Evaluation of tetracycline and fluoroquinolone therapy against Japanese spotted fever: Analysis based on individual data from case reports and case series.

OBJECTIVES: Although approximately 40 years have passed since Japanese spotted fever (JSF) was first reported in Japan, its treatment has not yet been standardised. As in other rickettsial infections, tetracycline (TC) is the first-line treatment, but successful instances of fluoroquinolone (FQ) combination therapy in severe cases have been reported. However, the effectiveness of TC plus FQ combined treatment (TC+FQ) remains controversial. Therefore, the antipyretic effect of TC+FQ was evaluated in this study. METHODS: A comprehensive search of published JSF case reports was conducted to extract individual patient data. In cases where it was possible to extract temperature data, after homogenising patient characteristics, time-dependent changes in fever type from the date of the first visit was evaluated for the TC and TC+FQ groups. RESULTS: The primary search yielded 182 cases, with individual data evaluations resulting in a final analysis of 102 cases (84 in the TC group and 18 in the TC+FQ group) that included temperature data. The TC+FQ group had significantly lower body temperature compared with the TC group from Days 3 to 4. CONCLUSIONS: Although TC monotherapy for JSF can eventually result in defervescence, the duration of fever is longer compared with other rickettsial infections such as scrub typhus. The results suggest that the antipyretic effect of TC+FQ was more effective, with a potential shortening of the duration that patients suffer from febrile symptoms.

Prognostic value of 1,5-anhydro-D-glucitol incorporating syntax score in acute coronary syndrome.

The utility of adding information on 1,5-anhydro-D-glucitol (1,5-AG), a marker for postprandial hyperglycemia, to a pre-existing scoring system in acute coronary syndrome (ACS) patients is unknown. This retrospective cohort study included 266 ACS patients. The end point was major adverse cardiac and cerebral events (MACCE) through 5 years of follow-up. To evaluate incremental benefits of combining 1,5-AG with the syntax score, we applied time-dependent receiver operating curve (ROC) analysis, net reclassification improvement (NRI), integrated discrimination improvement (IDI) and decision curve analysis (DCA). Temporal changes to the area under time-dependent ROC curves showed that addition of 1,5-AG parameters to syntax score did not provide any incremental value (area under the curve for syntax alone, 0.673 (95% confidence interval (CI), 0.599-0.747) vs. with 1,5-AG combined, 0.671 (95%CI 0.596-0.746; Delong p = 0.65). Incorporating 1,5-AG into syntax score yielded a significant NRI of 0.291 (95%CI 0.015-0.567) and IDI of 0.055 (95%CI 0.018-0.093), while DCA analysis showed the limited net benefit in combination with 1,5-AG and syntax score. 1,5-AG values exhibited significant discriminatory utility for detecting MACCE within the ACS population. However, 1,5-AG levels contributed limited utility beyond syntax score based on time-dependent ROC and DCA analyses.Trial registration: UMIN000023837.

Estimated excretion and clearance of uric acid as optimal surrogate indices for daily urinary uric acid excretion.

OBJECTIVES: Daily uric acid excretion is an essential index for patients with gout/hyperuricemias. We identified alternative indices most correlated with 24-hour uric acid clearance (Cua 24h) and 24-hour uric acid excretion (Eua 24h) using data from the reference interval of urinary clearance and excretion of urate study. METHODS: The subjects were indoor workers aged 20 to 65 who met the Clinical and Laboratory Standards Institute Guidelines C28-A3c. Alternative indices using spot urine were urine uric acid creatinine ratio, uric acid clearance - creatinine clearance ratio (Cua/Ccr), uric acid excretion - creatinine clearance ratio (Eua/Ccr), estimated uric acid clearance (eCua), and estimated uric acid excretion (eEua). eCua and eEua are the values obtained by multiplying Cua/Ccr and Eua/Ccr by the estimated glomerular filtration rate. RESULTS: The final number of subjects analyzed was 739. Among the indices using spot urine, eCua and eEua showed the highest correlation with Cua 24h and Eua 24h, respectively. Compared with Cua 60min and Eua 60min obtained from 60-minute urine collection, eCua and eEua showed lower root means squared error, lower bias, and significantly higher accuracy of within 30% and within 15%. CONCLUSIONS: The newly proposed eCua and eEua may be appropriate from a practical perspective.

