Load transfer in tilted implants with varying cantilever lengths in an all‐on‐four situation

Background: The aim of this study was to evaluate if tilting of the distal implant at different angulations (30° and 40°) with different cantilever lengths (4 mm and 12 mm) affects the stress and strain distribution in an ‘all‐on‐four’ situation. Methods: A completely edentulous mandible was modelled with four tapered implants placed within the interforaminal region to receive an all acrylic fixed prosthesis. The two posterior implants were tilted at an angle of 30° and 40°. The prosthesis cantilever was given two different variables of 4 mm and 12 mm. For all models, the equivalent von Mises stress and strain was analysed using three‐dimensional finite element analysis. Results: Statistical significance (p < 0.05) was seen when a comparison was made for the stress developed on the implant and cortical bone between the 30° and 40° distally tilted posterior implants in both situations. No significance was seen in the trabecular bone and on the strain developed in these situations. Conclusions: The study shows that increasing the tilt of the distal implants does not increase the stress significantly. It also shows that the architecture of the mandible plays a major role during treatment planning of a completely edentulous patient.     

Human podocytes adhere to the KRGDS motif of the alpha3alpha4alpha5 collagen IV network

Podocyte adhesion to the glomerular basement membrane is required for proper function of the glomerular filtration barrier. However, the mechanism whereby podocytes adhere to collagen IV networks, a major component of the glomerular basement membrane, is poorly understood. The predominant collagen IV network is composed of triple helical protomers containing the alpha3alpha4alpha5 chains. The protomers connect via the trimeric noncollagenous (NC1) domains to form hexamers at the interface. Because the NC1 domains of this network can potentially support integrin-dependent cell adhesion, it was determined whether individual NC1 monomers or alpha3alpha4alpha5 hexamers support podocyte adhesion. It was found that, although human podocytes did not adhere to NC1 domains proper, they did adhere via integrin alphavbeta3 to a KRGDS motif located adjacent to alpha3NC1 domains. Because the KRGDS motif is a site of phosphorylation, its interactions with integrin alphavbeta3 may play a critical role in cell signaling in physiologic and pathologic states.     

Carotid artery stump pressure and associated neurological changes in predominantly symptomatic carotid artery disease patients undergoing awake carotid endarterectomy

Aim

To determine the mean carotid artery stump pressure (SP) at which patients develop neurological changes while undergoing awake carotid artery endarterectomy (CEA) under cervical block anaesthesia (CBA).

Methods

A prospective analysis was carried out of patients undergoing awake CEA under CBA between February 2004 and April 2007. All patients had mean SP measured, with selective shunting on those who developed neurological symptoms on carotid artery clamping regardless of stump pressure. A ball connected to a pressure sensor was put in the patient’s contra-lateral hand.

Results

Fifty-nine patients had awake CEA, 40 were males with a mean age of 64 years. Indications for CEA were asymptomatic high-grade stenosis in 12 (20%) patients and symptomatic stenosis in 47 (80%). Seven (12%) patients required shunting, one for transient ischaemic attack (TIA) and six for loss of consciousness. Six of these patients had presented with symptomatic disease.Taking the threshold of mean carotid SP of 50 mmHg as an indication for shunting, 22% (6/27) of patients with a mean SP of < 50 mmHg required shunting and only 3% (1/32) with a mean carotid SP of > 50 mmHg needed a shunt. This was not statistically significant. Using a mean carotid SP of ≤ 40 mmHg as the threshold for shunting, 40% (4/10) of patients required shunting and 3% (1/31) with a mean carotid SP of > 40 mmHg required shunting. This was statistically significant. Thirteen (22%) patients were complicated by transient hoarseness of voice. One (2%) had a haematoma that required re-exploration. None of these patients had any major postoperative neurological or cardiological complications.

Conclusion

Even though the sample in this study was small, awake CEA under local anaesthesia was seen as a safe procedure. It would appear to be safe to use the mean SP of 40 mmHg as a threshold for selective shunting in CEA under general anaesthesia.     

