Unusual Combination of Holt‐Oram Syndrome and Persistent Left Superior Vena Cava

Holt‐Oram (HO) is a syndrome characterized by congenital cardiovascular malformations, specifically atrial and ventricular septal defects, and skeletal abnormalities of the upper limbs bones. Associations of HO cardiac disorders with other congenital cardiac malformations, specifically persistent left superior vena cava (PLSVC) are rarely reported and its real incidence is unknown. We present a case of this unusual combination in a patient undergoing cardiac resynchronization therapy (CRT) device implant. Methods and Results. A 63‐year‐old male with HO and a history of repaired atrial septal defect was presented for implantable cardioverter defibrillator (ICD) upgrade to CRT. The old implant was located in the right prepectoral area. The old device pocket in the right was accessed and a venous access to the right subclavian vein was obtained. The coronary sinus (CS) was easily cannulated and a long sheath advanced into the CS. A contrast injection revealed an unusually big‐sized CS, with a diameter 2.5 times the fully deployed balloon. A 0.035 wire was advanced retrograde reaching the confluence of the innominate and left subclavian veins. The outer sheath was advanced to this location and contrast venography through the sheath allowed visualization of the left jugular and subclavian veins and visualization of the PLSVC draining into the CS. No target veins for lead implant were identified. The patient was referred for surgical implant of an epicardial lead. Transesophageal echocardiogram showed a CS identified as an unusually big vascular structure located between the left atrium and the left atrial appendage. Conclusion. We report an uncommon association of HO and PLSVC. This association was only reported twice in the past and this is the first one that constitutes a casual finding during the attempt of CRT device implant. This is a combination that may complicate a device implant and recognition of it in advance may avoid performing potentially unsuccessful procedures.     

Cutaneous pseudolymphoma: an unusual eyelid presentation

Pseudolymphoma is an inflammatory response to known or unknown stimuli that results in a lymphomatous-appearing but benign accumulation of inflammatory cells. Resemblance to lymphoma is usually most apparent histologically. Most cases are idiopathic. Approximately three-quarters of cases of cutaneous pseudolymphoma are localized with the most common site on the face (70%), chest, and upper extremities. We would like to report an unusual eyelid presentation of cutaneous pseudolymphoma, not previously reported. It is therefore important to consider cutaneous pseudolymphoma as a differential diagnosis of eyelid lesions.     

A recessive major gene controls the mitsuda reaction in a region endemic for leprosy

BACKGROUND: Leprosy is a chronic infectious disease caused by Mycobacterium leprae. The Mitsuda reaction is a delayed granulomatous skin reaction elicited by intradermal injection of heat-killed M. leprae. Interestingly, results of the Mitsuda test are positive in the majority of individuals, even in areas not endemic for M. leprae. Like leprosy, the Mitsuda reaction is thought to be genetically controlled, but its mode of inheritance is unknown, although the role of the NRAMP1 gene has previously been reported. METHODS: We conducted a segregation analysis of quantitative Mitsuda reactivity in 168 Vietnamese nuclear families ascertained through patients with leprosy. RESULTS: We found strong evidence (P<10-9) for a major gene controlling the Mitsuda reaction independently of leprosy clinical status. Subsequent linkage analysis showed that this major gene was distinct from NRAMP1. Under the major-gene model, approximately 12% of individuals are homozygous for the recessive predisposing allele and are predicted to display high levels of Mitsuda reactivity (mean, approximately 10 mm, versus 5 mm in other individuals). CONCLUSION: We provide evidence that the Mitsuda reaction is controlled by a major gene. Our study paves the way for the identification of this gene and should provide novel insight into the mechanisms involved in granuloma formation, especially in M. leprae infection.     

Safety and immunogenicity of an HIV subtype B and E prime-boost vaccine combination in HIV-negative Thai adults

ALVAC-HIV (vCP1521) and AIDSVAX B/E were evaluated in a phase 1/2 trial of human immunodeficiency virus (HIV)-negative Thai adults. Of 133 volunteers enrolled, 122 completed the trial. There were no serious vaccine-related adverse events, nor were there intercurrent HIV infections. Lymphoproliferative responses to glycoprotein 120 E were induced in 63% of the volunteers, and HIV-specific CD8 cytotoxic T lymphocyte responses were induced in 24%. Antibody responses increased in frequency and magnitude in association with the dose level of AIDSVAX B/E. Binding and neutralizing antibodies to the MN strain were induced in 100% and 98%, respectively, of the volunteers receiving 600 microg of AIDSVAX B/E, and such antibodies to E strains were induced in 96% and 71%, respectively, of these volunteers. This vaccine combination was well tolerated and was immunogenic, meeting milestones for advancement to phase 3 evaluation.     