Relationship of body mass index to clinical outcomes after percutaneous coronary intervention.

BACKGROUND: Elevated body mass index (BMI) demonstrates lower all-cause and cardiovascular mortalities compared with normal-weight or lean patients in chronic diseases. This study investigated relationships between BMI and clinical outcomes following percutaneous coronary intervention (PCI) in coronary artery disease (CAD) patients, together with the sex-specific impacts of BMI on mortality. METHODS: We reviewed 1104 CAD patients who underwent PCI between 2006 and 2015. Patients were divided by BMI into three groups: lean, <18.5 kg/m2 ; normal, 18.5-24.9 kg/m2 ; and overweight/obese, ≥25 kg/m2 . The primary endpoint was all-cause mortality, and the secondary endpoint was 3-point major adverse cardiovascular events (MACE). RESULTS: Kaplan-Meier survival analysis demonstrated risks of all-cause death, and 3-point MACE were higher in lean patients compared with normal-weight and overweight/obese subjects (log-rank p < .001). Cox proportional hazard modelling showed overweight/obese was significantly associated with all-cause death (hazard ratio (HR) 0.68, 95% confidence interval (CI) 0.48-0.95; p = .03), and lean was significantly associated with 3-point MACE (HR 2.02, 95% CI 1.15-3.53; p = .01). Cox proportional hazard analysis with restricted cubic spline showed non-linear associations between BMI and both all-cause mortality and 3-point MACE (p for effect = .002 and = .003, respectively). No significant interaction was evident between sex and BMI for all-cause mortality (p for interaction = .104) or 3-point MACE (p for interaction =0.122). CONCLUSIONS: Lean category was associated with adverse outcomes among CAD patients. An obesity paradox regarding the independent association of elevated BMI with reduced mortality after PCI is evident in both males and females.

Aseptic Meningitis after Amenamevir Treatment for Herpes Zoster in the First Branch of the Trigeminal Nerve.

Amenamevir has been approved for the treatment of herpes zoster (HZ); however, its therapeutic efficacy against central nervous system (CNS) infection may be insufficient due to its low spinal fluid permeability. We herein report a case of aseptic meningitis in a 91-year-old Japanese man treated with amenamevir for HZ in the trigeminal nerve region. Several cases of CNS infection have been reported in patients receiving amenamevir treatment for HZ. Patients with CNS complications often have skin rashes near the trigeminal region. Thus, we should be alert for signs of CNS infection when administering amenamevir to patients with such rashes.

Relationships between sodium levels, haemodynamics and metalloproteinases in heart failure patients.

To estimate the associations between dysnatraemia and inflammatory marker [including interleukin-6 (IL-6)], and tissue remodelling marker [matrix metalloproteinase (MMP)-9 and tissue inhibitor of MMP (TIMP)-1], the pulmonary capillary wedge pressure (PCWP), mean pulmonary artery pressure (PAP), and left ventricular end-diastolic pressure (EDP), and the prognostic relevance in patients with heart failure. The serum sodium level and circulating levels of IL-6, MMP-9, and TIMP-1 were measured in 173 heart failure patients. Dual heart catheterisation was performed to measure PCWP, mean PAP, and EDP. All-cause mortality was assessed during the follow-up period (mean 88 ± 49 months). Restricted cubic spline (RCS) regression showed a U-shaped association of serum sodium level with TIMP-1, with the lowest values in the 138-140 mmol/L range (P for effect = 0.042, P for non-linearity = 0.017). IL-6 and MMP-9 levels showed non-significant associations with serum sodium level. U-shaped associations of serum sodium level with PCWP (P for effect = 0.004, P for non-linearity = 0.001) and mean PAP (P for effect = 0.042, P for non-linearity = 0.017) were found with the RCS regression model. The random forest model revealed that TIMP-1, MMP-9, and IL-6 were important predictors for serum sodium levels. Restricted cubic spline Cox regressions demonstrated that TIMP-1 levels indicated a U-shaped, concaved, non-linear association with all-cause mortality (P for effect = 0.011, P for non-linearity = 0.022). Dysnatraemia is an index of TIMP-1 aggravation and elevated PCWP, mean PAP; hence, it is associated with worsening all-cause mortality.Clinical Trial Registration: UMIN000023840.

