Adult-onset deletion of Pten increases islet mass and beta cell proliferation in mice

Aims/hypothesis

Adult beta cells have a diminished ability to proliferate. Phosphatase and tensin homologue (PTEN) is a lipid phosphatase that antagonises the function of the mitogenic phosphatidylinositol 3-kinase (PI3K) pathway. The objective of this study was to understand the role of PTEN and PI3K signalling in the maintenance of beta cells postnatally.

Methods

We developed a Pten ^lox/lox; Rosa26 ^lacZ; RIP-CreER ⁺ model that permitted us to induce Pten deletion by treatment with tamoxifen in mature animals. We evaluated islet mass and function as well as beta cell proliferation in 3- and 12-month-old mice treated with tamoxifen (Pten deleted) vs mice treated with vehicle (Pten control).

Results

Deletion of Pten in juvenile (3-month-old) beta cells significantly induced their proliferation and increased islet mass. The expansion of islet mass occurred concomitantly with the enhanced ability of the Pten-deleted mice to maintain euglycaemia in response to streptozotocin treatment. In older mice (>12 months of age), deletion of Pten similarly increased islet mass and beta cell proliferation. This novel finding suggests that PTEN-regulated mechanisms may override the age-onset diminished ability of beta cells to respond to mitogenic stimulation. We also found that proteins regulating G1/S cell-cycle transition, such as cyclin D1, cyclin D2, p27 and p16, were altered when PTEN was lost, suggesting that they may play a role in PTEN/PI3K-regulated beta cell proliferation in adult tissue.

Conclusions/interpretation

The signals regulated by the PTEN/PI3K pathway are important for postnatal maintenance of beta cells and regulation of their proliferation in adult tissues.     

Abiotrophia Endocarditis in Children with No Underlying Heart Disease: A Rare but a Virulent Organism

Infective endocarditis is extremely rare in children with structurally normal hearts. The most common etiological agents are staphylococcal and streptococcal species. Nutritionally variant streptococci also classified as Abiotrophia species are a group of fastidious organisms that account for only 5% to 6% of all cases of culture‐negative infective endocarditis. Only seven cases of Abiotrophia infective endocarditis have been previously reported in children with no underlying structural heart disease. We report two cases of Abiotrophia infective endocarditis in children without any predisposing factors. Both patients presented with nonspecific symptoms leading to delay in diagnosis. While bacteriological clearance was achieved in both cases, both had a complicated course including development of brain mycotic aneurysms, splenic infarction, renal failure, and irreversible damage to the mitral valve. Both patients required surgical removal of the native mitral valve and replacement. We also present review of seven cases with similar diagnosis published previously in literature and highlight important differences. Our cases highlight special challenges in management of Abiotrophia endocarditis in pediatric patients. As the organism may not be isolated in routine culture media, may present with atypical clinical symptoms and may have a complicated course even without antibiotic failure, a high index of suspicion should be maintained in children with subacute symptoms even with no underlying structural cardiac disease.     

A case report of T cell prolymphocytic leukemia and Kaposi sarcoma and a review of T cell prolymphocytic leukemia

T cell prolymphocytic leukemia (T-PLL) is a rare mature T cell lymphoproliferative disease. It has been associated with an aggressive course, a poor response to conventional chemotherapy and a short median survival. Here we present a rare case of concurrent T-PLL and Kaposi sarcoma who achieved a complete hematologic and cytogenetic remission after a very short course of treatment with alemtuzumab. A review of T-PLL was done. In this review, clinical features, laboratory features and current therapeutic strategies of T-PLL are presented.     

Non-organ-specific autoantibodies in Indian patients with chronic liver disease

Background

Autoantibody testing is used to diagnose autoimmune hepatitis (AIH), a cause of chronic liver disease (CLD). However, various autoantibodies are often detectable in patients with CLD due to other causes too. Since data on autoantibody prevalence in Indian patients with CLD are limited, we decided to undertake the current study.

Methods

Patients with CLD with a known cause other than AIH and a separate group of patients with CLD in whom no cause could be identified were studied. Indirect immunofluorescence assays were used to detect anti-nuclear antibodies (ANA), anti-smooth muscle antibodies (ASMA) and anti-liver-kidney microsomal antibodies (anti-LKM). Serum dilutions tested were 1:80 for ANA and 1:40 for other autoantibodies.

Results

Of the 175 patients with CLD of a known cause, 69 (39?%) had one or more autoantibodies, including ANA in 35 (20?%) patients and ASMA in 44 (25?%) patients. None had anti-LKM. The prevalence rates of any autoantibody, ANA and ASMA were similar in patients with CLD due to alcohol (34?%, 20?%, and 24?%, respectively), HCV infection (43?%, 20?%, and 26?%) and HBV infection (40?%, 18?%, and 25?%). The most common ANA pattern observed was speckled (29/35 patients), followed by nucleolar (5/35) and homogeneous (1/35). The ASMA titers did not exceed 1:80. The antibody prevalence rates were similar in patients with liver cirrhosis and chronic hepatitis, and in those with different disease severity. Serum IgG levels were similar in patients with and without detectable autoantibodies. Patients with no known cause of CLD (n?=?50) had similar prevalence rates of autoantibodies, ANA or ASMA.

Conclusion

Autoantibodies were detected in a large proportion of patients with CLD, both cryptogenic and with known cause. Detection of autoantibodies in CLD does not necessarily indicate a diagnosis of AIH, and presence of homogenous pattern of ANA may be more relevant. Indiscriminate testing for autoantibodies in patients with CLD, especially those with a known cause, may not be warranted.     

Low-Dose Rituximab Therapy for Antibody-Mediated Rejection in a Highly Sensitized Heart-Transplant Recipient

Antibody-mediated rejection is the B-cell–mediated production of immunoglobulin G antibody against the transplanted heart. The currently available therapies for antibody-mediated rejection have had marginal success, and chronic manifestations of rejection can result in an increased risk of graft vasculopathy and perhaps require repeat transplantation. Rituximab, a monoclonal antibody directed against the CD20 receptor of B-lymphocytes and approved as therapy for lymphoma, can be used in heart-transplant patients for the management of antibody-mediated rejection.We present the case of a 52-year-old woman with high allosensitization (pre-transplantation panel reactive antibody level, 72%) who underwent successful orthotopic heart transplantation. Postoperatively, her acute antibody-mediated rejection with concomitant cellular rejection was successfully treated with low-dose rituximab. The patient died 5 months later because of multiple other medical problems. The present case suggests a role for low-dose rituximab as therapy for antibody-mediated rejection in heart-transplant patients.Key words: Antibodies, monoclonal/therapeutic use; antigens, CD20/immunology; B-lymphocytes/immunology; graft rejection/drug therapy; heart transplantation/pathology; HLA antigens/immunology; immunity, humoral/physiology/therapy; immunoglobulins, intravenous/metabolism; plasmapheresis; rituximab; time factorsAntibody-mediated rejection (AMR) in heart-transplant recipients is mediated by donor-specific antibodies and is histologically defined by linear deposits of immunoglobulin (Ig) and complement in the myocardial capillaries.¹ Antibody-mediated rejection is often accompanied by hemodynamic compromise and is associated with diminished graft survival. Standard immunosuppressive therapy, designed to target T-cell immune function, is largely ineffective against this B-cell–driven process. Various therapies for AMR, although available, can be of marginal use secondary to patients'' comorbidities.^2,3 We present the case of a woman with a history of ventricular assist device (VAD) implantation, dialysis dependence, and severe thrombocytopenia who responded well to the addition of anti-CD20 monoclonal antibody therapy with rituximab after heart transplantation.