High-risk screening for Anderson-Fabry disease in patients with cardiac, renal, or neurological manifestations.

Anderson-Fabry disease (AFD) is an X-linked lysosomal storage disorder caused by abnormalities in the α-galactosidase (Gal) A gene (GLA; MIM:300644). The reduced activity of the lysosomal enzyme, α-galactosidase A (α-Gal A) leads to classic early manifestations and vascular disease of the heart, kidneys, and brain. As a high-risk screening for symptomatic AFD using an enzymatic assay on dried blood spot samples, we enrolled 2325 individuals (803 females and 1522 males; median age: 66 years) with cardiac, renal, or neurological manifestations that met at least one of the following criteria: (a) family history of early-onset cardiovascular diseases; (b) typical classic manifestations, such as acroparesthesias, clustered angiokeratoma, cornea verticillata, and hypo-anhidrosis; (c) proteinuria; (d) receiving dialysis; (e) left ventricular hypertrophy on electrocardiography or echocardiography; or (f) history of stroke. Ninety-two patients displayed low α-Gal A activity. Four males and two females had different pathogenic GLA mutations (0.26%) including a novel mutation c.908-928del21. Four males (0.17%) harbored the GLA c.196G>C (p.E66Q) variant. This simple screening protocol using dried blood spot samples is useful for early diagnosis of AFD in high-risk and underdiagnosed patients suffering from various cardiac, renal, or neurological manifestations.

Unexpectedly High Prevalence of Coronary Spastic Angina in Patients With Anderson-Fabry Disease.

BACKGROUND: Although we and others have reported cases of patients with Anderson-Fabry disease (AFD) complicated by coronary spastic angina (CSA), the prevalence of CSA in these patients remains unknown. Methods and Results: We performed the acetylcholine-induced provocation test, according to the Japanese guidelines for the diagnosis and treatment of patients with CSA, in 9 consecutive patients having 5 independent AFD pedigrees. Coronary spasms were provoked in conjunction with symptoms and ECG ischemic changes in 8 of 9 (89%) patients with AFD. CONCLUSIONS: We found an unexpectedly high prevalence of CSA in patients with AFD.

Case of Invasive Streptococcus Dysgalactiae Infection Presenting as Infective Endocarditis with Multiple Brain Embolisms.

A 65-year-old Japanese man complaining of general malaise and presenting with high fever was admitted to our hospital. He had untreated diabetes and hepatocellular carcinoma with liver cirrhosis. Overall findings of the patient indicated sepsis. Two blood cultures were positive for Streptococcus dysgalactiae, a group C or G Streptococcus. Transthoracic and transesophageal echocardiography revealed vegetations on the aortic and mitral valves. Although antimicrobial therapy with aminobenzyl penicillin was effective for controlling infection, multiple cerebral embolisms occurred in the clinical course of the disease. Primary care doctors should consider invasive Streptococcus dysgalactiae infections when treating elderly patients with underlying diseases, and Streptococcus dysgalactiae should be included in the list of microorganisms considered to cause endocarditis in such patients.

Evaluation of the Japanese Metabolic Syndrome Risk Score (JAMRISC): a newly developed questionnaire used as a screening tool for diagnosing metabolic syndrome and insulin resistance in Japan.

OBJECTIVES: To prevent the onset of lifestyle-related diseases associated with metabolic syndrome (MetS) in Japan, research into the development of a useful screening method is strongly desired. We developed a new screening questionnaire (JAMRISC) utilizing a logistic regression model and evaluated its ability to predict the development of MetS, type 2 diabetes and other lifestyle-related diseases in Japanese populace. METHODS: JAMRISC questionnaire was sent to 1,850 individuals in Rumoi, a small city in Hokkaido. We received a total of 1,054 valid responses. To maximize the target individuals accurately diagnosed with MetS, logistic regression analysis was used to generate a unique metabolic syndrome score calculation formula as taking into consideration the clinical relevance of each question item as individual coefficients. RESULTS: The results of our comparative research utilizing both JAMRISC and Finnish Diabetes Risk Score (FINDRISC) questionnaires revealed the usefulness of JAMRISC for its ability to detect risks for MetS, pre-MetS, diabetes, and pre-diabetes. Study of disease risk detection via JAMRISC questionnaire targeting the 4283 residents of Rumoi indicated a high detection rate for pre-MetS (98.8 %), MetS (94.2 %), pre-diabetes (85.1 %) and type 2 diabetes (94.9 %). In addition, JAMRISC was useful not only as a MetS risk score test, but also as a screening tool for diagnosing insulin resistance. CONCLUSIONS: JAMRISC questionnaire is a useful instrument for the detection of early risk of not only MetS and type 2 diabetes but also insulin resistance.

