Cytokine Gene Polymorphisms Associating With Severe Acute Graft-Versus-Host Disease in HLA-Identical Sibling Transplants

It is now well known that the initial phase of graft-versus-hostdisease (GVHD) involves cytokine release during preconditioning of therecipient of an allogeneic bone marrow transplant (BMT). Tumor necrosisfactor (TNF), in particular, has been implicated in pathologicaldamage and is released pretransplant due to irradiation and cytotoxicpreconditioning regimens. Interleukin-10 (IL-10), a naturalimmunosuppressant of TNF , may be involved in downregulation ofthese responses, which may be an individual patient-specific effect. Inthis study, we determined the genotype for polymorphisms associatedwith TNF and IL-10 in 80 potential allo-BMT recipients andcorrelated the genotype with the severity of GVHD in 49 patients forwhom clinical data relating to GVHD was available. The widely studiedTNF 308 polymorphism does not show any significantassociations, but the d3 homozygous allele of the TNFd microsatelliteis preferentially associated with grade III/IV GVHD (7 of 11 patients)compared with its occurrence in 8 of 38 patients with grade 0/II GVHD(P = .006). Alleles of the IL-10 1064 promoterregion microsatellite polymorphism that possess greater numbers ofdinucleotide (CA) repeats also significantly associate with more severeGVHD. This region has been demonstrated to be important in theregulation of the IL-10 promoter. Eighteen of 38 patients with grade0-II GVHD possessed alleles with greater numbers (12 or more) ofdinucleotide repeats, compared with 9 of 11 cases with grade III-IVGVHD (P < .02). Of the 38 patients with grade 0-II GVHD, 3 of38 had a both TNFd3/d3 and IL-10 (12-15) genotype,compared with 6 of 11 patients with grade III-IV GVHD (P < .001). There was no association of either the TNFd or IL-10 microsatellite polymorphisms with mortality (P = .43 and .51, respectively). Our results suggest that patient cytokine gene polymorphism genotypes may influence GVHD outcome by affecting cytokineactivation during the pretransplant conditioning regimens, and theseresults are the first to suggest a genetic predisposition to thisimportant transplant-related complication.     

Presence of autoantibodies to interleukin-8 or neutrophil-activating peptide-2 in patients with heparin-associated thrombocytopenia

Eighty-seven patients with heparin-associated thrombocytopenia (HAT) showed either a positive heparin platelet aggregometry test result and/or the presence of antibodies to heparin-platelet factor 4 (H-PF4) complexes by enzyme-linked immunosorbent assay (ELISA). Fifteen of these patients lacked antibodies to H-PF4, and plasma from these patients was analyzed for the presence of antibodies to PF4-related chemokines, Neutrophil-activating peptide-2 (NAP-2) and interleukin-8 (IL-8). Of these 15 patients, 6 showed antibodies to IL-8 and 3 to the platelet basic protein (PBP)-derived protein, NAP-2. Antibodies to IL-8 and NAP-2 were not observed in control patients (n = 38), patients with HAT and H-PF4 autoantibodies (n = 72), patients with autoimmune diseases (n = 21), or patients with non-HAT thrombocytopenia (n = 30). Five of these nine patients with anti-IL-8 or anti-NAP-2 developed thrombosis during heparin treatment, which is not statistically different from the patients with H-PF4 antibodies. The existence of autoantibodies to IL-8 and NAP-2 in HAT patients highlights the significance of chemokines in the pathogenesis of HAT. The contribution of heparin in vitro was minimal in patients with anti-IL-8 and anti-NAP- 2 antibodies, suggesting a biologic difference from the majority of patients with HAT and anti-PF4 antibodies. It may be that antibodies to IL-8 and NAP-2 have weaker affinity for heparin and that the ELISA system may not reflect in vivo heparin-chemokine complex formation. Alternatively, antichemokine autoantibodies may predate heparin exposure, and the role of heparin in initiating HAT may be to mobilize the chemokines and to target them to platelets, neutrophils, or endothelial cells. Subsequent chemokine-binding autoantibodies then lead to cell activation resulting in thrombocytopenia and thrombosis.     

