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Islet transplantation is a promising therapy for T1DM. Key factors influencing islet yield have been identified with conflicting results. In this study, we analyzed 276 isolations to identify variables for islet yield and, additionally, islet size and size distribution. Pearson correlation analyses demonstrated that BMI had a positive correlation with pancreas size, actual islet count (AIC), and islet equivalent (IEQ)/g (all p ≤0.009), while CIT had a negative correlation with AIC and IEQ/g (all p ≤0.003). In mixed linear regression, BMI also had a positive correlation with islet size but only for shorter digestion times (≤15 min); there was no association between BMI and islet size for longer digestion times (>15 min). CIT was not associated with islet size. Donor age, sex, and preservation solutions were shown to have no correlation with islet yields or size distribution. Pancreas size had a positive correlation with AIC and a negative association with IEQ/g; it also had positive association with islet size but only for females, not males. Overdigestion was positively associated with islet counts; however, there was also a greater proportion of smaller islets when digestion rate was >74% ( p = 0.005). Of the three collagenases analyzed, Sigma V had the lowest digestion rate (mean = 65%), approximately 5% or 10% lower than Roche Liberase HI ( p = 0.04) and Serva NB1 ( p = 0.0003), respectively; however, the Sigma V group showed better islet size preservation. Yet, the enzymes resulted in similar IEQ/g digested tissue. Of the isolated islets, 70.2% were smaller than 150 μm and contributed only 20.4% to the total IEQ, while 7.4% of the islets were larger than 250 μm but contributed 42.4% to the total IEQ. In summary, BMI, pancreas size, and CIT are useful variables for predicting islet yield, but selection of enzyme and balancing digestion time and rate are also important.

Background and Aims: Dietary quality affects cardiometabolic risk, yet its pathways of influence on regional adipose tissue depots involved in metabolic and diabetes risk are not well established. We aimed to investigate the relationship between dietary quality and regional adiposity., Methods and Results: We investigated 5079 individuals in the Multi-Ethnic Study of Atherosclerosis (MESA) who had food-frequency questionnaires and measurement of pericardial fat and hepatic attenuation at the baseline study visit in MESA, as well as a subgroup with imaging for visceral and subcutaneous fat (N = 1390). A dietary quality score (DietQuality) was constructed to include established food group constituents of a Mediterranean-type diet. Linear models estimated associations of dietary score as well as its constituents with regional adiposity. Baseline mean age was 61 (± 10) years, and approximately half of the participants (47%) were male. Those with a higher DietQuality score were generally older, female, with a lower body mass index, C-reactive protein, and markers of insulin resistance. After adjustment, a higher DietQuality score was associated with lower visceral fat (lowest vs. highest dietary score quartile: 523.6 vs. 460.5 cm(2)/m; P < 0.01 for trend), pericardial fat (47.5 vs. 41.3 cm(3)/m; P < 0.01 for trend), lesser hepatic steatosis (by hepatic attenuation; 58.6 vs. 60.7 Hounsfield units; P < 0.01 for trend), but not subcutaneous fat (P = 0.39). Greater fruits, vegetables, whole grains, seeds/nuts and yogurt intake were associated with decreased adiposity, while red/processed meats were associated with greater regional adiposity., Conclusion: A higher quality diet pattern is associated with less regional adiposity, suggesting a potential mechanism of beneficial dietary effects on diabetes, metabolic, and cardiovascular risk., (Copyright © 2016 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Marrow stroma-derived cells (MSC) are highly proliferative, multipotential cells that have been considered as ideal candidate cells for autologous tissue engineering applications. In this study, we have characterized the chondrogenic potential of human MSCs in both a PLA/alginate amalgam and pure PLA macrostructure as model three-dimensional constructs to support both chondrogenic differentiation and proliferation following TGF-beta treatment. MSCs were seeded in experimental groups that consisted of PLA-loaded constructs and PLA/alginate amalgams with and without recombinant human TGF-beta1. Chondrogenesis of the PLA and the PLA/alginate amalgam cultures was assessed at weekly intervals by histology, immunohistochemistry, scanning electron microscopy, sulfate incorporation, and RT-PCR. Chondrogenic differentiation occurs within a polymeric macrostructure with TGF-beta1 treatment as indicated by histological, immunohistochemical, sulfate incorporation, and gene expression profiles. This macrostructure can be further encased in an alginate gel/solution to optimize cell shape and to confine growth factors and cells within the polymer construct, while the polymeric scaffold provides appropriate mechanical/tissue support. The stable three-dimensional PLA/alginate amalgam represents a novel candidate system of mesenchymal chondrogenesis, which is amendable to investigation of mechanical and biological factors that normally modulate cartilage development and formation as well as a potential tissue engineering construct for cartilage repair.

