Basic and clinical studies on imipenem/cilastatin sodium in the pediatric field

Basic and clinical studies have been performed on imipenem/cilastatin sodium (MK-0787/MK-0791) in the pediatric field. Antibacterial activities of MK-0787 against 14 clinical isolates of S. aureus and 67 isolates of E. coli were determined. The MIC of MK-0787 was 0.10 microgram/ml or less against all 14 strains of S. aureus. The MIC of MK-0787 was 0.39 microgram/ml or less against all 67 strains of E. coli. The pharmacokinetics of MK-0787/MK-0791 was studied at dose levels of 10 mg/10 mg/kg and 20 mg/20 mg/kg. The peak serum levels of MK-0787 achieved approximately 1 hour after the administration of 10 mg/10 mg/kg and 20 mg/20 mg/kg doses were 38.6 micrograms/ml and 36.2 micrograms/ml, respectively. The serum half-lives were 0.8 hour and 0.9 hour, respectively. The total 6-hour urinary excretions were 82.1% and 66.7%, respectively. The MK-0787/MK-0791 was administered to 13 children with bacterial infections. The clinical results were excellent or good in all cases. The overall efficacy rate was 100%. As a side effect, diarrhea was observed in 1 patient. Abnormalities in laboratory findings observed were elevation of direct bilirubin in 1 patient, thrombocytosis in 2, and a prolonged prothrombin time in 1 patient. Based on the above results, it can be concluded that MK-0787/MK-0791 is a safe and effective drug to use for the treatment of pediatric infections.     

A comparison of the insulinotropic and the insulin-inhibitory actions of gut peptides on newborn and adult rat islet cells

The objective of this study was to examine the release of insulin from cultured islet cells, taken from the pancreas of newborn and adult rats, in response to gastric inhibitory polypeptide (GIP), cholecystokinin-8 (CCK-8), calcitonin gene-related peptide (CGRP), and pancreastatin. GIP (10(-9)-10(-7) M) potentiated glucose-stimulated release of insulin in a dose-dependent fashion from both newborn and adult islet cells. CCK-8 (greater than 10(-8) M) also increased glucose-stimulated release of insulin from newborn islet cells, however its effect was not significant and not as strong as that observed with adult islet cells. Culture of newborn islet cells for 3 weeks with media containing high concentrations of glucose (16.7 mM) enhanced insulin release in response to CCK-8. CGRP did not affect the release of insulin from newborn islet cells, whereas at 10(-10) M, it reduced the release of insulin from adult islet cells by 66 +/- 4%. Pancreastatin (10(-9)-10(-8) M) did not affect the release of insulin from newborn islet cells when cells were incubated with 4.2 mM glucose, whereas it stimulated the release of insulin from adult islet cells in a dose-dependent fashion. When incubated with 16.7 mM glucose, pancreastatin inhibited the release of insulin from both newborn and adult islet cells. These results indicate that newborn islet cells experience developmental changes which render them responsive to enteric peptides.     

Effects of insulin on diacylglycerol-protein kinase C signaling in rat diaphragm and soleus muscles and relationship to glucose transport

Insulin was found to provoke rapid increases in diacylglycerol (DAG) content and [3H]glycerol incorporation into DAG and other lipids during incubations of rat hemidiaphragms and soleus muscles. Insulin also rapidly increased phosphatidic acid and total glycerolipid labeling by [3H]glycerol, suggesting that insulin increases DAG production at least partly through stimulation of the de novo pathway. Increased DAG production may activate protein kinase C (PKC) as reported previously in the rat diaphragm. We also observed apparent insulin-induced translocation of PKC from cytosol to membrane in the rat soleus muscle. The importance of insulin-induced increases in DAG-PKC signaling in the stimulation of glucose transport in rat diaphragm and soleus muscles was suggested by 1) PKC activators phorbol esters and phospholipase C stimulation of [3H]-2-deoxyglucose (DOG) uptake and 2) PKC inhibitors staurosporine and polymixin B inhibition of insulin effects on [3H]-2-DOG uptake. Although phorbol ester was much less effective than insulin in the diaphragm, phospholipase C provoked increases in [3H]-2-DOG uptake that equaled or exceeded those of insulin. In the soleus muscle, phorbol ester, like phospholipase C, was only slightly but not significantly less effective than insulin. Similar variability in effectiveness of phorbol ester has also been noted previously in rat adipocytes (weak) and BC3H1 myocytes (strong), whereas DAG, added exogenously or generated by phospholipase C treatment, stimulates glucose transport to a degree that is quantitatively more comparable to that of insulin in each of the four tissues. Differences in effectiveness of phorbol ester and DAG could not be readily explained by postulating that the latter acts independently of PKC, because DAG provoked the apparent translocation of the enzyme from cytosol to membranes in rat adipocytes, and effects of DAG on [3H]-2-DOG uptake were blocked by inhibitors of PKC in both rat adipocytes and BC3H1 myocytes. Collectively, our findings provide further support for the hypothesis that insulin increases DAG production and PKC activity, and these processes are important in the stimulation of glucose transport in rat skeletal muscle and other tissues.     