The HLA-DRB1*15:01–Restricted Goodpasture’s T Cell Epitope Induces GN

Human anti-glomerular basement membrane (GBM) disease strongly associates with HLA-DRB1*15:01. The target autoantigen in this disease is the noncollagenous domain of the α3 chain of type IV collagen, α3(IV)NC1, but critical early T cell epitopes presented by this human MHC class II molecule are unknown. Here, by immunizing HLA-DRB1*15:01 transgenic mice with whole recombinant α3(IV)NC1 and with overlapping α3(IV)NC1 peptides, we defined a HLA-DRB1*15:01–restricted α3(IV)NC1 T cell epitope (α3_136–146) with four critical residues. This peptide was not immunogenic in HLA-DRB1*01:01 transgenic or C57BL/6 mice. The T cell epitope is naturally processed from α3(IV)NC1. CD4⁺ T cell clones, generated from HLA-DRB1*15:01 transgenic mice and specific for α3_136–146, transferred disease into naive HLA-DRB1*15:01 transgenic mice, evidenced by the development of necrotizing crescentic GN, albuminuria, renal impairment, and accumulation of CD4⁺ T cells and macrophages in glomeruli. Because Fcγ receptors are implicated in disease susceptibility, we crossed HLA transgenic mice onto an FcγRIIb-deficient background. Immunization with either α3_136–146 or α3(IV)NC1 induced GN in HLA-DRB1*15:01 transgenic FcγRIIb-deficient mice, but HLA-DRB1*01:01 transgenic FcγRIIb-deficient mice were unaffected. Taken together, these results demonstrate that the HLA-DRB1*15:01–restricted T cell epitope α3_136–146 can induce T cell responses and injury in anti-GBM GN.Goodpasture’s disease, also known as anti-glomerular basement membrane (GBM) disease, is characterized by rapidly progressive GN with crescentic and necrotizing glomerular lesions, and in some patients, pulmonary hemorrhage. It is caused by autoreactivity to the noncollagenous domain of the α3 chain of type IV collagen, α3(IV)NC1, expressed in the GBM.^1,2 The diagnosis of anti-GBM disease is made by detecting serum α3(IV)NC1-reactive IgG autoantibodies, with linear IgG deposition in glomeruli.³ Treatment includes immunosuppressive agents and plasmapheresis to remove pathogenic autoantibodies.³ Cellular effectors also seem to play a role, based on studies in human anti-GBM disease⁴ and in experimental autoimmune anti-GBM GN.^5–9The MHC class II allele HLA-DRB1*15:01 is a key susceptibility element in anti-GBM disease.¹⁰ It confers a markedly increased relative risk for anti-GBM GN (odds ratio, 8.5; 95% confidence interval, 5.5–13.1). Most other HLA-DR alleles do not predispose people to developing anti-GBM disease and may even be protective (e.g., HLA-DRB1*01:01 [odds ratio, 0.6; 95% confidence interval, 0.3–1.0]). The strong HLA-DRB1*15:01 association and the accuracy of diagnostic criteria allow meaningful studies on how the MHC II molecule confers risk in mechanistic terms.Key human B cell epitopes in anti-GBM disease have been defined. Autoantibodies bind to the conformational α3(IV)NC1 epitopes “E_A” α3_17–31 and “E_B” α3_127–141 (all amino acid numbering, including other cited epitopes, follows Netzer et al.).¹¹ Studies examining T cell epitopes in human anti-GBM disease are less common, although an important study showed reactivity to two peptides, α3_68–89 and α3_129–148 (close to the E_B autoantibody epitope), in all six patients studied.¹² However, in the Wistar Kyoto (WKY) rat, T cell reactivity occurs in several different areas.^13–15 T cell–mediated disease can be induced by α3_14–26 and α3_11–25^15–17 and there is evidence of epitope spreading to involve B cell epitopes.^16,18Our hypothesis was based on studies in humans with anti-GBM GN showing strong MHC II association and suggesting key epitopes. We hypothesized that either the regions in or around α3_68–89 or α3_129–148 (or both) would be immunogenic in the context of HLA-DRB1*15:01 but not other MHC II molecules, and could be defined as nephritogenic CD4⁺ T cell epitopes. Therefore, HLA-DRB1*15:01 would permit binding of one or both of these peptides at an appropriate avidity, allowing naïve autoreactive CD4⁺ cells to escape negative selection in the thymus, thus explaining why people who express HLA-DRB1*15:01 are more susceptible to anti-GBM GN. We studied mice that were entirely deficient in mouse MHC II,^19,20 but that coexpressed the essentially nonpolymorphic HLA-DRA1*01:01, with either HLA-DRB1*15:01 or DRB1*01:01. HLA transgenic mice, especially those lacking all murine MHC II elements,¹⁹ have been powerful tools in studying the pathogenesis of autoimmune disease,^20,21 because their CD4⁺ T cell repertoire is shaped by the presence of human (but not mouse) MHC II molecules. We found that in anti-GBM GN, α3_136–146 is an immunodominant and nephritogenic CD4⁺ T epitope in DRB1*15:01 Tg mice, but not in DRB1*01:01 Tg or C57BL/6 mice. Importantly, CD4⁺ responses to this epitope induce severe anti-GBM GN.     

