Diabetes in an infant with cystic fibrosis

Cystic fibrosis (CF)-related diabetes mellitus is an unusual complication in very young pediatric patients with CF. It is generally associated with more severe clinical manifestations of CF. In this report, we describe a case of diabetes and CF starting in infancy. The patient manifested a form of intermittent diabetes without fasting hyperglycemia, which was exacerbated by steroid treatment during pulmonary disease and occasionally required insulin therapy. Insulin responses to oral and intravenous glucose challenge were low. The clinical and radiological status was stable during the 9-yr follow-up. Our patient demonstrates that diabetes may not only represent a complication of CF, as previously maintained, but can also be a co-morbid condition proceeding along with the exocrine disease. The early occurrence of hyperglycemia in this case may highlight an impairment of beta-cell function, which might be genetically determined. Careful monitoring of the glucose profile and of beta-cell function is indicated in patients with CF to avoid late recognition of diabetes.     

The effects of oral amino acid intake on ambulatory capacity in elderly subjects

BACKGROUND AND AIMS: The combination of high prevalence of inactivity in the older population, and high risk of ill-health and disability associated with inactivity, suggests that interventions that are successful in increasing levels of activity may have a great impact on population health in later life. With advancing age, the risk of developing serious nutritional deficiencies also increases. This study was designed to assess the effects of dietary amino acid supplementation on effort tolerance in healthy elderly subjects with reduced physical activity. METHODS: Forty-four subjects (age > 65 years) with sedentary life-style and lower health-related quality of life were studied. Subjects, in an open-label fashion, received an oral amino acid mixture (AAM, 12 g/day) containing essential and non-essential amino acids for a 3-month period. Ambulatory dysfunction resulting in sedentary life-style was assessed by a 6-min walk test. A walking impairment questionnaire (WIQ) was used to evaluate self-perceived ambulatory dysfunction. Maximal isometric muscular strength of the right hand was measured during isometric exercise by a handgrip dynamometer. RESULTS: The 6-min walk distance increased from 214.5 +/- 32 to 262.8 +/- 34.8 m (p < 0.001) after AAM treatment. The baseline scores on the three subscales of WIQ changed significantly during treatment: WIQ distance increased from 56.2 +/- 12.9 to 66.3 +/- 12.8% (p < 0.001); WIQ speed from 52 +/- 12.6 to 69.2 +/- 14.8% (p < 0.001) and WIQ stairs from 74.4 +/- 22.6 to 94.2 +/- 25% (p < 0.001), as did maximal isometric muscular strength (16.6 +/- 2.4 vs 19.2 +/- 2.2 kg, p < 0.001). Changes in plasma glucose (+11 +/- 11 mg/dL), total cholesterol (0 +/- 39 mg/dL), HDL cholesterol (0 +/- 17 mg/dL), and triglycerides (-11 +/- 58 mg/dL) were not significant between baseline and AAM. CONCLUSIONS: An oral amino acid supplement, as used in this pilot study, improves ambulatory capacity and maximal isometric muscle strength in elderly subjects without affecting the main metabolic parameters. Amino acid supplementation may thus represent useful non-pharmacological intervention to maintain physical fitness in these subjects.     

Microsphere-integrated collagen scaffolds for tissue engineering: effect of microsphere formulation and scaffold properties on protein release kinetics.

A promising approach to control the time and space distribution of signalling molecules inside tissue engineering scaffolds consists in entrapping biodegradable microspheres releasing the protein locally for long time frames. However, a rational design of microsphere-integrated scaffolds requires the knowledge of protein release profiles directly within the polymeric template. In this work, PLGA microspheres encapsulating rhodamine-labelled bovine serum albumin (BSA-Rhod) as a model protein were produced in different formulation conditions and tested for their release features in solution and in collagen and collagen/hyaluronic acid (HA) scaffolds. BSA-Rhod release profiles from single microspheres in solution and within the scaffold were assessed by using a confocal laser scanning microscopy (CLSM)-assisted method. Results suggest that the same diffusion-erosion process controls BSA-Rhod release from microspheres in solution and collagen. Nonetheless, two main factors contribute protein release within the scaffold, that is water activity in the release environment and transport properties of the protein in the gel. While microsphere formulation mainly controls the induction time necessary to activate protein release, polymer scaffold composition governs the release rate. Thus, the fine regulation of a tissue engineering construct may be obtained by an appropriate combination of microspheres and scaffolds, providing a spatial and temporal control over signalling molecule delivery.     

How cyclodextrin incorporation affects the properties of protein-loaded PLGA-based microspheres: the case of insulin/hydroxypropyl-beta-cyclodextrin system.

The aim of this work was to study the influence of cyclodextrin (CD) incorporation on the properties of protein-loaded poly(lactide-co-glycolide) (PLGA) microspheres, with particular regards to protein release kinetics. To this purpose, insulin-loaded microspheres were prepared by spray-drying emulsion or solution formulations, with or without hydroxypropyl-beta-cyclodextrin (HPbetaCD), and fully characterized for encapsulation efficiency and release kinetics of both insulin and cyclodextrin. Homogeneous populations of spherical microparticles entrapping both insulin and HPbetaCD were obtained. In order to get an insight into insulin/HPbetaCD interactions occurring inside microspheres, Fourier transform infrared (FTIR) analysis in the Amide I region was performed. FTIR spectra of dried microspheres containing HPbetaCD showed a change in insulin secondary structure, attributed to the presence of insulin/HPbetaCD complexes within microspheres. Insulin release was affected by the presence of HPbetaCD depending on the initial formulation conditions. In the case of microspheres prepared from emulsion, cyclodextrin reduced only insulin burst, whereas in the case of microspheres obtained from solution, the overall insulin release rate was slowed down. Combining the release kinetics of HPbetaCD with the FTIR results on hydrated microspheres, it was concluded that the formation of insulin/HPbetaCD complexes inside microspheres is critical to decrease protein diffusivity in the polymer matrix and achieve an effective modulation of protein release rate.     

