A mouse model of mtDNA disease
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Journal Article↗
Biomedical subjects
H Jacobs
Publications and source records attributed to H Jacobs.
DNA double-strand breaks in immunoglobulin genes undergoing somatic hypermutation.
How rearranged immunoglobulin (Ig) genes are further diversified by somatic hypermutation is unknown. Using VDJ passenger Ig heavy chain (IgH) knockin mouse strains, we now demonstrate a high frequency of DNA double-strand breaks (DSBs) in the targeted VDJ passenger gene of germinal center (GC) B cells. These DSBs parallel the distribution of mutations in the targeted hypermutation domain and are found preferentially at RGYW motifs, the intrinsic hot spots of somatic hypermutation. The introduction of DSBs appears to depend on transcriptional activity. Thus, secondary diversification of rearranged V gene segments relates to an error-prone nonhomologous DSB repair system acting in B cells of the GC.
Animals↗
Proctoriones A-C: 2-acylcyclohexane-1,3-dione derivatives from peperomia proctorii.
The structures of three new compounds isolated from Peperomia proctorii, named proctoriones A-C, have been established by spectroscopic and chemical methods as 2,3-dihydro-5, 8-dihydroxy-2-pentadecyl-4H-benzopyran-4-one (1) and enolic forms of 4-hydroxy-2-octadecanoylcyclohexane-1,3-dione (2) and 4-hydroxy-2-octadec-(11Z)-enoylcyclohexane-1,3-dione (3).
Cyclohexanes↗
Cardiovascular disease in women with polycystic ovary syndrome at long-term follow-up: a retrospective cohort study.
OBJECTIVE: Polycystic ovary syndrome (PCOS) is associated with higher prevalence of cardiovascular risk factors but the relative prevalence of cardiovascular disease in women with PCOS has not previously been reported. We have compared cardiovascular mortality and morbidity in middle-aged women previously diagnosed with PCOS and age-matched control women. DESIGN: A retrospective cohort study of women diagnosed with PCOS in the United Kingdom before 1979. PATIENTS: Seventy cohort members died before 31 March 1999. Morbidity data were collected from 319 women with PCOS and 1060 age-matched control women. Sixty-one women with PCOS and 63 control women attended a clinical examination. MEASUREMENTS: Data were collected from death certificates, general practitioners' records and questionnaires with measurement of cardiovascular risk factors in a subsample of questionnaire respondents. RESULTS: All-cause and cardiovascular mortality in the cohort were similar to women in the general population (standardized mortality ratios (95% CI): 93 (72-117) and 78 (45-124), respectively). Women with PCOS had higher levels of several cardiovascular risk factors: diabetes (P = 0.002) hypertension (P = 0.04), hypercholesterolaemia (P < 0.001), hypertriglyceridaemia (P = 0.02) and increased waist:hip ratio (P = 0.004). After adjustment for BMI, odds ratios (OR) were 2.2 (0.9-5. 2) for diabetes, 1.4 (0.9-2.0) for hypertension and 3.2 (1.7-6.0) for hypercholesterolaemia. A history of coronary heart disease (CHD) was not significantly more common in women with PCOS (crude OR (95%CI) 1.5 (0.7-2.9)) but the crude OR for cerebrovascular disease was 2.8 (1.1-7.1). CONCLUSION: At long-term follow-up, a history of nonfatal cerebrovascular disease and cardiovascular risk factors including diabetes are more prevalent among women with polycystic ovary syndrome. Morbidity and mortality from of coronary heart disease among women with polycystic ovary syndrome is not as high as previously predicted. This finding challenges our understanding of the aetiology of coronary heart disease in women.
Aged↗
Impaired sarcoplasmic calcium release inhibits myocardial contraction in experimental sepsis.
