The plasma proteome is linked with left ventricular and left atrial function parameters in patients with chronic heart failure.

BACKGROUND: Examining the systemic biological processes in the heterogeneous syndrome of heart failure with reduced ejection fraction (HFrEF), as reflected by circulating proteins, in relation to echocardiographic characteristics, may provide insights into HF pathophysiology. OBJECTIVE: We investigated the link of 4210 repeatedly measured circulating proteins with repeatedly measured echocardiographic parameters, as well as with elevated left atrial pressure (LAP), in HFrEF patients, to provide insights into underlying mechanisms. METHODS: In 173 HFrEF patients, we performed six-monthly echocardiography and trimonthly blood sampling during a median follow-up of 2.7(IQR:2.5-2.8) years. We investigated circulating proteins in relation to echocardiographic parameters of left ventricular (left ventricular ejection fraction[LVEF], global longitudinal strain[GLS]), and left atrial function (left atrial reservoir strain[LASr]) and elevated LAP(E/e' ratio >15), and used gene enrichment analyses to identify underlying pathophysiological processes. RESULTS: We found 723, 249, 792 and 427 repeatedly measured proteins, with significant associations with LVEF, GLS, LASr and E/e' ratio, respectively. Proteins associated with LASr reflected pathophysiological mechanisms mostly related to the extracellular matrix (ECM). Proteins associated with GLS reflected cardiovascular biological processes and diseases, whereas those associated with LVEF reflected processes involved in the sympathetic nervous system. Moreover, 49 proteins were associated with elevated LAP; after correction for LVEF, three proteins remained: Cystatin-D, Fibulin-5 and HSP40. CONCLUSION: Circulating proteins show varying associations with different echocardiographic parameters in HFrEF patients. These findings suggest that pathways involved in atrial and ventricular dysfunction, as reflected by the plasma proteome, are distinct.

Prognostic value of temporal patterns of left atrial reservoir strain in patients with heart failure with reduced ejection fraction.

BACKGROUND: We investigated whether repeatedly measured left atrial reservoir strain (LASr) in heart failure with reduced ejection fraction (HFrEF) patients provides incremental prognostic value over a single baseline LASr value, and whether temporal patterns of LASr provide incremental prognostic value over temporal patterns of other echocardiographic markers and NT-proBNP. METHODS: In this prospective observational study, 153 patients underwent 6-monthly echocardiography, during a median follow-up of 2.5 years. Speckle tracking echocardiography was used to measure LASr. Hazard ratios (HRs) were calculated for LASr from Cox models (baseline) and joint models (repeated measurements). The primary endpoint (PEP) comprised HF hospitalization, left ventricular assist device, heart transplantation, and cardiovascular death. RESULTS: Mean age was 58 ± 11 years, 76% were men, 82% were in NYHA class I/II, mean LASr was 20.9% ± 11.3%, and mean LVEF was 29% ± 10%. PEP was reached by 50 patients. Baseline and repeated measurements of LASr (HR per SD change (95% CI) 0.20 (0.10-0.41) and (0.13 (0.10-0.29), respectively) were both significantly associated with the PEP, independent of both baseline and repeated measurements of other echo-parameters and NT-proBNP. Although LASr was persistently lower over time in patients with PEP, temporal trajectories did not diverge in patients with versus without the PEP as the PEP approached. CONCLUSION: LASr was associated with adverse events in HFrEF patients, independent of baseline and repeated other echo-parameters and NT-proBNP. Temporal trajectories of LASr showed decreased but stable values in patients with the PEP, and do not provide incremental prognostic value for clinical practice compared to single measurements of LASr.

Decreased left atrial function in obesity patients without known cardiovascular disease.

Obesity is a risk factor for heart failure with preserved ejection fraction (HFpEF). We hypothesized that assessment of left atrial (LA) strain may be useful to reveal precursors of HFpEF in obesity patients. Echocardiograms of obesity patients without known cardiovascular disease who underwent bariatric surgery, and echocardiograms of age- and gender matched controls were analyzed. The echocardiogram was repeated 1 year after bariatric surgery. LA reservoir strain (LASr), LA conduit strain (LAScd), and LA contractile strain (LASct) were measured. 77 Obesity patients were compared with 46 non-obese controls. Obesity patients showed a significantly decreased LA function compared with non-obese individuals (LASr 32.2% ± 8.8% vs. 39.6% ± 10.8%, p < 0.001; LAScd 20.1% ± 7.5% vs. 24.9% ± 8.3%, p = 0.001; LASct 12.1% ± 3.6% vs. 14.5% ± 5.5%, p = 0.005). There was no difference in prevalence of diastolic dysfunction between the obesity group and controls (9.1% vs. 2.2%, p = 0.139). One year after bariatric surgery, LASr improved (32.1% ± 8.9% vs. 34.2% ± 8.7%, p = 0.048). In the multivariable linear regression analysis, BMI was associated with LASr, LAScd, and LASct (ß = - 0.34, CI - 0.54 to - 0.13; ß = - 0.22, CI - 0.38 to - 0.06; ß = - 0.10, CI - 0.20 to - 0.004). Obesity patients without known cardiovascular disease have impairment in all phases of LA function. LA dysfunction in obesity may be an early sign of cardiac disease and may be a predictor for developing HFpEF. LASr improved 1 year after bariatric surgery, indicating potential reversibility of LA function in obesity.

