Associations of reproductive factors with incidence of myocardial infarction and ischemic stroke in postmenopausal women: a cohort study

Background To assess the association between the reproductive factors of age at menarche, age at menopause, and reproductive span and the incidence of myocardial infarction (MI) and ischemic stroke (IS). Methods We used a population-based retrospective cohort study from the National Health Insurance Service database of Korea including a total of 1,224,547 postmenopausal women. Associations between age at menarche (≤ 12, 13–14 [reference], 15, 16, and ≥ 17years), age at menopause (< 40, 40–45, 46–50, 51–54 [reference], and ≥ 55years), and reproductive span (< 30, 30–33, 34–36, 37–40 [reference], and ≥ 41years) and the incidence of MI and IS were assessed by Cox proportional hazard models with adjustment for traditional cardiovascular risk factors and various reproductive factors. Results During a median follow-up of 8.4years, 25,181 MI and 38,996 IS cases were identified. Late menarche (≥ 16years), early menopause (≤ 50years), and short reproductive span (≤ 36years) were linearly associated with a 6%, 12–40%, and 12–32% higher risk of MI, respectively. Meanwhile, a U-shaped association between age at menarche and risk of IS was found, with a 16% higher risk in early menarche (≤ 12years) and a 7–9% higher risk in late menarche (≥ 16years). Short reproductive span was linearly associated with an increased risk of MI, whereas both shorter and longer reproductive spans were associated with an increased risk of IS. Conclusions This study demonstrated different patterns of association between age at menarche and incidence of MI and IS: a linear association for MI versus a U-shaped association for IS. Female reproductive factors in addition to traditional cardiovascular risk factors should be considered when assessing overall cardiovascular risk in postmenopausal women

Occupational Asthma and Rhinitis Induced by a Herbal Medicine, Wonji (Polygala tenuifolia)

Occupational asthma is induced by many agents, including herbal materials, that are exposed in working places. Although there are a few case reports for occupational allergy induced by herbal materials, there is none for that induced by Wonji (Polygala tenuifolia). This study was conducted to evaluate clinical characteristics and immunologic mechanism of Wonji-induced asthma in a exposed-worker. A patient who complained of asthma and rhinitis symptoms, and who had worked in a herbal manufacturing factory for 8 yr, underwent a skin prick test with crude extract of Wonji under the impression of occupational asthma induced by the agent. The patient had a strong positive response to the extract on the skin prick test. Allergen bronchial challenge to the extract demonstrated a typical dual response. Serum specific IgE level to the extract was higher in the patient than in healthy controls, and ELISA inhibition test revealed complete inhibition of IgE binding with the extract, but no inhibition with Der p 2 or mugwort extracts. Six IgE binding components to the extract (10, 25, 28, 36, 50, and 90 kDa) were detected using SDS-PAGE and immunoblot analysis. These findings suggest that Polygala tenuifolia, a herbal material, can induce IgE-mediated bronchoconstriction in exposed workers

Posterior auricular pain caused by the trigger points in the sternocleidomastoid muscle aggravated by psychological factors -A case report-

Psychological factors play a significant role in the pain mechanism, and psychological approaches may be useful complements to traditional medical and surgical treatments in pain management. The authors report a case of recurrent severe posterior auricular pain caused by trigger points in the right sternocleidomastoid muscle and influenced by stressful psychological situations (e.g., family affairs, job loss) in a 50-year-old man

Successful Hemostasis with Recombinant Activated Factor VII in a Patient with Massive Hepatic Subcapsular Hematoma

Recombinant activated coagulation factor VII (rFVIIa) is known to be effective in the management of acquired deficiencies of factor VII and platelet function defects. But recently, rFVIIa has been successfully used to treat ongoing bleeding in disseminated intravascular coagulopathy (DIC) condition. The patient reported here was suspected to be suffering from toxic hepatitis on admission. After percutaneous liver biopsy, bleeding occurred and did not stop even after right hepatic artery embolization. The patient developed a severe hemorrhage that resulted in hypovolemic shock, hemoperitoneum, and a massive subcapsular hematoma. The patient then developed DIC due to massive transfusion, as well as acute liver necrosis. The patient was given 400 μg/kg of rFVIIa. Recombinant factor VIIa was administered in an attempt to control the bleeding. This stabilized the hemoglobin levels of the patient. The patient gradually recovered in 4 months. In conclusion, this case suggests that rFVIIa can be successfully used for the hemostasis of uncontrolled bleeding in DIC

Weekly Paclitaxel and Trastuzumab as a First-Line Therapy in Patients with HER2-Overexpressing Metastatic Breast Cancer: Magnitude of HER2/neu Amplification as a Predictive Factor for Efficacy

We evaluated the efficacy and safety of weekly paclitaxel plus trastuzumab as firs-tline chemotherapy in women with HER2-overexpressing metastatic breast cancer (MBC), and we investigated the prognostic factors including magnitude of HER2/neu amplification in this population. We analyzed 54 patients with HER2-overexpressing MBC that were treated with weekly paclitaxel plus trastuzumab as first-line chemotherapy from February 2004 to December 2006. At a median follow-up of 28 months, median time to progression (TTP) was 16.6 months (95% CI, 9.4 to 23.7 months) and median overall survival was 25.6 months (95% CI, 21.8 to 27.3 months). Therapy was generally well tolerated, although three patients (5.5%) experienced reversible, symptomatic heart failure. Of the 27 patients evaluable for the HER2 FISH, patients with a HER2/CEP17 ratio of ≤4.0 had significantly shorter TTP than those with a HER2/CEP17 ratio of >4.0 (10.8 vs. 23.2 months, P=0.034). A HER2/CEP17 ratio of >4.0 was identified as significant predictive factor of TTP by multivariate analysis (P=0.032). The combination of weekly paclitaxel plus trastuzumab as first-line chemotherapy is an effective regimen in patients with HER2-FISH-positive MBC. Furthermore, the magnitude of HER2 amplification is an independent predictive factor of TTP