PURPOSE: In septic shock, myocardial dysfunction develops over the course of illness, but the mechanism of this depression is not clear. In this study, mechanisms of myocardial dysfunction were examined in a porcine model of Escherichia coli sepsis. MATERIALS AND METHODS: Animals were subjected to 4 hours of bacteria infusion (n = 5) (septic group) or saline infusion (n = 5) (nonseptic group), after which trabeculae were removed from the right ventricle and placed into a recirculating water bath. Measurements of steady-state contraction (SSC) were obtained at 0.5, 1, and 2 Hz. Indirect indices were used to assess abnormalities in myocardial calcium metabolism in sepsis. Extrasystoles (ES) were used to assess transsarcolemmal (TSL) calcium flux and were measured at 300 milliseconds, 400 milliseconds, and 500 milliseconds after the preceding stimulus. Postrest contraction (PRC) is an indicator of SR recirculation from the uptake to the release site and was obtained after interposing intervals of rest between steady-state beats at 0.5 Hz. Rapid-cooling contracture (RCC) is an indicator of sarcoplasmic reticulum (SR) content and was obtained at 0.5, 1, and 2 Hz and after interposing intervals of rest at 0.5 Hz. RESULTS: SSC was not different between groups at 0.5 Hz, but compared with the nonseptic group, SSC decreased at 1 and 2 Hz in the septic group (P < .05). PRC and TSL were not different between groups. During rest intervals, calcium leaks out of SR through the ryanodine channel (ie, SR calcium release channel). In the septic group, as assessed by RCC, SR calcium leak was less than that found in the nonseptic group. CONCLUSION: These results indicate that myocardial dysfunction in sepsis is frequency dependent, and that the mechanism is most likely caused by inhibition of SR calcium release owing to blockade of the ryanodine channel.
Analysis of Variance↗
Anharmonicity of potentials of atoms in potassium hydrogensulfide (KDS) determined by neutron single-crystal diffraction
Potassium hydrogensulfide (KHS) is an ionic compound with an anionic molecular group HS(-). The fast reorientational disorder of the anions was determined for the ambient temperature modification [R3;m; Jeffrey (1974). Can. J. Phys. 52, 2370-2378]. Single crystals are available now as protonated or deuterated specimens. With neutron single-crystal diffraction at room temperature, a considerable anharmonicity of the atom potential of the H or D atoms was observed. Even the thermal motions of K and S atoms show small deviations from an isotropic probability density function, which can be modelled using anharmonic temperature factors. The temperature factors of the atoms were expanded into a Gram-Charlier series [Kuhs (1992). Acta Cryst. A48, 80-98] in order to evaluate the anharmonicity quantitatively. Parameters up to a fourth-order approximation are relevant for the D atoms. Results from neutron single-crystal diffraction are compared with split-atom models extracted from neutron powder diffraction patterns of fully deuterated samples.
Journal Article↗
Sexuality in young patients with Parkinson's disease: a population based comparison with healthy controls.
Answers from a multiple choice questionnaire on the opinions about public sexual attitudes, on emotion from personal sexual practice, on personal sexual function, and on general health perception were compared between 121 patients with Parkinson's disease (mean age 45 years) and 126 age and sex matched community derived controls. Patients were more dissatisfied with their present sexual functioning and relationship, and perceived their general health as poorer than the controls, whereas opinions about public sexual attitudes were only marginally different. No differences were found for sexual function. Further analysis showed that the perception of sexual functioning and general health in younger patients with Parkinson's disease is considerably influenced by depression and state of unemployment.
Adult↗
Neuropsychological abnormalities in first degree relatives of patients with familial Parkinson's disease.
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Humans↗
Impaired hepatic extraction and increased splanchnic production contribute to lactic acidosis in canine sepsis.
In septic shock, the extent to which lactic acidosis (LA) is a consequence of splanchnic lactate overproduction (SLP) or impaired hepatic lactate extraction (HLE) is not clear. We examined SLP and HLE in E. coli sepsis in dogs. We further determined the effects of vasopressor treatments, which included phenylephrine, dopamine, norepinephrine, and a combination of dobutamine and norepinephrine treatment, on SLP and HLE in respective groups. The animals were studied while anesthetized and ventilated. During sepsis, SLP increased as compared with presepsis (-0.017 versus 0.07 mmol/min, p < 0.05), but this increase could not be explained by reduced splanchnic oxygen delivery (SOD). During sepsis, HLE increased as compared with baseline (0.8 versus 8%, p < 0.05), but was significantly lower than that found during lactic acid loading in nonseptic dogs. None of the vasopressor treatments had a detrimental effect on SLP. These results indicate that LA in sepsis occurs secondary to an increase in splanchnic lactate production that is not related to reduced splanchnic oxygen delivery, as well as to a decrease in hepatic lactate extraction. Effects of different vasoactive agents did not alter either splanchnic lactate production or hepatic lactate extraction in this sepsis model.
Acidosis, Lactic↗
Association studies of Parkinson's disease and parkin polymorphisms.
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Adolescent↗
PIM1 reconstitutes thymus cellularity in interleukin 7- and common gamma chain-mutant mice and permits thymocyte maturation in Rag- but not CD3gamma-deficient mice.
