Lessons of organ-induced tolerance learned from historical clinical experience

Although the reductionist approach has served science well for 400 years, the accumulation of details can obscure the truth if the original premise is incorrect. One such premise has been that successful organ transplantation and bone marrow engraftment are fundamentally different outcomes involving separate and distinct mechanisms. Some historical clinical observations pointed to a different conclusion almost from the beginning and included clues about how to induce tolerance with the aid of immunosuppression.     

A novel deletion mutation in the <Emphasis Type=Italic>TUSC3</Emphasis> gene in a consanguineous Pakistani family with autosomal recessive nonsyndromic intellectual disability

Background  

Intellectual disability (ID) is a serious disorder of the central nervous system with a prevalence of 1-3% in a general population. In the past decades, the research focus has been predominantly on X-linked ID (68 loci and 19 genes for non syndromic X linked ID) while for autosomal recessive nonsyndromic ID (NSID) only 30 loci and 6 genes have been reported to date.     

Contribution of mitral valve leaflet length and septal wall thickness to outflow tract obstruction in patients with hypertrophic cardiomyopathy

We sought to examine whether elongation of the mitral valve leaflets in patients with hypertrophic cardiomyopathy (HCM) is synergistic to septal wall thickness (SWT) in the development of left ventricular outflow tract obstruction (LVOTO). HCM is a common genetic cardiac disease characterized by asymmetric septal hypertrophy and predisposition towards LVOTO. It has been reported that elongation of the mitral valve leaflets may be a primary phenotypic feature and contribute to LVOTO. However, the relative contribution of this finding versus SWT has not been studied. 152 patients (76 with HCM and 76 non-diseased age, race and BSA-matched controls) and 18 young, healthy volunteers were studied. SWT and the anterior mitral valve leaflet length (AMVLL) were measured using cine MRI. The combined contribution of these variables (SWT × AMVLL) was described as the Septal Anterior Leaflet Product (SALP). Peak LVOT pressure gradient was determined by Doppler interrogation and defined as “obstructive” if?≥?30 mmHg. Patients with HCM were confirmed to have increased AMVLL compared with controls and volunteers (p?<?0.01). Among HCM patients, both SWT and SALP were significantly higher in patients with LVOTO (N?=?17) versus without. SALP showed modest improvement in predictive accuracy for LVOTO (AUC?=?0.81) among the HCM population versus SWT alone (AUC?=?0.77). However, in isolated patients this variable identified patients with LVOTO despite modest SWT. Elongation of the AMVLL is a primary phenotypic feature of HCM. While incremental contributions to LVOTO appear modest at a population level, specific patients may have dominant contribution to LVOTO. The combined marker of SALP allows for maintained identification of such patients despite modest increases in SWT.     

Genetic analysis of four Pakistani families with achromatopsia and a novel S4 motif mutation of <Emphasis Type="Italic">CNGA3</Emphasis>

Background  

To identify the causative variants of achromatopsia (ACHM) in four Pakistani families presenting autosomal recessive ACHM.     

Chemical shift sodium imaging in a mouse model of thromboembolic stroke at 9.4 T

Purpose:

To estimate changes in the ²³Na density and in the ²³Na relaxation time T₂* in the anatomically small murine brain after stroke.

Materials and Methods:

Three‐dimensional acquisition weighted chemical shift imaging at a resolution of 0.6 × 0.6 × 1.2 mm³ was used for sodium imaging and relaxation parameter mapping. In vivo measurements of the mouse brain (n = 4) were performed 24 hours after stroke, induced by microinjection of purified murine thrombin into the right middle cerebral artery. The measurement time was 14 minutes in one mouse and 65 minutes in the other three. An exponential fit estimation of the free induction decay was calculated for each voxel enabling the reconstruction of locally resolved relaxation parameter maps.

Results:

The infarcted areas showed an increase in sodium density between 160% and 250%, while the T₂* relaxation time increased by 5%–72% compared to unaffected contralateral brain tissue.

Conclusion:

²³Na chemical shift imaging at a resolution of 0.6 × 0.6 × 1.2 mm³ enabled sodium imaging of the anatomical small mouse brain and the acquired data allowed calculating relaxation parameter maps and hence a more exact evaluation of sodium signal changes after stroke. J. Magn. Reson. Imaging 2011;. © 2011 Wiley‐Liss, Inc.     

