Chronic renal allograft injury: early detection,accurate diagnosis and management

Chronic renal allograft injury (CRAI) is a multifactorial clinical/pathological entity characterised by a progressive decrease in glomerular filtration rate, generally associated with proteinuria and arterial hypertension. Classical views tried to distinguish between immunological (sensitization, low HLA compatibility, acute rejection episodes) and non-immunological factors (donor age, delayed graft function, calcineurin inhibitors [CNI] toxicity, arterial hypertension, infections) contributing to its development. Defining it as a generic idiopathic entity has precluded more comprehensive attempts for therapeutic options. Consequently, it is necessary to reinforce the diagnostic work-up to add etiopathogenetic diagnosis in any case of graft dysfunction, specially transplant vasculopathy and transplant glomerulopathy, reserving the term interstitial fibrosis and tubular atrophy (IFTA) when a case of CRAI is unspecific and no clear contributing factors or a specific etiology is possible in diagnosis.Earlier detection and intervention of CRAI remain as key challenges for transplant physicians. Changes in SCr levels and proteinuria often occur late in disease progression and may not accurately represent the underlying renal damage. Deterioration of renal function over time, determined through slope analysis, is a more accurate indicator of CRAI, and earlier identification of renal deterioration may prompt earlier changes in immunosuppressive therapies. The crucial point is probably to distinguish between nonimmunological or toxic CRAI and immunological-derived CRAI cases. Conversion to nonnephrotoxic immunosuppressants, such as mTOR inhibitors, holds promise in reducing the impact of toxic CRAI by both avoiding and reducing the impact of CNIs and reducing smooth muscle cell proliferation in the kidney. CRAI due to chronic antibody mediated rejection is an important entity, better and better defined that carries a bad prognosis and is associated with graft loss. The best prevention is adequate immunosuppression and tight patient monitoring, from the clinical, analytical and histological standpoint. While clinical trial evidence is needed for early detection and intervention in patients with CRAI, this review represents the current knowledge upon which clinicians can base their strategies. New prospective, ideally well-controlled trials are needed to establish the usefulness of different potentially therapeutic regimens. These evidences should demonstrate the benefits before extended uncontrolled use of drugs such as rituximab, bortezomib or eculizumab, which are expensive and frequently iatrogenic.     

Operative treatment and outcome of unstable distal radial fractures using a palmar T-miniplate at a non-specialized institution

Treatment options for displaced distal radial fractures are still a controversial topic of discussion. Although good results for the palmar plating of high-volume centers have been published, evidence of its successful use in smaller institutions is still lacking. We report the clinical and radiological results of the treatment for 84 distal radial fractures with a single 2.4-mm T-miniplate in an institution performing <30 procedures per year. According to the AO classification system, there were 30 A, 5 B, and 49 C fractures with a patients mean age of 64 years. After a minimum of 12-month follow-up, we found very good and good results according to the Gardland and Sarmiento scores and a DASH of 5.6. Only five patients were classified as having a moderate outcome. A remaining intra-articular step-off of more than 1 mm was seen in 15 patients. In a comparison of grip strength between the injured and uninjured hands, we saw a difference of 6.8 % less on the injured side. We saw two instances of tendon rupture and one of tendon irritation due to prominent dorsal screws and necessitating revision surgery. Flexor tendon irritation was noted in one patient, requiring a second operation. Modern treatment for distal radial fractures can be performed successfully and with good clinical outcome in smaller institutions. Based on the high and increasing incidence of distal radial fractures, there is no need to transfer these patients into high-volume centers. Level of evidence Case study, Level IV.     

Regulatory T cells in chronic lymphocytic leukemia: implication for immunotherapeutic interventions

Identification of regulatory T cells (Tregs) has led to breaking the dichotomy of the Th1/Th2 axis in the immunopathology of several diseases such as autoimmune diseases and cancer. Despite the presence of extensive information about immunobiology of Tregs in pathogenesis of autoimmune diseases, little is known about the frequency and function of these cells in hematologic malignancies, particularly chronic lymphocytic leukemia (CLL). Recent data have demonstrated increased frequency and intact functional capacity of CD4⁺ Tregs in CLL patients. However, the precise role of these cells in the immunopathology of CLL is not well known. While targeting Tregs in cancer diseases seems to be an interesting immunotherapeutic approach, such therapeutic interventions in CLL might be deleterious due to suppression of the tumor-specific adaptive and innate immune responses. Thus, the precise biological and regulatory functions of all Tregs subsets should be carefully investigated before planning any immunotherapeutic interventions based on targeting of Tregs. In this communication, we review the recent data published on immunobiology of Tregs in CLL and discuss about the possibility of targeting Tregs in CLL.     

Comparison of two separation techniques for the determination of blood mononuclear cell magnesium content.

