Autopsy-proven untreated previous pulmonary thromboembolism: frequency and distribution in the pulmonary artery and correlation with patients' clinical characteristics.

BACKGROUND: This study aimed to evaluate untreated, previous pulmonary thromboembolism (PE) in patients with acute fatal PE. PATIENTS AND METHODS: We studied 64 patients diagnosed as having died from acute PE by medico-legal autopsy. Previous PE was histologically confirmed on the basis of organized thrombi (OT). The distributions of OT were analyzed in five different sizes of pulmonary artery branches in each of 18 pulmonary segmental arteries (90 in total). The frequency of OT in each patient was evaluated by determining the percentage of examined sections containing OT. RESULTS: OT were confirmed in 59 of 64 (92%) patients. The mean frequency of OT per patient was 27% of the 90 branches. Among the segmental arteries, the right posterior basal lobe showed the highest frequency of OT; among the five artery branches examined, the subsegmental branch showed the highest frequency of OT. OT were not detected in arterioles. Patients with recent trauma or surgery and inpatients showed significantly lower frequencies of OT than those without these risk factors. The 26 patients with prolonged pre-existing symptoms lasting more than a day showed a higher frequency of OT than the 12 patients who suffered for less than a day and the 26 without pre-existing symptoms. CONCLUSIONS: Most patients with acute fatal PE have a subclinical history of recurrent PE. The frequency of their untreated PE is suspected to correlate with specific risk factors for venous thromboembolism and their clinical course.

Inhibition of intestinal cholesterol absorption might explain cholesterol-lowering effect of telmisartan.

WHAT IS KNOWN AND OBJECTIVE: Telmisartan, an angiotensin II type 1 receptor blocker (ARB), acts as a partial agonist for peroxisome proliferator-activated receptor-γ, and thus improves abnormalities of glucose metabolism and hypertriglyceridaemia in addition to its documented blood pressure-lowering effects. Recently, it has been demonstrated that telmisartan also lowers the levels of total cholesterol and low-density lipoprotein (LDL) cholesterol levels. This study was designed to investigate the mechanism of cholesterol reduction. METHODS: We measured serum levels of cholestanol, a cholesterol absorption marker, and lathosterol, a cholesterol synthesis marker, in 20 patients with both hypercholesterolaemia and hypertension. Ten patients were treated with telmisartan and the remaining 10 with fluvastatin. RESULTS: After 3 months of treatment, total and LDL cholesterol levels decreased in the telmisartan group (P<0.01 for both total and LDL cholesterol levels) and the fluvastatin group (P<0.001 for both total and LDL cholesterol levels). The change in cholestanol level after 3 months of treatment was positively correlated with the levels of total (R=0.72, P<0.05) and LDL cholesterol (R=0.81, P<0.01) in the telmisartan group. The change in lathosterol level was positively correlated with the levels of total (R=0.88, P=0.001) and LDL cholesterol (R=0.89, P=0.001) in the fluvastatin group. WHAT IS NEW AND CONCLUSIONS: Our results suggest that the cholesterol-lowering effect of telmisartan might be caused by inhibition of cholesterol absorption, whereas that of statins is by inhibition of cholesterol synthesis. If confirmed, co-treatment with the two agents may be useful for synergistically lowering cholesterol in hypertensive patients.

Possible emergence of drug-resistant variants of Babesia gibsoni in clinical cases treated with atovaquone and azithromycin.

BACKGROUND: There is no well-established treatment strategy for Babesia gibsoni infection. A new therapeutic protocol using atovaquone (ATV) and azithromycin (AZM) has been proposed, but there is concern about the possible induction of relapse and the emergence of ATV-resistant variants after treatment. OBJECTIVE: To evaluate the clinical use of combination therapy with ATV and AZM as a first-line treatment of clinical B. gibsoni infection in dogs, and to investigate the emergence of ATV-resistant variants. ANIMALS: Eight B. gibsoni naturally infected dogs showing signs of acute onset of disease. METHODS: Retrospective case study. Eight clinical cases received combination therapy with ATV and AZM at Kagoshima University Veterinary Teaching Hospital during 2007-2008, and their clinical courses and clinicopathological parameters were evaluated. In addition, alterations in the cytochrome b (CYTb) gene of B. gibsoni were analyzed by polymerase chain reaction and DNA sequencing techniques. RESULTS: All of the dogs responded well to the treatment, with rapid improvement in their clinical condition and hematological parameters. However, 5 of the 8 dogs relapsed after treatment. Analysis of the CYTb gene strongly suggested the emergence of ATV-resistant variants after treatment. CONCLUSIONS AND CLINICAL IMPORTANCE: The combination of ATV and AZM can be used as a first-line treatment for dogs with babesiosis, but relapses occur. Attention should be paid to the possible in vivo selection of drug-resistant variants.