Anti-GAD antibodies in Chinese patients with youth and adult-onset IDDM and NIDDM

Summary An autoimmune basis for the pathogenesis of insulin-dependent diabetes mellitus (IDDM) is supported by the frequent presence of autoantibodies – islet cell antibodies (ICAs) and GAD antibodies (GADab). However, in Chinese patients with clinical IDDM, a low prevalence of ICAs was observed. In non-insulin-dependent diabetic (NIDDM) patients, it has been suggested that the presence of GADab may identify a subset of latent autoimmune diabetes in adults (LADA). We determined the frequency of GADab in a large group of 134 IDDM and 168 NIDDM Chinese patients, and assessed the relation with ICAs status. Results showed that 39.6 % IDDM and 16.1 % NIDDM patients had GADab, and 20.1 % and 4.8 %, respectively had detectable ICAs. Frequency of GADab positivity was not influenced by whether the patients had youth or adult-onset IDDM or NIDDM, or by duration of diabetes. NIDDM patients seropositive for GADab shared similar clinical characteristics and fasting C-peptide levels with those who were GADab negative. Presence of GADab therefore did not serve to identify a sub-group of patients with latent or slow-onset IDDM. Half (53 %) of our IDDM patients had neither GADab nor ICAs. The reason for this observation is unclear. One theory is that other autoantigens yet to be identified may be contributory. Alternatively, in the Chinese, autoimmunity may not be the major factor in the pathogenesis of IDDM. [Diabetologia (1997) 40: 1425–1430] Received: 11 March 1997 and in revised form: 13 May 1997     

Early-outgrowth bone marrow cells attenuate renal injury and dysfunction via an antioxidant effect in a mouse model of type 2 diabetes

Cell therapy has been extensively investigated in heart disease but less so in the kidney. We considered whether cell therapy also might be useful in diabetic kidney disease. Cognizant of the likely need for autologous cell therapy in humans, we sought to assess the efficacy of donor cells derived from both healthy and diabetic animals. Eight-week-old db/db mice were randomized to receive a single intravenous injection of PBS or 0.5 × 10(6) early-outgrowth cells (EOCs) from db/m or db/db mice. Effects were assessed 4 weeks after cell infusion. Untreated db/db mice developed mesangial matrix expansion and tubular epithelial cell apoptosis in association with increased reactive oxygen species (ROS) and overexpression of thioredoxin interacting protein (TxnIP). Without affecting blood glucose or blood pressure, EOCs not only attenuated mesangial and peritubular matrix expansion, as well as tubular apoptosis, but also diminished ROS and TxnIP overexpression in the kidney of db/db mice. EOCs derived from both diabetic db/db and nondiabetic db/m mice were equally effective in ameliorating kidney injury and oxidative stress. The similarly beneficial effects of cells from healthy and diabetic donors highlight the potential of autologous cell therapy in the related clinical setting.     

R-spondin3 prevents mesenteric ischemia/reperfusion-induced tissue damage by tightening endothelium and preventing vascular leakage

Inflammation and vascular injury triggered by ischemia/reperfusion (I/R) represent a leading cause of morbidity and mortality in a number of clinical settings. Wnt and its homolog partners R-spondins, in addition to regulating embryonic development have recently been demonstrated to serve as wound-healing agents in inflammation-associated conditions. Here we ask whether R-spondins could prevent inflammation-associated tissue damage in ischemic disorders and thus investigate the role of R-spondin3 (R-spo3) in a mouse model of mesenteric I/R. We demonstrate that R-spo3 ameliorates mesenteric I/R-induced local intestinal as well as remote lung damage by suppressing local and systemic cytokine response and deposition of IgM and complement in intestinal tissues. We also show that decreased inflammatory response is accompanied by tightening of endothelial cell junctions and reduction in vascular leakage. We conclude that R-spo3 stabilizes endothelial junctions and inhibits vascular leakage during I/R and thereby mitigates the inflammatory events and associated tissue damage. Our findings uniquely demonstrate a protective effect of R-spo3 in I/R-related tissue injury and suggest a mechanism by which it may have these effects.     