The comprehensive medical preparedness in chemical emergencies: 'the chain of chemical survival'.

Medical management of victims of chemical incidents includes supportive therapy, decontamination and antidote administration. Chemical weapons of mass destruction are available to many countries and are a possible alternative to conventional weapons for terrorist groups. During the last 5 years, some Italian institutions have made big efforts to establish a national system of antidote stockpiling and distribution. Little or no efforts have been addressed to other aspects of the medical management of patients exposed to chemical agents, such as decontamination, personal protective equipment, and specific supportive therapy. Although antidotes are indispensable instruments for some poisonings, as nerve agent and botulin intoxication, antidote stockpiling cannot be considered the only objective of a comprehensive medical preparedness for chemical emergencies. This paper addresses the medical priority when approaching victims of chemical emergencies. The priority actually is to establish a chain of chemical survival in which antidote administration is one out of several links.     

Hyaluronidase increases electrogene transfer efficiency in skeletal muscle

Electrogene transfer (EGT) of plasmid DNA into skeletal muscle is a promising strategy for the treatment of muscle disorders and for the systemic secretion of therapeutic proteins. We report here that preinjecting hyaluronidase (HYAse) significantly increases the gene transfer efficiency of muscle EGT. Three constructs encoding mouse erythropoietin (pCMV/mEPO), secreted alkaline phosphatase (pCMV/SeAP), and luciferase (pGGluc) were electroinjected intramuscularly in BALB/c mice and rabbits with and without HYAse pretreatment. Preinjection 1 or 4 hr before EGT increased EPO gene expression by about 5-fold in mice and maintained higher gene expression than plasmid EGT alone. A similar increment in gene expression was observed on pretreatment with HYAse and electroinjection of pCMV/mEPO into rabbit tibialis muscle. The increment of gene expression in rabbits reached 17-fold on injection of plasmid pCMV/SeAP and 24-fold with plasmid pGGluc. Injection of a plasmid encoding beta-galactosidase (pCMV/beta gal/NLS) and subsequent staining with 5-bromo-4-chloro-3-indolyl-beta-D-galactopyranoside indicated that HYAse increased the tissue area involved in gene expression. No irreversible tissue damage was observed on histological analysis of treated muscles. HYAse is used in a variety of clinical applications, and thus the combination of HYAse pretreatment and muscle EGT may constitute an efficient gene transfer method to achieve therapeutic levels of gene expression.     

Increased risk of recurrent thrombosis in patients with essential thrombocythemia carrying the homozygous JAK2 V617F mutation

Evidence suggests that the JAK2 V617F mutation is associated with an increased risk of first thrombosis in patients with essential thrombocythemia (ET). Whether this mutation is also a risk factor for recurrent thrombosis is currently unknown. To investigate the impact of the JAK2 V617F mutation on the risk of recurrent thrombosis in patients with ET, we carried out a multicentre retrospective cohort study. We recruited 143 patients with previous arterial (64.4%) or venous major thrombosis (34.8%) or both (0.8%); 98 of them (68.5%) carried the mutation. Thrombosis recurred in 43 of the patients (30%); overall, after adjustment for sex, age, presence of vascular risk factors, and treatment after the first thrombosis, the presence of the JAK2 mutation did not predict recurrence (multivariable hazard ratio, HR, 0.88, 95% CI 0.46?1.68). Indeed, the individuals homozygous for the JAK2 V617F (allele burden >50%) mutation had an increased risk of recurrence in comparison with wild-type patients (HR 6.15, 95% CI 1.51–24.92). In conclusion, a homozygous JAK2 V617F mutation is an independent risk factor for recurrent thrombosis in patients with ET.     

Fragrance material review on 2-methyl-4-phenylpentanol

A toxicologic and dermatologic review of 2-methyl-4-phenylpentanol when used as a fragrance ingredient is presented. 2-Methyl-4-phenylpentanol is a member of the fragrance structural group Aryl Alkyl Alcohols and is a primary alcohol. The AAAs are a structurally diverse class of fragrance ingredients that includes primary, secondary, and tertiary alkyl alcohols covalently bonded to an aryl (Ar) group, which may be either a substituted or unsubstituted benzene ring. The common structural element for the AAA fragrance ingredients is an alcohol group -C-(R1)(R2)OH and generically the AAAs fragrances can be represented as an Ar-C-(R1)(R2)OH or Ar-Alkyl-C-(R1)(R2)OH group. This review contains a detailed summary of all available toxicology and dermatology papers that are related to this individual fragrance ingredient and is not intended as a stand-alone document. Available data for 2-methyl-4-phenylpentanol were evaluated then summarized and includes physical properties, acute toxicity, skin irritation, mucous membrane (eye) irritation, skin sensitization, repeated dose, and genotoxicity data. A safety assessment of the entire Aryl Alkyl Alcohols will be published simultaneously with this document; please refer to Belsito et al. (2012) for an overall assessment of the safe use of this material and all Aryl Alkyl Alcohols in fragrances.