Echocardiographic Features of Ventricular Septal Rupture with Right Ventricular Aneurysm After Acute Myocardial Infarction

Postinfarction ventricular septal defect is a life-threatening disorder that may be adequately treated if the diagnosis is obtained promptly. Two-dimensional color Doppler echocardiography is a reliable tool for this diagnosis and gives additional information regarding its location, size, and shape. The authors emphasize the feasibility of this method to depict a particular form of postinfarction interventricular septal rupture, which developed an aneurysm inside the right ventricular cavity. Its characteristics were completely defined by color Doppler echocardiography and confirmed at surgery.     

In vivo and in vitro effects of different anaesthetics on platelet function

Different effects of thiopental, propofol and sevoflurane on platelets have been reported. Patients undergoing thyroid surgery were anaesthetized with thiopental-fentanyl-sevoflurane (n = 11) or propofol-fentanyl-sevoflurane (n = 9). Platelet aggregation and thromboxane A2 generation were studied at baseline, and at the end of anaesthesia induction and surgery. Dose-response experiments were also performed in vitro with single agents. Thiopental-fentanyl-sevoflurane significantly reduced collagen-induced aggregation by the end of induction, while ADP-induced aggregation and thromboxane generation were unaffected. Propofol-fentanyl-sevoflurane had no effect on platelets. Thiopental dose-dependently inhibited platelets in vitro, while fentanyl or propofol did not. In conclusion, thiopental reduces platelet function both ex vivo and in vitro and propofol might be considered haemostatically safer.     

Efficacy of N-acetyl-cysteine in combination with thiamphenicol in sequential (intramuscular/aerosol) therapy of upper respiratory tract infections even when sustained by bacterial biofilms

A total of 102 patients with recurrent upper respiratory tract infections underwent microbiological exploration with appropriate sampling and direct biopsies of the infected sites. Therapy was then started and on day 1 each patient received two intramuscular injections of thiamphenicol glycinate acetylcysteinate (TGA). From day 2 to 10 sequential therapy with the same drug was continued employing TGA administered by aerosol. All putative etiologic agents recovered were susceptible to thiamphenicol and only 24 demonstrated the ability to produce in vitro biofilms. The organisms comprised 10 Staphylococcus aureus, 6 Streptococcus pyogenes, 4 Streptococcus pneumoniae and 3 Haemophilus influenzae. Of the 24 subjects in whom biofilms were demonstrated to be present in vivo by Scanning Electron Microscopy, clinical and bacteriological cure was obtained in 21 cases (87.5%) following sequential therapy with TGA. Failures were considered to be persistent signs and symptoms at day 15 after initiation of treatment and lack of eradication of 3 S. aureus strains, despite their in vitro susceptibility to thiamphenicol. Very few adverse events attributable to TGA were reported in this cohort of patients. In no case was discontinuation of treatment deemed necessary by the attending physician.     

Clinical Characteristics and Survival of European Patients with Resectable Large Hepatocellular Carcinomas

Purpose

Large hepatocellular carcinoma (HCC) presents on cirrhosis or in the absence of cirrhosis. Prognostic factors include both tumor and liver factors. Evaluate clinical and tumor characteristics of a group of large resected HCC in European patients.

Methods

Data for patients with HCC >7 cm who underwent liver resection between 1992 and 2011 were analyzed. Patients were dichotomized into those with tumor diameters of 7–10 cm or >10 cm and their characteristics and outcomes were compared.

Results

A total of 65 hepatectomies for HCC ≥7 cm were performed. Severe fibrosis or cirrhosis was present in 41.5 % of patients. Thirty-seven (56.9 %) patients had HCC ≥10 cm. Mortality and morbidity rates were 1.5 % and 37.5 %, respectively. Preoperative blood platelet levels and serum alkaline phosphatase (ALKP) levels showed significant differences between the groups. The 3-year survival was 43.5 % and 17.4 % for patients with tumors 7–10 and ≥10 cm, respectively.

Conclusions

Patients with large size HCC and preserved liver function can be resected with low operative risk. ALKP levels and platelet counts were higher in the larger tumors. Given these patterns of clinical and biochemical characteristics, this group of tumors may be a selected subset of large HCCs and might potentially benefit from surgical resection.     

