Modulation of neural responses in inferotemporal cortex during the interpretation of ambiguous photographs

Ambiguous images are interpreted in the context of biases about what they might be; these biases and the behavioral consequences induced by them may influence the processing of images. In this report, we examine neural responses in inferotemporal cortex (IT) during the interpretation of ambiguous photographs created by morphing between two photographs. Monkeys classified different images as being one of two choices and learned to classify most of the samples correctly. For one image (the ambiguous sample) reward was administered randomly for either possible choice, and the monkeys were free to classify that image based on their own interpretation, with no learning possible. The ambiguous samples were not classified randomly: the monkey interpreted the samples differently during different sessions. The interpretation of the ambiguous sample was, in turn, highly correlated with the normalized response of individual neurons in IT to the ambiguous sample. If an ambiguous sample was interpreted as a particular choice during a session, the response to that ambiguous sample more closely resembled the response to that choice. Identical ambiguous images were interpreted differently during different sessions, and neural responses reflected the differing interpretations of the image during that session. The relationship between the interpretation of the image and neural responses strengthened over the course of a session because neural responses shifted to more closely resemble the response to the initial interpretation of the image. The data support a flexible representation of visual stimuli in higher visual areas.     

Propensity-matched analysis of association between preoperative anemia and in-hospital mortality in cardiac surgical patients undergoing valvular heart surgeries

Introduction:

Anaemia is associated with increased post-operative morbidity and mortality. We retrospectively assess the relationship between preoperative anaemia and in-hospital mortality in valvular cardiac surgical population.

Materials and Methods:

Data from consecutive adult patients who underwent valvular repair/replacement at our institute from January 2010 to April 2014 were collected from hospital records. Anaemia was defined according to WHO criteria (hemoglobin <13g/dl for males and <12g/dl for females). 1:1 matching was done for anemic and non-anemic patients based on propensity for potentially confounding variables. Logistic regression was used to evaluate the relationship between anaemia and in-hospital mortality. MatchIt package for R software was used for propensity matching and SPSS 16.0.0 was used for statistical analysis.

Results:

2449 patients undergoing valvular surgery with or without coronary artery grafting were included. Anaemia was present in 37.1% (33.91% among males & 40.88% among females). Unadjusted OR for mortality was 1.6 in anemic group (95% Confidence Interval [95% CI] – 1.041-2.570; p=0.033). 1:1 matching was done on the basis of propensity score for anaemia (866 pairs). Balancing was confirmed using standardized differences. Anaemia had an OR of 1.8 for mortality (95% CI- 1.042 to 3.094, P=0.035). Hematocrit of < 20 on bypass was associated with higher mortality.

Conclusion:

Preoperative anaemia is an independent risk factor associated with in-hospital mortality in patients undergoing valvular heart surgery.     

Common variable immunodeficiency is associated with defective functions of dendritic cells

Common variable immunodeficiency (CVID) is characterized by hypogammaglobulinemia and defects in T-cell functions that could be primary or secondary. We addressed whether CVID is associated with impairment in the dendritic cell (DC) compartment, as DCs play a central role in the development of adaptive immunity. We demonstrate that DCs from CVID patients display severely perturbed differentiation, maturation, and function, and express markedly reduced levels of the costimulatory molecules that are critical for T-cell stimulation. Patients' DCs induced weak proliferation of allogeneic T cells and produced significantly low amounts of interleukin-12 (IL-12) upon CD40 signaling. Multiple defects in the immune system, including malfunctioning of DCs, appear to be prominent features of CVID patients. Impairment in both the innate and adaptive compartments of the immune system may thus cumulatively account for the inability of CVID patients to eradicate pathogens through conventional immune pathways, thus resulting in an increased risk for recurrent bacterial infections.     

Structural determinants of agonist-induced signaling and regulation of the angiotensin AT1 receptor

Angiotensin II (Ang II) regulates aldosterone secretion by stimulating inositol phosphate production and Ca(2+) signaling in adrenal glomerulosa cells via the G(q)-coupled AT(1) receptor, which is rapidly internalized upon agonist binding. Ang II also binds to the heptahelical AT(2) receptor, which neither activates inositol phosphate signaling nor undergoes receptor internalization. The differential behaviors of the AT(1) and AT(2) receptors were analyzed in chimeric angiotensin receptors created by swapping the second (IL2), the third (IL3) intracellular loops and/or the cytoplasmic tail (CT) between these receptors. When transiently expressed in COS-7 cells, the chimeric receptors showed only minor alterations in their ligand binding properties. Measurements of the internalization kinetics and inositol phosphate responses of chimeric AT(1A) receptors indicated that the CT is required for normal receptor internalization, and IL2 is a determinant of G protein activation. In addition, the amino-terminal portion of IL3 is required for both receptor functions. However, only substitution of IL2 impaired Ang II-induced ERK activation, suggesting that alternative mechanisms are responsible for ERK activation in signaling-deficient mutant AT(1) receptors. Substitution of IL2, IL3, or CT of the AT(1A) receptor into the AT(2) receptor sequence did not endow the latter with the ability to internalize or to mediate inositol phosphate signaling responses. These data suggest that the lack of receptor internalization and inositol phosphate signal generation by the AT(2) receptor is a consequence of its different activation mechanism, rather than the inability of its cytoplasmic domains to couple to intracellular effectors.     