Nutrition and quality of life following small intestinal transplantation

BACKGROUND: The outcome from small bowel transplantation (SBTx) has improved progressively over the past decade raising questions as to whether indications should be broadened from those currently followed based on "TPN (total parenteral nutrition) failure." OBJECTIVE AND METHODS: To assess current outcome, we studied the effect of transplantation on nutritional autonomy, organ function, and quality of life (QoL) measured by a validated self-administered questionnaire containing 26 domains and 130 questions, for a minimum of 12 months in a cohort of 46 consecutively transplanted patients between June 2003 and July 2004. The majority of transplanted patients (76%) had intestinal failure because of extreme short bowel, the remainder having either chronic pseudo-obstruction or porto-mesenteric vein thrombosis (PMVT). All but the PMVT patients were dependent on home TPN (HPN) (median 2, range 0-25 yr) and had developed serious recurrent infective complications with (25%) or without central vein thrombosis and liver failure. Sixty-one percent received a liver in addition to a small intestine. RESULTS: Follow-up was for a mean of 21 (range 12-36) months. Five patients died, two with chronic graft rejection. All the remaining patients have graft survival with an average of 1.2 (range 0-5) episodes of acute rejection. All patients were weaned from TPN by a median of 18 days (range 1-117 days) and from tube feeding by day 69 (range 22-272 days). There was a significant improvement in overall assessment of QoL and in 13 of 26 of the specific domains examined. CONCLUSION: Our results confirm the claim that a new era has dawned for SBTx, such that, with continued progress, it can potentially become an alternative to HPN for the management of permanent intestinal failure, rather than a last-chance treatment for "TPN failure."     

Evaluation of serum adiponectin levels in diabetic nephropathy

IntroductionDiabetic nephropathy is one of the major microvascular complications of diabetes mellitus. Adiponectin is an adipose tissue-derived cytokine that was identified in a human adipose tissue cDNA library. Serum adiponectin levels are found to be reduced in various pathological states including obesity, diabetes mellitus, ischaemic heart disease and arteriosclerosis obliterans and elevated in end stage renal diseases. Objective: to assess the level of plasma adiponectin as an early predictor of microvascular complications in patients with type 2 diabetes mellitus.Methods44 patients with type 2 diabetes recruited from outpatient diabetes clinic in Kasr Alainy hospital. All patients were subjected to full laboratory work-up including: Fasting blood glucose and Post prandial blood glucose, Glycated haemoglobin A1C, Serum creatinine, Serum total cholesterol, Triglycerides, Low density lipoprotein, High density lipoprotein, C-reactive protein titre, serum adiponectin and Urinary albumin/creatinine (UAC) ratio.ResultsThe present study demonstrated that serum adiponectin concentrations had significant positive correlation with UAC ratio (r = 0.534, p = 0.0001). Adiponectin levels showed significant positive correlation in patients with diabetes and hypertension with microalbumiuria (p = .001) or normoalbumiuria (p = 0.004).ConclusionSerum adiponectin level can be a good predictor of diabetic nephropathy in patients with type 2 diabetes mellitus.     

The role of SAP in murine CD150 (SLAM)-mediated T-cell proliferation and interferon gamma production

CD150 (signaling lymphocyte activation molecule [SLAM]) is a self-ligand cell surface glycoprotein expressed on T cells, B cells, macrophages, and dendritic cells. To further explore the role of CD150 signaling in costimulation and T(H)1 priming we have generated a panel of rat antimouse CD150 monoclonal antibodies. CD150 cell surface expression is up-regulated with rapid kinetics in activated T cells and lipopolysaccharide/interferon gamma (IFN-gamma)-activated macrophages. Anti-CD150 triggering induces strong costimulation of T cells triggered through CD3. DNA synthesis of murine T cells induced by anti-CD150 is not dependent on SLAM-associated protein (SAP, SH2D1A), because anti-CD150 induces similar levels of DNA synthesis in SAP(-/-) T cells. Antibodies to CD150 also enhance IFN-gamma production both in wild-type and SAP(-/-) T cells during primary stimulation. The level of IFN-gamma production is higher in SAP(-/-) T cells than in wild-type T cells. Anti-CD150 antibodies also synergize with interleukin 12 (IL-12) treatment in up-regulation of IL-12 receptor beta(2) mRNA during T(H)1 priming, and inhibit primary T(H)2 polarization in an IFN-gamma-dependent fashion. Cross-linking CD150 on CD4 T cells induces rapid serine phosphorylation of Akt/PKB. We speculate that this is an important pathway contributing to CD150-mediated T-cell proliferation.     