Deletion of microRNA-155 reduces autoantibody responses and alleviates lupus-like disease in the Faslpr mouse

MicroRNA-155 (miR-155) regulates antibody responses and subsequent B-cell effector functions to exogenous antigens. However, the role of miR-155 in systemic autoimmunity is not known. Using the death receptor deficient (Fas^lpr) lupus-prone mouse, we show here that ablation of miR-155 reduced autoantibody responses accompanied by a decrease in serum IgG but not IgM anti-dsDNA antibodies and a reduction of kidney inflammation. MiR-155 deletion in Fas^lpr B cells restored the reduced SH2 domain-containing inositol 5′-phosphatase 1 to normal levels. In addition, coaggregation of the Fc γ receptor IIB with the B-cell receptor in miR-155^−/−-Fas^lpr B cells resulted in decreased ERK activation, proliferation, and production of switched antibodies compared with miR-155 sufficient Fas^lpr B cells. Thus, by controlling the levels of SH2 domain-containing inositol 5′-phosphatase 1, miR-155 in part maintains an activation threshold that allows B cells to respond to antigens.MicroRNA-155 (miR-155) plays a critical role in the generation of effective antibody responses to exogenous antigenic challenges in mice (1–3). MiR-155 levels have been reported to be elevated in B but low in T cells from patients with systemic lupus erythamosus (4), yet it is not known whether miR-155 controls autoimmune responses and the expression of related pathology.Mice harboring ubiquitous or B-cell-specific ablation of the death receptor Fas develop a severe lupus-like disease. B-cell-specific deletion of the death receptor (fas^−/−) fas^−/− mice develop an excessive germinal center (GC)-derived IgG autoantibody deposition in their kidneys and succumb to renal failure (5). It has been suggested that loss of tolerance in lpr mice results from the down-regulation of the low-affinity IgG inhibitory receptor FcγRIIB (Fc γ receptor IIB), thereby rendering their B cells incapable of terminating stimulatory signals delivered by autoantigen-containing immune complexes (6–8). However, the mechanisms whereby lack of FcγRIIB engagement would lead to autoimmunity, and whether additional factors contribute to autoimmunity, are still unclear.The SH2 domain-containing inositol 5′-phosphatase 1 (SHIP-1) phosphatase acts downstream of inhibitory cell-surface receptors (9–12), including the FcγRIIB, which is essential in opposing B-cell activation signals in mice and humans (13, 14). FcγRIIB inactivation has been implicated in the development of autoreactive GC B cells and plasma cells (15), as well as in the regulation of the persistence and longevity of bone marrow plasma cells (16). After coligation of the FcγRIIB with the B-cell receptor (BCR), FcγRIIB recruits SHIP-1 to the plasma membrane, where it negatively regulates cell survival, Ca²⁺-dependent effector functions, and ERK activation, thus controlling cell proliferation, anergy, and apoptosis (17–23). As a consequence of these wide-ranging activities, germ-line or B-cell-specific deletion of FcγRIIB or SHIP-1 in mice results in a severe lupus-like disease characterized by high-titer serum IgG antinuclear autoantibodies, lymphadenopathy, splenomegaly, renal failure, and increased mortality (23–27). MiR-155 has been reported to regulate SHIP-1 expression in mammalian myeloid and malignant B cells (28–31). However, it is not known whether SHIP-1 regulation by miR-155 affects GC reactions or peripheral tolerance during a protective immune response or in an autoimmune environment, such as that in Fas^lpr mice.To understand the role of miR-155 in autoimmunity, we crossed Fas^lpr mice with our bic/miR-155^−/− mice to generate miR-155^−/−-Fas^lpr animals. Here we demonstrate that deletion of miR-155 reduced serum IgG but not IgM anti-dsDNA autoantibody levels and kidney damage. Further, we show that the absence of miR-155 derepresses the expression of SHIP-1, thus mitigating B-cell activation, proliferation, and autoimmune responses. We provide evidence that miR-155 could be targeted to control autoimmunity and lupus nephritis.     

In vivo ultrasound modulated optical tomography with a persistent spectral hole burning filter

We present in vivo ultrasound modulated optical tomography (UOT) results on mice, using the persistent spectral hole burning (PSHB) effect in a Tm³⁺:YAG crystal. Indocyanine green (ICG) solution was injected as an optical absorber and was clearly identified on the PSHB-UOT images, both in the muscle (following an intramuscular injection) and in the liver (following an intravenous injection). This demonstration also validates an experimental setup with an improved level of performance combined with an increased technological maturity compared to previous demonstrations.