Impact of cellular microenvironment and mechanical perturbation on calcium signalling in meniscus fibrochondrocytes.

Mechanical signals regulate a multitude of cell functions and ultimately govern fibrous tissue growth, maintenance and repair. Such mechanotransduction processes often involve modulation of intracellular calcium concentration ([Ca2+]i). However, most studies interrogate these responses in cells in simplified culture systems, thereby removing potentially important inputs from the native extracellular microenvironment. The objective of this study was to test the hypothesis that the intracellular calcium response of meniscus fibrochondrocytes (MFCs) is dependent on both the microenvironmental context in which this perturbation is applied and on the tensile deformation. Using a custom micro-mechanical tester mounted on a confocal microscope, intracellular calcium activity in MFCs in response to incremental tissue strains (0, 3, 6 and 9 %) was monitored in situ (i.e., in the native tissues) on MFC-seeded aligned scaffolds and MFC-seeded silicone membranes. The [Ca2+]i regulation by MFCs within the native meniscus tissue microenvironment was considerably different from [Ca2+]i regulation by MFCs on either aligned nanofibrous scaffolds or flat silicone membranes. Additionally, increasing levels of tensile deformation resulted in a greater number of responding cells, both in situ and in vitro, while having no effects on temporal characteristics of [Ca2+]i signalling. Collectively, these findings have significant implications for mechanobiology of load-bearing fibrous tissues and their responses to injury and degeneration. In addition, from a tissue engineering perspective, the findings establish cellular benchmarks for maturing engineered constructs, where native tissue-like calcium mechano-regulation may be an important outcome parameter to achieve mechanical functionality comparable to native tissue.

Health-related quality-of-life results from multinational clinical trials of insulin lispro. Assessing benefits of a new diabetes therapy.

OBJECTIVE: To compare health-related quality of life (HRQOL) in patients with diabetes receiving insulin lispro with patients receiving regular human insulin (Humulin R). RESEARCH DESIGN AND METHODS: We performed two randomized comparative studies over a 6-month period (3 months per treatment). Primary analyses used crossover baseline to 3-month changes in HRQOL scores. Ninety-three principal investigators in Canada, France, Germany, and the U.S. participated in these studies. One HRQOL crossover study included 468 patients with type I diabetes; the other HRQOL crossover study included 474 patients with type II diabetes. In both studies, patients were taking insulin at least 2 months before enrollment. Primary outcomes included two generic HRQOL domains, energy/fatigue and health distress, and two diabetes-specific domains, treatment satisfaction and treatment flexibility. Thirty secondary outcomes included both generic and diabetes-specific measures. Secondary outcome domains were controlled for multiplicity in the analyses. RESULTS: Primary analyses showed that treatment satisfaction scores (P < 0.001) and treatment flexibility scores (P = 0.001) were higher for insulin lispro in type I diabetic patients. No other significant treatment differences were detected using the data from these 6-month crossover studies. CONCLUSIONS: Treatment satisfaction and treatment flexibility were significantly improved in patients with type I diabetes using insulin lispro. Other HRQOL findings were comparable for insulin lispro and regular human insulin. Insulin lispro appears to have a measurable impact on lifestyle benefits in patients with type I diabetes, as demonstrated by increased treatment satisfaction and treatment flexibility.

Human growth hormone and Creutzfeldt-Jakob disease.

For more than 20 years cadaver-derived human growth hormone (HGH) was used successfully to enhance linear growth in short children. In 1985 the US Food and Drug Administration (FDA) stopped use of the hormone in response to reported deaths due to Creutzfeldt-Jakob (CJD) agent in 3 former HGH recipients. To date, a total of 9 patients have been identified who both received HGH and became infected with CJD agent (7 in the United States, 1 in Britain, and 1 in New Zealand). Circumstances make it likely that HGH contaminated with a slow growing, viral-like particle may have been responsible for these fatalities. In Oklahoma at least 60 children and adolescents previously received HGH and are potentially at risk of developing CJD. It is important that health care providers responsible for the care of these individuals be aware of this fatal illness and remain informed of new developments in the field.

Effects of capsaicin (C) and dihydrocapsaicin (DC) on serum ethanol (ET) concentration of ET treated CF-1 mice.