Clinical and genetic investigation of a Japanese family with cardiac fabry disease. Identification of a novel α-galactosidase A missense mutation (G195V).

Fabry disease is an X-linked lysosomal storage disorder caused by mutations of the α-galactosidase A gene (GLA), and the disease is a relatively prevalent cause of left ventricular hypertrophy mimicking idiopathic hypertrophic cardiomyopathy. We assessed clinically 5 patients of a three-generation family and also searched for GLA mutations in 10 family members. The proband had left ventricular hypertrophy with localized thinning in the basal posterior wall and late gadolinium enhancement (LGE) in the near-circumferential wall in cardiovascular magnetic resonance images and her sister had vasospastic angina pectoris without organic stenosis of the coronary arteries. LGE notably appeared in parallel with decreased α-galactosidase A activity and increased NT-pro BNP in our patients. We detected a new GLA missense mutation (G195V) in exon 4, resulting in a glycine-to-valine substitution. Of the 10 family members, 5 family members each were positive and negative for this mutation. These new data extend our clinical and molecular knowledge of GLA gene mutations and confirm that a novel missense mutation in the GLA gene is important not only for a precise diagnosis of heterozygous status, but also for confirming relatives who are negative for this mutation.

[Bortezomib plus dexamethasone treatment followed by reduced-intensity allogeneic stem cell transplantation for multiple myeloma refractory to high-dose chemotherapy with autologous transplantation].

We present two long-term survivors after allogeneic transplantation with reduced-intensity conditioning regimen following relapse after autologous stem cell transplantation (ASCT) for multiple myeloma (MM). The first case was a 47-year-old male with IgG MM treated with 2 courses of high-dose melphalan along with ASCT and thalidomide, resulting in a minimal response. He then received 2 courses of bortezomib plus dexamethasone (BD) regimen, which was discontinued due to peripheral neuropathy. Allogeneic peripheral stem cell transplantation (PBSCT) from a sibling donor was performed after pretreatment with fludarabin (125 mg/m(2)) and melphalan (100 mg/m(2)). Engraftment was observed on day 11 and monoclonal IgG had disappeared 5 months after transplantation. The patient has been in complete remission for more than two and a half years with moderate chronic graft-versus-host disease (GVHD). The second case was a 51-year-old male who relapsed after ASCT for IgA MM. After 3 courses of BD treatment, irradiation to lumbar plasmacytoma, and thalidomide therapy, he received allogeneic PBSCT from a related donor after the same reduced intensity conditioning as performed in case 1. A complete response was observed 6 months after PBSCT. The patient has remained relapse-free for two years without GVHD. BD treatment followed by allogeneic stem cell transplantation with reduced intensity conditioning is supposed to be one of the most powerful strategies for patients showing relapse after ASCT.

Antimitochondrial Antibody-associated Myopathy with Slowly Progressive Cardiac Dysfunction.

A 45-year-old woman was referred to our hospital for the evaluation of proximal muscle weakness and serum creatine kinase elevation [corrected]. She had atrial fibrillation and left ventricular asynergy. She was diagnosed with myopathy, accompanied by cardiomyopathy of unknown etiology. She was treated with prednisolone. After long-term follow-up and a detailed examination, the patient was diagnosed with antimitochondrial antibody (AMA)-associated myopathy with cardiac involvement. Although the patient received medical treatment, including beta-blockers and prednisolone, her cardiac function deteriorated progressively. Physicians should consider AMA-associated myopathy when diagnosing myopathies of unknown etiology. The presence of cardiac involvement should be proactively investigated in AMA-associated myopathy.