Profiles of Multidrug Resistance Protein-1 in the Peripheral Blood Mononuclear Cells of Patients with Refractory Epilepsy

BACKGROUND: About one third of patients with epilepsy become refractory to therapy despite receiving adequate medical treatment, possibly from multidrug resistance. P-glycoprotein, encoded by multidrug resistance protein-1 (MDR1) gene, at the blood brain barrier is considered as a major factor mediating drug efflux and contributing to resistance. Given that peripheral blood mononuclear cells (PBMNCs) express MDR1, we investigated a MDR1 status of PBMNCs in various subsets of epilepsy patients and demonstrated their association with clinical characteristics. METHODOLOGY/PRINCIPAL FINDINGS: Clinical and MDR1 data were collected from 140 patients with epilepsy, 30 healthy volunteers, and 20 control patients taking anti-epileptic drugs. PBMNCs were isolated, and basal MDR1 levels and MDR1 conformational change levels were measured by flow cytometry. MDR1 profiles were analyzed according to various clinical parameters, including seizure frequency and number of medications used in epilepsy patients. Epilepsy patients had a higher basal MDR1 level than non-epilepsy groups (p<0.01). Among epilepsy patients, there is a tendency for higher seizure frequency group to have higher basal MDR1 level (p = 0.059). The MDR1 conformational change level was significantly higher in the high-medication-use group than the low-use group (p = 0.028). Basal MDR1 (OR = 1.16 [95% CI: 1.060-1.268]) and conformational change level (OR = 1.11 [95% CI: 1.02-1.20]) were independent predictors for seizure frequency and number of medications, respectively. CONCLUSIONS/SIGNIFICANCE: The MDR1 profile of PBMNCs is associated with seizure frequency and medication conditions in patients with epilepsy

Peroxiredoxin 3 deficiency induces cardiac hypertrophy and dysfunction by impaired mitochondrial quality control

Mitochondrial quality control (MQC) consists of multiple processes: the prevention of mitochondrial oxidative damage, the elimination of damaged mitochondria via mitophagy and mitochondrial fusion and fission. Several studies proved that MQC impairment causes a plethora of pathological conditions including cardiovascular diseases. However, the precise molecular mechanism by which MQC reverses mitochondrial dysfunction, especially in the heart, is unclear. The mitochondria-specific peroxidase Peroxiredoxin 3 (Prdx3) plays a protective role against mitochondrial dysfunction by removing mitochondrial reactive oxygen species. Therefore, we investigated whether Prdx3-deficiency directly leads to heart failure via mitochondrial dysfunction. Fifty-two-week-old Prdx3-deficient mice exhibited cardiac hypertrophy and dysfunction with giant and damaged mitochondria. Mitophagy was markedly suppressed in the hearts of Prdx3-deficient mice compared to the findings in wild-type and Pink1-deficient mice despite the increased mitochondrial damage induced by Prdx3 deficiency. Under conditions inducing mitophagy, we identified that the damaged mitochondrial accumulation of PINK1 was completely inhibited by the ablation of Prdx3. We propose that Prdx3 interacts with the N-terminus of PINK1, thereby protecting PINK1 from proteolytic cleavage in damaged mitochondria undergoing mitophagy. Our results provide evidence of a direct association between MQC dysfunction and cardiac function. The dual function of Prdx3 in mitophagy regulation and mitochondrial oxidative stress elimination further clarifies the mechanism of MQC in vivo and thereby provides new insights into developing a therapeutic strategy for mitochondria-related cardiovascular diseases such as heart failure. © 20221

Pyruvate Dehydrogenase Kinase Is a Metabolic Checkpoint for Polarization of Macrophages to the M1 Phenotype

Metabolic reprogramming during macrophage polarization supports the effector functions of these cells in health and disease. Here, we demonstrate that pyruvate dehydrogenase kinase (PDK), which inhibits the pyruvate dehydrogenase-mediated conversion of cytosolic pyruvate to mitochondrial acetyl-CoA, functions as a metabolic checkpoint in M1 macrophages. Polarization was not prevented by PDK2 or PDK4 deletion but was fully prevented by the combined deletion of PDK2 and PDK4; this lack of polarization was correlated with improved mitochondrial respiration and rewiring of metabolic breaks that are characterized by increased glycolytic intermediates and reduced metabolites in the TCA cycle. Genetic deletion or pharmacological inhibition of PDK2/4 prevents polarization of macrophages to the M1 phenotype in response to inflammatory stimuli (lipopolysaccharide plus IFN-γ). Transplantation of PDK2/4-deficient bone marrow into irradiated wild-type mice to produce mice with PDK2/4-deficient myeloid cells prevented M1 polarization, reduced obesity-associated insulin resistance, and ameliorated adipose tissue inflammation. A novel, pharmacological PDK inhibitor, KPLH1130, improved high-fat diet-induced insulin resistance; this was correlated with a reduction in the levels of pro-inflammatory markers and improved mitochondrial function. These studies identify PDK2/4 as a metabolic checkpoint for M1 phenotype polarization of macrophages, which could potentially be exploited as a novel therapeutic target for obesity-associated metabolic disorders and other inflammatory conditions