Keloid fibroblast responsiveness to epidermal growth factor and activation of downstream intracellular signaling pathways.

Keloids, which overgrow the boundaries of the original injury, represent aberrations in the fundamental process of wound healing that include over-abundant cell in-migration, cell proliferation, and inflammation, as well as increased extracellular matrix synthesis and defective remodeling. To understand the key events that result in the formation of these abnormal scars would open new avenues for better understanding of excessive repair, and might provide new therapeutic options. We examined epidermal growth factor receptor (EGFR)-induced cell motility in keloid fibroblasts, as this receptor initiates cell migration during normal wound repair. We show that keloid fibroblasts respond to EGF-induced cell migration but the response is somewhat diminished compared to normal adult fibroblasts (approximately 30% reduced); the mitogenic response was similarly blunted (approximately 5% reduced). Keloid fibroblasts express near normal levels of EGFR (82%), but show a much more attenuated activation of EGFR itself and the motility-associated phospholipase C-gamma. This was reflected in part by rapid loss of EGFR upon exposure to EGF. Interestingly, while extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK-MAPK) activation was relatively robust in keloid fibroblasts, the downstream triggering of the motility-associated calpain activity was blunted. This was reflected by high cell-substratum adhesiveness in the keloid fibroblasts. Thus, the blunted migratory response to EGF noted in keloid fibroblasts appears due to limited activation of two important biochemical switches for cell motility.     

Perceived adherence to prescribed treatment in juvenile idiopathic arthritis over a one‐year period

Objective

To document perceived adherence to treatment (taking medications and performing exercises) in patients with juvenile idiopathic arthritis (JIA) over a 1‐year period and to identify related factors.

Methods

We surveyed parents of patients with JIA at the Montreal Children's Hospital and British Columbia's Children's Hospital in Vancouver. Parents were asked to respond to a series of questionnaires every 3 months over a 12‐month period. Perceived adherence was evaluated on a 100‐mm visual analog scale (VAS) in the Parent Adherence Report Questionnaire (PARQ). Parental coping, distress, child function, disease severity and duration, perceived helpfulness of treatment, problems encountered, and sociodemographic data were also assessed.

Results

The mean age of our sample of 175 children was 10.2 years; mean age at diagnosis was 6.1 years and mean disease duration was 4.1 years. Perceived adherence to medications was consistently high, with average adherence at baseline, 3, 6, 9, and 12 months being 86.1, 91.7, 90.4, 92.0, and 88.8, respectively, on the PARQ VAS. Perceived adherence to exercise was lower but remained steady, with corresponding means of 54.5, 64.1, 61.2, 63.0, and 54.3, respectively. Using generalized estimating equation analysis, factors associated with higher perceived adherence to medications included perceived helpfulness of medications and lower disease severity; those associated with higher perceived adherence to exercise were younger age of the child, child involvement in responsibility for treatment, and higher perceived helpfulness of the treatment.

Conclusion

Belief in helpfulness of treatment is associated with higher parental perceived adherence to treatment.     

Antioxidant Activity of Limonene on Normal Murine Lymphocytes: Relation to H2O2 Modulation and Cell Proliferation

Abstract: Limonene is a monoterpene present in citrus fruit and is used as flavouring agents of foods. It was shown that monoterpenes possess antioxidant activity. Previously, it was demonstrated that limonene exerts anti‐proliferative action on a lymphoma cell line without modifying normal lymphocyte viability. H₂O₂ has a modulator role in cell proliferation. In the present study, the effect of limonene on normal lymphocytes proliferation and its relation with H₂O₂ level modulation was analysed, evaluating its effect on the activity of cell antioxidant enzymes, such as catalase, peroxidase and superoxide dismutase. Limonene exerted a biphasic effect on cell proliferation; the increase in cell proliferation was related to the decrease in H₂O₂ level by the increase in catalase and peroxidase activities. Moreover, limonene protected the cells to the oxidative stress induced by exogenous addition of H₂O₂. In view of these results, it is possible that limonene could protect normal lymphocytes from diseases related to oxidative stress, including cancer, but further research is necessary to establish the role of limonene as a potential antioxidant that can effectively protect lymphocytes from oxidative stress and mitochondrial dysfunction.     

Antibiotic prescribing for chronic skin wounds in primary care

The aim of this study was to describe and quantify systemic antibiotic prescribing for patients with chronic skin wounds presenting at the primary care, nonspecialist setting. Data for 1 year were extracted from a general practice morbidity database comprising approximately 185,000 patients attending family medical practitioners in Wales. Patients with chronic wounds (PCW) were identified using Read Codes and compared with nonwound patients who were randomly selected after matching for age-band, sex, and general practice. PCW received a significantly greater number of antibiotic courses than nonwound patients (p<0.001). This increased level of prescribing was evident for flucloxacillin, co-amoxiclav, cefaclor, cefalexin, erythromycin, trimethoprim, metronidazole, and ciprofloxacin (p<0.01 for all). While PCW also had a significantly higher prevalence of diabetes (16.5% compared with 6.6%, p<0.001), and attended at general practice significantly more frequently than nonwound patients (median (interquartile range) of 25 (17-40) visits per year compared with 12 (4-20), p<0.001), importantly, exclusion of diabetic patients and analysis of the proportion of visits on which patients received antibiotics did not affect the significance of the difference in antibiotic consumption. These data show a strong association between occurrence of chronic wounds and prescribing of antibiotics in primary health care, and wide variation in the type and duration of antibiotic therapy for chronic wounds. Further work is now indicated to rationalize this prescribing and determine the role that this exposure to antibiotics plays in the prevalence of antibiotic resistance in this at-risk elderly population.     

