Elucidation of Substituent-Responsive Reactivities via Hierarchical and Asymmetric Assemblies in Crystalline p-Quinodimethane Derivatives.

We propose a mechanism for substituent-responsive reactivities of p-quinodimethane derivatives with four ester groups through their hierarchical and asymmetric assembly modes. Four asymmetric 7,8,8-tris(methoxycarbonyl)-p-quinodimethanes with a 7-positioned ethoxycarbonyl (2 a(H)), 2'-fluoroethoxycarbonyl (2 b(F)), 2'-chloroethoxycarbonyl (2 c(Cl)), or 2'-bromoethoxycarbonyl (2 d(Br)) were synthesized and crystallized. 2 a(H), 2 b(F) and 2 d(Br) afforded only one shape crystal, while 2 c(Cl) did two polymorphic 2 c(Cl)-α and 2 c(Cl)-ß. UV-irradiation induced topochemical polymerization for 2 a(H), no reactions for 2 b(F) and 2 c(Cl)-α, and [6+6] photocycloaddition dimerization for 2 c(Cl)-ß and 2 d(Br). Such substituent-responsive reactivities and crystal structures were compared with those of the known symmetric 7,7,8,8-tetrakis(alkoxycarbonyl)-p-quinodimethanes such as 7,7,8,8-tetrakis(methoxycarbonyl)- (1 a(Me)-α and 1 a(Me)-ß), 7,7,8,8-tetrakis(ethoxycarbonyl)- (1 b(Et)), and 7,7,8,8-tetrakis(bromoethoxycarbonyl)- (1 c(BrEt)). The comparative study clarified that the reactivities and crystal structures are classified into four types that link to each other. This linkage is understandable when we analyze the crystal structures through the following hierarchical and asymmetric assemblies; conformers, dimers, one dimensional (1D)-columns, two dimensional (2D)-sheets, and three dimensional (3D)-stacked sheets (3D-crystals). This supramolecular viewpoint is supported by intermolecular interaction energies among neighbored molecules with the density functional theory (DFT) calculation. Such research enables us to elucidate the substituent-responsive reactivities of the crystals, and reminds us of the selection of the right path in a so-called "maze game".

Clinical Features of Heart Failure in Patients With Hypertrophic Cardiomyopathy in a Regional Japanese Cohort　- Results From the Kochi RYOMA Study.

BACKGROUND: The clinical features of heart failure (HF) in patients with hypertrophic cardiomyopathy (HCM) in Japan have not been fully elucidated.Methods and Results: In 293 patients with HCM (median age at registration, 65 (57-72) years) in a prospective cardiomyopathy registration network in Kochi Prefecture (Kochi RYOMA study), HF events (HF death or hospitalization for HF) occurred in 35 patients (11.9%) (median age, 76 (69-80) years), including 11 HF deaths during a median follow-up of 6.1 years. The 5-year HF events rate was 9.6%. Atrial fibrillation, low percentage of fractional shortening, and high B-type natriuretic peptide level at registration were predictors of HF events. The combination of these 3 factors had a relatively high positive predictive value (55%) for HF events and none of them had a high negative predictive value (99%). There were 4 types of HF profile: left ventricular (LV) systolic dysfunction (40%), severe LV diastolic dysfunction (34%), LV outflow tract obstruction (LVOTO) (20%), and primary mitral regurgitation (MR) (6%). HF deaths occurred in patients with LV systolic dysfunction or LV diastolic dysfunction, but none of patients with LVOTO or primary MR due to additional invasive therapies. CONCLUSIONS: In a Japanese HCM cohort, HF was an important complication, requiring careful follow-up and appropriate treatment.

Associated factors with poor treatment response to initial glucocorticoid therapy in patients with adult-onset Still's disease.

