Fixation by osmium tetroxide and glutaraldehyde of zymogen granules isolated from rat parotid and pancreas was investigated. Protein determinations showed that osmium tetroxide caused rapid release of most of the soluble protein of the granule during fixation in buffered isotonic sucrose. Such granules when examined in the electron microscope after shadow casting appeared quite flat, indicating that most of the contents had indeed been removed. Numerous damaged membranes of the granules were also observed. In contrast, zymogen granules fixed by glutaraldehyde and shadow cast essentially retained the spherical shape and the protein contents. The application of the shadow-casting technique in quantitative studies on the protein content of zymogen granules is discussed.

Aldehydes↗

PubMedDate not supplied

Novel dihydropyridines with positive inotropic action through activation of Ca2+ channels.

Transmembrane influx of extracellular calcium through specific calcium channels is now accepted to have an important role in the excitation-contraction coupling of cardiac and smooth muscle. The importance of such slow calcium channels has been underlined by the development of specific calcium channel blocking agents, the 'calcium antagonists', typified by verapamil, nifedipine and diltiazem. These drugs have been used to investigate the properties of slow calcium channels in a variety of tissues. We have found that small modifications to the nifedipine molecule produce other dihydropyridine derivatives (see Fig. 1) with effects diametrically opposite to those of the calcium antagonists: cardiac contractility is stimulated and smooth muscle is contracted. These effects are competitively antagonized by nifedipine. Apparently, nifedipine and the novel compounds bind to the same specific dihydropyridine binding sites in or near the calcium channel. In contrast to nifedipine, however, the new compounds promote--instead of inhibiting--the influx of Ca2+ ions. We report here the properties of BAY K 8644 (methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)- pyridine-5-carboxylate), one of the most potent of these novel compounds.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMedDate not supplied

Safety of aztreonam and SQ 26,992 in elderly patients with renal insufficiency.

Aztreonam is hydrolyzed (2%-7%) in vivo to a noncyclic compound, SQ 26,992, which has a serum half-life of 26 hr in healthy volunteers. In a study of whether SQ 26,992 accumulates to potentially toxic levels in patients with renal insufficiency, serum concentrations were measured daily in nine elderly patients (average age, 72 years) with diminished renal function and urinary tract infections. The dosage of aztreonam (1.5, 3.0, or 6.0 g per day) was selected according to the creatinine clearance rate (5-49 ml/min) and the severity of infection. Trough levels of aztreonam for eight patients averaged 34.2 micrograms/ml before the third or fourth dose and 32.7 micrograms/ml on the fifth day of therapy (P = .77). Trough levels of SQ 26,992 at the same times averaged 3.2 and 9.1 micrograms/ml, respectively (P = .04). In the one patient who was undergoing hemodialysis, trough levels of aztreonam averaged 55 micrograms/ml for seven days, and trough levels of SQ 26,992 increased progressively from 2.6 to 38.2 micrograms/ml. For all nine patients, the ratio of the SQ 26,992 concentration on day 5 to that on day 1 was inversely related to the creatinine clearance rate (r = -.89). No adverse clinical reactions or laboratory test abnormalities were detected during therapy. Thus, aztreonam should prove to be safe in elderly patients with diminished renal function.

Aged↗

PubMedDate not supplied

Modulation of calcium ion influx by the 1,4-dihydropyridines nifedipine and BAY K 8644.

We examined the effects of the new dihydropyridine calcium agonist BAY K 8644 on calcium influx and mechanical activity in rabbit aortic rings and compared them with those of the classical calcium antagonist nifedipine. The vasodilating effects of nifedipine and the vasoconstricting effects of BAY K 8644 can be explained by the calcium influx modulating activity of these two dihydropyridines. Only at the high concentration of 3 X 10(-6) mol/L BAY K 8644 is there a marked difference between increased calcium influx and reduced contraction.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMedDate not supplied

Clinical outcome and quantitative evaluation of periprosthetic bone-remodeling of an uncemented femoral component with taper design. A prospective study.

The rationale of uncemented taper stems is based on fixation in the proximal portion of the femoral diaphysis, a self-locking principle, and a low modulus of elasticity. The aim of this study was to evaluate a collarless femoral component designed to be a three-dimensional taper for press-fit insertion with regard to clinical outcome, efficacy of fixation, incidence of osteolysis, and periprosthetic bone-remodeling. The first 48 consecutive patients (50 hips) with osteoarthritis who had had primary total hip arthroplasty using the Cerafit Multicone stem and the Cerafit Triradius-M press-fit cup with alumina-alumina pairing (Ceraver Osteal, Paris, France) were followed-up for a mean of 2.3 years (2 to 2.5 years). The mean age of patients at index operations was 52.5 years. Current criteria were used for clinical and radiological assessment. Quantitative evaluation of periprosthetic bone-remodeling was prospectively assessed using computed tomography. Clinical and radiological follow-up was obtained in all hips. Forty-nine hips (98%) were clinically rated good or excellent, one hip (2%) was rated fair, owing to a persisting limp. The mean preoperative Harris Hip Score was rated 62, and it has improved to 93.5 at the time of follow-up. One hip (2%) had marked postoperative thigh pain. This pain had disappeared at 3-month follow-up. All stems showed radiological signs of stable fixation by bone ingrowth. No stem required revision. Thirty-four hips (68%) had either no change in femoral bone density or only patchy loss of bone density isolated to Gruen zones 1 and 7. Sixteen hips (32%) had some reduction of bone density isolated to zone 1. Radiolucencies without progression were found in zones 1 and 7 in 3 hips (6%), and in zone 1 alone in 3 other hips (6%). A slight cortical hypertrophy was seen in 3 hips (6%). Twenty-three hips (46%) developed radiographic appearance of bone apposition at the stem tip as partial pedestal (19 hips) and as complete pedestal (4 hips). No signs of cup loosening were detected at follow-up. Twenty-four patients (25 hips) were eligible for computed tomography. The mean decrease of the overall bone mineral density in the metaphyseal portion of the femur one year after insertion of the stem was rated 15.4%, and the mean decrease of the cortical bone mineral density was rated 17.2%. On the other hand, a mean decrease of the cortical bone mineral density of less than 5% was observed in the diaphyseal portion of the femur around the implant. The clinical and radiological results of the Cerafit Multicone stem at a mean follow-up of 2.3 years are very promising and do not contrast with those achieved using other uncemented stems with tapered design. Furthermore, results of quantitative evaluation of periprosthetic bone-remodeling were considered satisfactory favourably with others reported in the literature using stems inserted without cemented.