Time dependent changes of striatal interneurons after focal cerebral ischemia in rats.

The cellular damage over time and the alterations of neuronal subtypes was characterized in the striatum after 90-min middle cerebral artery occlusion and reperfusion in rats. We investigated the immunohistochemical alterations of choline acetyltransferase (ChAT)-positive (cholinergic-positive), gamma-aminobutyric acid (GABA)ergic parvalbumin (PV)-positive, GABAergic nNOS (neuronal nitric oxide synthase)-positive interneurons, neuronal nuclei (NeuN)-positive spiny projection neurons, glial fibrillary acidic protein (GFAP)-positive strocytes and microglial response factor-1 (MRF-1)-positive microglia in the striatum after focal cerebral ischemia in rats. In the present study, transient focal cerebral ischemia in rats caused severe damage against interneurons as well as spiny projection neurons in the striatum. In contrast, a significant increase in the number of GFAP-immunopositive astrocytes was observed in the ipsilateral striatum 15 days after focal cerebral ischemia. Furthermore, a significant increase of MRF-1 immunoreactivity was observed in microglia of the ipsilateral striatum 7 days and 15 days after focal cerebral ischemia. Among three types of cholinergic interneurons, GABAergic PV-positive interneurons and GABAergic nNOS-positive interneurons, the severe damage of cholinergic and GABAergic PV-positive interneurons was more pronounced than that of GABAergic nNOS-positive interneurons after transient focal cerebral ischemia in rats. Furthermore, the present results suggest that GABAergic nNOS-positive interneurons in the striatum after focal cerebral ischemia undergo cellular death in a delayed manner.

Clinical manifestations and natural history of Japanese heterozygous females with Fabry disease.

Fabry disease is an X linked lysosomal storage disorder resulting from deficiency of α-galactosidase A activity. Although disease manifestations in heterozygous females with Fabry disease have been considered to be rare and mild, heterozygous patients with severe symptoms have recently been reported. In this study we focused on the clinical characteristics of Japanese females patients with Fabry disease and analysed data from 36 women. Data on clinical manifestations such as acroparaesthesia, hypohidrosis, angiokeratoma, corneal opacities, proteinuria, end-stage renal disease (ESRD), left ventricular hypertrophy (LVH) and cerebral infarction were obtained by questionnaire; these analysed by the Kaplan-Meier method and compared with the data from Japanese male patients. Eighty-six per cent of female patients had at least one clinical sign of Fabry disease. Their most common symptoms were acroparaesthesia and corneal opacities, and diagnosis was most commonly based on family history. The cumulative incidences of angiokeratoma, corneal opacities, proteinuria, ESRD, LVH and cerebral infarction were significantly lower in female than in male patients. However, corneal opacities, proteinuria and LVH developed progressively in female patients as well as in male patients. The incidence of LVH was especially high in older female patients and the cumulative incidence of LVH in women over 68 years of age was 100%. We consider that the term X-linked 'recessive' is inappropriate for Fabry disease because of the high prevalence of its pathognomonic signs in heterozygous female patients. Careful and long-term evaluation of clinical signs is important in heterozygous females patients with Fabry disease.

Low response rate of second-line chemotherapy for recurrent or refractory clear cell carcinoma of the ovary: a retrospective Japan Clear Cell Carcinoma Study.