BACKGROUND: High-dose glucocorticoids (GC) are first-line treatment for adult-onset Still's disease (AOSD); however, some of the patients remain refractory to initial GC therapy, or rapidly relapse. The aim of this study was to identify prognostic factors for poor treatment response to initial GC therapy for AOSD. METHODS: Data on newly diagnosed AOSD patients were extracted from our database (n=71, mean age 51.6 years). The primary outcome was a poor treatment outcome at 4 weeks, which was defined as failure to achieve remission or relapse after achieving remission within 4 weeks, followed by administration of two or more rounds of GC pulse therapy or of any other immunosuppressive drugs. RESULTS: The initial mean dose ± standard deviation of prednisolone was 0.82 ± 0.23 mg/kg/day, and 34 (47.3%) patients received GC pulse therapy at week 0. Twenty-nine of 71 patients exhibited a poor treatment outcome at 4 weeks (40.8%). The second round of GC pulse therapy or immunosuppressive drugs was added in 17 or 24 of the 29 patients, respectively. These patients had higher baseline white blood cell (WBC) counts, serum ferritin levels, systemic feature score based on clinical symptoms (modified systemic feature score, mSFS), more hemophagocytic syndrome (HPS) over the 4 weeks, and the higher severity score based on modified Pouchot score or severity index of the Japanese Ministry of Health, Labour and Welfare, than the remaining 42 patients. Multivariable logistic regression model identified baseline WBC count as a prognostic factor for poor outcome (odds ratio per 1000/µl increment: 1.12, 95% CI 1.04-1.29), while thrombocytopenia, hyperferritinemia, and mSFS at baseline did not achieve statistical significance. Receiver-operating characteristic curve analysis showed that the optimal cut-off for WBC count was 13,050/µl. The Kaplan-Meier method showed the cumulative rate of poor treatment outcome to be 60.0% in patients with WBC ≥13,050/µl and 23.5% in those with WBC <13,050/µl. CONCLUSIONS: A higher WBC count but not thrombocytopenia, hyperferritinemia, and mSFS at baseline was a significant prognostic factor for poor treatment outcome at week 4 in this retrospective cohort of AOSD patients. Our findings provide important information for determining the initial treatment strategy of newly-diagnosed AOSD.

Clinical significance of new-onset atrial fibrillation in patients with hypertrophic cardiomyopathy.

AIMS: There is limited information about the clinical significance of atrial fibrillation (AF), particularly new-onset AF, in patients with hypertrophic cardiomyopathy (HCM) in a community-based patient cohort. This study was carried out to clarify the prevalence and prognostic impact of AF in Japanese HCM patients. METHODS AND RESULTS: In 2004, we established a cardiomyopathy registration network in Kochi Prefecture as a prospective study, and finally, 293 patients with HCM were followed. In the patients' cohort, we recently reported the clinical outcomes including mortality and HCM-related morbid events. HCM-related adverse cardiovascular events were defined in the following: (i) sudden cardiac death (SCD)-relevant events including SCD, spontaneous sustained ventricular tachycardia, and appropriate implantable cardioverter defibrillator discharge; (ii) heart failure (HF) events with the composite of HF death and hospitalization for HF; and (iii) embolic events included embolic stroke-related death and admission for embolic events. In the present study, we focused on AF and conducted a detailed investigation. At registration, the mean age of the patients was 63 ± 14 years, and 86 patients (29%) had documented AF including paroxysmal AF. Patients with AF at registration were characterized by worse clinical profiles including more advanced age, more symptomatic, more advanced left ventricular, and left atrial remodelling at registration. During a mean follow-up period of 6.1 ± 3.2 years, a total of 77 HCM-related adverse events occurred, and the presence of AF at registration was associated with an increased risk of HCM-related adverse events, particularly heart failure events. During the follow-up period, an additional 31 patients (11%) had documentation of AF for the first time, defined as new-onset AF, with an annual incidence of approximately 1.8%, and finally, a total of 117 patients (40%) showed AF. The presence of palpitation and enlarged left atrial diameter, particularly left atrial diameter ≥50 mm, at registration were significant predictors of new-onset AF. Importantly, the incidence of overall HCM-related adverse events was further higher in patients with new-onset AF observed from AF onset than in patients with AF at registration. CONCLUSIONS: In our HCM registry in an aged Japanese community, a significant proportion developed AF. The presence of AF, particularly new-onset AF, was associated with increased incidence of HCM-related events. AF may not be just a marker of disease stage but an important trigger of adverse events.