Rare Case of Small-Cell Carcinoma Arising from the Endometrium with Paraneoplastic Retinopathy

We present the fourth known case of endometrial carcinoma, and the second case of endometrial small-cell carcinoma, to be associated with paraneoplastic retinopathy. Initial symptoms were decreased visual acuity and a narrowing of the visual field. Endometrial carcinoma was diagnosed several months later. An antibody to 34-kDa bovine retinal antigen was detected in the patient's serum. Thus, autoimmunity was suspected as the cause of the retinopathy. In patients with endometrial carcinoma with visual disturbance of unknown cause, paraneoplastic retinopathy should be suspected.     

β-Adrenergic stimulation does not regulate Na pump function in voltage-clamped ventricular myocytes of the rat heart

Summary Na pump current was measured in rat ventricular myocytes to determine if -adrenergic stimulation can directly modulate Na,K-ATPase activity. Enzymatically-isolated heart cells were voltage-clamped with a single patch electrode and Na pump current was briefly activated by rapidly increasing extracellular [K⁺] from 0 to 15 mM for 3–5 s after other ionic currents were blocked or inactivated. The salt solution in the voltage-clamping electrode included (in mM): (1) 100 Na⁺, 10 EGTA, (2) 5 Na⁺, 10 EGTA, or (3) 100 Na⁺, 7.5 Ca²⁺, 10 EGTA (free [Ca²⁺]=480 nM). With all three electrode solutions, Na pump current was not significantly changed after 2–4 min in the presence of 10 M isoprenaline. -adrenergic pathways were still intact as evidenced by the two-fold increase in Cd²⁺-sensitive Ba²⁺ current through calcium channels that was observed in the presence of isoprenaline. Thus, -adrenergic stimulation does not appear to directly regulate Na,K-ATPase activity in rat ventricular myocytes.     

Immunoelectron microscopic observations of hypothalamic TRH-containing neurons in rats

Summary Immunoreactive TRH-containing neurons and their synaptic associations were studied electron microscopically in the paraventricular nucleus (PVN) and dorsomedial nucleus (DMH) of the rat hypothalamus. In propylthiouracil (PTU)-treated rats, the immunoreactive cell bodies in the PVN appeared to be activated, showing a hypertrophic perikaryon, well developed Golgi bodies and numerous secretory granules. No such alterations were evident in the TRH neurons in the DMH. These findings suggest that the PVN-TRH neurons are involved in the hypothalamic-hypophysial-thyroid axis. Further, it was shown that unlabeled nerve terminals containing small and large clear vesicles make synaptic contacts with the TRH perikarya in the PVN. Thus it is likely that PVN-TRH neurons are regulated both by thyroid hormones and by other neuronal signals. In the DMH, unlabeled nerve terminals containing small and large clear vesicles, and immunoreactive terminals form synapses with TRH neurons. Thus the DMH-TRH neurons may be under dual neuronal control. It was further noted that in the DMH and PVN, TRH nerve terminals make synaptic contacts with other unlabeled neurons. It is evident that TRH acts as a neurotransmitter or neuromodulator, although the origin of TRH terminals should be elucidated.     

Axonal trajectory of single group Ia and Ib fibers in the cat spinal cord

Intracellular staining with HRP of physiologically identified group Ia and Ib afferent fibers in the adult cat lumbosacral cord revealed that group Ia and Ib fibers take a similar course in the dorsal funiculus, but the collaterals emerging from them show a different topographical distribution and a different mode of branching in the gray matter. Ia collaterals terminate in laminae VI, VII, IX, and sometimes VIII, whereas Ib collaterals terminate only in lamina VI, or both VI and IX. In lamina IX, two large motor-type neurons received terminations of both Ia and Ib fibers at the same time.