Clear cell carcinoma (CCC) of the ovary has been recognized to show resistance to anticancer agents in the first-line chemotherapy. Our aim was to evaluate the effect of second-line chemotherapy in a retrospective study. A total of 75 patients diagnosed with CCC and treated between 1992 and 2002 in collaborating hospitals were reviewed. Criteria for the patients' enrollment were 1) diagnosis of pure-type CCC at the initial operation, 2) treatment after one systemic postoperative chemotherapy, 3) measurable recurrent or refractory tumor, 4) at least two cycles of second-line chemotherapy and assessable for the response, and 5) adequate clinical information. Regimens of first-line chemotherapy were conventional platinum-based therapy in 33 cases, paclitaxel plus platinum in 24 cases, irinotecan plus platinum in 9 cases, and irinotecan plus mitomycin C in 7 cases. Treatment-free periods were more than 6 months in 24 cases (group A) and less than 6 months in 51 cases (group B). In group A, response was observed in two cases (8%): one with conventional platinum therapy and another with irinotecan plus platinum. In group B, three cases (6%) responded: two with platinum plus etoposide and one case with irinotecan plus platinum. Median overall survival was 16 months in group A and 7 months in group B (P = 0.04). These findings suggest recurrent or resistant CCC is extremely chemoresistant, and there is only small benefit of long treatment-free period in CCC patients. Another strategy including molecular-targeting therapy is warranted for the treatment of recurrent or refractory CCC.

Vitamin D and intact PTH status in patients with hip fracture.

INTRODUCTION: The prevalence of hypovitaminosis D in patients with acute hip fracture was examined in a population on Sado Island in Japan. There were 85 cases of hip fracture among this population in 2004, giving an overall incidence of hip fracture of 121.4 per 100,000 population per year. This study included 50 of the 85 cases, and these cases were defined as the hip fracture group. Patients older than 70 years without established osteoporosis who were admitted to the hospital on the island during almost the same period for treatment of an orthopedic condition other than a hip fracture were defined as the control group. MATERIALS AND METHODS: The levels of serum 25-hydroxyvitamin D (25-OHD), intact parathyroid hormone (intact PTH), alkaline phosphatase (ALP), albumin, and the number of remaining teeth were examined in each group. In the hip fracture group, serum calcium, serum phosphorus, urine N-terminal cross-linking telopeptide of type I collagen (NTx), bone mineral density (BMD) of the nonfractured hip, the presence of a vertebral fracture on X-ray, severity of dementia, and physical activity level were also examined. RESULTS: Both the serum 25-OHD and serum albumin levels were significantly lower in patients with hip fracture than in controls, and the intact PTH level was significantly higher in patients with hip fracture. The number of remaining teeth was correlated with age, and was also significantly correlated with 25-OHD. In the hip fracture group, 62% of the subjects had hypovitaminosis D (25-OHD <20 ng/ml) and one-fifth of cases with hypovitaminosis D showed elevated PTH levels (>65 pg/ml). On the other hand, in the control group, hypovitaminosis D occurred in 18.9% of the subjects, and only one case showed elevated PTH. The serum 25-OHD level showed a decrease as the severity of dementia progressed and the activity level decreased. CONCLUSION: Our results indicate that about two-thirds (62%) of hip fracture patients had vitamin D insufficiency, suggesting that this condition may be closely associated with hip fracture in elderly people. Therefore, the serum 25-OHD level may be a useful index for the risk of hip fracture in elderly people.

Leptin resistance conferred by a combination of single nucleotide polymorphism and the adoption of a Western lifestyle in urban areas of Thailand.

OBJECTIVES: An increasing number of lifestyle disorders have emerged in response to the rapid urbanization that has occurred in Thailand. Recently, leptin resistance has been nominated as a possible marker for the onset of metabolic disorders in Asian countries. The research aimed to assess the relationship between leptin-resistance and environmental and/or genetic factors by comparing urban and rural inhabitants in Thailand. METHODS: A total of 212 age- and sex-matched subjects from an urban area (Bangkok) and from rural areas (Sai Noi) participated in the study. Anthropometric measurements, blood biochemistry, single nucleotide polymorphism analyses, and interviews concerning lifestyles and dietary habits were conducted individually. Backward elimination multiple regression analyses and least trimmed sum of square methods were used to estimate the effects of possible factors. RESULTS: A transition of staple food from rice to bread (decreased rice intake; p < 0.01 and increased bread intake; p < 0.05) was significant in urban areas. Leptin levels were higher in urban groups, with a significant difference in women (p < 0.001 in women and p = 0.06 in men), but not in men. Predictors selected for leptin-resistance in women were genotypes of UCP2, PPARg2, bread intake, living area, and smoking habit (r = 0.510); in men, genotypes of UCP2 and UCP3p, smoking habit, and rice intake (r = 0.315). CONCLUSIONS: Urban women with del/del type of UCP2 exhibited significant leptin resistance. A combination of urbanization and UCP2 genotype were considered to be responsible.