Predominant tubulointerstitial lupus nephritis with preceding pernicious anemia.

Predominant tubulointerstitial nephritis with negligible glomerular lesions is a rare form of lupus nephritis. Although tubulointerstitial changes occur in two-thirds of patients with lupus nephritis, these lesions were mostly accompanied by glomerulonephritis. Predominant tubulointerstitial lupus nephritis has been reported to be only 13 cases in the literature as far as we surveyed. Here, we present a case of a 72-year-old male who had pancytopenia associated with pernicious anemia and later developed a mild proteinuria and renal insufficiency. Although urinary tubulointerstitial markers increased, serological screening tests for tubulointerstitial nephritis were all negative. Three months later, the patient was diagnosed as systemic lupus erythematosus, based on polyarthritis, positive antinuclear antibody, immunological disorder and hematological disorder. Renal biopsy revealed severe infiltration of mononuclear cells in the interstitium with minimal abnormalities in glomeruli. Positive IgG and C1q staining with immunofluorescence antibody method in the tubular basement membrane and dense deposits in the same region with electron microscopy confirmed a diagnosis of predominant tubulointerstitial lupus nephritis. Since the patient's renal function declined rapidly, treatment with intravenous 500 mg methyl prednisolone followed by 40 mg/day of oral prednisolone was initiated. The patient's renal function improved and became stable even after tapering of prednisolone. Although lupus nephritis is generally accompanied by multiple symptoms such as fever, malaise, arthralgia, rashes, this case showed only pernicious anemia and tubulointerstitial nephritis initially.

Sudden Cardiac Death-Relevant Events of Hypertrophic Cardiomyopathy in a Regional Japanese Cohort　- Results From the Kochi RYOMA Study.

Background: Sudden cardiac death (SCD) is a most devastating complication of hypertrophic cardiomyopathy (HCM). The aim of this study was to clarify the clinical features of HCM in patients who experienced SCD-relevant events in an aged Japanese community. Methods and Results: In 2004, we established a cardiomyopathy registration network in Kochi Prefecture, and herein report on 293 patients with HCM who are followed as part of the registry. The mean (±SD) age at registration and diagnosis was 63±14 and 56±16 years, respectively. SCD-relevant events occurred in 19 patients during a mean follow-up period of 6.1±3.2 years (incidence rate 1.0%/year): sudden death in 9 patients, successful recovery from cardiopulmonary arrest in 4 patients, and appropriate implantable cardioverter-defibrillator discharge in 6 patients. At registration, 13 patients were in the dilated phase of HCM (D-HCM). During the follow-up period, HCM developed to D-HCM in 21 patients; thus, 34 patients in total had D-HCM. Multivariate analysis revealed that D-HCM at registration or during follow-up and detection of non-sustained ventricular tachycardia (NSVT) during follow-up were significant predictors of SCD-relevant events. Conclusions: In this HCM population in an aged Japanese community, the annual rate of SCD-relevant events was 1.0%. HCM developed to D-HCM in a considerable number of patients, and D-HCM and NSVT were shown to be independently associated with an increased risk of SCD-relevant events.

Clinical Profile of Thromboembolic Events in Patients With Hypertrophic Cardiomyopathy in a Regional Japanese Cohort　- Results From Kochi RYOMA Study.