Conservation of HIV-1 T cell epitopes across time and clades: Validation of immunogenic HLA-A2 epitopes selected for the GAIA HIV vaccine

HIV genomic sequence variability has complicated efforts to generate an effective globally relevant vaccine. Regions of the viral genome conserved in sequence and across time may represent the “Achilles’ heel” of HIV. In this study, highly conserved T-cell epitopes were selected using immunoinformatics tools combining HLA-A2 supertype binding predictions with relative global conservation. Analysis performed in 2002 on 10,803 HIV-1 sequences, and again in 2009, on 43,822 sequences, yielded 38 HLA-A2 epitopes. These epitopes were experimentally validated for HLA binding and immunogenicity with PBMCs from HIV-infected patients in Providence, Rhode Island, and/or Bamako, Mali. Thirty-five (92%) stimulated an IFNγ response in PBMCs from at least one subject. Eleven of fourteen peptides (79%) were confirmed as HLA-A2 epitopes in both locations. Validation of these HLA-A2 epitopes conserved across time, clades, and geography supports the hypothesis that such epitopes could provide effective coverage of virus diversity and would be appropriate for inclusion in a globally relevant HIV vaccine.     

Inhibition of Podocyte FAK Protects against Proteinuria and Foot Process Effacement

Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase that plays a critical role in cell motility. Movement and retraction of podocyte foot processes, which accompany podocyte injury, suggest focal adhesion disassembly. To understand better the mechanisms by which podocyte foot process effacement leads to proteinuria and kidney failure, we studied the function of FAK in podocytes. In murine models, glomerular injury led to activation of podocyte FAK, followed by proteinuria and foot process effacement. Both podocyte-specific deletion of FAK and pharmacologic inactivation of FAK abrogated the proteinuria and foot process effacement induced by glomerular injury. In vitro, podocytes isolated from conditional FAK knockout mice demonstrated reduced spreading and migration; pharmacologic inactivation of FAK had similar effects on wild-type podocytes. In conclusion, FAK activation regulates podocyte foot process effacement, suggesting that pharmacologic inhibition of this signaling cascade may have therapeutic potential in the setting of glomerular injury.The glomerulus forms the filtration barrier of the kidney and is composed of a fenestrated endothelium, glomerular basement membrane (GBM), and the podocytes that interdigitate to form slit diaphragms.^1,2 When the podocytes are damaged, foot process fusion occurs. This process involves the rearrangement of the actin cytoskeleton and retraction of the foot processes toward the cell body, allowing mechanical forces and signaling events to be transmitted into the cell. Since the identification that mutations of the podocyte slit diaphragm specific NPHS1 gene cause congenital nephrotic syndrome,^3–5 podocytes have been recognized as critical regulators of glomerular injury. Other podocyte slit diaphragm proteins such as podocin, synaptopodin, and CD2AP have generated further interest in the regulation of the kidney filtration barrier^6–8; however, little is still known about cell–matrix interactions in podocytes. Mice lacking the focal adhesion protein integrin-linked kinase (ILK), specifically in the podocytes, also develop proteinuria, resulting in renal failure and death.⁹ Moreover, mice lacking α3β1 integrin have demonstrated inability to form mature foot processes.¹⁰ These cell–matrix interactions, which seem important in podocyte development, may also play a critical role after podocyte injury, because the process of podocyte effacement requires cell process retraction and movement, processes that suggest focal adhesion disassembly.Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase, in which integrin- or growth factor–induced autophosphorylation at tyrosine 397 results in activation of critical signaling pathways required for focal adhesion turnover.^11–16 It has been demonstrated that cell spreading and migration are significantly diminished in cells lacking FAK.¹⁷ This inhibition in motility has brought excitement in cancer therapeutics, resulting in the development and use of FAK inhibitors.^18–21 In a recent study, inhibition of urokinase plasminogen activator (uPAR), a glycosylphosphatidylinositol-anchored protein that is important for cell invasion and metastasis, has been demonstrated to reduce proteinuria and podocyte effacement significantly, suggesting that this dynamic podocyte cell movement may mimic the molecular signaling events observed in cancer cell invasion.²²In this study, we demonstrated that after podocyte injury in vivo and in vitro, FAK activation was significantly increased in wild-type (WT) mice, prompting us to address whether inhibition or loss of FAK activation would reduce podocyte cell motility by inhibiting focal adhesion turnover, thereby preventing proteinuria and effacement. Because complete FAK gene deletion results in lethality at embryonic day 8.5, a time point before glomerular development has been initiated, the ability to study this protein''s role in podocyte development as well as repair after injury has been limited.¹⁷ Hence, selective loss of FAK expression in the podocytes of the kidney was achieved using a Cre-loxP approach.^23,24 These mice were born without evidence of podocyte/glomerular developmental defects but were resistant to the foot process fusion and subsequent proteinuria that typically accompany LPS and rabbit anti-mouse GBM-induced podocyte damage. We postulate this inhibition of foot process effacement is due to diminished podocyte spreading and motility, supported by our in vitro data. In addition, pharmacologic treatment of WT mice using the FAK inhibitor TAE-226 significantly reduced proteinuria and podocyte effacement, raising the possibility for therapeutic use in glomerular diseases.     