The majority of lymphomas induced in Rag-deficient mice by Moloney murine leukemia virus (MoMuLV) infection express the CD4 and/or CD8 markers, indicating that proviral insertions cause activation of genes affecting the development from CD4(-)8(-) pro-T cells into CD4(+)8(+) pre-T cells. Similar to MoMuLV wild-type tumors, 50% of CD4(+)8(+) Rag-deficient tumors carry a provirus near the Pim1 protooncogene. To study the function of PIM proteins in T cell development in a more controlled setting, a Pim1 transgene was crossed into mice deficient in either cytokine or T cell receptor (TCR) signal transduction pathways. Pim1 reconstitutes thymic cellularity in interleukin (IL)-7- and common gamma chain-deficient mice. In Pim1-transgenic Rag-deficient mice but notably not in CD3gamma-deficient mice, we observed slow expansion of the CD4(+)8(+) thymic compartment to almost normal size. Based on these results, we propose that PIM1 functions as an efficient effector of the IL-7 pathway, thereby enabling Rag-deficient pro-T cells to bypass the pre-TCR-controlled checkpoint in T cell development.
Animals↗
Raging hormones miss the target
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Journal Article↗
Tuning somatic hypermutation by transcription.
The dependence of somatic hypermutation on transcription was studied in three mutant immunoglobulin heavy chain (IgH) insertion mice in which a targeted non-functional VHB1-8 passenger transgene was either placed under the transcriptional control of a truncated DQ52 promoter (p delta), its own RNA polymerase II dependent IgH promoter (pII) or a RNA polymerase I dependent promoter (pI). The relative mutation-frequency of the VHB1-8 passenger transgene in memory B cells of p delta, pI and pII mice (7%, 60% and 100%) correlated with the relative levels of transgene-specific pre-mRNA expressed in germinal center B cells isolated from the mutant mice (8%, 72% and 100%, respectively). These data indicate that the mutation load of rearranged Ig genes can be tuned by transcription. The question, whether somatic hypermutation requires transcription per se or a specific component of the RNA polymerase II complex, is under investigation.
Animals↗
Early but not delayed continuous arteriovenous hemofiltration improves cardiovascular function in sepsis in dogs.
OBJECTIVE: Continuous arteriovenous hemofiltration (CAVH) has been advocated as treatment to remove inflammatory mediators and thereby to improve hemodynamic parameters in sepsis. However, the results obtained with CAVH have been inconsistent. In a canine model of bacteremic Pseudomonas aeruginosa pneumonia, we tested the hypothesis that the time course of the institution of CAVH may be important in obtaining a beneficial treatment effect. METHODS: Two protocols were performed in phenobarbital-anesthetized dogs. In the early hemofiltration study (EHS), CAVH for 3 h was initiated 2 h post-pneumonia before mean arterial pressure (MAP) fell. In the late hemofiltration study (LHS), CAVH for 3 h was initiated at 5 h post-pneumonia when a decrease in MAP had already occurred. Hemodynamic measurements included cardiac output (CO), stroke volume (SV), and stroke work (SW). Myocardial depressant activity [filterable cardiodepressant substance (FCS)] found in plasma was assessed by bioassay at each measurement interval. RESULTS: In EHS, after 5 h of sepsis, SW, CO, and SV in the hemofiltered pneumonia group were higher as compared with the nonhemofiltered pneumonia group. In contrast, in LHS, no differences in hemodynamic parameters were found between the two pneumonia groups. In both EHS and LHS, plasma FCS activity was decreased to similar extents by CAVH. CONCLUSION: These results suggest the time course of institution of CAVH may be important in obtaining a beneficial treatment effect in sepsis.
Animals↗
Serum vascular endothelial growth factor concentrations in in vitro fertilization cycles predict the risk of ovarian hyperstimulation syndrome.
