Search

Background: Cardiac microangiopathy may be involved in the development of heart failure in diabetes mellitus. Objective: To evaluate the effect of angiotensin II receptor blockade on cardiac function and fine [...]

Background: Postsystolic shortening (PSS) is considered myocardial shortening after the point of aortic valve closure and can be observed physiologically in healthy individuals. However, the incidence and magnitude of PSS in myocardial disorders have not been investigated. Objectives: We performed strain imaging to characterize PSS in patients with hypertrophic cardiomyopathy (HCM) versus healthy individuals. Methods: Thirty patients with HCM (22 men and 8 women; mean age 62+/-6 years) and 30 control subjects (20 men and 10 women; mean age 61 +/- 9 years) were studied. For both groups, patterns of myocardial strain curves were assessed by the 18-segment model using apical 2-chamber, 4-chamber, and long-axis views. PSS was defined if the peak strain existed beyond aortic valve closure. The severity of PSS was assessed as postsystolic index (strain amplitude beyond aortic closure divided by whole strain amplitude) for each segment. Results: As compared with control subjects, patients with HCM had a greater isovolumic relaxation time (105 +/- 31 vs 74 +/- 28 milliseconds, P < .001), despite the comparable value of left ventricular ejection fraction (65 +/- 6% vs 65 +/- 4%, P = not significant). The number of segments having PSS was greater in patients with HCM than in control subjects (12.6 +/- 3.0 vs 8.4 +/- 3.7, P < .001). This was associated with greater values of postsystolic index in all segments for patients with HCM. In patients with HCM, the number of segments having PSS correlated significantly with the isovolumic relaxation time (r = 0.36, P < .05). Conclusions: Patients with HCM have more pathologic PSS, which may have etiologic contribution to the functional heterogeneity of this disease entity, especially diastolic dysfunction.

A practical synthesis of triethylammonium (Z)-2-[2-(N-tert-butoxycarbonylamino)thiazol-4-yl]-2-(triphenylmethyloxyimino)acetate (1) which is the C-7 side chain of cefmatilen, a new cephalosporin antibiotic, is described. The conditions were optimized to control the impurity and to increase the yield. Selective acetylation of oxime group before tert-butoxycarbonylation reduced the amount of Boc2O. Compound 1 was synthesized from compound 6 by this improved process in 80% overall yield (12% higher than that for the medicinal process) via a four-reaction sequence (95% per reaction).

A practical large-scale process for the synthesis of cefmatilen hydrochloride hydrate (1), a new oral cephalosporin antibiotic, is described. Several impurities are isolated from a bulk drug and identified. Side reactions are discussed in order to prevent them. The conditions were optimized to control the formation of impurities. The process is amenable to a multikilogram-scale preparation. Several kilograms of compound 1 for clinical trials were successfully prepared by this process from the three starting materials (7-aminocephem hydrochloride 4, triethylammonium acetate 5, and triazole 7) on a pilot scale in overall yields of 61−65% (10−14% higher than those for the previous process).

Control of crystal habit and size of cefmatilen hydrochloride hydrate (1) with a habit modifier is described here. One of the related substances, impurity 2, which has a diphenylmethyl group at the N3-position of the triazolyl group of cefmatilen, acts as a habit modifier. The crystal habit and size of compound 1 depended upon the amount of impurity 2 in the crystallizing system. Since the amount of impurity 2 can be controlled by the temperature during the addition of AlCl3 to a suspension of compound 3 in the deprotection step, the crystal habit and size can be controlled by the temperature of addition of AlCl3. The addition of small amounts of hydroxyalkylcelluloses or polyvinyl derivatives to the crystallizing system can also modify the crystal habit and size of compound 1.

Peflin, a newly identified 30-kDa Ca(2+)-binding protein, belongs to the penta-EF-hand (PEF) protein family, which includes the calpain small subunit, sorcin, grancalcin, and ALG-2 (apoptosis-linked gene 2). We prepared a monoclonal antibody against human peflin. The antibody immunoprecipitated a 22-kDa protein as well as the 30-kDa protein from the lysate of Jurkat cells. Western blotting of the immunoprecipitates revealed that the 22-kDa protein corresponds to ALG-2. This was confirmed by Western blotting of the immunoprecipitates of epitope-tagged peflin or ALG-2 whose cDNA expression constructs were transfected to human embryonic kidney (HEK) 293 cells. Gel filtration of the cytosolic fraction of Jurkat cells revealed co-elution of peflin and ALG-2 in fractions eluting earlier than recombinant ALG-2, further supporting the notion of heterodimerization of the two PEF proteins. Surprisingly, peflin dissociated from ALG-2 in the presence of Ca(2+). Peflin and ALG-2 co-localized in the cytoplasm, but ALG-2 was also detected in the nuclei as revealed by immunofluorescent staining and subcellular fractionation. Peflin was recovered in the cytosolic fraction in the absence of Ca(2+) but in the membrane/cytoskeletal fraction in the presence of Ca(2+). These results suggest that peflin has features common to those of other PEF proteins (dimerization and translocation to membranes) and may modulate the function of ALG-2 in Ca(2+) signaling.

Summary Light- and electron-microscopic studies and immunohistochemical procedures were carried out on blood eosinophils and left ventricular endomyocardial biopsies from a 68-year-old man with an eosinophilia of 8.2 × 109/l and congestive cardiac failure due to eosinophilic endomyocardial disease. Some blood eosinophils were vacuolated and degranulated, and reversal of the normal staining pattern of eosinophil granules was seen by means of electron microscopy. The biopsies showed degenerative changes in the cardiac myocytes, with interstitial fibrosis and infiltration by numerous eosinophils, mast cells, and macrophages. Eosinophils infiltrating the myocardium showed a decrease in the number of granules, many of which were indistinct or contained dissolving crystalloids, which occasionally were seen to be discharged onto the surface of adjacent cardiac myocytes. Immunohistochemical studies of the endomyocardial biopsies with a monoclonal antibody, which is specific for activated eosinophils and binds to the secreted forms of eosinophil cationic protein (ECP) and eosinophil protein-X (EP-X), demonstrated that the lesions contained numerous activated eosinophils and secreted ECP and EP-X. These findings support the concept that in eosinophilic endomyocardial disease, activated eosinophils infiltrate and degranulate in the myocardium, releasing eosinophil cationic proteins which then damage adjacent myocardial cells.

The bacterial cell-wall peptidoglycan peptides and related compounds coupled with some fatty acids were synthesized, and their immunostimulating property was examined by carbon clearance assay. All the new compounds (2–6) proved to possess significant potencies superior to that of FK-156 (1).