Mitotane treatment for adrenocortical carcinoma: an overview

Adrenocortical carcinoma (ACC) is a rare aggressive endocrine neoplasm characterized by a 5-year survival of less than 50%. Due to the widespread use of imaging techniques in clinics, ACC is increasingly recognized as an incidentally discovered tumor. Mostly characterized by poor prognosis, ACC is often diagnosed at an advanced stage of disease. Early diagnosis is uncommon; when diagnosed, ACCs are usually large and have invaded adjacent organs, even if metastatic spread to distant sites can be absent. Complete surgical resection is the only potentially curative treatment for patients with localized disease; however, due to a recurrence rate of 50-70% after apparent radical surgery, there is a strong rationale for a concomitant systemic treatment. Adrenolytic therapy with mitotane (o,p?-DDD), administered alone or in combination with others antineoplastic agents, is the primary treatment for patients with advanced ACC and is increasingly used also in an adjuvant setting, even if controversy exists on this issue due to the limitations of the available literature. Despite being in use for many years, the rarity of ACC precluded the organization of randomized trials; thus, many areas of uncertainty and controversy remain regarding the role of this old drug in the clinical management of patients with ACC. The purpose of this paper is to review the current evidence on mitotane treatment in patients with advanced disease and in ACC patients after complete surgical resection as adjuvant treatment.     

Accelerated cellular recovery after an ischemic renal injury.

To determine the mode of action of the beneficial effect of adenosine triphosphate (ATP)-MgCl2, recovery of microinjected inulin, proximal tubular pressure (PTP), and cellular damage as quantitated by histomorphometric analysis of necrosis and swelling were evaluated at 2, 6, and 24 hours after 45 minutes of renal ischemia in rats treated with either normal saline or ATP-MgCl2. At 2 hours both groups of rats demonstrated increased permeability to inulin, elevated PTP, and severe ischemic damage and necrosis. By 6 hours ATP-MgCl2 rats had less tubular back leak of inulin, PTP was modestly reduced, and ultrastructural studies demonstrated improved cellular morphologic features with evidence of early regenerative changes. The saline rats had progressive ischemic cellular damage. At 24 hours ATP-MgCl2 rats had reestablished tubular integrity, PtP had fallen, and ischemic alterations were improved, with only focal evidence of necrosis. Saline-treated rats still had a back leak of inulin, elevated PTP, and progressive ischemic injury. This study demonstrates that 1) cellular damage continues to occur for 6 hours after renal ischemia; 2) ATP-MgCl2 enhances recovery of tubular integrity and cellular morphologic features. The salutary effect of ATP-MgCl2 appears related to the preservation of sublethally injured cells and acceleration of the process of restoration and repair of damaged cells.     

A Study of Financial Incentives to Reduce Plasma HIV RNA Among Patients in Care

The role of financial incentives in HIV care is not well studied. We conducted a single-site study of monetary incentives for viral load suppression, using each patient as his own control. The incentive size ($100/quarter) was designed to be cost-neutral, offsetting estimated downstream costs averted through reduced HIV transmission. Feasibility outcomes were clinic workflow, patient acceptability, and patient comprehension. Although the study was not powered for effectiveness, we also analyzed viral load suppression. Of 80 eligible patients, 77 consented, and 69 had 12 month follow-up. Feasibility outcomes showed minimal impact on patient workflow, near-unanimous patient acceptability, and satisfactory patient comprehension. Among individuals with detectable viral loads pre-intervention, the proportion of undetectable viral load tests increased from 57 to 69 % before versus after the intervention. It is feasible to use financial incentives to reward ART adherence, and to specify the incentive by requiring cost-neutrality and targeting biological outcomes.