Metabotropic glutamate receptor subtypes independently modulate neuronal intracellular calcium

Metabotropic glutamate receptors (mGluRs) modulate several G-protein-related signal transduction pathways including intracellular calcium (iCa(2+)) that control both neuronal development and demise. As an initial investigation, we characterized the ability of specific mGluR subtypes to modulate iCa(2+) by using Fura-2 microfluorometry in primary hippocampal neurons. Activation rather than inhibition of the metabotropic system with the group I and group II mGluR agonist 1S, 3R-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD), the specific group I agonist (S)-3,5-dihydroxyphenylglycine (DHPG), and the specific group II agonist (2S,1'S,2'S)-2-(carboxycyclopropyl)glycine (LCCG-I) increased iCa(2+) with increasing concentrations. In contrast, the group III mGluR agonist, L(+)-2-amino-4-phosphonobutyric acid (L-AP4) produced no significant increase in iCa(2+). Through the pharmacological modulation of individual mGluR subtypes, we further examined the role of iCa(2+) release by the mGluR system. Release of iCa(2+) by both 1S,3R-ACPD and LCCG-I was prevented only through the administration of the antagonists (2S)-alpha-ethylglutamic acid (EGlu; mGluR2 and mGluR3) and (2S,1'S,2'S,3'R)-2-(2'-carboxy-3'-phenylcyclopropyl)glycine (PCCG-IV; mGluR2), suggesting that the mGluR2 subtype was responsible for the release of iCa(2+). As a control, the group I antagonists, L(+)-2-amino-3-phosphonopropionic acid (L-AP3) and (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA), prevented DHPG release of iCa(2+) but were ineffective against iCa(2+) release by 1S,3R-ACPD. Although extracellular calcium influx did not significantly contribute to the release of iCa(2+) by the mGluR system, pharmacological inhibition of calcium-induced calcium-release-sensitive calcium pools played a critical role in the release of iCa(2+). Further characterization of the cellular calcium pools modulated by the mGluR subtypes may provide greater insight into the mechanisms that mediate neuronal function.     

N-nitro- -arginine methylester is protective against ethanol-induced gastric damage in cholestatic rats

In this study the effect of nitric oxide (NO) synthesis inhibition on ethanol-induced gastric damage was evaluated in bile duct-ligated, sham-operated and unoperated rats. The animals were injected intraperitoneally with saline, -arginine (200 mg/kg) or N^G-nitro- -arginine methylester ( -NAME) in doses of 5, 15 and 30 mg/kg, 30 min before ethanol administration. The animals were killed 1 h after ethanol administration and their stomachs were removed for measurement of gastric mucosal damage. The results showed that -NAME significantly enhanced the development of gastric mucosal lesions in sham-operated and unoperated rats, while in bile duct-ligated animals, -NAME decreased and -arginine enhanced the potentiation of ethanol-induced gastric mucosal damage. The plasma level of nitrite and nitrate was also measured and was significantly higher in bile duct-ligated rats than in control groups. The results suggest that inhibition of NO synthase with -NAME has different effects on ethanol-induced gastric damage in cholestatic groups and in normal rats and that these effects can be explained by overproduction of NO in bile duct-ligated animals.     

Matrix Metalloproteinase Inhibitors: Applications in Oncology

Matrix metalloproteinases (MMP) are a group of zinc dependentenzymes which include the interstitial collagenases, stromelysins,gelatinases and membrane-type metalloproteinases. They are involvedin the remodelling and turnover of the extracellular matrixproteins. They play a role in wound healing and the pathogenesis ofarthritis. In malignancies they play a role in tumor invasion,metastasis and angiogenesis. A number of synthetic matrixmetalloproteinase inhibitors (MMPIs) have been developed forclinical use. In preclinical tumor models they have shown promisingactivity in achievinginhibition of MMPs and reducing tumor growth and metastatic spread.Some have also shown additive or synergistic effects with cytotoxicagents. Phase I and II studies in human subjects have defined themain side effects of these agents as beingmusculoskeletal pains or arthralgias. As they are cytostatic agentsrather than cytotoxic in activity conventional measurements ofradiological response for assessment are not applicable in trials.Biological activity has been demonstrated in certain cancers by theeffects on levels of tumor markers as surrogate markers of tumorresponse and also by a fibrotic stromal reaction seen in tumortissue. Newer agents have been developed withselective inhibition of certain MMPs in an attempt to reduce theside effects. A number of phase III human clinical trialsevaluating MMPs are being carried out at present but onlyone has been formally reported so far. This study suggested thatmarimastat had no survival advantage when compared to chemotherapywith gemcitabine in advanced pancreatic carcinoma. Current trialsare assessing efficacy of MMPIs in maintenance of remission afterother modalities of therapy or in combination with cytotoxicagents. MMPs have also been demonstrated to play an important rolein the articular cartilage destruction seen in both rheumatoidarthritis and osteoarthritis. The use of MMPIs in both exvivoand in vivomodels have shown promising resultsand trials are in process to assess their potential role in thecontrol of articular destruction. The true therapeutic role ofMMPIs await the results of these randomized studies.     