Spontaneous iliopsoas hematoma with hip pain and ecchymosis of the thigh.

We report an elderly patient with spontaneous iliopsoas hematoma. Primary care physicians should consider iliopsoas hematoma when patients complain of hip pain and thigh ecchymosis.

A newly estimated glomerular filtration rate is independently associated with arterial stiffness in Japanese patients.

Chronic kidney disease (CKD) is associated with an increased risk of cardiovascular disease, and thus is a major worldwide public health problem. Recently, an estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease equation for Japanese patients was proposed by the Japanese Society of Nephrology. However, the role of eGFR in the assessment of atherosclerosis is not well understood in Japanese patients. We analyzed the relationship between eGFR and severity of arterial stiffness using brachial-ankle pulse wave velocity (baPWV) in 647 adult Japanese patients. baPWV correlated significantly and positively with age, hypertension, diabetes, prior cardiovascular disease, blood pressure, pulse pressure and heart rate, and negatively with eGFR (r=-0.405, p<0.0001). A multiple regression analysis revealed that baPWV correlated independently with eGFR. Furthermore, there was a stepwise increase in baPWV, corresponding to advances in CKD through stages 1 to 5. When CKD stage 3 was divided at eGFR 45 mL/min/1.73 m2, the baPWV of stage 3b (eGFR 30 to 44) was significantly higher than that of stage 3a (eGFR 45 to 59) independent of traditional risk factors, suggesting that an eGFR of 45 mL/min/1.73 m2 may be a critical cut off value to predict arterial stiffness in CKD. In conclusion, the newly proposed eGFR is significantly associated with arterial stiffness, independent of traditional risk factors for cardiovascular disease.

Hyperinsulinemia is an independent predictor for complex atherosclerotic lesion of thoracic aorta in non-diabetic patients.

OBJECTIVE: Hyperinsulinemia is a well known risk factor for cardiovascular event. However, it is not known whether hyperinsulinemia facilitates atherosclerotic complex lesions of aorta in non-diabetic patients. We investigated whether hyperinsulinemia is an independent marker of severity of atherosclerosis in thoracic aorta of non-diabetic patients using multiplane transesophageal echocardiography (TEE). RESEARCH DESIGN AND METHODS: Non-diabetic 90 patients with cardiovascular disease underwent TEE, and were analyzed for plasma insulin levels of oral glucose tolerance test, conventional atherosclerotic risk factors and coronary angiographic features. RESULTS: Thoracic aortic plaques were detected in 84 patients (93%). The complex atherosclerotic lesions were observed in 35 (39%) patients, most frequently at the part of aortic arch (p<0.005), showing the greatest atheroma score in thoracic aorta (p<0.05). Univariate analysis showed age, male gender, smoking, coronary artery disease, HDL-cholesterol, insulin levels in glucose tolerance test and homeostasis model assessment insulin resistance index (HOMA index) were found to be significant predictors of complex atherosclerotic lesions. Multivariate regression analysis revealed that HOMA index was an independent predictor of complex atherosclerotic lesions (odds ratio 1.93, p=0.006). There was a significant positive correlation between HOMA index and the atheroma score of thoracic aorta (p<0.001). CONCLUSIONS: Hyperinsulinemia is an independent predictor of complex atherosclerotic lesions detected by TEE in the thoracic aorta of non-diabetic patients.

Aberrant methylation and silencing of the BNIP3 gene in colorectal and gastric cancer.