Single nucleotide polymorphism and lifestyle-related diseases in the Asia-Pacific region: comparative study in Okinawa, Palau and Thailand.

Genetic differences between Asians and Caucasians may be involved in the rapid increase in lifestyle-related diseases in the Asia-Pacific region that has coincided with Westernisation of diets in the region. In the present study, we assessed correlation between 10 single nucleotide polymorphisms (SNPs) and chronic disease risk factors in age-matched and population-based groups in four Asian-Pacific locations: Okinawa, Palau and Thailand (two areas). The following allelic SNP profiles significantly differed (p<0.01) among the four populations, in both men and women: uncoupling protein 2 (UCP2), uncoupling protein 3 promoter (UCP3p), leptin receptor (LEPR) exon 6, and angiotensinogen (AGTa-20c). Multiple regression analyses showed significant associations between SNPs and clinical data. For men, these associations were between beta3 adrenergic receptor (beta3AR) and diastolic blood pressure (DBP) (p<0.01), UCP3p and total cholesterol (p<0.01), UCP2 and age (p<0.05), and AGTa-20c and age (p<0.01). For women, these associations were between LEPR exon 14 and body mass index (BMI) (p<0.05), UCP2 and systolic blood pressure (p<0.05), UCP3p and DBP (p<0.05), UCP2 and DBP (p<0.01), apolipoprotein E (ApoE)nd total cholesterol (p<0.01), beta3AR and triglyceride (p<0.05), AGTa-20c and triglyceride (p<0.05), and UCP2 and age (p<0.05). These results illustrate the interrelationships among SNPs and risk factors in the Asia-Pacific including China and Japan.

Acute myocardial infarction associated with myocardial bridge and coronary artery vasospasm.

A 65-year-old man was admitted to our hospital with acute myocardial infarction (MI). Emergency coronary angiography showed no significant organic lesions, but a myocardial bridge was found at the mid-left anterior descending artery An acetylcholine provocation test revealed 90% spastic stenosis just proximal to the myocardial bridge. His acute MI could have been caused by both a coronary spasm and the myocardial bridge.

Questionnaire-based assessment of pelvic organ dysfunction in Parkinson's disease.

Although patients with Parkinson's disease (PD) experience pelvic organ dysfunction of the urinary bladder, bowel and genital organs, an accurate incidence of the dysfunction and its characteristics have yet to be ascertained. We devised a detailed questionnaire on these three pelvic organ functions in PD patients and control subjects, in our search for a hallmark that would distinguish between the two groups. The PD group comprised 115 patients; 52 men and 63 women, age range 35-69 (average 59) years old, average duration of illness 6 years, median Hoehn and Yahr stage 3. All were taking levodopa with/without dopamine agonists. The control group comprised 391 local individuals who were undergoing an annual health survey; 271 men and 120 women, age range 30-69 (average 48) years old. The questionnaire had three parts: bladder (nine questions), bowel (four questions), and sexual (three questions for women, five for men) function. Each question was scored from 0 (none) to 3 (severe) with an additional quality of life (QOL) index scored from 0 (satisfied) to 3 (extremely dissatisfied). The completion rate was 100% for bladder and bowel functions, whereas for sexual function, it was 95% (control) and 88% (PD) for men and 82% (control) and 60% (PD) for women. As compared with the control group, the frequency of dysfunction in the PD group was significantly higher for urinary urgency (women 42%, men 54%), daytime frequency (28%, 16%), nighttime frequency (53%, 63%), urgency incontinence (25%, 28%), retardation (44% of men), prolongation/poor stream (men 70%), straining (women 28%); constipation (63%, 69%), difficulty in expulsion (men 57%), diarrhea (men 21%); decrease in libido (84%, 83%), decrease in sexual intercourse (55%, 88%), decrease in orgasm (men 87%), and in men, decreases in erection (79%) and ejaculation (79%). The QOL index for the PD patients was significantly higher for bladder (27%, 28%) and bowel (46%, 59%) but not for sexual dysfunction, despite the group's high prevalence of sexual dysfunction. In the PD patients, fecal incontinence was associated with urinary incontinence. Stress urinary incontinence and a decrease in libido were more common in women than in men. Bladder and bowel dysfunction, but not sexual dysfunction increased with the Hoehn and Yahr stage. Sexual dysfunction, but neither bladder nor bowel dysfunction, increased with age. Patients taking levodopa and bromocriptine more frequently had bladder (voiding phase) dysfunction than those taking levodopa only. The findings show that bladder, bowel and sexual dysfunction are all prominent in patients with PD. Amelioration of pelvic organ dysfunction, particularly bowel dysfunction which most affects the quality of life, therefore should be a primary target in the treatment of patients with PD.