False positive results in severe acute respiratory coronavirus 2 (SARS-CoV-2) rapid antigen tests for inpatients.

Severe acute respiratory syndrome coronavirus 2 rapid antigen detection (RAD) test kits are widely used as primary screening test in Japan because rapid diagnosis of coronavirus disease 2019 (COVID-19) is critical for infection control. We report cases with RAD test false-positive results in a ward for patients with disabilities. RAD tests potentially evoke hospital operational risk. It is desirable that performing PCR test appropriately when patients admitted to a medical treatment ward with COVID-19 symptoms instead of RAD test.

Associations between cachexia and metalloproteinases, haemodynamics and mortality in heart failure.

BACKGROUND: Addressing cachexia in chronic heart failure (CHF) patients is an urgent issue in Japan, the most aged country in the world. We investigated the possible relationships between cachexia and, metalloproteinases and haemodynamics assessed by the cardiac catheterization. We also clarified the prognostic value of cardiac cachexia in the Japanese CHF population. METHODS AND RESULTS: A total of 370 participants (median age, 69 years; 35% women) were included. The haemodynamic effects of cachexia were analysed by right heart catheterization. The serum levels of matrix metalloproteinase (MMP) and tissue inhibitors of MMP (TIMP), as myocardial collagen turnover markers, were also assessed. Cachexia was present in 88 patients (31%). Overall, 59 patients (16%) had all-cause death. Serum MMP-2 and TIMP-2 levels were higher in cachectic patients than in noncachectic patients (797.5 [649.0-1066.8] vs 610.0 [461.8-756.8] ng/mL; P = .004 and 39.0 [28.0-49.0] vs 24.0 [19.0-37.0] ng/mL; P = .008, respectively). Cachectic patients had greater values of pulmonary vascular resistance (PVR) (161.9 [119.4-225.4] vs 127.8 [90.7-164.8] dynes/sec/cm-5 , P = .020). Kaplan-Meier survival analysis demonstrated higher probabilities of all-cause death in the cachexia group (log-rank P = .010). Cox proportional hazards modelling showed cachexia was an independent predictor of mortality (hazard ratio, 1.89; 95% confidence interval, 1.06-3.37; P = .029). The random forest model showed that C-reactive protein, age, haemoglobin, PVR and MMP-2 were predictors of cardiac cachexia. CONCLUSIONS: Cachexia, applying the globally accepted definition, was associated with adverse outcomes in the Japanese CHF population and accompanied by increased activity of MMP species and PVR.

Association between matrix metalloproteinase-9 and worsening heart failure events in patients with chronic heart failure.