Mesenchymal stem cells are a rare population of undifferentiated cells, isolated from adult tissue sources, that have the capacity to differentiate into mesodermal lineages, including bone, fat, muscle, cartilage, tendon, and marrow stroma. These cell populations may be expanded in culture and subsequently permitted to differentiate into the desired lineage. This directed differentiation may be reached by the application of bioactive molecules, specific growth factors, and signaling molecules. Understanding the functional potential of these cells and the signaling mechanisms underlying their differentiation should lead to innovative protocols for clinical orthopaedic interventions. Clinically applicable techniques to isolate, expand, and reimplant these autogenous cells will become part of the repertoire of orthopaedic therapy. In the presence of extrinsic signaling molecules, provided by both the clinician and the local cellular environment, the intrinsic multipotential nature of the stem cells may be realized for applications such as the replacement of bone graft for segmental defects, nonunions, and spinal fusions. Additional applications may include treatment of full-thickness articular defects and articular resurfacing by site-specific delivery of stem cells. The ultimate goal is directed cellular regeneration of damaged or diseased musculoskeletal tissue. Currently, the limitation is our knowledge and ability to direct this differentiation, but with further study molecular orthopaedic interventions should become a reality.

New Zealand White rabbits were treated orally with 0 (controls), 50, 100, or 150 mg/kg phenytoin on days 14-16 of pregnancy. Total and free plasma concentrations of phenytoin were determined in maternal plasma 2, 6, and 24 hr after the final dose in all animals. In addition, after administration of 150 mg/kg maternal plasma concentrations were also determined after 12 and 48 hr, the concentrations in amniotic fluid after 6 hr, and those in fetal tissue 6 and 24 hr after the final treatment. A high degree of plasma protein binding was observed in maternal blood. Treatment with 50 mg/kg resulted in free plasma concentrations of up to 5.0 mumol/l during the 24 hr period following the final dose. Significantly higher free plasma concentrations were observed at the two higher dose levels; up to 9.7 mumol/l at 100 mg/kg and 12.7 mumol/l at 150 mg/kg. Digital hypoplasia was not seen in the control group or the animals treated with 50 mg/kg. However, treatment with 100 mg/kg resulted in hypoplasia in a single or a few digits in approximately 50% of the fetuses, and 150 mg/kg provoked hypoplasia in almost all digits in all fetuses. These results show that even though the doses which caused digital defects in rabbits are much higher than those used therapeutically, the resulting free concentrations of phenytoin are similar to those which are associated with the same type of defects in humans. These data indicate that the pharmacologically induced fetal hypoxia/ischemia and vascular disruption preceding malformations of this type, which were observed in a previous study in rabbits, may be of human relevance.

The growth-promoting potential of growth hormone-releasing hormone(1-29)-NH2 (GHRH(1-29)-NH2) in a new formulation for intranasal use was examined in a 6-month pilot study of eight short prepubertal children. The maximal plasma concentration of growth hormone (GH) was below 12 micrograms/l in two stimulation tests (arginine, insulin), but above 12 (24-90) micrograms/l after intravenous GHRH, 1 microgram/kg. GHRH, 50 micrograms/kg, was insufflated intranasally three times per day over 6 months. On day 1, GHRH insufflations were followed by distinct GHRH and GH plasma peaks, ranging from 1.2 to 5.4 micrograms/l and from 10 to 85 mIU/l, respectively. Peak amplitudes were variably reduced after 6 weeks in most patients, and further reduced at 6 months. GHRH antibodies (initially negative) were positive in three patients after 6 weeks. The mean knemometric growth rate rose from 0.24 to 0.48 mm/week after 6 weeks of treatment (p = 0.03) and then rapidly declined; the mean 6-month stadiometric height velocity did not increase. Local tolerance was good in one patient; most others reported sneezing immediately after insufflation, rhinorrhoea and mild mucosal burning. Treatment was discontinued in two patients after 6 and 12 weeks. It is concluded that intranasal GHRH, though non-invasive, is not suitable in its present form for use in children, because of decreasing absorption and effectiveness with concomitant development of antibodies and local reactions.