The determination of blood mononuclear cell magnesium content may be a predictor of total body magnesium status. Separation techniques employing Ficoll-Hypaque have been used for this assay; however, Hypaque contains a significant concentration of iodine that may be toxic to the cell membrane and affect the results. We developed a different separation technique using arabinogalactan (Stractan) at concentrations of 13.0 and 17.7%. The blood from 16 normal volunteers was divided and assayed for mononuclear cell magnesium content using both methods. The results (mean +/? standard deviation) with the Ficoll-Hypaque method were 83.6 +/? 30.8 fg/cell, and with the arabinogalactan method they were 78.4 +/? 25.5 fg/cell. A paired sample t test comparing the results between the two methods gave a t value of 1.05 (P greater than .3). The purest population of blood mononuclear cells was obtained with the Ficoll-Hypaque method. Thus, these two separation materials do not have a significant effect on the blood mononuclear cell magnesium content, and the better separation of cells was obtained with Ficoll-Hypaque.     

Magnesium variability of lymphocytes from cell culture.

We determined the magnesium content for two different Burkitt's lymphoma cell lines (EW 36 and CA 46) after transfer to new media for 7 consecutive days. Aliquots of the cell culture were washed and the cell pellet was obtained by centrifugation and lysed with distilled water with and without the addition of 0.25% lanthanum oxide. Magnesium was determined by atomic absorption spectrophotometry. The addition of lanthanum permitted the detection of between 8 and 40% more magnesium. The increased magnesium liberated by the addition of lanthanum was calculated as the “bound” magnesium. The results show that the total magnesium is inversely related and the bound magnesium directly related to the age of the cell culture. Thus, there is a decrease of lymphocyte magnesium content and an increase in the percentage of magnesium bound for these two cell lines with increasing age of the cell culture.     

Role of apoptosis in HESA-A teratogenicity in mouse fetus

HESA-A is a natural compound of herbal-marine origin with cytotoxic and antitumor effects. The anticancer effects of HESA-A has been the subject of both in vivo and in vitro studies. This study was to investigate the mechanism of HESA-A teratogenicity. We assessed the HESA-A-induced apoptosis in mouse fetus in vitro by using the vital staining and TUNNEL methods. HESA-A, in lower doses, had no significant effect on apoptosis but, in higher doses of 20 and 40?μL, increased cell death. A dose of 100?μL induced the cell death with both apoptosis and necrosis mechanisms. HESA-A changed the cell-death pattern; in moderate doses of the drug, the apoptosis-to-necrosis ratio was more than 1, and in higher doses, this ratio was less than 1.     

Gastrointestinal mucormycosis complicated by arterio-enteric fistula in a patient with non-Hodgkin's lymphoma

Gastrointestinal mucormycosis is a rare, often fatal, systemic infection found predominantly in immunocompromised patients. We report a case of gastrointestinal mucormycosis in a 53-year-old female with non-Hodgkin's lymphoma. Following her first course of chemotherapy, bowel obstruction developed as a result of mucormycosis. Despite treatment with antifungal therapy, she required a laparotomy owing to severe haemorrhage caused by mucormycosal invasion of her iliac artery. With continued antifungal treatment and further chemotherapy, she ultimately underwent reversal of her Hartmann's procedure and remains disease-free.     

Akt as a mediator of cell death

Protein kinase B/Akt possesses prosurvival and antiapoptotic activities and is involved in growth factor-mediated neuronal protection. In this study we establish Akt deactivation as a causal mediator of cell death. Akt deactivation occurs in multiple models of cell death including N-methyl-d-aspartate excitotoxicity, vascular stroke, and nitric oxide (NO)- and hydrogen peroxide (H2O2)-elicited death of HeLa, PC12, and Jurkat T cells. Akt deactivation characterizes both caspase-dependent and -independent cell death. Conditions rescuing cell death, such as treatment with poly(ADP-ribose) polymerase or NO synthase inhibitors and preconditioning with sublethal concentrations of N-methyl-d-aspartate, restore Akt activity. Infection of neurons with adenovirus expressing constitutively active Akt prevents excitotoxicity, whereas phosphatidylinositol 3-kinase inhibitors or infection with dominant negative Akt induce death of untreated neuronal cells.     

Cardiac abnormalities and Wolfram (DIDMOAD) syndrome: a case report

Cardiac abnormalities are very rarely reported to be associated with Wolfram (DIDMOAD) syndrome. We report a child who presented with cyanotic heart disease and was operated twice for cardiac lesion. At the age of 6 years, the case developed osmotic symptoms and, during evaluation, diabetes insipidus, optic atrophy and deafness were reported. DIDMOAD syndrome with atrial septal defect, severe pulmonary stenosis and hypoplastic right ventricle is not previously reported. In addition to our case, in a literature survey on all reported cases of DIDMOAD syndrome (more than 700), only 11 cases with cardiac abnormalities have been stated. Common abnormalities found are pulmonary stenosis, followed by tetralogy of Fallot and ventricular septal defects. Impact of DIDMOAD syndrome on cardiovascular development needs to be elucidated.