OBJECTIVE: To explore the value of serum vascular endothelial growth factor (VEGF) concentrations during IVF cycles in predicting the risk of ovarian hyperstimulation syndrome (OHSS). DESIGN: Prospective study. SETTING: London Women's Clinic. PATIENT(S): One hundred seven women undergoing IVF. Mild OHSS developed in 10 women, moderate OHSS in 7, and severe OHSS in 3. INTERVENTION(S): Serum VEGF concentrations were measured before treatment, after pituitary desensitization, and on the days of hCG administration, oocyte collection, and ET. MAIN OUTCOME MEASURE(S): Serum VEGF concentrations. RESULT(S): Serum VEGF concentrations were higher in women in whom OHSS developed. The increase in the VEGF concentration that occurred between the day of hCG administration and the day of oocyte collection (the "VEGF rise") was an important marker of OHSS. The VEGF rise was higher in women in whom OHSS developed. A higher VEGF rise predicted all cases of OHSS and moderate/severe cases of OHSS with a sensitivity of 100% and a specificity of 60%. A likelihood ratio test showed that adding the VEGF rise or the VEGF concentration on the day of oocyte collection to a regression model as a continuous variable to the number of follicles, the E2 concentration, and the presence of polycystic ovaries significantly contributed to predicting the risk of OHSS. CONCLUSION(S): The results support the role of VEGF as an important nonsteroidal index of ovarian response. The VEGF rise may have an advantage over the E2 concentration, the number of follicles, and the number of oocytes, which individually predict only 15%-25% of cases of OHSS.
Adult↗
Degradation of nitrogen containing organic compounds by combined photocatalysis and ozonation.
The combination of TiO2-assisted photocatalysis and ozonation in the degradation of nitrogen-containing substrates such as alkylamines, alkanolamines, heterocyclic and aromatic N-compounds has been investigated. A laboratory set-up was designed and the influence of the structure of the N-compound, the TiO2 and ozone concentration on the formation of breakdown products were examined. The experimental results showed that a considerable increase in the degradation efficiency of the N-compounds is obtained by a combination of photocatalysis and ozonation as compared to either ozonation or photocatalysis only. The mineralization of the model substances was monitored by measurements of the TOC and ion-chromatographic determinations of the formed NO2- and NO3-. The temporal changes of concentrations of breakdown products, such as NH4+, short chain alkyl- and alkanolamines were determined by single column ion chromatography (SCIC) and as well as by electrospray mass spectrometry (EI-MS).
Biodegradation, Environmental↗
Alvaradoins A-D. Anthracenone C arabinosides from alvaradoa jamaicensis
The aerial parts of Alvaradoa jamaicensis have yielded four new compounds. These are both C-10 epimers of 10-C-[4'-O-acetyl-3'-O-(3-methylbut-2-enoyl)]-beta-D-arabinopyranosyl -1,8-dihydroxy-6-methoxy-3-methyl-anthracen-9(10H)-one (3 and 4) and of 10-C-[4'-O-acetyl-3'-O-(3-methylbut-2-enoyl)]-beta-D-arabinopyranosyl -1,8,10-trihydroxy-6-methoxy-3-methyl-anthracen-9-one (5 and 6). The anthraquinones chrysophanol (1) and physcion (2) were also isolated.
Journal Article↗
Anti-GAD monoclonal antibody delays the onset of diabetes mellitus in NOD mice.
Insulin Dependent Diabetes Mellitus (IDDM type I) is the result of autoimmune destruction of insulin producing pancreatic beta-cells by the cellular immune system, specifically, autoreactive T cells. Disease progression is evident by multiple autoantibodies responding to self-antigens in a cascade mechanism, wherein the first self-antigen induces the activation of the immune system, leading to the destruction of beta-cells and consequently, exposure of other antigens. Glutamic Acid Decarboxylase (GAD) is recognized in the literature as a primary autoantigen involved in the cascade. We questioned the immunological involvement of this autoantigen in the overall progression of the disease, specifically if antigen recognition by the cellular immune system (T cells) is necessary for organ specific autoimmunity and cellular toxicity. We tested this hypothesis by isolating, purifying and injecting monoclonal antibodies against GAD (anti-GAD Ab; 0.1 mg or 0.3 mg) into non-obese diabetic (NOD) mice on a weekly basis. We suggest that the anti-GAD Ab will bind to the GAD antigen, or perhaps bind to the epitope presented in association with APC-MHC and prevent T cell recognition, thereby delaying disease onset. Our results demonstrate a delay in the onset of diabetes and a decrease in the severity of insulitis in our test animals, when compared to controls. The mechanism of action of the anti-GAD Ab may be associated with a passive protection mechanism, as evidenced by the fact that splenocytes transferred from anti-GAD Ab treated mice did not prevent or delay diabetes in syngeneic irradiated NOD mice. The mechanism of diabetes prevention by administration of anti-GAD antibody could be associated with an interference in recognition of GAD by T cells, and continuing research will be perform to investigate this hypothesis.
Animals↗