The growth hormone-releasing hormone analogue GHRH(1-29)-NH2 was administered intravenously or intranasally to 30 healthy men aged 19-43 years. Intravenous injection of the lowest dose tested, 0.25 microgram/kg body weight, elicited significant release of growth hormone (GH). Maximal release (mean GH peaks of about 90 mU/l) was obtained with a dose of 1-2 micrograms/kg. Although GHRH(1-29)-NH2 was rapidly eliminated after intravenous injection, GH levels were elevated for about 3 hours. Absorption of GHRH(1-29)-NH2 through the nasal mucosa was found to be low, and the bioavailability was only 3-5%. There was a dose-dependent release of GH after intranasal administration of GHRH(1-29)-NH2, with the maximal response obtained with about 50 micrograms/kg; this dose was approximately as potent as 1 microgram/kg injected intravenously. The GH response after repeated intranasal administration of GHRH(1-29)-NH2 was sustained; there was no suppression of GH secretion during the night following a day when GHRH(1-29)-NH2 had been given three times intranasally. Based on these findings and the obvious convenience of intranasal administration compared with injections, it would be justified to test intranasal therapy for treatment of short stature in children with GH deficiency caused by hypothalamic damage.

The plasma concentrations of lidocaine and prilocaine after dermal application of EMLA cream 5% were determined in two clinical studies. The cream (10-16 g) was applied to a total surface area of 100-160 cm2. Each area was covered by a Tegaderm dressing (3M) in order to obtain occlusion. An application time of 2 hours was used. Two age groups of ten children were studied: 2-3 years and 6-8 years. In both groups venous blood samples were drawn prior to application and at 2, 3, 4 and 5 hours. In addition, in one of the studies, the cream was used during the surgical removal of mollusca in order to study the analgesic effect of the cream. The absorption of the local anaesthetics as indicated by plasma concentrations was far below toxic levels. The highest individual concentration of lidocaine was 315 ng/ml and of prilocaine 215 ng/ml. The analgesic effect was sufficient--eight out of ten patients experienced no or slight pain. Transient local reactions (paleness, redness) were frequently observed. In one patient with eczema present at the application site prior to the application, a reaction persisted for one week. Dermal analgesia provided by EMLA is a safe and effective method for alleviation of pain from removal of mollusca and the plasma concentrations are innocuous.

We have measured plasma concentrations of local anaesthetics, and the substance fraction of methaemoglobin (MetHb), in infants less than 3 months of age, after application of a lignocaine-prilocaine cream (EMLA). A total of EMLA 2 g was applied over four different skin areas, totalling 16 cm2, for 4 h before anaesthesia for a minor surgical procedure. Sampling was carried out before and 4, 8 and 12 h after application. Maximum MetHb values (median = 2.24%) were obtained usually at 8 h and were significantly (P less than 0.001) higher than before application (median 1.32%). The plasma concentrations of local anaesthetics were low (maximum values: prilocaine 78 ng ml-1, lignocaine 412 ng ml-1). The activity of erythrocyte MetHb reductase (cytochrome b5 reductase) was analysed. Data from a previously studied group of infants aged 3-12 months were included also. Enzyme activity did not reach adult levels until after the age of 3 months. It showed a good inverse correlation with the maximum MetHb values after application of EMLA. Although the MetHb concentrations in the infants younger than 3 months were small, the enzyme capacity may be overloaded when EMLA is administered at the same time as other MetHb-inducing agents. It is concluded that the use of EMLA should be restricted in this age group.

The use of a new device for reconstitution and storage of growth hormone (GH), Genotropin KabiVial, was studied in 20 children, aged 9-17 years, who had been receiving GH therapy using conventional administration systems. After 2 weeks of treatment, the convenience of the device and the patients' tolerance of it were assessed by the patients/families through a questionnaire. They were asked to compare the new device with the conventional method (standard vials and syringes). Most of the patients found the new device superior to the conventional method; they found that it was easier to reconstitute the GH and considered the multi-dose system and the smaller injection volume to be advantageous. Ninety per cent of the patients (p less than 0.001) expressed a preference for Genotropin 16 IU KabiVial for their future therapy.

