Viral infections as potential triggers of type 1 diabetes

During the last decades, the incidence of type 1 diabetes (T1D) has increased significantly, reaching percentages of 3% annually worldwide. This increase suggests that besides genetical factors environmental perturbations (including viral infections) are also involved in the pathogenesis of T1D. T1D has been associated with viral infections including enteroviruses, rubella, mumps, rotavirus, parvovirus and cytomegalovirus (CMV). Although correlations between clinical presentation with T1D and the occurrence of a viral infection that precedes the development of overt disease have been recognized, causalities between viruses and the diabetogenic process are still elusive and difficult to prove in humans. The use of experimental animal models is therefore indispensable, and indeed more insight in the mechanism by which viruses can modulate diabetogenesis has been provided by studies in rodent models for T1D such as the biobreeding (BB) rat, nonobese diabetic (NOD) mouse or specific transgenic mouse strains. Data from experimental animals as well as in vitro studies indicate that various viruses are clearly able to modulate the development of T1D via different mechanisms, including direct beta-cell lysis, bystander activation of autoreactive T cells, loss of regulatory T cells and molecular mimicry. Data obtained in rodents and in vitro systems have improved our insight in the possible role of viral infections in the pathogenesis of human T1D. Future studies will hopefully reveal which human viruses are causally involved in the induction of T1D and this knowledge may provide directions on how to deal with viral infections in diabetes-susceptible individuals in order to delay or even prevent the diabetogenic process.     

Effect of rotator cuff dysfunction on the initial mechanical stability of cementless glenoid components

The functional outcome of shoulder replacement is related to the condition of the rotator cuff. Rotator cuff disease is a common problem in candidates for total shoulder arthroplasty; this study relates the functional status of the rotator cuff to the initial stability of a cementless glenoid implant. A 3D finite element model of a complete scapula was used to quantify the effect of a dysfunctional rotator cuff in terms of bone-implant interface micromotions when the implant is physiologically loaded shortly after surgery. Four rotator cuff conditions (from fully intact to progressively ruptured rotator cuff tendons) as well as two bone qualities were simulated in a model. Micromotions were significantly larger in the worst modeled cuff dysfunction (i.e. the supraspinatus and infraspinatus tendons were fully dysfunctional). Micromotions were also significantly different between conditions with healthy and poor bone quality. The implant’s initial stability was hardly influenced by a dysfunctional supraspinatus alone. However, when the infraspinatus was also affected, the glenohumeral joint force was displaced to the component’s rim resulting in larger micromotions and instability of the implant.     

Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications

Platelets have a central role in the development of arterial thrombosis and subsequent cardiovascular events. An appreciation of this complex process has made antiplatelet therapy the cornerstone of cardiovascular disease management. However, numerous patients will experience a recurrent atherothrombotic vascular event despite adequate antiplatelet therapy. Individual differences in the rate of platelet activation and reactivity markedly influence normal hemostasis and the pathological outcome of thrombosis. Such an individual variability is largely determined by environmental and genetic factors. These are known to either hamper platelets' response to agonists, and thereby mimic the pharmacological modulation of platelet function or mask therapy effect and sensitize platelets. In this article, we reviewed the antiplatelet mechanisms of aspirin and clopidogrel and the possible role of different polymorphisms, which may affect the efficacy of antiplatelet therapy. Heterogeneity in the way patients respond to aspirin and clopidogrel may in part reflect variation in cyclooxygenase (COX)-1, COX-2, glycoprotein (GP) Ib alpha, GP Ia/IIa, GP IIb/IIIa, UGT1A6*2, P2Y₁, P2Y₁₂, CYP2C9, CYP3A4 and CYP3A5 genotypes.     

Favorable Glucose Tolerance and Lower Prevalence of Metabolic Syndrome in Offspring without Diabetes Mellitus of Nonagenarian Siblings: The Leiden Longevity Study

OBJECTIVES: To explore measures of metabolic syndrome and glucose metabolism in families with exceptional longevity. DESIGN: Case–control study. SETTING: A university hospital in Leiden, the Netherlands. PARTICIPANTS: One hundred twenty‐one offspring of nonagenarian siblings, who were enriched for familial factors promoting longevity, and 113 of their partners. No subject had diabetes mellitus. MEASUREMENTS: Prevalence of metabolic syndrome was determined according to the criteria of the Third Report of the National Cholesterol Education Program. Glucose tolerance was assessed according to a 2‐hour oral glucose tolerance test. RESULTS: The offspring of nonagenarians siblings had a lower prevalence of metabolic syndrome (P=.03), similar body composition, lower mean fasting blood glucose levels (4.99 vs 5.16 mmol/L; P=.01), lower mean fasting insulin levels (5.81 vs 6.75 mU/L; P=.04), a higher mean homeostasis model assessment of insulin sensitivity (0.78 vs 0.65; P=.02), and a more‐favorable glucose tolerance (mean area under the receiver operating characteristic curve for glucose (13.2 vs 14.3; P=.007) than their partners. No significant differences were observed between the offspring and their partners in β‐cell function (insulogenic index 13.6 vs 12.5; P=.38). CONCLUSION: Despite similar body composition, the offspring of nonagenarian siblings showed a lower prevalence of metabolic syndrome and better glucose tolerance than their partners, centralizing the role of favorable glucose metabolism in familial longevity.     