Estrogen up-regulates inducible nitric oxide synthase, nitric oxide, and cyclooxygenase-2 in splenocytes activated with T cell stimulants: role of interferon-gamma

Estrogen is implicated in many autoimmune diseases and is a robust immunomodulator. For example, it regulates interferon (IFN)-gamma, a cytokine believed to up-regulate inducible nitric oxide synthase (iNOS). A notable gap in the literature is a lack of information on the regulation of nitric oxide in immune tissues by estrogen. We now show that activation of splenocytes with T cell stimulants [concanavalin-A (Con-A) or anti-CD3 antibodies] results in copious release of nitric oxide in splenocyte cultures from estrogen-treated but not placebo-treated mice. Moreover, even a low dose of T cell stimulants induced nitric oxide in splenocytes from estrogen-treated, but not placebo-treated, mice. Con-A-activated splenocytes from estrogen-treated mice also have up-regulated iNOS mRNA, iNOS protein, and cyclooxygenase-2 (a nitric oxide-regulated downstream proinflammatory protein) when compared with controls. Our studies suggest that the induction of nitric oxide by activated splenocytes from estrogen-treated mice is mediated in part by IFNgamma. First, blocking costimulatory signals mediated through interactions of CD28 and B7 molecules by CTLA-4Ig markedly decreased not only IFNgamma but also nitric oxide. Second, estrogen treatment of IFNgamma-knockout (IFNgamma(-)/(-)) mice did not induce iNOS protein or nitric oxide. Finally, in vitro addition of recombinant IFNgamma to Con-A-activated splenocytes from IFNgamma((-)/(-)) mice induced iNOS protein primarily in estrogen-treated mice. Overall, this is the first report to show that estrogen treatment up-regulates IFNgamma-inducible-iNOS gene expression, iNOS protein, nitric oxide, and cyclooxygenase-2 as an indirect consequence of activation of T cells. These findings may have wide implications to immunity and inflammatory disorders including female-predominant autoimmune diseases.     

Value of duplex scanning in differentiating embolic from thrombotic arterial occlusion in acute limb ischemia

BackgroundManagement of acute limb ischemia (ALI) is largely based on the etiology of arterial occlusion (embolic vs. thrombotic). To our knowledge, the ability of duplex scanning to differentiate embolic from thrombotic occlusion has not been previously reported.PurposeTo determine the ability of duplex scanning to differentiate embolic from thrombotic acute arterial occlusion.MethodsWe prospectively recruited 97 patients (50.3±19.7 years; 55% males) with 107 nontraumatic ALI in native arteries. All patients underwent surgical revascularization. Preoperative duplex scan detected arterial occlusion in the following arteries: iliac (11), femoral (38), popliteal (38), infrapopliteal (3), subclavian (3), axillary (1), brachial (9), and forearm arteries (4). We measured the arterial diameters at the site of occlusion (d_occl) and at the corresponding contralateral healthy side (d_CONTRA). The difference (Δ) between the two diameters was calculated as d_OCCL?d_CONTRA. Duplex scan was also used to assess the state of the arterial wall whether healthy or atherosclerotic and the presence of calcification or collaterals. According to surgical findings, limbs were classified into embolic (E group=55 limbs) and thrombotic (T group=52 limbs) groups.ResultsBoth groups were comparable regarding age, diabetes, hypertension, smoking, atrial fibrillation, and time of presentation. The status of arterial wall at the site of occlusion and presence of calcification or collaterals were all similar in both groups. Δ in the E group was 0.95±0.92 mm vs. ?0.13±1.02 mm in the T group (P<.001). A value of ≥0.5 mm for Δ had 85% sensitivity and 76% specificity for the diagnosis of embolic occlusion (CI 0.72–0.90, P<.001), whereas a value of less than ?0.5 mm for Δ had 85% sensitivity and 76% specificity for thrombotic occlusion (CI 0.72–0.90, P<.001).ConclusionIn acute arterial occlusion, ≥0.5 mm dilatation or diminution in the occluded artery diameter is a useful duplex sign for diagnosing embolic or thrombotic occlusion, respectively.