The convenience of Genotropin KabiQuick, a novel single-use disposable injection system for growth hormone (GH) administration, was studied in 20 GH-treated children aged 8-16 years. The convenience of the device and tolerance to it were assessed by means of a questionnaire, which was completed by the patients and their families after a treatment period of 2 weeks. The families were asked to compare the new device with the conventional system of GH administration, involving the use of standard ampoules and ordinary syringes. The majority of patients considered the new device superior to the conventional system; 85% of patients found reconstitution easier and 70% found dosing easier. Sixty-five per cent of patients expressed a preference for using Genotropin KabiQuick for future therapy. It is concluded that Genotropin KabiQuick is well tolerated and that the majority of patients prefer it to conventional injection systems for GH administration.

The aim of the study was to evaluate the effect of a lidocaine-prilocaine cream (EMLA cream, Astra) in relieving pain during arterial cannulation. The study had a random, double-blind, placebo-controlled design and included altogether 90 patients. All the patients were premedicated with an opioid before cannulation. An EMLA application time of 60 minutes was used in 60 patients (30 EMLA/30 placebo) and there was no difference in the pain reaction measured on a visual analogue scale (VAS) or on an observer's verbal scale. The study was extended with a further 30 patients (15 EMLA/15 placebo) with an application time exceeding 90 minutes. Between these groups pain experience measured by VAS did not show any significant difference although the mean value was lower in the EMLA group. Observer ratings showed a significant (p less than 0.01) difference in distribution towards lower ratings in the EMLA group. In conclusion EMLA was found to have a weak, but measurable effect when the application time exceeded 90 minutes but not after 60 minutes.

The single-dose kinetics of D-propoxyphene, acetyl salicylic acid and phenazone, given in a combination tablet (Doleron), were compared in young and elderly subjects. Serial blood samples were taken 0--48 hours after administration. The plasma concentrations of propoxyphene and of its major metabolite, norporpoxyphene, were assessed by mass fragmentography, those of phenazone by gas chromatography, and those of acetyl salicylic acid plus salicylic acid by spectrofluorometry. Neither for propoxyphene, norpropoxyphene, acetyl salicylic acid nor phenazone did the areas under the concentration curves or the elimination half-lives differ between young and elderly subjects. These data do not provide pharmacokinetic support for a general reduction of the Doleron dosage in elderly subjects.

The analgesic effect and the usefulness of EMLA cream 5% in connection with venous blood-sampling was investigated in 42 Tanzanian schoolchildren. Approximately 2.5 g EMLA was applied to the right cubital fossa for a minimum of 120 min. The analgesic effect was pronounced--93% of the venepunctures were pain-free and no child experienced severe pain. No adverse reactions were observed and the children could continue normal school work during the application time.

The aim of the study was to measure the plasma levels of lidocaine and prilocaine after dermal application of EMLA in infants and to evaluate whether this procedure increases the levels of methaemoglobin (Met-Hb). Two groups of infants, 3-6 (n = 12) and 6-12 months (n = 10) of age, were studied. In total, 2 ml of EMLA was applied to 4 x 4 cm of skin surface for 4 h and blood samples for detection of Met-Hb and plasma levels of local anaesthetics were taken at 0, 2, 4 and 8 h after the application. After removal of the cream the infants were operated mainly for minor procedures under general anaesthesia. The plasma concentrations of lidocaine and prilocaine were in all cases below toxic levels and there were only minor increases in Met-Hb in a few infants. In conclusion, EMLA can be used safely in infants above 3 months of age provided that the recommendations with regard to dose, application area and time are followed. The use of EMLA in smaller infants and in children taking other Met-Hb-inducing drugs needs further evaluation.

The influence of food intake on the bioavailability of a frequently used short-acting sulfonamide, sulfaisomidine (Elkosin), has been examined in eight healthy volunteers. The drug was administered as a single oral dose, both on an empty stomach and together with a standardized breakfast. Numerous venous blood samples were drawn for the first eight hours after ingestion of the drug, and the concentration of unmetabolized sulfonamide in serum was assessed by spectrophotometry. The observations indicate that concomitant food intake alters neither absorption rate, peak concentration, time to reach peak concentration, elimination rate, nor total amount of sulfonamide reaching the general circulation. Thus, the absorption of orally administered sulfaisodimidine is not at all affected by concomitant intake of food. This finding contrasts with previous observations on some other sulfonamides, and it may signify a therapeutic advantage of sulfaisodimidine. In addition, the amount absorbed showed only a little interindividual variation. This suggests that the use of standardized size and interval of sulfaisodimidine dosage can be recommended. The present findings emphasize that conclusions about the absorption of a certain drug should not be derived from studies with other, albeit chemically related, compounds.