UR-3216: a manageable oral GPIIb/IIIa antagonist.

UR-3216, a prodrug, is a novel, selective, and orally active platelet surface glycoprotein (GPIIb/IIIa) receptor antagonist. The most important property of UR-3216 is the very tight binding of its active metabolite to platelets (Ki for resting platelets is < 1 nM). UR-2992, the active form of UR-3216, binds to platelets for a long period of time, while the unbound drug is rapidly cleared. Therefore, after an initial loading dose of 0.1 mg/kg, only once daily repeated low maintenance doses of UR-3216 (< 0.05 mg/kg p.o.) are required. This regimen maintains a high level of inhibition of platelet aggregation and, due to a small peak-to-trough ratio, severe bleeding is avoided. The therapy with UR-3216 is easy to manage, because it has low peak-to-trough ratio and high efficacy (> 80% inhibition of platelet aggregation). In addition, UR-3216 does not produce excessive bleeding or thrombocytopenia and does not interact with abciximab. UR-3216 is excreted mostly in bile, so that it will not accumulate in patients with chronic renal dysfunction. UR-2316 has the following abciximab-like features: (a) its half-lives for residence on platelets, inhibition of platelets aggregation and bleeding time prolongation are 60 to 80 h, 24, and 2 h, respectively; (b) its receptor binding occupancy is similar to that of abciximab (Mab1 is inhibited and Mab2 is unaltered). In conclusion, UR-3216 is a promising, orally active GPIIb/IIIa antagonist for the treatment of cardiovascular diseases.

Phenolic constituents of licorice. VIII. Structures of glicophenone and glicoisoflavanone, and effects of licorice phenolics on methicillin-resistant Staphylococcus aureus.

Two new phenolic compounds, glicophenone (1) and glicoisoflavanone (2), were isolated from commercial licorice, and their structures were elucidated on the basis of spectroscopic data. Antibacterial assays of licorice phenolics for Staphylococcus aureus, including four strains of methicillin-resistant S. aureus (MRSA), and also for Escherichia coli K12 and Pseudomonas aeruginosa PAO1, were then examined. Two compounds among them, 8-(gamma,gamma-dimethylallyl)-wighteone (21) and 3'-(gamma,gamma-dimethylallyl)-kievitone (28), showed remarkable antibacterial effects [minimum inhibitory concentrations (MICs), 8 microg/ml on the MRSA strains and methicillin-sensitive S. aureus. Licochalcone A (14), gancaonin G (20), isoangustone A (24), glyasperins C (30) and D (31), glabridin, (32), licoricidin (33), glycycoumarin (34) and licocoumarone (40) showed antibacterial effects on the MRSA strains with MIC values of 16 microg/ml. Effects on the beta-lactam resistance of the MRSA strains were also examined, and licoricidin (33) noticeably decreased the resistance of the MRSA strains against oxacillin, as shown by the reduction in the MICs of oxacillin (lower than 1/128-1/1000 in the presence of 8 microg/ml of 33, and 1/8-1/32 in the presence of 4 microg/ml of 33). Mechanistic study suggested that 33 does not inhibit the formation of penicillin-binding protein 2' (PBP2'), but affects the enzymatic function of PBP2'.

Minor flavonoids from licorice.

Three minor flavonoids, licofuranocoumarin, isotrifoliol and glisoflavanone, were isolated from licorice (underground part of Glycyrrhiza uralensis), and their structures with 3-arylcoumarin, coumestan and isoflavanone skeletons were respectively elucidated on the basis of spectroscopic data.

Pharmacokinetic and pharmacodynamic evaluation of central effect of the novel antiallergic agent betotastine besilate.