Docking protein Gab2 is phosphorylated by ZAP-70 and negatively regulates T cell receptor signaling by recruitment of inhibitory molecules.

To maintain various T cell responses and immune equilibrium, activation signals triggered by T cell antigen receptor (TCR) must be regulated by inhibitory signals. Gab2, an adaptor protein of the insulin receptor substrate-1 family, has been shown to be involved in the downstream signaling from cytokine receptors. We investigated the functional role of Gab2 in TCR-mediated signal transduction. Gab2 was phosphorylated by ZAP-70 and co-precipitated with phosphoproteins, such as ZAP-70, LAT, and CD3zeta, upon TCR stimulation. Overexpression of Gab2 in Jurkat cells or antigen-specific T cell hybridomas resulted in the inhibition of NF-AT activation, interleukin-2 production, and tyrosine phosphorylation. The structure-function relationship of Gab2 was analyzed by mutants of Gab2. The Gab2 mutants lacking SHP-2-binding sites mostly abrogated the inhibitory activity of Gab2, but its inhibitory function was restored by fusing to active SHP-2 as a chimeric protein. A mutant with defective phosphatidylinositol 3-kinase binding capacity also impaired the inhibitory activity, and the pleckstrin homology domain-deletion mutant revealed a crucial function of the pleckstrin homology domain for localization to the plasma membrane. These results suggest that Gab2 is a substrate of ZAP-70 and functions as a switch molecule toward inhibition of TCR signal transduction by mediating the recruitment of inhibitory molecules to the TCR signaling complex.

[Angiography of pulmonary hypertension].

In the present report, we reviewed articles on pulmonary angiography for patients with pulmonary hypertension. The use of a non-ionic, low-osmolarity agent and improvements in catheters reduced periprocedual complications, but attention should be paid to the pre-existing poorer physical state. Digital pulmonary angiography has similar diagnostic power to conventional angiography. Wedged pulmonary angiography could demonstrate distal lesions of the pulmonary artery which couldn't be detected by conventional pulmonary angiography. Typical pulmonary angiograms from pulmonary hypertension due to pulmonary embolism, primary pulmonary hypertension, collagen diseases, Takayasu's arteritis and porto-pulmonary hypertension were shown. Pulmonary angiography is relatively less valuable than before because of advances in other diagnostic imaging tools, but still remains the gold standard.

Uncoupling protein 3 and peroxisome proliferator-activated receptor gamma2 contribute to obesity and diabetes in palauans.

We examined the genetic contribution of single nucleotide polymorphisms (SNPs) of the energy metabolism-related genes, including beta 3 adrenergic receptor (beta3AR), apolipoprotein E (apo-E), promoter of uncoupling protein 3 (UCP3-p), peroxisome proliferator-activated receptor gamma 2 (PPARgamma2) and leptin receptor (LEPR) to metabolic disorders, in 118 inhabitants of Palau. The data were statistically analyzed and ethnically compared to correlate SNPs and their metabolic parameters. UCP3-p (P < 0.01) and PPARgamma2 (p = 0.05) correlated with plasma HbA1c, and UCP3-p correlated with fasting blood glucose (P < 0.01) in males, but not in females. UCP3-p correlated with body fat (%) (P < 0.01) in females, but not in males. Plasma leptin levels and apo-E were correlated in both groups. The frequency of SNPs for PPARgamma2, LEPR, and UCP3-p are significantly different between Palauans and Caucasians.