In this study adult male CF-1 mice were treated on a daily basis as follows: Group A - controls, Group B - ethanol (ET) treated (1.25 g ET/kg body weight (b.wt.], Group C - ET plus 4 mg Capsaicin (C)/kg b.wt., and Group D - ET plus 4 mg dihydrocapsaicin (DC)/kg b.wt. At the end of the sixth week experimental period the animals were anesthetized, exsanguinated and hepatectomized. Our study suggests that ET administered at the rate of 1.25 g ET/kg b.wt. reaches a mean serum value of 43 + 14 mg/dL within 15 minutes. In addition, chronic ET ingestion significantly decreases mean hepatic glycogen content and mean serum triglyceride concentration of the animals. Conjoint administration of ET plus C decreases significantly mean body weight and mean ET and the triglyceride concentration of the serum. Prolonged ET ingestion plus DC administration decreases mean wet liver weight and lowers significantly the mean serum ET, cholesterol and triglyceride concentrations of CF-1 mice.

Comparison of postoperative intraocular pressures after use of Miochol and Miostat.

Over 100 cases of standard extracapsular cataract extraction with intraocular lens implantation were reviewed and the effects of two commercially available pharmacological agents were compared. The treatment groups received either acetylcholine chloride (Miochol) or carbachol (Miostat). Intraocular pressures were measured preoperatively and 20 to 24 hours postoperatively. The difference in mean pressures between the treatment groups was statistically significant. The results of the study showed Miostat to be the better pharmacological agent for controlling intraocular pressure 20 to 24 hours later. Since the majority of surgeons use Miochol rather than Miostat, the conclusions of this study appear to be significant.

Dihydrocapsaicin (DC) protects against serum hyperlipidemia in guinea pigs fed a cholesterol-enriched diet.

Juvenile guinea pigs were maintained either on a standard diet (cholesterol-free) or a 0.5% cholesterol-enriched vitamin C deficient diet for six weeks. Half of the animals of each dietary group were treated with dihydrocapsaicin (DC) at the rate of 8 mg per animal per day. DC administration significantly altered food consumption, body weight, and dry weight of feces of animals maintained on the standard diet. In addition, the mean serum triglyceride concentration of these animals was significantly decreased with DC treatment. Food consumption, body weight and (wet) fecal weight of animals maintained on the 0.5% cholesterol-enriched diet were significantly lower than the corresponding values in control animals even though the liver was much larger in proportion to the total body weight. The mean serum cholesterol concentration of the animals fed a cholesterol-enriched diet was significantly elevated. However, in animals also receiving DC, the cholesterol and triglyceride levels were comparable to controls fed a regular diet. The gross and microscopic fatty infiltration of the liver observed in the cholesterol-fed animal were minimized in those animals fed cholesterol and DC.

The use of morphologic tissue examinations as novel technique for estimation of drug adverse reactions in hospitalized patients.

Morphologic evaluation of tissue specimens from a hospital population was used to identify and classify adverse reactions to drugs. With the use of this novel technique, the incidence of adverse tissue reactions was found to be 3.6% out of which 1.5% were found to be definitely caused by a specific pharmacological agent. Adverse tissue reactions were both sex- and age-related occurring more often in women and more frequently between the ages of 51-60 years. Although adverse tissue reactions were noted less frequently in males, a definite causative agent was identified in over 50% of males in which a tissue reaction was observed. Endometrium and liver were the predominant tissues altered morphologically in our hospital population. Estrogenic preparations and alcohol were found to be most frequently implicated in the observed adverse tissue reactions. In comparison to the observation of symptoms associated with drug use, our study provides an alternate means of relating an adverse reaction to pharmacological agent employed in that subjective bias can successfully be removed. Although the present system described appears to be more rigorous in identification of adverse reactions, evidence indicates that tissue adverse reaction technique may be advantageous in determination of an unwanted response in patients under 60 years of age. It is hoped that the tissue adverse reaction evaluation may provide a more accurate prediction of possible adverse effects and perhaps may be a more reliable, sensitive system for estimation of adverse effects in hospitalized patients.

Autopsy tissue examination: a novel method to estimate adverse reactions to pharmacological agents.

Autopsy tissue examination was employed as a measure to remove subjective bias observation in the identification and numerical computation of adverse reactions to drugs. With the the use of this novel technique, the incidence of adverse reactions was 26%, of which 82% were produced by a specific causative agent. Adverse reactions occurred most frequently in autopsied tissues taken from patients who were male and in the 61 and over age group. Further the predominant tissue altered morphologically in autopsied specimens examined was liver. The most common causative agent associated with an adverse tissue reaction was identified as alcohol. In light of the difference between evaluation by physicians of drug adverse reactions and the technique of autopsy tissue examination, our findings provide a more accurate measure of adverse reactions to non-prescription pharmacological agents.