BNIP3 protein is a proapoptotic member of the Bcl-2 family that is expressed in hypoxic regions of tumors. To examine its role in the progression of gastrointestinal cancer, we examined the expression and DNA methylation status of BNIP3 gene in a panel of colorectal and gastric cancer cell lines. BNIP3 was not expressed in 14 of the 24 cell lines tested, and its absence was not caused by gene mutation or by altered expression of hypoxia inducible factor-1, a key transcription factor that regulates BNIP3 expression. On the other hand, methylation of the 5' CpG island of BNIP3 was closely correlated with silencing the gene. Moreover, treating methylated cells with the methyltransferase inhibitor 5-aza-2'-deoxycytidine restored hypoxia-induced expression of BNIP3 mRNA and protein, which in turn led to cell death. Aberrant methylation of BNIP3 was also detected in 66% of primary colorectal and 49% of primary gastric cancers, but not in normal tissue samples collected from areas adjacent to the tumors. Apparently, epigenetic alteration of BNIP3 is a frequent and cancer-specific event, which suggests that inactivation of BNIP3 likely plays a key role in the progression of some gastrointestinal cancers and that it may be a useful molecular target for therapy.

Renal artery stenosis emerged after angiotensin-converting enzyme inhibitor treatment for myocardial infarction: a case report.

A 76-year-old woman with acute myocardial infarction underwent percutaneous coronary angioplasty followed by treatment with an angiotensin-converting enzyme (ACE) inhibitor, lisinopril. Her renal function deteriorated after the administration of lisinopril, so it was changed to another ACE inhibitor, temocapril. Renography suggested a complication of severe right renal artery stenosis, and renal angiography revealed bilateral renal artery stenoses. Her renal hemodynamics were assessed by (99m)Tc-Mercaptoacetyltriglycine ((99m)Tc-MAG(3))-renography before and after withdrawal of temocapril. The authors concluded the patient had essential hypertension complicated by atherosclerotic renovascular disease. In the treatment of elderly patients with heart disease, hypertension, or both, with ACE inhibitor, the possibility of coexisting renal artery stenosis should be considered. Renography is recommended as a reliable tool for detecting renal artery stenosis.

Successful Treatment with an Antihypertensive Drug Regimen Including Eplerenone in a Patient with Malignant Phase Hypertension with Renal Failure.

A 28-year-old man was referred to our hospital for the treatment of congestive heart failure and severe hypertension. The patient was diagnosed with malignant phase hypertension based on the presence of marked hypertension with left ventricular hypertrophy, exudate retinopathy, and renal failure. Intensive therapy for hypertension and heart failure with a combination of antihypertensive drugs including nitroglycerin, nifedipine, eplerenone and candesartan successfully lowered his blood pressure and further improved the renal function. Eplerenone could be one of the choices of antihypertensive drugs in combination therapy in patients with malignant phase hypertension with progressive heart and renal failure.

A case of nephrotic syndrome associated with renovascular hypertension successfully treated with candesartan.

A sixty eight-year-old man was referred to our hospital for evaluation of hypertension and hypokalemia. His chief complaints were fatigability and weakness of the lower extremities. Atrophy of the right kidney was noted on computed tomography. The laboratory findings demonstrated massive proteinuria, markedly elevated plasma renin activity, hypokalemia, and renal insufficiency. Angiography showed total occlusion of the right renal artery. The patient was diagnosed as having nephrotic syndrome associated with renovascular hypertension. Treatment with candesartan, an angiotensin-II-receptor blocker (ARB), controlled both hypertension and proteinuria satisfactorily without worsening of his renal function. This is the first report on the effect of ARB on nephrotic syndrome associated with renovascular hypertension. Based on the results, ARB can be considered a promising agent for the treatment of patients with renovascular hypertension with massive proteinuria and renal insufficiency.

[Secondary nephrotic syndrome due to cardiovascular disease].

Cardiovascular diseases ralely evoke nephrotic syndrome. Especially hypertensive renal disease (nephroscrelosis) and renovascular hypertension occasionally may lead to nephrotic syndrome. We reported a case of nephrotic syndrome with renovascular hypertension successfully treated with candesartan. In eldery patients cardiovascular diseases are appeared. It is very important for clinicians to detect the mechanism of nephrotic syndrome caused by cardiovascular diseases.

Monitoring with serum SP-A, SP-D, and KL-6 in a patient with interstitial pneumonia complicated with ANCA-associated glomerulonephritis.

