patients with well-controlled blood pressure (p <0.001) and 34% greater in those with uncontrolled blood pressure (p = 0.002). In conclusion, an increased HR is a long-term predictor of cardiovascular events in patients with high-risk hypertension. This effect was not modified by good blood pressure control. It is not yet known whether a therapeutic reduction of HR would improve cardiovascular prognosis.

Prospective study on procalcitonin and other systemic infection markers in patients with leukocytosis.

OBJECTIVE: To better assess the diagnosis of an infection in patients presenting at an emergency department with peripheral blood leukocytosis (>10 x 10(9) cells/l) on laboratory testing. METHODS: We prospectively evaluated serum procalcitonin concentration (PCT), C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR). Patients were divided into two groups according to their final diagnosis: patients with infection and those without infection. PCT, CRP, and ESR were compared between these groups. Sensitivity, specificity, positive predictive values, negative predictive values, receiver operating characteristic curves, and areas under the curves were calculated for each biological measurement. RESULTS: Out of 173 patients, 99 (57%) had a final diagnosis of systemic infection. If a cutoff point of 0.5 ng/ml is considered, procalcitonin concentration had a sensitivity of 0.57, a specificity of 0.85, a negative predictive value of 0.59, and a positive predictive value of 0.84 for the diagnosis of a systemic infection. Adding CRP or ESR to PCT gave no more information (p=0.84). CONCLUSIONS: Only about half of the patients attending the emergency department with leukocytosis were suffering from an infection. Determination of the procalcitonin level may be useful for these patients, particularly in the case of a value higher than 0.5 ng/ml.

A Mechanistic Explanation of The Physical Properties of Undisturbed Loess, February, 1968

The relation between the properties and the water content of an undisturbed loess were investigated to provide insight into the mechanical behavior of the natural soil. Hand-carved samples from a single deposit, at their natural water contents, and at water contents modified in the laboratory to provide a range from 870 to 3270, were subjected to unconsolidated-undrained triaxial compression tests, consolidation tests, and initial negative pore water pressure tests. In addition, the clay-size fraction was separated from the remainder of the loess for a separate series of tests to establish its properties. The natural water content of the deposit in the field was measured at regular intervals for one year to provide an example of the range in properties that would be encountered. at this site. The test results are presented and their interpretation leads to conclusions regarding the volumetric relations that exist as the water content varies. The significance of the water content in relation to the properties of the natural soil is explored and the concept of a critical water content for loess is introduced.

Hereditary hepatic and systemic amyloidosis caused by a new deletion/insertion mutation in the apolipoprotein AI gene.

We report a Spanish family with autosomal-dominant non-neuropathic hereditary amyloidosis with a unique hepatic presentation and death from liver failure, usually by the sixth decade. The disease is caused by a previously unreported deletion/insertion mutation in exon 4 of the apolipoprotein AI (apoAI) gene encoding loss of residues 60-71 of normal mature apoAI and insertion at that position of two new residues, ValThr. Affected individuals are heterozygous for this mutation and have both normal apoAI and variant molecules bearing one extra positive charge, as predicted from the DNA sequence. The amyloid fibrils are composed exclusively of NH2-terminal fragments of the variant, ending mainly at positions corresponding to residues 83 and 92 in the mature wild-type sequence. Amyloid fibrils derived from the other three known amyloidogenic apoAI variants are also composed of similar NH2-terminal fragments. All known amyloidogenic apoAI variants carry one extra positive charge in this region, suggesting that it may be responsible for their enhanced amyloidogenicity. In addition to causing a new phenotype, this is the first deletion mutation to be described in association with hereditary amyloidosis and it significantly extends the value of the apoAI model for investigation of molecular mechanisms of amyloid fibrillogenesis.

Reassessing the status of antiphospholipid syndrome in systemic lupus erythematosus.

The antiphospholipid syndrome was initially described in 1986. To reassess the validity of antiphospholipid antibodies in systemic lupus erythematosus (SLE), 95 patients with SLE were studied. Their antiphospholipid antibody profile was analysed and correlated with clinical findings such as thrombosis, abortions, or thrombocytopenia. A low prevalence of these antibodies was found (13 patients; 14%) with a high specificity for thrombosis (92%) and abortions (92%). The importance of anticardiolipin antibodies as a risk factor for thrombosis or abortions, or both, in patients with SLE is reaffirmed by this work.