AIMS: Matrix metalloproteinase (MMP) is up-regulated during heart failure (HF) and influences ventricular remodeling. We hypothesized that disparity between MMP-9 and tissue inhibitors of MMP-1 (TIMP-1) results in clinical manifestations and is related to prognostic risk in patients with chronic HF. METHODS AND RESULTS: Plasma levels of MMP-9, TIMP-1, and brain natriuretic peptide (BNP) were measured in 173 patients with chronic HF. Combined endpoints of worsening HF events were assessed during follow-up (median 109 months). MMP-9 and TIMP-1 levels and the MMP-9/TIMP-1 ratio increased with increasing severity of the New York Heart Association class (P for trend = 0.003, 0.011, and 0.005, respectively). Patients with HF events (n = 35) had significantly higher MMP-9 than those without HF events (P = 0.004). Kaplan-Meier analysis demonstrated a higher probability of HF events with high MMP-9 values (>23.2 ng/mL; P = 0.005). A multivariate Cox proportional hazard model showed that high MMP-9 values were an independent predictor of HF events (hazard ratio, 3.73; 95% confidence interval (CI), 1.03-13.46; P = 0.043). In patients with lower BNP levels (≤210 pg/mL), the adjusted hazard ratio for HF events was 3.63 (95% CI, 1.20-11.02; P = 0.023) among patients with high MMP-9 values compared with patients with low BNP and low MMP-9 values. CONCLUSIONS: MMP-9 and TIMP-1 levels correlate with the severity of chronic HF. MMP-9 is a strong predictor of HF events, suggesting that a disparity between MMP-9 and TIMP-1 levels and increased MMP-9 levels may help predict HF events.

Predictive utility of the changes in matrix metalloproteinase-2 in the early phase for left ventricular reverse remodeling after an acute myocardial infarction.

BACKGROUND: The relationship between the serum levels of matrix metalloproteinase (MMP) and tissue inhibitors of MMP (TIMP) and left ventricular (LV) reverse remodeling (LV-RR) after an acute myocardial infarction (AMI) has not been sufficiently examined. METHODS AND RESULTS: In 25 patients with successful reperfusion after an AMI and 15 normal control subjects, the serum MMP-2 and TIMP-2 levels were measured on days 1, 2, 3, and 7 and at 1 and 6 months after the AMI onset. LV-RR was defined as a >15% decrease in the LV end-systolic volume index at 6 months after the AMI. The MMP-2 level on day 1 and TIMP-2 levels throughout the study period were comparable between the patients with and without LV-RR. The MMP-2 on day 7 (P<0.05) and the changes in the MMP-2 from day 1 to day 7 (∆MMP-2; P<0.01) were lower in patients with than in those without LV-RR. The ∆MMP-2 was strongly correlated with the changes in the LV volume and ejection fraction from 1 month to 6 months after the AMI. The ∆MMP-2 value of <-158.5 ng/mL predicted LV-RR with a high accuracy (91.7% sensitivity and 76.9% specificity; area under the curve=0.82). CONCLUSIONS: Changes in MMP-2 are associated with LV-RR after an AMI. The ΔMMP-2 might be a useful predictor of subsequent LV-RR.

Acute hyperglycemia causes microvascular damage, leading to poor functional recovery and remodeling in patients with reperfused ST-segment elevation myocardial infarction.

BACKGROUND: Although acute hyperglycemia (AHG) is associated with poor outcomes in ST-segment elevation myocardial infarction (STEMI) patients, underlying mechanisms have not been fully elucidated. We investigated the influence of AHG on myocardial microcirculation in reperfused STEMI patients. METHODS AND RESULTS: Thirty-four STEMI patients were divided into 2 groups according to the presence (Group H, n 5 11) or the absence (Group L, n 5 23) of AHG. Myocardial blood flow (MBF) and myocardial flow reserve (MFR) in the infarct-related area were compared between 2 groups, using ¹³N-ammonia positron emission tomography. Wall motion abnormality scores (WMASs) and end-diastolic volume indices (EDVI) were also assessed at 1 and 6 months after the onset. Although resting MBF was similar, MFR was lower in Group H than in Group L (1.69 ± 0.37 vs 2.39 ± 0.56, P = .001). WMAS was greater in Group H than in Group L at both 1 month (7.4 ± 3.7 vs 3.7 ± 3.0, P = .011) and 6 months (7.3 ± 3.9 vs 3.1 ± 3.4, P = .015). EDVI tended to be greater in Group H than in Group L at 6 months (103.8 ± 42.9 vs 73.9 ± 16.0 mL/m2, P = .071). Multivariate analysis showed AHG to be independently associated with low MFR. CONCLUSIONS: In STEMI patients, AHG impaired myocardial microcirculation, leading to poor functional recovery and remodeling despite successful reperfusion.