A 69-year-old woman was admitted to hospital, complaining of fatigue and dry cough. Her renal function deteriorated rapidly, and the laboratory findings showed elevated myeloperoxidase-specific anti-neutrophil cytoplasmic antibody (ANCA). Renal biopsy examination revealed crescentic glomerulonephritis (pauci-immune type), and linear opacities and a honeycomb appearance in both lower lobes was evident on the chest computed tomography scan. The patient was diagnosed as having ANCA-associated glomerulonephritis complicated with mild interstitial pneumonia (IP). Treatment with methylprednisolone pulse therapy improved both her renal function and IP, but her lung lesions worsened during the course of tapering the prednisolone doses. After careful observation, her IP improved gradually without specific treatment. Worsening or improvement of her lung lesions was accompanied by changes in the serological markers of IP, namely, surfactant protein-A, surfactant protein-D, and KL-6. We found that monitoring these markers was helpful in diagnosing and managing IP in our patient with ANCA-associated vasculitis.

A retrospective clinical analysis of Japanese patients with peripheral T-cell lymphoma not otherwise specified: Hokkaido Hematology Study Group.

Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) comprises a group of heterogeneous lymphomas that do not fit any other identified PTCL-subgroup and show poor prognosis. To clarify clinical aspects of Japanese PTCL-NOS patients, the Hokkaido Hematology Study Group conducted a multicenter retrospective analysis. The median age of the 107 patients (male 65.4 %) was 67 years. The majority (82.4 %) had stage III/IV disease. Following the international prognostic index, 65.7 % were categorized as high intermediate or high risk. Primary chemotherapy was selected in 96 (90 %) patients, 86 of whom received anthracycline regimens. Sixteen patients received high-dose chemotherapy with autologous stem cell transplantation. Forty-eight (52 %) of the 92 evaluable patients achieved complete remission (CR) or CR/unconfirmed after the primary treatment, in which 22 (46 %) relapsed. The estimated 5-year overall survival (OS) of all patients was 35 %. Three independent risk factors (RFs) associated with OS, bulky disease (hazard ratio HR = 5.324; p = 0.019), age >60 years (HR = 3.015; p = 0.025), and platelet count less than 10 × 10(4)/µL (HR = 3.999; p = 0.036), were identified in a multivariate analysis. Using these three RFs, the OS curves were significantly stratified into three risk groups (low risk, 0 RFs, 3-year-OS 72 %; intermediate risk, one RF, 30 %; high risk, two or three RFs, 0 %; p = 0.0005). These findings may provide valuable information for the management of Japanese PTCL-NOS patients.

Epidemiology and treatment outcome of invasive fungal infections in patients with hematological malignancies.

Invasive fungal infection (IFI) causes morbidity and mortality among patients with hematological malignancies who receive cytotoxic chemotherapy or hematopoietic stem cell transplantation (HSCT). We evaluated the incidence and treatment outcomes of proven and probable IFI in 22 institutions between 2006 and 2008 following the recent European Organization for Research and Treatment of Cancer/Mycosis Study Group (EORTC/MSG) consensus criteria. We analyzed 2,821 patients with hematological malignancies, including 597 who had undergone HSCT; these included patients with acute leukemia (n = 697), myelodysplastic syndrome (n = 284), lymphoma (n = 1465), or multiple myeloma (n = 375). IFIs were diagnosed in 38 (1.3%) patients (18 proven and 20 probable), including 20 patients who underwent HSCT and 18 who received chemotherapy alone; these included patients with aspergillosis (n = 23), candidiasis (n = 6), mucormycosis (n = 6), trichosporonosis (n = 2), and geotrichosis (n = 1). The incidence of IFI was 5.4 % in allogeneic HSCT patients, 0.4 % in autologous HSCT patients, and 0.8 % in patients receiving chemotherapy alone. Eighteen patients with aspergillosis were diagnosed with probable pulmonary IFI as determined by computed tomography scan and positive galactomannan assay. Overall, antifungal targeted therapies resulted in successful outcomes in 60.0 % of patients. IFI-attributable mortality rate was higher in HSCT patients than in those receiving chemotherapy alone, but the difference was not statistically significant.