Betotastine besilate (betotastine CAS 125602-71-3, TAU-284) is a novel antiallergic agent with histamine H1 receptor antagonistic activity. As the classical antihistamines are known to produce drowsiness, the present study was conducted to assess a possible influence of betotastine on the central nervous system (CNS). Measurement of the drug concentration in brain and plasma after i.v. administration revealed that betotastine, as well as cetirizine and epinastine, poorly penetrate into the CNS, while terfenadine do so slightly more and ketotifen remarkably more. In vitro receptor binding assays demonstrated that betotastine is a highly specific histamine H1 receptor ligand, having no significant binding affinity for histamine H3, adrenergic alpha 1, alpha 2, beta, dopamine D2L, serotonin 5-HT2, muscarinic, and benzodiazepine receptors. On global behavior of mice, oral administration of betotastine did not produce any marked changes at the doses of 100-1000 mg/kg, but suppressed huddling behavior at 1000 mg/kg and caused slight mydriasis at 300 mg/kg and more. Betotastine did not significantly affect spontaneous motor activity (SMA) and hexobarbital-induced anesthesia in mice up to 300 mg/kg p.o. In the sleep-wakefulness pattern of cats, it reduced the total duration of sleep at 10 mg/kg p.o., but did not show significant effect at 30 and 100 mg/ kg p.o. Cetirizine showed a similar profile as betotastine in these experiments, whereas ketotifen and epinastine induced sedative signs or toxic symptoms in lower doses, and terfenadine affected SMA and the anesthesia at a high dose. These results suggest the very low liability of betotastine to produce sedative side-effect in a therapeutic dose range.

[The effectiveness of anal submucosal injection of methotrexate for relapsed prostatic cancer--a case report].

The case is a 77-year-old man who was first examined in August 1980 (at age 67). Prostatic biopsy revealed a poorly-differentiated adenocarcinoma, and clinically, diagnosis was made as stage B. Castration and DES administration were carried out. Subsequent chemotherapy with BLM, MMC, and 5-FU led to CR. A periodical check-up in September 1985 detected a pelvic lymph node metastasis, which was, however, completely remitted by radiotherapy and chemotherapy. In April 1990, local relapse was noted in the left lobe of the prostate. Biopsy revealed a poorly-differentiated adenocarcinoma. Three courses of intravenous administration of CDDP, THP, and VP-16 caused no change. From August 1990 on, anal submucosal injection of MTX was started. 20 mg of MTX administration once a week, for consecutive 5 weeks, followed by 4-week interruption on ambulatory basis formed one course. The tumor was distinctly reduced following one course, disappeared (MRI) following two courses and showed only a few viable cells (biopsy) following four courses. We consider that the present method is a hopeful new therapeutic approach.

[An adult case of virus-associated hemophagocytic syndrome (VHAS) and a review of this syndrome in adults in Japan].

An adult case of Virus-associated hemophagocytic syndrome (VAHS) was reported and a review of this syndrome in adults in Japan was also made. A 79 year-old woman was referred to our hospital for detailed examination for sustained generalized fatigue lasting for about two weeks. Other clinical manifestations of this patient included fever, generalized lymphadenopathy, hepatosplenomegaly, anemia and mild liver dysfunction. The biopsy of the lymph node revealed hyperplasia of histiocyte with hemophagocytosis. There was also an elevation of IgG antibody against EB virus and the patient was therefore diagnosed to have VAHS. The prednisolone therapy was then initiated and the patient responded to this treatment very well. By the review of the Japanese literatures, seven adult cases of VAHS were found. Based on the descriptions on these cases, the prognosis of this syndrome appeared to be extremely poor which is totally different from VAHS in children. Our case showed a very favourable clinical course following steroid therapy and this suggested that steroid therapy should be considered even at the early stage of this syndrome in adults.

[A case of histiocytosis X of the penis].

A case of localized histiocytosis X of the penis was reported. The patient was a 9-year-old boy who had several tumor lesions on the glans penis and inner layer of prepuce. Biopsy specimens were studied by H-E staining and immunohistochemical staining for S-100 protein (S-100), lysozyme (Lys), leucocyte common antigen (LCA), and Leu-M1. They revealed diffuse infiltration of many atypical histiocytes, which were shown to be S-100+, Lys+, LCA- and Leu-M1-. This indicates that these cells were derived from T-zone histiocyte system. After complete remission of these tumors, the other one arose from anal mucosa. In the literature we could find only one case of a primary penile lesion reported by Myers and others.

[A case of adrenal myelolipoma].

A case of adrenal myelolipoma is presented. The patient was a 61-year-old woman who complained of lumbago this time. A tumor of the left adrenal gland, however, had been found by computed tomography 4 years earlier. Judging from the CT, the size of this tumor had not changed at all, although the density of the mass on admission had reduced, compared with that of 4 years earlier. Laboratory examinations of adrenal function was normal. Left adrenalectomy was performed. Histologically, this tumor consisted of adipose and some hematopoietic tissue. We reviewed 43 cases of adrenal myelolipoma resected surgically in Japan.

[Cutaneous metastases from transitional cell carcinoma of the bladder].