An approach to protein restriction in children with renal insufficiency

Children with mild to moderate renal insufficiency may be at an increased risk for developing glomerulosclerosis and subsequent renal failure. Low protein diets (LPD) have been shown to delay the progression of renal insufficiency in laboratory animals and may be of benefit in adult humans. The nutritional costs of a LPD in adults are reportedly minimal. We review the protein and caloric requirements of growing children and discuss the potential harmful effects and benefits of an LPD in this population. We also discuss dietary adherence and the difficulty of designing an LPD for children. We conclude that the protein content of a typical American diet can safely be reduced to, but not below, the recommended daily allowance for protein if diets are carefully planned, patients and their parents extensively counseled, and if dietary supplements are given to help meet the caloric and vitamin-mineral nutrient needs of growing children. In addition, ongoing nutritional assessment, counseling, and frequent monitoring of growth, diet and biochemical indicators of protein status are essential for maintaining the health of these children.     

Development of the Home Care Client Satisfaction Instrument

Abstract Client (patient) satisfaction has been studied extensively in the health care sector, yet those receiving home health care services have been the focus of few studies. The purpose of this study was to test the reliability and validity of the Home Care Client Satisfaction Instrument (HCCSI). A total of 400 clients, randomly selected from 20 randomly chosen home care agencies in one state, completed the HCCSI and demographic form. Most respondents were older adults with multiple health problems and their families or informal support systems. Since data were skewed, item analysis was used. The revised instrument (HCCSI-R) is unidimensional and includes 12 items rated on a 5-point Likert scale measuring specific aspects of care. In addition, there are three global measures of satisfaction rated on a 10-point scale. All items except one had significant item-total correlations greater than .59. The total score correlates with likeliness to recommend the agency to others (.37, p = .0001), showing some evidence for criterion-related validity.     

Effect of Food on the Pharmacokinetics of a New Hydroxypropyl-β-Cyclodextrin Formulation of Itraconazole

Study Objective . To compare the pharmacokinetics of a single 100-mg oral dose of itraconazole administered as 10 ml of a 10-mg/ml itraconazole solution in hydroxypropyl-β-cyclodextrin under fasting versus postprandial conditions. Design . Open-label, two-way, randomized, crossover study. Setting . Janssen Research Foundation, Belgium. Patients . Twelve healthy volunteers. Interventions . Blood samples were obtained for pharmacokinetic analyses immediately before dosing and at regular intervals up to 96 hours after each dose. Blood and urine samples were obtained for hematologic, biochemical, and urinary safety analyses at baseline and at the end of the study. Measurements and Main Results . The mean peak plasma concentrations of both itraconazole and its active metabolite hydroxy-itraconazole were significantly higher under fasting conditions than under postprandial conditions. The mean times to peak concentration for both the parent compound and its metabolite were significantly shorter under fasting than under nonfasting conditions. The mean areas under the curve (AUC_0–∞ and AUC_{0–24 hrs}) were also significantly higher under fasting than under postprandial conditions. Conclusions . Our findings suggest that the higher bioavailability of this new formulation of itraconazole may be of benefit in seriously ill patients who are not able to ingest adequate quantities of food. The fact that the solution was also well tolerated and was not associated with clinically significant changes in any laboratory value further underscores the potential utility of this dosing form.     

Morphine-3-glucuronide: hyperglycemic and neuroendocrine potentiating effects

The greater potency of morphine-6-glucuronide (M6G) as well as the inactivity of morphine-3-glucuronide (M3G) with respect to the antinociceptive effects of the parent molecule, morphine (MOR), have been well established. It has been suggested that M3G is an antagonist of MOR's antinociceptive and respiratory depressive effects. The present study addressed the central nervous system (CNS) interaction of these opiate metabolites on their metabolic and hormonal effects. Whole body glucose kinetics were assessed on conscious, chronically catheterized, unrestrained rats. M3G (5 μg) or H₂O (5 μl) was injected intracerebroventricularly (i.c.v.) 15 min prior to the bolus administration of H₂O (5 μl), M6G (1 μg), or MOR (80 μg). i.c.v. M3G (5 μg) resulted in behavioral excitation, hyperglycemia (+50%), stimulation of glucose rate of appearance (R_a; +100%), glucose rate of disappeaance (R_d; +70%), and metabolic clearance rate (MCR; +33%) within 30 min after injection with no alterations in hormone concentrations. i.c.v. M6G and MOR produced progressive hyperglycemia with significantly high catecholamine and corticosterone levels. M3G pretreatment resulted in enhanced elevations in plasma glucose levels (+52% and +18%), plasma lactate (+138% and +108%), norepinephrine (+96% and +30%), and epinephrine (+62% and +67%) in response to both i.c.v. MOR and M6G administration. These findings suggest a non-opiate and non-hormonal mechanism for M3G-induced hyperglycemia. In contrast, the metabolic and hormonal responses to i.c.v. M6G and MOR are associated with elevations in catecholamine and corticosterone levels, which are remarkably enhanced by M3G pretreatment, most likely through accelerated catecholamine release. Our findings suggest a modulatory role for MOR glucuronidation, not only by rendering it inactive, as in the case of M3G, but by an interplay of the metabolic effects of the parent molecule and its metabolite