B. Van der Schueren

Distribution of the beta 1 subgroup of the integrins in human cells and tissues.

We studied the distribution of the beta 1 integrin subfamily in human tissues and cells by light microscopy, electron microscopy, and immunoblotting, using monoclonal antibody DH12, previously shown to react with the beta 1 subunit of the human fibronectin receptor. Crossreaction with the other beta subunits of the integrin family, which have 45% and 47% primary amino acid sequence identity with the beta 1 subunit, was excluded, as MAb DH12 did not react with the beta 2 subunit in granulocytes and the beta 3 subunit in thrombocytes. Reactivity with the anti-beta 1 antibody was found in skin, lung, heart, striated and smooth muscle, blood cells, liver, kidney, intestine, spleen and placenta. Thus, cells of mesodermal, ectodermal, and entodermal origin express the beta 1 subunit. In skin fibroblasts cultured in vitro, beta 1 subunit was also detected intracellularly. The wide distribution of the beta 1 family, originally detected in activated T-lymphocytes after prolonged culture in vitro, contrast with the restricted distribution of the beta 2 integrins on leucocytes.

Differential expression of multiple cell-surface heparan sulfate proteoglycans during embryonic tooth development.

Heparan sulfate accumulates on cell surfaces and at cell-matrix interfaces, and functionally modulates several of the effector molecules that support the interactions, growth, and differentiation of developing tissues. Using heparin sulfate-specific monoclonal antibodies MAb, we obtained evidence that extracts from rodent embryos contain multiple forms of cell surface-associated heparan sulfate proteoglycan (PG). Taking tooth development in the mouse embryo as a model to further investigate the relevance of this PG redundancy and using MAb against heparan sulfate, antibodies specific for syndecan (syndecan-1) and fibroglycan (syndecan-2) (two distinct members of a larger family of cell-surface heparan sulfate PGs), and specific cDNA probes for these two cell-surface PGs, we obtained in situ evidence for regulated and differential expression of multiple cell-surface heparan sulfate PGs. The unique, distinctive, and coordinated changes in the expressions of these PGs during morphogenesis and differentiation of dental tissues suggest that the various cell-surface PGs are not truly redundant but play important, specific, and potentially complementary roles during embryonic development.

Powder deposition in selective metal powder sintering

Selective metal powder sintering is a layer‐by‐layer manufacturing system producing metallic parts with good mechanical properties. Describes why an Fe‐Cu powder mixture has been selected as the basic material for the process. Deals with the powder deposition issue and proposes a mechanism which can deposit thin powder layers on top of a recipient. Shows that the powder deposition mainly depends on the powder properties. States that the required powder properties are partially compatible with the specifications set by the technology of selective sintering but that some properties are in conflict with one another. Discusses the resulting compromises needed in the powder mixtures and the required modifications to the deposition mechanism.

Calcitonin Gene-Related Peptide8-37 Antagonizes Capsaicin-Induced Vasodilation in the Skin: Evaluation of a Human in Vivo Pharmacodynamic Model

The purpose of this study was to identify the mediators involved in capsaicin-induced vasodilation in the human skin and to evaluate a pharmacodynamic model for the early clinical evaluation of calcitonin gene-related peptide (CGRP) receptor antagonists. Dermal blood flow (DBF) response of the forearm skin to topically applied capsaicin was measured using laser Doppler perfusion imaging in 22 subjects. The effect of intra-arterially administered CGRP8-37 (1200 ng · min–1 · dl–1 forearm), indomethacin (5 μg · min–1 · dl–1 forearm), and NG-monomethyl-l-arginine (l-NMMA; 0.2 mg · min–1 dl–1 forearm), and orally administered aprepitant (375 mg) on capsaicin-induced dermal vasodilation was assessed. Furthermore, the diurnal variation of the DBF response to capsaicin was studied. CGRP8-37 inhibited the capsaicin-induced DBF increase: 217(145, 290)% in infused versus 370 (254, 486)% in the noninfused arm [mean (95% CI); p = 0.004]. In contrast, indomethacin, l-NMMA, aprepitant, and the time of assessment did not affect the DBF response to capsaicin. Thus, capsaicin-induced vasodilation in the human forearm skin is largely mediated by CGRP, but not by vasodilating prostaglandins, nitric oxide, or substance P. The response to capsaicin does not display a circadian rhythm. A pharmacodynamic model is proposed to evaluate CGRP receptor antagonists in humans in vivo.

Age-dependent decline of β-cell function in type 1 diabetes after diagnosis: a multi-centre longitudinal study.

C‐peptide secretion is currently the only available clinical biomarker to measure residual β‐cell function in type 1 diabetes. However, the natural history of C‐peptide decline after diagnosis can vary considerably dependent upon several variables. We investigated the shape of C‐peptide decline over time from type 1 diabetes onset in relation to age at diagnosis, haemoglobin A1c (HbA1c) levels and insulin dose.

BMI is an important driver of β-cell loss in type 1 diabetes upon diagnosis in 10 to 18-year-old children

OBJECTIVE Body weight-related insulin resistance probably plays a role in progression to type 1 diabetes, but has an uncertain impact following diagnosis. In this study, we investigated whether BMI measured at diagnosis was an independent predictor of C-peptide decline 1-year post-diagnosis. DESIGN Multicentre longitudinal study carried out at diagnosis and up to 1-year follow-up. METHODS Data on C-peptide were collected from seven diabetes centres in Europe. Patients were grouped according to age at diagnosis (<5 years, n=126; >5 years <10 years, n=295; >10 years <18 years, n=421; >18 years, n=410). Linear regression was used to investigate whether BMI was an independent predictor of change in fasting C-peptide over 1 year. Models were additionally adjusted for baseline insulin dose and HbA1c. RESULTS In individuals diagnosed between 0 and 5 years, 5 and 10 years and those diagnosed >18 years, we found no association between BMI and C-peptide decline. In patients aged 10-18 years, higher BMI at baseline was associated with a greater decline in fasting C-peptide over 1 year with a decrease (β 95% CI; P value) of 0.025 (0.010, 0.041) nM/kg per m(2) higher baseline BMI (P=0.001). This association remained significant after adjusting for gender and differences in HbA1c and insulin dose (β=0.026, 95% CI=0.0097, 0.042; P=0.002). CONCLUSIONS These observations indicate that increased body weight and increased insulin demand are associated with more rapid disease progression after diagnosis of type 1 diabetes in an age group 10-18 years. This should be considered in studies of β-cell function in type 1 diabetes.