Adult↗

PubMedDate not supplied

Blocking of catecholamine activation of adenylate cyclase by N, N'dicyclohexyl carbodiimide in turkey erythrocytes.

Incubation of erythrocytes or their isolated membranes with N, N'dicyclohexyl carbodiimide (DCC) blocked isoproterenol activation of the adenylate cyclase. Fluoride activation remained unaffected. L-epinephrine and DL-propranolol partially and transiently protected the system against DCC. D-Epinephrine and dopamine did not protect. The enzyme system preactivated by isoproterenol plus Gpp(NH)p was no longer sensitive to DCC. In contrast to the water insoluble DCC, a water soluble carbodiimide acted only at high concentration and blocked fluoride as well as catecholamine activation of the adenylate cyclase. The findings indicate that DCC attacks a group on, or near, the beta-adrenergic receptor and that this group is located in a hydrophobic region of the cell membrane. It is argued that a low nominal concentration of DCC in the aqueous suspension of erythrocytes actually represents a very high concentration of DCC in the hydrophobic region of the cell membranes, near the beta-adrenergic receptor. The reaction with DCC may prove to be a useful tool in future analyses of beta-adrenergic receptor function.

Adenylyl Cyclases↗

PubMedDate not supplied

Calcium channel modulation: ability to inhibit or promote calcium influx resides in the same dihydropyridine molecule.

BAY K 8644, a dihydropyridine of the nifedipine type, was shown to increase coronary resistance and to enhance myocardial contractility (Schramm et al., Nature 1983;303:535-7), in contrast to the well-known vasodilating and negative inotropic effects of the "classical" calcium channel blockers. In the isolated perfused guinea pig heart at high concentrations (greater than 3 microM), however, the coronary constricting and positive inotropic effects of BAY K 8644 progressively reverse until the drug has a negative inotropic effect and decreases coronary resistance, thus mimicking the effects of the "classical" calcium antagonists. On the other hand, in the same experimental model, calcium antagonists like nifedipine, nitrendipine, and nicardipine are shown to exert a small but definite positive inotropic effect at low concentrations, indicating a calcium agonistic action at those concentrations. To explain the pharmacological effects of BAY K 8644 and the calcium channel blockers of the dihydropyridine type, a model is proposed that suggests the existence of two dihydropyridine binding sites per channel. According to this model, it depends on the chemical structure of the respective dihydropyridine whether, after occupation of the first site, which increases the calcium influx through the channel, the occupation of the second site is unimpaired, turning the channel to one with low calcium permeability; or whether occupation of the second site is hindered, leaving the channel in the high conductance state.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMedDate not supplied

Neural expression profile of Elav-like genes in human brain.

BACKGROUND: Hel-N1 and HuD belong to the elav gene family and have a considerable role in neuronal development. However, there is only limited information available on the expression profile in human brain and neural tumor cell lines. METHOD: Therefore, RT-PCR analysis has been performed on human fetal, normal adult, and psychiatric brains (from patients with schizophrenia, Alzheimer's disease, and alcoholism) as well as 20 glioblastoma and 9 medulloblastoma cell lines. RESULTS: Both, Hel-N1 and HuD were abundantly expressed in all brain samples with no obvious difference. However, the neural tumor cell lines showed a differential expression pattern. The medulloblastoma cell lines expressed at least one of the genes in a frequency of 67% for HuD and 78% for Hel-N1 transcripts, respectively. In contrast to the glioblastoma cell lines, which revealed no evidence for HuD RT-PCR products. Surprisingly, 55% of the glioblastoma cell lines showed Hel-N1 expression. CONCLUSION: These observations indicate that Hel-N1 and HuD participate in molecular processes in human brain, both during development and in the mature adult brain. Hel-N1 and HuD transcriptional activity are stable markers for medulloblastoma cell lines, a tumor, which is thought to be derived from a neuronal precursor cell. The role of Hel-N1 in glioblastomas, the most prominent representative of the glial tumors is presently unclear. This finding is the first indication for a possible involvement of an Elav-like gene product in the glial cell lineage.

Alcoholism↗