Wavelet Analysis of High-Resolution Signal-Averaged Electrocardiograms in Postinfarction Patients with Bundle Branch Block

Time-domain analysis of the signal-averaged electrocardiogram (SAECG) can accurately predict risk of sustained ventricular tachycardia (VT) in patients with previous myocardial infarction (MI). Unfortunately, these patients often have bundle branch block (BBB) that obscures late potentials. We hypothesized that wavelet analysis might help predict VT risk in patients with BBB. We identified subjects with coronary disease and BBB who had undergone SAECG and programmed ventricular stimulation (PVS). We applied a modulated Gaussian wavelet to transform the ECG signal and looked for singularities in the wavelet coefficients. SAECG and PVS were obtained in 32 patients. Half had inducible sustained monomorphic VT by PVS and half had no inducible VT. There were no significant clinical differences between the groups. Comparing the number of singularities, we found no significant difference between the groups. Compared to previous work in patients without BBB, our patients with BBB had on average four times more singula- rities using an identical analysis technique. In the presence of BBB, abnormal myocardial activation patterns can generate ECG waveforms with time–frequency characteristics similar to those of cardiac late potentials. Wavelet-based methodologies may have limited ability to distinguish late potentials from the disordered ventricular activation occurring with BBB alone.     

Monoclonal antibody and intravenous immunoglobulin therapy for rheumatic diseases: rationale and mechanisms of action

Advances in our understanding of the pathogenesis of rheumatic diseases such as rheumatoid arthritis and systemic lupus erythematosus have led to the emergence of immunoglobulin-based therapy as a major therapeutic force. Numerous monoclonal antibodies that target proinflammatory cytokines or their receptors (e.g. infliximab, adalimumab, tocilizumab, belimumab, HuMax-IL-15), and cell-surface or co-stimulatory molecules (e.g. rituximab) are either in clinical development or have been approved for clinical use. These antibodies are safe and effective in the long-term therapy of many rheumatic diseases. In addition, polyclonal immunoglobulins (intravenous immunoglobulin) obtained from pooled plasma from healthy blood donors are an effective therapeutic approach in certain rheumatic diseases. The mechanisms of action of monoclonal antibodies and intravenous immunoglobulin include cytolysis of target cells through complement or antibody-dependent cell-mediated cytotoxicity, induction of apoptosis of target cells, blockade of co-stimulatory molecules, and neutralization of pathogenic antibodies and soluble factors such as cytokines and their receptors, which ultimately lead to amelioration of the inflammatory process. The success of currently available therapeutic immunoglobulins has led to considerable interest in the identification of novel molecular therapeutic targets in rheumatic diseases.     

Multiple patients with revertant mosaicism in a single Wiskott-Aldrich syndrome family

We previously reported on a 43-year-old patient with Wiskott-Aldrich syndrome (WAS) who experienced progressive clinical improvement and revertant T-cell mosaicism. Deletion of the disease-causing 6-bp insertion was hypothesized to have occurred by DNA polymerase slippage. We now describe 2 additional patients from the same family who also had revertant T lymphocytes that showed selective in vivo advantage. Somatic mosaicism was demonstrated on leukocytes cryopreserved in the first patient when he was 22 years old, 11 years before his death from kidney failure. The second patient is now 16 years old, has a moderate clinical phenotype, and developed revertant cells after the age of 14 years. These results support DNA polymerase slippage as a common underlying mechanism, and they indicate that T-cell mosaicism may have different clinical effects in WAS.     

Dual institution experience of extranodal marginal zone lymphoma reveals excellent long‐term outcomes

Extranodal marginal zone lymphoma (EMZL) is a B‐cell lymphoma arising from mucosa‐associated lymphoid tissue (MALT). The disease characteristics, clinical course and treatment vary considerably based on site of involvement. Because long‐term outcome data for EMZL are limited, we sought to describe the clinical details of a large number of patients with EMZL evaluated at the Case Comprehensive Cancer Center over a 12‐year period to identify prognostic markers including the impact of site of involvement. We identified 211 cases of EMZL involving the stomach (30%), ocular adnexa (19%), lungs (16%) and intestines (9%). Initial treatment included antibiotics (18%), radiation (21%), rituximab (20%), chemotherapy (3%), rituximab + chemotherapy (7%), surgery (17%) or observation (8%). After a median follow‐up of 44·3 months (range 2·2–214·9), median progression‐free survival (PFS) was 68·2 months (95% confidence interval [CI] 54·5–111·3) and median overall survival (OS) has not been reached. Age >60 years, elevated lactate dehydrogenase level (LDH), ≥4 lymph node groups involvement, and high follicular lymphoma international prognostic index (FLIPI) were associated with inferior PFS/OS. In summary, patients with EMZL have excellent prognosis with median OS in excess of 10 years. Age, elevated LDH, advanced disease, and high FLIPI score are associated with worse outcomes.