Reliability of proximal migration measurements in shoulder arthroplasty

Proximal migration is a complication in shoulder arthroplasty. Quantification of this phenomenon would help in identifying its cause. This study assessed the reliability of 4 methods of measuring proximal migration after shoulder arthroplasty on standard anteroposterior radiographs: the glenohumeral center-to-center measure, the glenohumeral arc measure, the acromiohumeral distance, and the scapular spine-humeral head center (spinohumeral) distance. Radiographs were taken of 12 embalmed shoulders, with matching metal humeral head replacements, in the neutral position and rotated both ways for 20 degrees along the vertical and horizontal axes. The measurements were tested for the reliability of the deviating projections against the neutral position, and an estimate of the interobserver and intraobserver reliability was made. Statistics included a paired t test and the interclass correlation coefficient. The acromiohumeral distance and spinohumeral center method proved most reliable. The spinohumeral center method was the least sensitive for projection errors, although only applicable as a relative measure. The coracoid process base can be used as a tell-tale sign for scapular projection.     

A posterosuperior approach to the shoulder

An approach for a better surgical exposure of the posterior part the glenoid and the rotator cuff is presented as an alternative for the long deltopectoral incision that might be considered in specially selected cases. In shoulder arthroplasty, it can be used for bone grafting to reorient the glenoid, revision of a glenoid component, or repair of a large rotator cuff tear. This posterosuperior approach consists of an osteotomy of the lateral rim and posterior corner of the acromion, with reflection of part of the medial and posterior insertion of the deltoid muscle. A special plate is used for stable fixation of the osteotomy. The method has been used since 1994 for shoulder prosthesis insertion in 79 patients. In 72 patients with a total shoulder or hemiarthroplasty, the cuff was attenuated or ruptured in 24 and could be repaired in 22. Twenty-two patients underwent a bony procedure to reorient the glenoid surface. The average correction of the superior tilt was 7 degrees . The external rotators are released from the bone and reattached, which might result in weakening of external rotation. This possible complication could not be confirmed at follow-up. The osteotomy healed in all but 1 patient. The fixation material had to be removed in 13.     

Effects of CRL 41034 on the adrenergic neuroeffector interaction in the canine saphenous vein

Experiments were designed to determine the effect of CRL 41034, a buflomedil analogue, on the adrenergic responsiveness of canine veins. Rings of saphenous vein (without endothelium) were suspended for isometric tension recording in modified Krebs-Ringer bicarbonate solution at 37 degrees C. CRL 41034 produced a concentration-dependent inhibition of the contractions evoked by the alpha adrenergic agonists norepinephrine, phenylephrine and UK 14304 which was insensitive to the blockade of neuronal uptake by cocaine. CRL 41034 was more potent in inhibiting the concentration-dependent contractions evoked by UK 14304 than those by phenylephrine and the antagonism it caused against the response to UK 14304 fulfilled the criteria for competitivity. CRL 41034, at 10(-5) M significantly depressed, and at 10(-4) M abolished the contractions induced by electrical stimulation of the adrenergic nerves and those evoked by the indirect sympathomimetic amine tyramine. Strips of canine saphenous vein were superfused after incubation with [3H] norepinephrine. During sympathetic nerve activation, CRL 41304 increased the stimulation-evoked overflow of [3H] norepinephrine and 3-methoxy-4-dihydroxyphenylglycol; in the presence of rauwolscine the compound only increased the stimulation-evoked overflow of 3,4-dihydroxyphenylglycol. These experiments suggest that the major vascular effects of CRL 41034 in canine veins are blockade of alpha 2-adrenoceptors on vascular smooth muscle, and inhibition of prejunctional alpha 2-adrenoceptors on adrenergic nerve endings.     

Antioxidant action of Vaccinium myrtillus extract on human low density lipoproteins in vitro: initial observations

Summary— Oxidative modifications of low density lipoproteins (LDL) are now recognised as one of the major processes in atherogenesis. Various drugs, as well as a number of natural products, have been proposed to inhibit such processes. Among the naturally-occurring constituents of plants which appear to possess antioxidant activity are polyphenolic compounds such as flavonoids. The aqueous extract of Vaccinium myrtillus is rich in such molecules. In this report, we describe the in vitro antioxidative potential of this extract on human LDL. The copper-induced oxidative modification of these lipoproteins was assessed using 1) measurement of oxidative resistance as determined by the lag-phase preceding conjugated diene formation; 2) quantification of the amount of lipoperoxides and thiobarbituric acid-reactive substances generated, and measurement of the modification in the net negative electrical charge of the lipoproteins, over a 7-hour time course experiment. Trace amounts of V myrtillus extract (15 to 20 μg/mL) induce statistically significant changes in the oxidation behaviour of LDL, which include 1) prolongation of the lag-phase of conjugated diene production ( P < 0.01); 2) reduction in the formation of lipoperoxides and of thiobarbituric acid-reactive substances up to 7 hours and especially between 1 and 5 hours ( P < 0.01); and 3) inhibition of modification in the net negative charge of LDL. These results demonstrate that V myrtillus extract exerts potent protective action on LDL particles during in vitro copper-mediated oxidation. Calculation of IC₅₀ values indicates that, on a molar basis, this extract may indeed be more potent than either ascorbic acid or butylated hydroxytoluene in the protection of LDL particles from oxidative stress.