BACKGROUND: There is limited information about the clinical profiles of patients with hypertrophic cardiomyopathy (HCM) and thromboembolic events in a community-based Japanese patient cohort.Methods and Results:In 2004, we established a cardiomyopathy registration network in Kochi Prefecture that comprised 9 hospitals, and finally 293 patients with HCM were followed. The mean age at registration was 63±14 years, and 197 patients (67%) were men. At registration, 86 patients (29%) had documented atrial fibrillation (AF). During a mean follow-up period of 6.1±3.2 years, thromboembolic events, including 3 embolic stroke deaths, occurred in 23 patients. The 5-year embolic event rate was 5.5%. During the follow-up period, an additional 31 patients (11%) had documentation of AF and finally a total of 117 patients (40%) developed AF. The 5-year embolic event rate in those 117 patients with AF was 12.3%. Of the 23 patients with embolic events, 12 had AF prior to the embolic complications and another 6 had documented AF after thromboembolism. AF was not detected in the remaining 5 patients. The CHADS2score did not correlate with the embolic outcome in HCM patients. CONCLUSIONS: In this community-based registry, thromboembolic events were not rare in patients with HCM. All patients with HCM in whom AF develops should be given anticoagulation therapy regardless of their CHADS2score.

Patients' Characteristics and Clinical Course of Hypertrophic Cardiomyopathy in a Regional Japanese Cohort　- Results From Kochi RYOMA Study.

BACKGROUND: There have been few studies on the clinical course of hypertrophic cardiomyopathy (HCM) in a community-based patient cohort in Japan.Methods and Results:In 2004, we established a cardiomyopathy registration network in Kochi Prefecture (the Kochi RYOMA study) that consisted of 9 hospitals, and finally, 293 patients with HCM were followed. The ages at registration and at diagnosis were 63±14 and 56±16 years, respectively, and 197 patients (67%) were male. HCM-related deaths occurred in 23 patients during a mean follow-up period of 6.1±3.2 years. The HCM-related 5-year survival rate was 94%. In addition, a total of 77 cardiovascular events that were clinically severe occurred in 70 patients, and the HCM-related 5-year event-free rate was 80%. Multivariate Cox proportional hazards model analysis showed that the presence of NYHA class III at registration was a significant predictor of HCM-related deaths and that the presence of atrial fibrillation, lower fractional shortening and presence of left ventricular outflow tract obstruction in addition to NYHA class III were significant predictors of cardiovascular events. CONCLUSIONS: In our unselected registry in an aged Japanese community, HCM mortality was favorable, but one-fifth of the patients commonly suffered from HCM-related adverse cardiovascular events during the 5-year follow-up period. Careful management of HCM patients is needed, particularly for those with the above-mentioned clinical determinants.

Impact of Statins Therapy for Ischemic Heart Disease Patients with Low-Density Lipoprotein Cholesterol Levels Less Than 100 mg/dL.

BACKGROUND: The objective of this study was to determine whether the use of statins prevents the progression of ischemic heart disease (IHD) in patients with low levels of low-density lipoprotein cholesterol (LDL-C). METHODS: We reviewed data obtained from IHD patients who underwent first percutaneous coronary intervention (PCI). Patients underwent follow-up coronary angiography (re-CAG) after PCI. However, only patients with LDL-C levels less than 100 mg/dL at PCI were included in this study. Ultimately, 92 patients were enrolled. All patients were divided into two groups: 1) patients who were treated with statins (n = 69), and 2) patients who were not treated with statins (n = 23). RESULTS: The two groups had similar LDL-C levels at PCI. At re-CAG, the ratio of patients who underwent PCI for de novo lesion in the statin group was lower than that in the non-statin group (12% vs. 48%) (p < 0.001). In multiple regression analysis, statin usage and LDL-C level at PCI were independent predictors of the ratio of patients undergoing PCI for de novo lesion. CONCLUSIONS: Statins therapy for patients whose LDL-C levels are less than 100 mg/dL has a beneficial effect on secondary prevention of IHD.

Impaired Tax-specific T-cell responses with insufficient control of HTLV-1 in a subgroup of individuals at asymptomatic and smoldering stages.