Two cases of transitional cell carcinoma of the bladder with cutaneous metastases are reported. In one patient, multiple nodular metastatic lesions appeared simultaneously with urethral recurrence after total cystectomy. In another patient, diffuse inflammatory metastatic lesion was generated after radiotherapy for pelvic lymph nodes. The pathways of metastatic dissemination from the transitional cell carcinoma of the bladder are discussed.

Peripheral blood stem cell autotransplantation in treatment of childhood cancer.

The levels of circulating hematopoietic progenitor cells were measured sequentially in eight children receiving chemotherapy for acute leukemia or neuroblastoma. Significant increases in the progenitor levels (up to 50-fold in CFU-GM numbers) were observed during post-chemotherapy cytopenia in all cases, but differences among individuals in the kinetics of recovery of less committed progenitors (CFU-mix) contrasted with the synchronized-mode of expansion of committed progenitors (CFU-GM). Peripheral blood cells were collected by repeated continuous-flow leukaphereses from three of the children during post-chemotherapy expansion of the progenitor pool and were cryopreserved after fractionation procedures. Infusion of these stored cells into the patients after marrow-ablative chemotherapy established trilineage hematopoiesis. This use of stem cell rescue should be useful as an alternative to bone marrow transplantation and extends the application of cure-oriented salvage therapy to childhood cancers.

[Renal artery thrombosis following surgical treatment of chyluria].

A case of segmental renal arterial thrombosis occurring after bilateral surgical stripping and interruption of renal pedicle lymphatics for chyluria is presented. This case showed elevation of serum creatinine (6.6 mg/dl) and lactate dehydrogenase (1131 IU/L) on the 4th day after operation, and on the 14th day, renal scintigraphy with 99 m-Tc diethylenetriamine penta acid acetic showed bilateral marked decrease of glomerular filtration rate. Aortography and selective left renal angiography demonstrated left segmental renal thrombosis, but right renal arteries were intact on the 20th day after operation. Systemic anticoagulation therapy was performed, but left renal function was destroyed completely. Excessive and prolonged retraction of the renal artery with vascular tape may have resulted in this unfortunate complication.

[Metastatic tumor of the spermatic cord from gastric cancer].

A 70-year-old male who had undergone gastrectomy due to gastric cancer 6 years previously visited our department complaining of perineal and bilateral scrotal mass. Biopsy specimen of the perineal mass showed well-differentiated adenocarcinoma. The spermatic cords were resected en bloc with the entire scrotal content, penis and perineal skin. Histological examination of the spermatic cord, epididymis and perineal subcutaneous tissue revealed well differentiated adenocarcinoma similar to that of the lesion resected from the stomach 6 years earlier. The patient was followed for 2 years with no evidence of recurrence. Metastatic tumors of the spermatic cord and epididymis resulting from gastric cancer are rare and 31 cases previously reported in the Japanese literature are reviewed.

[Renal cell carcinoma in the solitary kidney].

We have treated surgically 5 patients with renal cell carcinoma in the solitary kidney. The cause of renal absence was nephrectomy for renal stones, in 2 patients and renal tuberculosis, renal cyst and renal hypoplasia in 1 patient each. Four of the 5 patients died. One of the 4 patients died 5 days after surgery due to gastrointestinal bleeding, 1 due to metastasis, 1 due to gastric cancer and one due to hemodialysis complications. Surgical management of renal cell carcinoma of solitary kidney is discussed.

[Inverted papilloma of the ureter].

Two cases of ureteral inverted papilloma are reported. Case 1: A 48-year-old male had asymptomatic gross hematuria and filling defect of left middle ureter on intravenous pyelography. Segmental resection of ureter was performed. The specimen was a 1 cm polypoid lesion with histologic features resembling "multifocal bud-like proliferation", which was reported as the initial stage of the inverted urothelial tumor by Kunze et al. Case 2: A 64-year-old female with asymptomatic gross hematuria and complete obstruction of left middle ureter on ante- and retrograde pyelograms. Total nephroureterectomy was performed. A 4 cm lobulated and pedunculated lesion with histologic features of typical inverted urothelial papilloma was resected. Twenty-one cases of ureteral inverted papilloma in the literature, including our cases, are analyzed.

[A renal cell carcinoma with metastasis to the tongue].

A 42-year-old man had rapidly progressing metastasis to the tongue 3 months after nephrectomy due to renal cell carcinoma. He visited an otolaryngeal clinic with the chief complaint of bleeding and pain on his tongue. Biopsy of the tongue revealed metastasis from the renal cell carcinoma. After treatment with radiation and chemotherapy, the tongue tumor was disappeared macroscopically. Renal cell carcinoma metastasizing to the tongue is rare. Statistical studies on the report of metastasis to the tongue of renal cell carcinoma are reviewed.