Growth and development of ventricular walls in complete transposition of the great arteries with intact septum (simple transposition)

A morphometric assessment of the ventricles was made in a series of 31 normal hearts and in 69 hearts with complete transposition of the great arteries and intact septum (simple transposition). Specimens representing different age groups were compared in order to investigate the development of the ventricular walls during infancy and early childhood.In the series of normal hearts the left ventricular wall was always thicker than the right ventricular wall when related to both age and body weight. The increase in thickness of the left ventricular wall showed some linear correlation with both increasing age and weight; that of the right ventricular wall did not. In the hearts with simple transposition, the mean thickness of the left ventricular wall was similar to that of the normal wall at birth, but thereafter the rate of increase was less than normal. There was no linear relation between increasing wall thickness and either age or weight. The thickness of the right ventricular wall (already significantly greater than normal at birth) showed a weak linear relation with increasing age but not with body weight. Right ventricular muscle volume index was higher than that of the normal heart but right ventricular cavity volume index was not increased. Left ventricular cavity volume index increased with age, but muscle volume showed no difference from the normal.At birth the left ventricle in simple transposition is in some respects morphologically better adapted than the right ventricle to support the systemic circulation. However, increase in cavity size and failure of the wall thickness to develop may prevent the left ventricle from supporting the systemic circulation after the 1st months of life. The right ventricle in transposition, although structurally unsuited to support the systemic circulation, is able to adapt by increasing wall thickness, at least in early life.     

Engineered cartilage generated by nasal chondrocytes is responsive to physical forces resembling joint loading

OBJECTIVE: To determine whether engineered cartilage generated by nasal chondrocytes (ECN) is responsive to different regimens of loading associated with joint kinematics and previously shown to be stimulatory of engineered cartilage generated by articular chondrocytes (ECA). METHODS: Human nasal and articular chondrocytes, harvested from 5 individuals, were expanded and cultured for 2 weeks into porous polymeric scaffolds. The resulting ECN and ECA were then maintained under static conditions or exposed to the following loading regimens: regimen 1, single application of cyclic deformation for 30 minutes; regimen 2, intermittent application of cyclic deformation for a total of 10 days, followed by static culture for 2 weeks; regimen 3, application of surface motion for a total of 10 days. RESULTS: Prior to loading, ECN constructs contained significantly higher amounts of glycosaminoglycan (GAG) and type II collagen compared with ECA constructs. ECN responded to regimen 1 by increasing collagen and proteoglycan synthesis, to regimen 2 by increasing the accumulation of GAG and type II collagen as well as the dynamic modulus, and to regimen 3 by increasing the expression of superficial zone protein, at the messenger RNA level and the protein level, as well as the release of hyaluronan. ECA constructs were overall less responsive to all loading regimens, likely due to the lower extracellular matrix content. CONCLUSION: Human ECN is responsive to physical forces resembling joint loading and can up-regulate molecules typically involved in joint lubrication. These findings should prompt future in vivo studies exploring the possibility of using nasal chondrocytes as a cell source for articular cartilage repair.     

Use of alveolar distraction osteogenesis for implant placement: a case report with eight‐year follow‐up

Insufficient alveolar ridge width may impede the success of dental implants. Techniques for resolving this problem include autologous bone grafts, guided bone regeneration, bone splitting and bone spreading techniques. Recently, alveolar distraction osteogenesis has become an alternative method for alveolar augmentation. We propose the use of alveolar bone distraction for insufficient alveolar ridge width. A healthy 33‐year‐old female presented with missing teeth to our clinic. Clinical and radiographic examination revealed the alveolar ridge was too narrow for placement of dental implants. Therefore, horizontal distraction osteogenesis of the posterior mandibular ridge was chosen for augmentation. Two months later, two implants were placed. No significant marginal bone resorption was seen around the implants eight years after placement. Our results indicate that horizontal alveolar distraction is recommended to increase ridge width and allow placement of standard dental implants.     

Cyclic adenosine monophosphate and human gastric acid secretion

This report concerns gastric juice, plasma, and urinary levels of adenosine 3, 5-monophosphate (cAMP) in 27 subjects undergoing routine gastric analysis under maximum stimulation with betazole or pentagastrin. Cyclic AMP was measured by sensitive and specific radioimmunoassay. No increase in concentration of cAMP was noted in gastric juice, plasma, or urine following either betazole or pentagastrin stimulation. Betazolestimulated human gastric acid secretion was associated with an increased cAMP output into the gastric juice (P<0.05). There was no change in cAMP output following pentagastrin stimulation. The peak acid output produced by pentagastrin and betazole was similar. The lack of increase in cAMP concentration lends support to the concept that cyclic AMP is not a primary mediator in the stimulation of gastric acid secretion by betazole or pentagastrin in the human. The physiologic significance of the increase in cAMP output following betazole stimulation remains unresolved.Supported by Bureau of Medicine and Surgery Clinical Investigation Program Project No. 2-06-322.