Early treatment of juvenile xanthogranuloma of the iris with subconjunctival steroids.

Five infants with biopsy proved juvenile xanthogranuloma of the iris were reviewed. Early treatment with subconjunctival injection of steroids and topical steroid drops resulted in regression of the lesion in four patients. One patient, reviewed at the age of 8 months after glaucoma which had developed secondary to the iris xanthogranuloma, had been treated by surgery alone: the visual outcome was very poor.     

Free cytosolic calcium during spontaneous contractions in smooth muscle of the guinea-pig mesotubarium

The free intracellular calcium ion concentration ([Ca²⁺]_i) was measured simultaneously with isometric force in strips of guinea-pig mesotubarium using the Fura-2 technique. During the relaxed period (5–15 min) between spontaneous contractions [Ca²⁺]_i continues to decrease after full mechanical relaxation to reach a minimal level of 86±8 nM (n=9) just before the start of the next contraction. During the spontaneous contractions (5–15 min) [Ca²⁺]_i reached a maximum of 211±19 nM and then oscillated between 155±16 nM and 194±9 nM. Increased extracellular Ca²⁺ concentration to 10 mM from the standard concentration of 1.5 mM caused a decreased frequency of spontaneous contractions and an increase in [Ca²⁺]_i both in the relaxed and contracted states. In 10 mM extracellular Ca²⁺, addition of AlF₄ ^–, as 1 mM NaF + 10 M AlCl₃, caused a sustained increase in [Ca²⁺]_i and maintained force. Addition of verapamil (10 M) in this situation decreased [Ca²⁺]_i to the resting level. The results suggest that the cyclic appearance of trains of action potentials is related to variation in [Ca²⁺]_i, possibly via inactivation of Ca²⁺-dependent K⁺ channels.     

Different effects of depolarization and muscarinic stimulation on the Ca2+/force relationship during the contraction-relaxation cycle in the guinea pig ileum

The effects of K⁺ depolarization and of the muscarinic agonist carbachol on [Ca²⁺]_i and force were investigated in smooth muscle sheets of the longitudinal layer of the ileum loaded with Fura-2. K⁺ -rich solutions increased [Ca²⁺]_i and force to an initial peak value, which was determined by the concentration of [K⁺]_o. Thereafter, [Ca²⁺]_i and force declined to a lower maintained level. The Ca²⁺/force relationship observed during this contraction-relaxation cycle is represented by a clockwise hysteresis loop. At 140 mM [K⁺]_o, this loop consisted of three components while at lower [K⁺]_o a two-component loop was observed. The stimulation with 0.1 mM carbachol resulted in a transient increase of [Ca²⁺]_i and force followed by a continuous decline of these parameters despite the presence of the drug. Its EC₅₀ of relaxation was around 270 nM [Ca²⁺]_i. The Ca²⁺/force relationship proceeded along a counterclockwise hysteresis loop during the contraction-relaxation cycle. The extent of this loop decreased but remained unaltered in its direction during repeated stimulation with carbachol. These results suggest that (a) both agonists increase force and [Ca²⁺]_i during stimulation; (b) during depolarization with K⁺, desensitization to Ca²⁺ occurs resulting in a clockwise hysteresis loop; (c) during carbachol stimulation, a counterclockwise hysteresis is observed. This could be due to an increased sensitivity to Ca²⁺ mainly in tonic smooth muscle. These observations might be explained by a modulation of the Ca²⁺ sensitivity by sensitizing and desensitizing mechanisms. These modulations during different stimuli could be due to different myosin light-chain kinase/myosin light-chain phosphatase ratios.     

Posterior amorphous corneal dystrophy caused by a de novo deletion

We present a newborn diagnosed with posterior amorphous corneal dystrophy (PACD). PACD is a rare disorder with partial or complete posterior lamellar corneal opacification. Genetic screening showed a deletion of chromosome 12q21.33-q22 containing the identified four small leucine-rich proteoglycans (SLRP’s) associated with this particular dystrophy. Neither parents were carrier of the deletion. To our knowledge, this is the first report of a de novo mutation causing PACD.     

Market access of cancer drugs in European countries: improving resource allocation

Public health systems need to make well-founded choices in order to distribute their scarce resources in the most efficient way. Given the number of cancer patients, public/private investments in oncology research, the growing number of new anti-cancer agents and consequent budget impact of cancer care, market access of cancer drugs has become delicate over the last decade. Furthermore, decision makers are challenged by ethical objections and endeavour to provide fair and equal access to treatments for cancer patients. The aim of this study is to generate an overview of market access procedures for cancer drugs in eight European countries and formulate advice for improvement of resource allocation. Results are obtained through a literature review and a qualitative questionnaire and validated by experts with proven knowledge about procedures for price setting and reimbursement of drugs. Diverse measures are applied in the studied countries to optimize reimbursement of cancer drugs such as adjusted cost-effectiveness threshold, regulations for off-label use and new market access agreements. Additionally, innovative cancer drugs are excluded from explicit cost control measures such as payback of budget excess by pharmaceutical companies and lump-sum payments per diagnostic related groups (DRG) in the hospital. The results suggest that cancer is prioritized above other disease areas. Further research is necessary to address the question if society attaches higher value to cancer drugs than to treatments for other diseases.     