Relationship between microcirculatory dysfunction and resolution of ST-segment elevation in the early phase after primary angioplasty in patients with ST-segment elevation myocardial infarction.

BACKGROUNDS AND OBJECTIVES: The aim of this study was to evaluate relationships between the degree of resolution of the ST-segment elevation (ST segment resolution; STR) and the extent of microcirculatory dysfunction in infarct-related area (IRA) in patients with ST-segment elevation myocardial infarction (STEMI) using (13)N-ammonia positron emission tomography (N-PET). METHODS: The subjects comprised 33 patients with STEMI who underwent successful reperfusion. Serial 12-lead electrocardiography (ECG) was performed at the baseline and at 100 min after reperfusion to calculate STR. The myocardial flow reserve (MFR) was assessed quantitatively using N-PET at 2 weeks after the onset. The summed defect score (SDS) of (99m)Tc-tetrofosmin myocardial perfusion imaging was used as an index of the severity of myocardial infarction. To assess the extent of post-infarct left ventricular remodeling, the changes in the LVEDVI (ΔEDVI) were also calculated. RESULTS: A significant correlation of the STR to the MFR in IRA (r = 0.68, p < 0.0001) was observed. A significant correlation was also identified between the SDS and the baseline sum ST-segment elevation (r = 0.65, p < 0.0001), while no correlation was observed between the SDS and the STR. Furthermore, a significant inverse correlation of the STR with the ΔEDVI was also recognized (r = -0.58, p < 0.01). CONCLUSIONS: These data indicate that STR after successful reperfusion in STEMI is closely related to the extent of microcirculatory disturbance; in other words, incomplete STR may be a marker of persistent microcirculatory dysfunction after reperfusion therapy.

Number of endothelial progenitor cells in peripheral artery disease as a marker of severity and association with pentraxin-3, malondialdehyde-modified low-density lipoprotein and membrane type-1 matrix metalloproteinase.

AIMS: Circulating endothelial progenitor cells (EPCs) were mobilized in cardiac ischemia, heart failure and vascular injuries associated with endothelial damage. Despite the occurrence of endothelial dysfunction in peripheral artery disease (PAD), few data are available on EPC mobilization in this setting. METHODS: We investigated the correlations between EPC and disease severity and also other biomarkers in PAD. EPCs assessed as CD34(+) cells co-expressing CD45(dim), CD133 and vascular endothelial growth factor receptor-2 were studied in PAD (n =48) and non-PAD (n =22) patients. Membrane type-1 matrix metalloproteinase (MT1-MMP) on peripheral blood mononuclear cells, serum malondialdehyde-modified low-density lipoprotein (MDA-LDL) and plasma pentraxin-3 were also measured. RESULTS: The EPC level changed in the Fontaine and Trans-Atlantic Inter-Society Consensus (TASC) II classification. EPC was increased in Fontaine class IIa as compared with class IV and non-PAD patients (p < 0.05). EPCs and pentraxin-3 were increased in TASC II type A/B as compared with type C/D and non-PAD patients (p < 0.05), whereas the expression of MT1-MMP on peripheral blood mononuclear cells was significantly decreased in TASC II type A/B (both p < 0.05 versus type C/D and non-PAD patients). The EPC level showed a positive association with pentraxin-3 (r = 0.31; p < 0.05). There was an inverse association between the EPC level and MT1-MMP (r = -0.54; p < 0.01). The cardiovascular events was associated with reduced EPC and increased MDA-LDL (p < 0.05). CONCLUSION: EPC changed according to the Fontaine and TASC II classification and decreased in the advanced phases, and was associated with novel biomarkers and related to the severity of PAD.