Human T-cell leukemia virus type-1 (HTLV-1)-specific T-cell immunity, a potential antitumor surveillance system in vivo, is impaired in adult T-cell leukemia (ATL). In this study, we aimed to clarify whether the T-cell insufficiency in ATL is present before the disease onset or occurs as a consequence of the disease. We investigated T-cell responses against Tax protein in peripheral blood mononuclear cells (PBMCs) from individuals at earlier stages of HTLV-1-infection, including 21 asymptomatic HTLV-1 carriers (ACs) and four patients with smoldering-type ATL (sATL), whose peripheral lymphocyte count was in normal range. About 30% of samples tested showed clear Tax-specific interferon (IFN)-gamma producing responses. Proviral loads in this group were significantly lower than those in the other less-specific response group. The latter group was further divided to two subgroups with or without emergence of Tax-specific responses following depletion of CC chemokine receptor 4 (CCR4)(+) cells that contained HTLV-1-infected cells. In the PBMCs with Tax-specific responses, CD8(+) cells efficiently suppressed HTLV-1 p19 production in culture. The remaining group without the emergence of Tax-specific response after CCR4(+) cell-depletion included at least two sATL and one AC samples, which spontaneously produced HTLV-1 p19 in culture, where tetramer-binding, Tax-specific cytotoxic T-lymphocytes were either undetectable or unresponsive. Our results indicated that HTLV-1-specific T-cell responsiveness widely differed among HTLV-1 carriers, and that impairment of HTLV-1-specific T-cell responses was observed not only in advanced ATL patients but also in a subpopulation at earlier stages, which was associated with insufficient control of HTLV-1.

Severe tricuspid regurgitation in the aged: atrial remodeling associated with long-standing atrial fibrillation.

OBJECTIVES: Severe idiopathic tricuspid regurgitation (TR) occurs in the aged, but the mechanism of TR is unclear and there is little information on atrial abnormalities associated with this condition. This study retrospectively analyzed patients with severe functional TR presenting with common clinical features suggesting a distinct syndrome. METHODS: Eleven patients with severe functional TR were identified by reviewing the records of 16,235 consecutive patients. All patients had undergone clinical evaluation including echocardiography, electrocardiography and laboratory data. RESULTS: The median age of patients with severe functional TR was 78 years. All had a long-standing history of atrial fibrillation (median duration, 23 years). Clinical features are characterized by severe functional TR due to annular dilation, markedly dilated right atrium, episodes of right-sided heart failure, absent or diminished fibrillation waves on electrocardiogram, bradycardia probably due to partial atrial standstill, and decreased atrial natriuretic peptide secretion. During long-term follow up, right atrial size progressively increased in association with worsening TR. CONCLUSIONS: Severe functional TR occurs with long-standing atrial fibrillation and causes right-sided heart failure. The TR is caused by tricuspid valve systolic coaptation loss due to tricuspid annular dilation associated with atrial dilation. This condition is associated with atrial abnormalities, such as atrial standstill and impaired atrial natriuretic peptide secretion. We propose that atrial remodeling associated with atrial fibrillation is central to the occurrence of the syndrome.

Long-term prognosis of patients with mildly dilated cardiomyopathy.

The long-term prognosis of patients with mildly dilated cardiomyopathy (MDCM) was investigated in 21 patients. MDCM was defined as left ventricular ejection fraction < or = 40% and left ventricular end-diastolic volume < or = 120 ml/m2 by left ventriculography. During a follow-up period of 6.8+/-3.7 years, there were 9 cardiac events (5 heart failure deaths, 2 sudden deaths, and 2 re-hospitalizations for heart failure). Only in the patients without cardiac events was there a significant decrease in left ventricular size (end-diastolic dimension decreased from 58+/-6 mm to 50+/-8 mm, p<0.001) and an improvement in systolic function (fractional shortening increased from 17+/-5% to 26+/-11%, p=0.007). However, left atrial dilation was observed in the patients with an event (from 39+/-5 mm to 43+/-5 mm, p=0.02). Based on proportional hazard analysis, left ventricular end-diastolic pressure and mean pulmonary artery pressure at diagnosis and left atrial dimension at the time of follow-up were significant predictors of poor outcome. A subset of patients with MDCM has impaired hemodynamics at diagnosis, left atrial dilation at follow-up and a poor prognosis, and must be followed carefully even if the left ventricular dilatation is mild.