Breastfeeding and weaning practices in rural communities of Kelantan

A survey of infant-feeding and weaning practices of 566 mothers, systematically sampled from 15 rural villages, randomly selected in the district of Tumpat, Kelantan was carried out. Almost all mothers (97.3%) breastfed their children, reinforcing the previously reported high incidence of breast-feeding among rural Malaysian mothers. One hundred and seventeen (21.3%) of the 551 children breastfed were also given mixed feeding with infant fomulae as well. Weaning started before 4 months of age in 28.3% of the children and after 6 months of age in 12.8% of the children. The 3 most common type of food used in weaning were Nestum (45.0%), rice porridge or paste (42.6%) and wheat porridge or cakes (11.5%). Forty eight children (12.1%) discontinued breastfeeding once weaning was initiated. The main reasons for initiating weaning was mothers' perception that there was insufficient milk and that the child was always hungry (55.7%). Most mothers were also given advice by the health clinic staff on weaning, including the timing and the suitable weaning foods to give. All of the mothers were able to name at least one commercial weaning food product available in their community.     

Plasma melphalan and prednisolone concentrations during oral therapy for multiple myeloma

Summary Nine patients with myeloma were studied over 13 oral administrations of 10 mg melphalan and 5–10 mg prednisolone. Plasma melphalan concentrations were estimated by high-pressure liquid chromatography, prednisolone concentrations by quantitative thin-layer chromatography. The mean plasma half-life of unchanged melphalan was 0.9±0.5 (SD) h. The lag-time before melphalan was detected in the plasma varied from 1 to 4 h, the mean peak concentration was 96±21 ng/ml, and the mean area under the plasma concentration by time curve was 160±78 ng h/ml. This variability was consistent with observations made elsewhere following much higher oral doses of melphalan and illustrates the relatively wide interindividual variability of absorption. Observations made in the same subjects on two separate occasions showed lower variability. The melphalan elimination rate was not significantly affected by moderate impairment of creatinine clearance (to 31 ml/min). Absorption of prednisolone in five of these patients was apparently normal and unaffected by concurrent administration of melphalan.     

The surgical treatment of carcinoma of the colon and rectum: an index of quality care and sociologic and geographic distribution.

A comparative experience of 474 patients with primary carcinoma of the colon and rectum has been evaluated in several hospital settings, with particular respect to patient populations, geographic distribution, and surgical characteristics. The differences and similarities are interpreted with caution but may provide a format by which significant objective determinants become the basis for subsequent assessment of quality care in an illness which is prevalent and amenable to relatively standardized operative management. No difference in quality of medical care provided was detectable across the sociologic and geographic boundaries studied. Notable increases in extent of neoplasm and severity of co-existent illness in the urban, "indigent" population adversely influenced both short and long-term mortality rates.     

Controlled trial of frusemide as an antiepileptic drug in focal epilepsy

1 The antiepileptic activity of oral frusemide (120 mg daily) was compared with that of an identical placebo in a double-blind crossover trial in fourteen patients with severe focal epilepsy who were receiving long-term therapy with established antiepileptic drugs.

2 A statistically significant reduction in the frequency of focal fits was seen with the active drug.

3 Marked drowsiness occurred in three patients during frusemide therapy, causing their withdrawal from the trial.

4 A slight, but significant, rise in serum phenobarbitone concentrations was observed during frusemide therapy, but no change was seen in serum primidone or phenytoin concentrations.

5 Frusemide significantly lowered plasma sodium and potassium concentrations, and increased plasma bicarbonate.

     

Electrogustometry: strengths,weaknesses, and clinical evidence of stimulus boundaries

Electrogustometry is well established as a clinical tool for the estimation of taste detection thresholds. Nevertheless, the user is sometimes unaware of the impact of superficially minor procedural and psychophysical factors upon the reliability and comparability of threshold estimates. The inherent strengths and limitations of the procedure are outlined, and aspects of the control and specification of the stimulus that moderate threshold measures are discussed. In addition, threshold estimates from two individuals with severe unilateral taste loss are used to illustrate the level at which anodal dc current may elicit common, rather than taste, sensation. Where chorda tympani section is complete and historical (older than 7–14 days), very high stimulus levels, conservatively over 5 µA/mm² (100 µA linear current with a 5‐mm diameter electrode), are required to activate trigeminal responses.     

Abdominal cerebrospinal fluid pseudocyst

A case of an abdominal cerebrospinal fluid (CSF) pseudocyst in a patient with a ventriculoperitoneal shunt is reported to illustrate this known but rare complication. In the setting of a VP shunt, the frequency of abdominal CSF pseudocyst formation is approximately 3.2%, often being precipitated by a recent inflammatory or infective process or recent surgery. Larger pseudocysts tend to be sterile, whereas smaller pseudocysts are more often infected. Ultrasound and CT each have characteristic findings.