Clinical characteristics of acute pulmonary thromboembolism in Japan: results of a multicenter registry in the Japanese Society of Pulmonary Embolism Research.

BACKGROUND: Although the incidence of acute pulmonary thromboembolism (APTE) has been increasing in Japan, patient characteristics, management strategies, and outcome have not yet been assessed in large series. HYPOTHESIS: The present study was designed to investigate the current status of APTE in Japan. METHODS: Of a total of 533 registry patients with pulmonary thromboembolism, 309 with APTE were analyzed with respect to clinical symptoms and signs, predisposing factors, diagnostic procedures, estimation of deep venous thrombosis, treatment, and clinical course. RESULTS: Main risk factors were recent major surgery, cancer, prolonged immobilization, and obesity; only a few patients had coagulopathy and 36% were in cardiogenic shock at presentation. The majority of registry patients underwent lung scans or pulmonary angiography; 30% were diagnosed only by lung scanning. Venous ultrasonography was used in only 34 patients, while 188 patients underwent at least one diagnostic procedure for deep venous thrombosis. Thrombolysis was more frequently performed in patients with cardiogenic shock, and only a few patients received thromboembolectomy. In-hospital mortality rate was 14%. In patients with cardiogenic shock, the mortality rate was reduced by thrombolysis. The predictors of in-hospital mortality were male gender, cardiogenic shock, cancer, and prolonged immobilization. CONCLUSIONS: The patients in this registry had almost the same findings as those in Western patients, except for some points that had the possibility of demonstrating a difference between Westerners and Japanese in the development of APTE. These results can prove especially helpful in planning prospective, randomized trials that will clarify the impact of widely used treatment modalities on the outcome of patients with APTE.

Lack of association between duration of untreated illness and severity of cognitive and structural brain deficits at the first episode of schizophrenia.

OBJECTIVE: The purpose of the study was to determine whether the duration of illness before antipsychotic drug treatment for schizophrenia was associated with the severity of cognitive deficits and volumetric brain structure anomalies observed in some patients with a first episode of schizophrenia. METHOD: Duration of psychotic symptoms and of other symptoms marking a behavioral change was estimated from structured interviews with 50 patients who had a first episode of schizophrenia and their family members. Interviews were conducted within a month of the patients' hospitalization. Duration of untreated psychotic symptoms and of behavioral change was correlated with neuropsychological summary scores from a comprehensive cognitive battery and with measurements of lateral ventricular, temporal lobe, and cerebral hemispheric volumes. RESULTS: No significant correlations were observed between measures of untreated illness and the severity of either cognitive or structural brain deficits at baseline. CONCLUSIONS: The duration of untreated symptoms of schizophrenia, for which an association with an uncontrolled toxic brain process has been proposed, is unlikely to explain why first-episode patients with schizophrenia have widespread deficits in cognitive functioning and have detectable ventricular enlargement and some loss of cortical mass.

The effect of sodium hyaluronate on the expression of gelatinases in rabbit corneal epithelial wound healing.

PURPOSE: We investigated the effect of sodium hyaluronate (Na-HA) on the expression of gelatinases in a rabbit model with corneal epithelial defects. METHODS: Topical administration of Na-HA or phosphate-buffered saline (PBS) was carried out in the experimental eyes after surgical removal of the corneal epithelium. At 0, 6, 24, 48, and 72 hours after wounding, mRNA expression of 72 kDa type gelatinase (MMP-2), 92 kDa type gelatinase (MMP-9), and tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) were analyzed by reverse transcription polymerase chain reaction in those corneas. In addition, gelatinolytic activities were investigated using gelatin zymography. RESULTS: The levels of constitutive expression of MMP-2 and TIMP-1 mRNA persisted, whereas MMP-9 mRNA in the PBS-treated side was expressed temporarily after surgical removal. In the Na-HA-treated side, at 6 hours after wounding, a much higher expression of MMP-9 mRNA was reproducibly observed compared with that in the PBS-treated side. In zymography, the levels of gelatinolytic activity corresponding to proMMP-9 were significantly higher in the Na-HA-treated side than in the PBS-treated side at 6 hours after wounding. CONCLUSIONS: These results suggest a novel participation of Na-HA in the expression of MMP-9 in rabbit corneal epithelial wound healing.