Prevalence of persistent lipid abnormalities in statin-treated patients: Belgian results of the Dyslipidaemia International Study (DYSIS).

A substantial number of cardiovascular events are not prevented by statin therapy, which is still regarded as the first‐line therapy for hyperlipidaemia. Insights into the prevalence of lipid abnormalities of statin‐treated patients in Belgium are lacking and may shed light on an unmet medical need for optimal use of current lipid‐lowering therapies.

Immunohistochemical localization of human α2macroglobulin in connective tissue

SummaryThe localization of α2 macroglobulin (α2M) has been examined by an indirect immunofluorescent technique in frozen sections of various human tissues. The results indicate that α2M is present only in connective tissues and blood. The outer medulla of the kidney and the submucosa of the gut showed the strongest reaction. Epithelia or endothelial cells were unreactive. In liver, only the Kupffer cells were stained. These results were confirmed with the immunoperoxidase technique and by the study of tissue extracts in crossed immunoelectrophoresis (CIE). As a positive control a polyspecific antiserum prepared against whole human fibroblasts as well as anti-albumin were used. Our findings are interpreted in the light of the observations that α2M is synthesized and selectively ingested by fibroblasts.

Higher plasma motilin levels in obese patients decrease after Roux-en-Y gastric bypass surgery and regulate hunger

Objective Motilin-induced phase III contractions of the migrating motor complex (MMC) signal hunger in healthy volunteers. The current aim was to study the role of motilin as a hunger-inducing factor in obese patients and to evaluate the effect of Roux-en-Y gastric bypass (RYGB) surgery on plasma motilin levels and hunger scores. Design Motilin and ghrelin plasma levels were determined during a complete MMC cycle in controls and obese patients selected for RYGB before, 6 months and 1 year after surgery. 20 min after the end of the second phase III, obese patients received an intravenous infusion of 40 mg erythromycin. Hunger was scored every 5 min. Hedonic hunger was assessed in obese patients with the Power of Food Scale questionnaire. Results Obesity caused a switch in the origin of phase III from antrum to duodenum. Obese patients had significantly higher motilin levels compared with controls during the MMC but tended to lack the motilin peak prior to phase III necessary to trigger hunger. Hunger scores during phase III were significantly lower in obese patients, but could be restored to control levels through the administration of a low dose of the motilin agonist, erythromycin. After RYGB surgery motilin, but not ghrelin, levels decreased in parallel with hedonic hunger scores. Conclusions Motilin may be an important regulator involved in the pathogenesis of obesity.

Sumatriptan causes parallel decrease in plasma CGRP concentration and migraine headache during nitroglycerin-induced migraine attack.

Dear Sir Calcitonin-gene related peptide (CGRP) is a pivotal neuropeptide in the pathophysiology of migraine (1). It is well established that the plasma concentration of CGRP rises during spontaneous migraine attacks (2–5). In addition, Juhasz et al. have confirmed this in nitroglycerin-induced migraine attacks (6). In a subsequent study, recently published in Cephalalgia (7), Juhasz et al. demonstrated that the plasma CGRP concentration decreases after the administration of sumatriptan, a 5-HT1B/1D/1F receptor agonist (triptan), during a nitroglycerin-induced migraine attack. Interestingly, this decrease was present only in patients whose headache improved. Based on these observations and those from two previous studies (8, 9), the authors of this study and the accompanying editorial concluded (i) that triptans inhibit CGRP release, most likely by presynaptic inhibition of perivascular trigeminal nerves, and (ii) that this mechanism is, at least partially, responsible for the antimigraine efficacy of triptans. However, we feel that these conclusions are not (yet) justified as the observation of a correlation does not necessarily imply causality. First, we would like to point out that none of the studies reporting a triptan-induced decrease in plasma CGRP levels was placebo-controlled (7–9). Thus, one cannot rule out the possibility that CGRP levels decreased spontaneously during the course of the migraine attack. Indeed, evidence is available indicating that during untreated, spontaneous or nitroglycerin-induced migraine attacks CGRP plasma levels decrease after an initial increase within the first hour after the onset of the attack (4–6). Taking into account that, in the studies by Juhasz et al. (7) and others (8, 9), blood samples were taken several hours after the onset of the attack, it might well be that CGRP plasma levels were already decreasing spontaneously at the time of triptan administration. Second, even if a placebo-controlled study could provide definitive proof that the administration of a triptan during a migraine attack is associated with a decrease in CGRP plasma concentrations, the exact underlying mechanism would remain unclear. The triptan-induced decrease in CGRP release may be due to a direct inhibition via presynaptic 5-HT receptors on trigeminal nerve endings (10). Alternatively, it could be secondary to a decreased activation of perivascular trigeminal nerves as a result of cranial vasoconstriction (11). Separating these neuronal and vascular mechanisms of action has proven very difficult so far and is probably impossible by human in vivo research. Therefore, in our opinion it remains to be proven if and how triptans affect CGRP plasma concentrations during an acute migraine attack.