Beneficial effects of statin treatment on coronary microvascular dysfunction and left ventricular remodeling in patients with acute myocardial infarction.

BACKGROUND: Statin treatment has been shown to improve coronary endothelial function, irrespective of lipid-lowering effects. This study's aim was to elucidate the effects of statin treatment on coronary microvascular dysfunction and left ventricular remodeling in acute myocardial infarction (AMI) patients. METHODS: Thirty-five patients undergoing successful reperfusion following AMI were assigned to a statin-treated (Group S, 16) or a non-statin-treated (Group NS, 19) group, according to fasting serum low-density lipoprotein-cholesterol. (13)N-ammonia positron emission tomography was performed to assess myocardial flow reserve (MFR) in the infarct area. RESULTS: Infarct sizes and lipid profiles during the chronic period were similar between the two groups. At 2 weeks after AMI onset, mean MFR in the infarct area was significantly higher in Group S than in Group NS (2.34 ± 0.63 vs. 1.91 ± 0.43, p=0.0214). At 6 months post-AMI, Group S had a smaller left-ventricular end-diastolic volume index (69.4 ± 11.7 mL/m(2) vs. 88.5 ± 32.5 mL/m(2), p=0.0328) and higher left-ventricular ejection fraction (67.7 ± 9.2% vs. 59.2 ± 13.3%, p=0.0394) than Group NS. Serum asymmetric dimethylarginine was significantly increased in Group NS at 1 month post-AMI (0.43 ± 0.12 µmol/L (baseline) vs. 0.52 ± 0.14 µmol/L, p=0.0186), but unchanged in Group S. CONCLUSIONS: Statin treatment appears to beneficially attenuate left ventricular remodeling after AMI, which may be associated with restoring coronary endothelial function via endogenous nitric oxide.

Acarbose treatments improve arterial stiffness in patients with type 2 diabetes mellitus.

UNLABELLED: Aims/Introduction: Although the improvement of postprandial hyperglycemia by an alpha-glucosidase inhibitor (α-GI) has been associated with a risk reduction of cardiovascular events, the relationship between postprandial hyperglycemia and arterial stiffness has not been well understood. We therefore examined whether ameliorating the postprandial state by α-GI leads to an improvement in arterial stiffness. MATERIALS AND METHODS: A total of 22 patients with type 2 diabetes mellitus were treated with acarbose. Cardio-ankle vascular index (CAVI) as the arterial stiffness was measured by using a VaSera CAVI instrument before and 12 months after acarbose treatment. Serum high-sensitivity C-reactive protein (hs-CRP), pentraxin-3 (PTX3) and matrix metalloproteinase (MMP) -2, -9 were measured at the same time points. Furthermore, circulating peripheral blood mononuclear cells were examined for the frequencies of CD14 positive cells expressing membrane type-1 MMP (MT1-MMP) at the single cell level using flow cytometry. RESULTS: After acarbose treatment, postprandial glucose and glycosylated hemoglobin (HbA1c) were significantly decreased. Serum levels of hs-CRP, PTX3, MMP-2 and MMP-9 were significantly decreased. CAVI showed a significant reduction, although the changes were not significant in blood pressure and heart rate. MT1-MMP expression was significantly decreased by acarbose treatment. In multivariate analysis, improvement of blood glucose, decrease of PTX3 levels and MT1-MMP expression were independent predictors of beneficial change in CAVI. CONCLUSIONS: The present study showed that the beneficial effects of acarbose on arterial stiffness are mediated by an improvement of postprandial hyperglycemia and vascular remodeling markers. In conclusion, acarbose treatment might reduce the risk of cardiovascular diseases by altering the arterial stiffness in postprandial hyperglycemic status. (J Diabetes Invest, doi:10.1111/j.2040-1124.2010.00079.x, 2010).