The bioavailability of 6-propylthiouracil (PTU) has been examined in eight healthy volunteers, with respect to interindividual variation and influence of food intake. PTU was given as a single oral dose, both in a fasting state and together with a standardized breakfast. Numerous venous blood samples were taken during 5 hours after PTU ingestion, and the concentration of unmetabolized PTU in serum was determined by a specific gas-chromatographic technique. The observations indicate that the amount of PTU absorbed is subject to a large interindividual variation, and that concomitant food intake may exert a minor and non-systematic influence on PTU absorption. Hence, the major issue in PTU therapy is the individualization of the size and interval of dosage. Testing of single-dose PTU kinetics in patients would apparently be helpful.

Acute infarction of an appendix epiploica resulted in an inflammatory process involving the caudal aspect of the transverse colon and the adjacent greater omentum. Computed tomography demonstrated prominent linear soft tissue densities, an increase in CT number of the involved greater omentum, and posterior displacement of the small bowel. In the setting of acute abdominal pain the location and focal nature of the inflammatory process as seen on CT may allow the radiologist to suggest the correct diagnosis.

The influence of food on the bioavailability of hydralazine in noncoated and coated tablets was examined in 5 healthy males. Each subject received an oral 50-mg dose on four different occasions: two 25-mg noncoated tablets with and without food and one 50-mg coated tablet with and without food. The meal was a standardized breakfast of 440 calories. Venous blood samples were obtained during a 6-hr period, and the plasma concentrations of unmetabolized hydralazine were assessed by a selective and sensitive gas chromatographic method. The results indicate that food enhances the bioavailability of hydralazine 2- to 3-fold both when noncoated and coated tablets are used.

The influence of food intake on the bioavailability of isoniazid (INH) has been examined in nine healthy male volunteers. INH was administered as a single oral dose, both in fasting state and together with a standardized breakfast. Numerous venous blood samples were obtained 5 min-6 hours after the INH ingestion, and the concentrations of unmetabolized INH in serum were assessed by spectrophotometry. The observations indicate that both the peak concentration and the total amount of INH absorbed are greatly reduced when the drug is ingested together with food. Hence it is recommended that, in the treatment of tuberculosis with INH, the drug should be given on an empty stomach. The data may also have some bearing on the use of INH for assessing acetylation rates and estimating dosages of hydralazine and related drugs.

The influence of food intake on the bioavailability of canrenone, the major and active metabolite of spironolactone, was explored in 8 healthy male volunteers. Spironolactone was administered as a single oral dose of 100 mg, both in the fasting state and together with a standardized breakfast. Numerous venous blood samples were taken from 30 min to 96 hr after ingestion of the drug, and the plasma concentrations of canrenone were determined by spectrofluorometry. The results indicate that more canrenone enters the general circulation when spironolactone in ingested together with a meal.

The possible influence of food intake on the bioavailability of the anxiolytic drug oxazepam was assessed in eight healthy volunteers taking a single dose of the drug both on an empty stomach and together with a standardized breakfast meal. The serum concentrations of oxazepam were determined by gas chromatography on samples obtained before, and at numerous occasions up to 48 hours after drug administration. The results indicate that concomitant food intake has no essential influence on the bioavailability of oxazepam.

The influence of food intake on the bioavailability of three analgesic compounds--propoxyphene chloride, acetyl salicylic acid and phenazone--in a combination tablet, Doleron, has been examined in eight healthy volunteers. A single oral dose was given both on an empty stomach and together with a standardized breakfast meal. The plasma concentrations of propoxyphene, its major metabolite norpropoxyphene, salicylic acid and phenazone were determined by mass fragmentography, spectrofluorimetry and gas chromatography. Concomitant food intake had no consistent influence on the bioavailability of any of the components. Hence, doleron may be taken together with meals as well as between meals. Large interindividual variations in propoxyphene and phenazone concentrations were found, indicating that an optimal effect will not always be obtained by standard doses.

The possible influence of food intake on the bioavailability of one nonselective and one cardioselective beta adrenoceptor antagonist, propranolol and metoprolol, was examined by serial determinations of the drug concentrations in blood of healthy subjects, taking single doses of the drugs both on an empty stomach and together with a standardized breakfast. The results indicate that food enhances the bioavailability of both propranolol and metoprolol. They also confirm that there is extensive interindividual variation in the bioavailability of these drugs.