Mapping brain size and cortical gray matter changes in elderly depression.

BACKGROUND: In elderly depression, volumetric brain imaging findings suggest abnormalities of the frontal lobe, particularly the orbitofrontal cortex, and the hippocampus. No studies to date have mapped cortical abnormalities over the entire brain surface in major depression. Here, we conducted detailed spatial analyses of brain size and gray matter within the cortical mantle in elderly patients with major depression. METHODS: High-resolution, three-dimensional, structural magnetic resonance imaging data and cortical pattern matching methods were used in 24 depressed elderly patients and 19 group-matched controls to measure local brain size and proportions of gray matter at thousands of homologous cortical surface locations. RESULTS: Prominent brain size reductions were observed in the depressed subjects in the orbitofrontal cortex bilaterally. Cortical gray matter measurements revealed significant gray matter increases in the orbitofrontal cortex, adjacent to focal trend level significant decreases of gray matter in the same region. Depressed patients also exhibited significant gray matter increases in parietal cortices, as well as the left temporal cortex. CONCLUSIONS: Complex cortical changes may contribute to the brain size reduction of the orbitofrontal cortex and to the gray matter abnormalities detected in orbitofrontal cortex and temporoparietal cortices, thereby providing a potentially new window into the pathophysiology of elderly depression.     

Monoclonal Antibody Specific for TIRC7 Induces Donor-specific Anergy and Prevents Rejection of Cardiac Allografts in Mice

T cell immune response c-DNA (TIRC7) is up-regulated during the early stages of T-cell activation in response to alloantigens. In this study, we analyzed the effects of newly developed monoclonal antibodies (mAb) against TIRC7 in acute cardiac allograft rejection. Fully vascularized heterotopic allogeneic heart transplantation was performed in mice across a full-mismatch barrier (C57Bl/10 into CBA). Recipients received seven injections (day 0-7) of a novel anti-TIRC7 mAb or remained untreated. Graft survival, histology and ex vivo lymphocyte functions were tested. Targeting of TIRC7 with an anti-TIRC7 mAb diminishes lymphocyte infiltration into grafts resulting in delay of morphological graft damage and prolongation of allograft survival. The lymphocytes from anti-TIRC7 mAb-treated animals exhibit hypo-responsiveness without evidence of lymphocyte depletion against the donor allo-antigens. Proliferation and expression of interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) were down-regulated while interleukin-4 (IL-4) and IL-10 expression were spared. Moreover, anti-TIRC7 mAb enhanced up-regulation of CTLA-4 expression but suppressed up-regulation of CD25 on stimulated lymphocytes in vitro and in vivo. Ligation of TIRC7 has important effects on the regulation of co-stimulatory signaling pathways associated with suppressing of T-cell activation. Targeting of TIRC7 may therefore provide a novel therapeutic approach for modulating T cell immune responses during organ transplantation.     

Modeling of relationships between pharmacokinetics and blockade of agonist-induced elevation of intraurethral pressure and mean arterial pressure in conscious dogs treated with alpha(1)-adrenoceptor antagonists.

Fiduxosin is a new alpha(1)-adrenoceptor antagonist targeted for the treatment of symptomatic benign prostatic hyperplasia. The purpose of this study was to determine and compare the potencies of the alpha(1)-adrenoceptor antagonists terazosin, doxazosin, tamsulosin, and fiduxosin, based on relationships between plasma drug concentrations and blockade of phenylephrine (PE)-induced intraurethral (IUP) and mean arterial pressure (MAP) responses after single oral dosing in conscious male beagle dogs. Magnitude of blockade and plasma concentrations were evaluated at selected time points over 24 h. All drugs produced dose-dependent antagonism of PE-induced IUP and MAP responses. When IUP and MAP blockade effects were plotted against drug plasma concentrations, direct relationships were observed that were well described by the sigmoidal maximal effect model. IUP IC(50) values for terazosin, doxazosin, tamsulosin, and fiduxosin were 48.6, 48.7, 0.42, and 261 ng/ml, respectively. MAP IC(50) values were 12.2, 13.8, 1.07, and 1904 ng/ml, respectively. Uroselectivity index values, defined as MAP IC(50)/IUP IC(50), were 0.25, 0.28, 2.6, and 7.3, respectively. These results extend previous observations with terazosin in this model, showing that doxazosin exhibits a uroselectivity index comparable to terazosin, consistent with the lack of alpha(1)-adrenoceptor subtype selectivity or uroselectivity of these drugs. Tamsulosin, an alpha(1a)-/alpha(1d)-subtype selective agent, had an index value approximately 10-fold greater than the nonselective drugs. Based on its pharmacokinetic profile and a relative uroselectivity 29-fold greater than the nonselective drugs, fiduxosin is expected to exhibit greater selectivity for urethral compared with vascular alpha(1)-adrenoceptors in human and should be a novel, long-acting, uroselective alpha(1)-adrenoceptor antagonist.     

Substance abuse and schizophrenia: impediments to optimal care

With lifetime prevalence estimates of substance abuse among schizophrenics as high as 47.01%, there is an increasing awareness of the importance of this dual diagnosis and the global deficiencies in our knowledge about this comorbid condition. Patients with substance abuse disorders and schizophrenia are problematic from a clinical, economic, and health care systems perspective. The lack of systematic research into phenomenology, etiology, and treatment approaches (both psychotherapeutic and psychopharmacologic) has hindered the development of an adequate strategy to care for the needs of these patients. Thus, these patients place a significant burden on the mental health delivery system through chronic disability, social dysfunction, frequent rehospitalizations, and poor overall treatment compliance. The authors critically review the contemporary literature relevant to concurrent substance abuse and schizophrenia, highlight major deficiencies in our knowledge, and call for research to reduce the individual, economic, and social costs of this condition.     