Care delivery and outcomes among Belgian children and adolescents with type 1 diabetes

We aimed to investigate care processes and outcomes among children and adolescents with type 1 diabetes treated in hospital-based multidisciplinary paediatric diabetes centres. Our retrospective cross-sectional study among 12 Belgian centres included data from 974 patients with type 1 diabetes, aged 0–18?years. Questionnaires were used to collect data on demographic and clinical characteristics, as well as process of care completion and outcomes of care in 2008. Most patients lived with both biological or adoption parents (77?%) and had at least one parent of Belgian origin (78?%). Nearly all patients (≥95?%) underwent determination of HbA_1c and BMI. Screening for retinopathy (55?%) and microalbuminuria (73?%) was less frequent, but rates increased with age and diabetes duration. Median HbA_1c was 61?mmol/mol (7.7?%) [interquartile range 54–68?mmol/mol (7.1–8.4?%)] and increased with age and insulin dose. HbA_1c was higher among patients on insulin pump therapy. Median HbA_1c significantly differed between centres [from 56?mmol/mol (7.3?%) to 66?mmol/mol (8.2?%)]. Incidence of severe hypoglycaemia was 30 per 100 patient-years. Admissions for ketoacidosis had a rate of 3.2 per 100 patient-years. Patients not living with both biological or adoption parents had higher HbA_1c and more admissions for ketoacidosis. Parents' country of origin was not associated with processes and outcomes of care. Conclusion: Outcomes of care ranked well compared to other European countries, while complication screening rates were intermediate. The observed centre variation in HbA_1c remained unexplained. Outcomes were associated with family structure, highlighting the continuing need for strategies to cope with this emerging challenge.     

An important minority of prediabetic first-degree relatives of type 1 diabetic patients derives from seroconversion to persistent autoantibody positivity after 10?years of age

Aims/hypothesis

The appearance of autoantibodies (Abs) before diabetes onset has mainly been studied in young children. However, most patients develop type 1 diabetes after the age of 15?years. In first-degree relatives aged under 40?years, we investigated the frequency of seroconversion to (persistent) Ab positivity, progression to diabetes and baseline characteristics of seroconverters according to age.

Methods

Abs against insulin (IAA), glutamate decarboxylase (GADA), insulinoma-associated protein 2 (IA-2A) and zinc transporter 8 (ZnT8A) were measured during follow-up of 7,170 first-degree relatives.

Results

We identified 379 (5.3%) relatives with positivity for IAA, GADA, IA-2A and/or ZnT8A (Ab⁺) at first sampling and 224 (3.1%) at a later time point. Most seroconversions occurred after the age of 10?years (63%). During follow-up, Abs persisted more often in relatives initially Ab⁺ (76%) than in seroconverters (53%; p?Conclusions/interpretation Seroconversion to (persistent) Ab⁺ occurs regardless of age. Although the progression rate to diabetes is higher under age 10?years, later seroconverters (up to age 40?years) have similar characteristics when compared with age-matched initially Ab⁺ relatives and generate an important minority of prediabetic relatives, warranting their identification and, eventually, enrolment in prevention trials.     

Seasonality in clinical onset of Type 1 diabetes in Belgian patients above the age of 10 is restricted to HLA-DQ2/DQ8-negative males, which explains the male to female excess in incidence

Aims/hypothesis Type 1 diabetes arises from an interplay between environmental and genetic factors. The reported seasonality at diagnosis supports the hypothesis that currently unknown external triggers play a role in the onset of the disease. We investigated whether a seasonal pattern is observed at diagnosis in Belgian Type 1 diabetic patients, and if so whether seasonality varies according to age, sex and genetic risk, all known to affect the incidence of Type 1 diabetes.Methods The seasonal pattern at clinical diagnosis was assessed in 2176 islet antibody-positive diabetic patients aged 0 to 39 years diagnosed between 1989 and 2000. Additional stratification was performed for age, sex and HLA-DQ genotype.Results Overall, a significant seasonal pattern at clinical diagnosis of diabetes was observed (p<0.001). More subjects were diagnosed in the period of November to February (n=829) than during the period of June to September (n=619) characterised by higher averages of maximal daily temperature and daily hours of sunshine. However, the seasonal pattern was restricted to patients diagnosed above the age of 10 (0–9 years: p=0.398; 10–19 years: p<0.001; 20–29 years: p=0.003; 30–39 years: p=0.015). Since older age at diagnosis is associated with a male to female excess and a lower prevalence of the genetic accelerator HLA-DQ2/DQ8, we further stratified the patients aged 10 to 39 years (n=1675) according to HLA-DQ genotype and sex, and we found that the seasonal pattern was largely restricted to male subjects lacking DQ2/DQ8 (n=748; p<0.001 vs all others: n=927; p=0.031).Conclusions/interpretation In a subgroup of male patients diagnosed over the age of 10, the later stages of the subclinical disease process may be more driven by sex- and season-dependent external factors than in younger, female and genetically more susceptible subjects. These factors may explain the male to female excess in diabetes diagnosed in early adulthood.Abbreviations EURODIAB Europe and Diabetes - GADA glutamate decarboxylase antibodies - IA-2A insulinoma-associated protein 2 antibodies - IAA insulin autoantibodies - ICA islet cell cytoplasmic antibodies