Identification of Novel ROR2 Gene Mutations in Indian Children with Robinow Syndrome

Ob­jec­ti­ve: Robinow syndrome (RS) is an extremely rare genetic disorder characterized by short-limbed dwarfism, defects in vertebral segmentation and abnormalities in the head, face and external genitalia. Mutations in the ROR2 gene cause autosomal recessive RS (RRS) whereas mutations in WNT5A are responsible for the autosomal dominant (AD) form of RS. In AD Robinow patients, oral manifestations are more prominent, while hemivertebrae and scoliosis rarely occur and facial abnormalities tend to be milder.Methods: Three unrelated patients from different parts of India were studied. These patients were diagnosed as RRS due to presence of characteristic fetal facies, mesomelia, short stature, micropenis, hemivertebrae and rib abnormalities. One of the patients had fetal facies and micropenis but unusually mild skeletal features. This patient’s mother had mild affection in the form of short stature and prominent eyes. Testosterone response to human chorionic gonadotropin was investigated in two patients and were normal. The exons and exon-intron boundaries of the ROR2 gene were sequenced for all probands. Bioinformatics analysis was done for putative variants using SIFT, PolyPhen2 and Mutation Taster.Results: Patients 1, 2 and 3 were homozygous for c.G545A or p.C182Y in exon 5, c.227G>A or p.G76D in exon 3 and c.668G>A or p.C223Y in exon 6 respectively. Prenatal diagnosis could be performed in an ongoing pregnancy in one family and the fetus was confirmed to be unaffected. Conclusion: ROR2 mutations were documented for the first time in the Indian population. Knowledge of the molecular basis of the disorder served to provide accurate counseling and prenatal diagnosis to the families.     

PROTEIN KINASE C AND TRANSMITTER RELEASE

1. Protein kinase C (PKC) is an important second messenger-activated enzyme. In noradrenergic nerves it appears to be tonically activated by diacylglycerol (DAG) to facilitate transmitter release and the steps in this involve activation of phospholipase C, generation of DAG and activation of PKC. It is suggested that the subsequent facilitation of transmitter release is due to the phosphorylation of proteins involved in the release process distal to Ca²⁺entry, presumably those involved in vesicle dynamics. 2. There are differences between central noradrenergic neurons and sympathetic nerves. In central neurons PKC appears to be tonically active and its inhibition results in a decrease in noradrenaline release under most, if not all, conditions. 3. In sympathetic nerves PKC inhibitors only decrease transmitter release during high-frequency stimulation and not during low-frequency stimulation. At high frequency there is a gradual increase in the effect of PKC inhibitors on transmitter release during the first 15 s of a stimulation train. It is suggested that this is due to a progressive rise in intracellular Ca²⁺ and a consequent activation of PKC. 4. Activation of PKC by phorbol esters produces a large enhancement in action potential-evoked noradrenaline release in both the central nervous system and in peripheral tissues. The structural requirements of the phorbol esters for maximal effect suggest that the phorbol esters must access the interior of the nerve terminal to activate PKC and the neural membrane acts as a barrier for highly lipophilic phorbol esters, thereby reducing their activity. Activation of PKC represents one of the most powerful ways to enhance transmitter release and may have therapeutic potential.     

血清白细胞介素-8与溃疡性结肠炎的关系

背景:炎症细胞因子在溃疡性结肠炎（UC）的发病中可能起一定作用。目的:检测UC患者的血清白细胞介素（IL）-8含量,并分析其与UC病变范围、病变程度和复发与否的关系。方法:收集64例经内镜检查证实的UC患者的血清标本,用酶联免疫吸附测定（ELISA）检测IL-8含量,并与正常对照组进口比较。结果:UC患者的血清IL-8含量为685pg/ml±790pg/ml,正常对照组为25pg/ml±21pg/ml（P<0.000）。不同病变范围UC的血清IL-8含量分别为:愈合期病变289pg/ml±373pg/ml,直肠病变499pg/ml±736pg/ml,直乙状结肠病变686pg/ml±755pg/ml,左半结肠病变 1407pg/ml±846pg/ml,全结肠病变815 pg/ml±926pg/ml;左半结肠病变者的IL-8含量最高,与愈合期和直肠病变者相比有显著差异（P<0.01）。不同病咎程度UC的血清IL-8含量分别为:0级267pg/ml±364pg/ml,1级332pg/ml±418pg/ml,2级999pg/ml±943pg/ml,3级894pg/ml±851pg/ml;2级和3级病变者的含量较0级和1级病变者明显增高（P<0.05和P<0.01）,0级者的含量亦高于正常对照组（P<0.01）。初发患者的血清IL-8含量为758pg/ml±833pg/ml,与复发患者（696pg/ml±803pg/ml）相比无显著差异（p=0.77）。19例患者在正规5-氨基水杨酸（5-ASA）制剂治疗前后分别测定了血清IL-8含量,治疗前的IL-8含