Going, going, gone . . . ? Implicit and explicit tests of conceptual knowledge in a longitudinal study of semantic dementia

Patients suffering from semantic dementia provide important constraints on theories of the structure and organisation of semantic memory. In this article we report one such patient, AM, whose progressive deterioration of semantics enables us to address the much-debated issue of whether conceptual structure is hierarchically organised. The hierarchical account predicts that brain damage should impair lower levels of the hierarchy (property information) before affecting higher level (category) information (Warrington and Shallice, Q. J. Exp. Psychol. 1975, 27, 635–657). We evaluate this prediction by repeated testing of AM in two studies—a semantic priming task and a verification task—over an 18 month period, contrasting the progressive deterioration of properties (functional and perceptual) and category relations (category co-ordinates and category labels). Properties were preserved longer than category information, arguing against a hierarchical account of semantic memory. In addition, functional properties were most robust to brain damage, supporting our claim that functional information plays a special role in semantic representations (Durrant-Peatfield et al., Proc. 19th Ann. Conf. of the Cognitive Science Society. Erlbaum, Mahwah, NJ, 1997, pp. 193–198. Tyler et al., Cognitive Neuropsychol. 1997, 14, 511–545).     

Estimating IQ from Adaptive Behaviour Information in People with Moderate or Severe Intellectual Disability

It is often useful in studies of intellectual disability to be able to stratify the sample in terms of intellectual level. However, this information is sometimes difficult to obtain, and can involve a great deal of time if full IQ assessments are performed. This study explores the accuracy with which IQ scores can be projected by multiple regression from adaptive behaviour scores provided by informants. Fifty-one people with moderate, severe or profound intellectual disability received IQ assessments using the Kaufman Assessment Battery, and adaptive behaviour assessments using the Adaptive Behavior Scales (ABS). Ninety percent of projected estimates differed by less than 30% from that estimated by the K-ABC. Mean percentage divergence between actual and predicted estimates of IQ for the 51 cases for which all data were available was 15.0%. Limitations of the technique are discussed. The actual coefficients for calculating IQ are given in tabular form.     

Staphylococcus aureus nasal carriage in patients with rhinosinusitis

Toxic shock syndrome has been associated with rhinologic surgery and medical devices, and it has been linked to a circulating exotoxin of a toxogenic strain of Staphylococcus aureus. One hundred forty patients with rhinosinusitis were studied. Nasal cultures were obtained. The microbiological characteristics are described. The carrier rate for Staphylococcus aureus was 35%. Thirty percent of patients selected for surgery were Staphylococcus aureus carriers. Toxin-capable isolates were identified in 40% of those tested. Users of cocaine, topical decongestants, and steroid sprays had a statistically higher rate of Staphylococcus aureus carriage compared to non-users. It is hoped that by identifying the population at risk and defining the factors associated with the development of toxic shock syndrome, a cogent policy of prevention can be established.     

Mammalian response to subdermal implantation of textured microimplants

The development of small, textured implant particles suspended in a hydrogel has allowed for subdermal injection therapy to fill tissue defects. The microimplant particles were placed subdermally into the ears of white New Zealand rabbits in order to characterize the foreign body response and the permanence of the implant. Serial micrometer readings were performed on the implant sites to determine any change in thickness of the augmentation following baseline measurement. An initial increase in the thickness was noted approximately 20–30 days postimplantation, as expected. A stable thickness was noted for the remainder of the experiment. Serial histological sections were performed at irregular intervals from one week to one year. Histology demonstrated a mild foreign body response with collagen surrounding each individual microimplant particle. The response was stable after 30–40 days and has remained stable for over one year. It was determined that the histology demonstrated a Boros IA type, or nonimmunogenic, low-turnover foreign body reaction.     

Pretransplant Exposure to Donor HLA-DR Antigen in Random Transfusion Units and the Development of Donor Antigen-Specific Hyporeactivity

Our previous studies have shown that the in vitro assay of donor antigen-specific hyporeactivity is a useful marker for identifying solid organ transplant recipients (kidney, lung and heart) at low risk for immunologic complications (i.e., late acute rejection episodes and chronic rejection). Donor antigen-specific hyporeactivity is defined as a significantly decreased post- vs. pretransplant proliferative response to donor antigens while response to third-party controls remains unchanged. We analyzed whether exposure to the same HLA-DR antigen pretransplant via random blood transfusion and posttransplant via the transplanted organ influenced the development of hyporeactivity. Thirty previously nontransfused recipients, each receiving two 150 ml pretransplant random blood transfusions, were assessed for hyporeactivity at 1 year posttransplant. Of the 12 recipients with pretransplant exposure to kidney HLA-DR via transfusions, 6 (50%) developed hyporesponsiveness; in contrast, of the 18 recipients who were not preexposed, only 3 (15%) exhibited this form of immunomodulation. Of interest, 2 of the 3 hyporesponsive recipients who were not preexposed, received units containing HLA-DR antigens previously shown to share crossreactive epitopes with the kidney HLA-DR. In conclusion, these results suggest a increased incidence in the development of hyporeactivity in patients receiving pretransplant transfusions which share an HLA-DR antigen with the transplanted kidney.