Biochemical markers of compliance in the Physicians' Health Study

The Physicians' Health Study is a randomized, double-blind, placebo-controlled trial using a 2 x 2 factorial design to test the effects of low-dose aspirin on risk of cardiovascular disease and beta-carotene supplementation on the incidence of cancer. To evaluate self-reported compliance with assigned treatment, we measured serum thromboxane B2, which is decreased after aspirin use, and plasma beta-carotene in samples of study participants drawn from three geographic locations in three different time periods. Thromboxane B2 levels were markedly lower in those assigned to aspirin (median = 63.5 pg/mL) than in those given aspirin placebo (median = 3,600 pg/mL, P less than .0001). Similarly, those assigned to beta-carotene had significantly higher levels (median = 1,176 ng/mL) than those given placebo (median = 306 ng/mL, P less than .0001). In addition, there was a highly significant positive correlation between levels of these biochemical markers and the self-reports of compliance (r = 0.65 for thromboxane B2 and r = 0.69 for beta-carotene, P less than .0001). These findings support the validity of the self-reported compliance in the Physicians' Health Study.     

The organization of trigeminotectal and trigeminothalamic neurons in rodents: a double-labeling study with fluorescent dyes

Retrogradely transported fluorescent dyes (fast blue and diamidino-dihydrochloride yellow) were used to compare the distributions of trigeminofugal neurons that project to the superior colliculus and/or the thalamus in three rodent species. The objective was to determine what the projection and collateralization patterns of these trigeminofugal pathways are and whether they are similar among different species. In each anesthetized animal, one dye was injected into the superior colliculus and the other into the topographically congruent area of the thalamus. Counts of the numbers of yellow, blue, and double-labeled neurons were made throughout the trigeminal complex: principalis, pars oralis, pars interpolaris, and pars caudalis. Trigeminothalamic projections were similar in each of the rodent species studied. The densest concentration of retrogradely labeled neurons was in principalis, with substantially fewer neurons in pars interpolaris, and fewer still in pars oralis and pars caudalis. These neurons were generally small and tended to have round or fusiform somata. A common pattern was also noted among the three species for trigeminotectal neurons. Most trigeminotectal projections originated from neurons in pars interpolaris, somewhat fewer from pars oralis, and the fewest from principalis and pars caudalis. These neurons tended to be the largest in each subdivision and were often multipolar. Following paired injections of the tracers, double-labeled neurons were scattered throughout the sensory trigeminal complex and had morphologies characteristic of single-labeled trigeminotectal neurons. Although comparatively few double-labeled neurons were observed in any species, most of those seen were restricted to the ventrolateral portion of pars interpolaris, a position that corresponds to the representation of the vibrissae. These data indicate that, regardless of the rodent species, the vast majority of labeled trigeminal neurons project either to the superior colliculus or the thalamus, but not to both targets. This might be expected on the basis of the very different behavioral roles these structures play. On the other hand, a subpopulation of trigeminal neurons exists (mainly in pars interpolaris) that does project to both the superior colliculus and the thalamus, perhaps because both structures require some of the same somatosensory information to perform their behavioral functions.     

Direct measurement of the conduction velocity of single motor axons in man

The conduction velocity (CV) of single motor axons was measured in the ulnar and median nerve. Stimuli of submaximal intensities were delivered at the wrist and at the elbow using surface electrodes. The responses of single motor units were recorded by tungsten or steel microelectrodes. Changes of the stimulus intensity and of the position of the stimulation electrodes and subtraction of the responses frequently allowed the potential of the same motor unit to be identified following stimulation at both sites and to calculate its axonal CV. In all individuals, axonal CV's from the low to the high velocity range (40 to 63 m/s) could be measured. The method may provide a new approach to the investigation of various disorders of the peripheral nerve.     

Impairment of polymorphonuclear leukocyte function and metabolic control of diabetes.

OBJECTIVE--In this study, ingestion of Staphylococcus aureus and "bacteria killing" (BK) were measured to evaluate polymorphonuclear leukocyte (PMN) phagocytic functions and chemiluminescence response (CL) to phorbol-myristic acetate (PMA) as respiratory burst activity with regard to metabolic control parameters in diabetic patients. RESEARCH DESIGN AND METHODS--PMN phagocytic functions were assessed in 40 diabetic patients, all receiving insulin and in poor metabolic control, with 3H-thymidine-labeled Staphylococcus aureus in a modified radiometric assay. Bacteria killing was determined by pure-plate counting of surviving bacteria (colony-forming units [cfu]) and luminol-enhanced CL in response to PMA as a measure of respiratory burst. PMN function data were correlated to HbA1 as parameter of recent metabolic control. RESULTS--PMN of diabetic patients showed a significant reduction in Staphylococcus aureus (50.7 +/- 4.1%) and BK (29.4 +/- 4.2%) compared with healthy nondiabetic control subjects (76.6 +/- 4.6% and 16.3 +/- 3.1%, respectively, P less than 0.001), and PMN CL response was markedly reduced in diabetic patients also. Linear regression analysis showed a highly significant negative correlation of HbA1 versus Staphylococcus aureus (r = -0.67, P = 0.001) and a positive correlation for BK (r = 0.73, P less than 0.001). This was also true for CL, although this did not reach statistical significance (P = 0.06). CONCLUSIONS--The data obtained demonstrate impaired PMN phagocytic functions and CL response in diabetic patients. These findings suggest inhibitory effects of elevated glucose concentrations on PMNs, a possible role of protein glycosylation for impairing PMN function, thus contributing in part to altered host defense.     

The topologic and chronologic patterns of hematopoietic cell seeding in host femoral bone marrow after transplantation.

The early stages of homing, seeding, and engraftment of hematopoietic stem and progenitor cells are poorly characterized. We have developed an optical technique that allows in vivo tracking of transplanted, fluorescent-tagged cells in the host femurs. In this study we used fluorescence microscopy to monitor the topologic and chronologic patterns of hematopoietic cell seeding in the femoral bone marrow (BM) of mice. PKH-labeled cells homed to the femur within minutes after injection into a peripheral vein. Most cells drifted within the marrow space and gradually seeded in clusters close to the endosteal surface of the epiphyseal cortex. Three days after transplantation 85% to 94% (14%) of PKH-labeled cells in the femoral marrow were located within 100 microm of the epiphyseal bone surface (P <.001 versus the more central cells), whereas labeled cells were absent in the femoral diaphysis. Primary seeding of juxtaendosteal, epiphyseal marrow occurred independently of recipient conditioning (myeloablated and nonconditioned hosts), donor-recipient antigen disparity, or the phenotype of the injected cells (whole BM and lineage-negative cells) and was consistently observed in secondary recipients of BM-homed cells. Seeding in regions close to the epiphyseal bone was also observed in freshly excised femurs perfused ex vivo and in femurs assessed without prior placement of optical windows, indicating that the site of primary seeding was not affected by surgical placement of optical windows. Four to 5 days after transplantation, cellular clusters appeared in the more central regions of the epiphyses and in the diaphyses. Centrally located cells showed decreased PKH fluorescence, suggesting that they were progeny of the seeding cells, and brightly fluorescent cells (quiescent first-generation seeding cells) were observed close to the bone surface for as long as 24 days after transplantation. These data indicate that the periphery of the femoral marrow hosts primary seeding and that quiescent cells continue to reside in the periphery for weeks and do not divide. The site of proliferation of transplanted cells is the center of the marrow space.     

Morphologic and immunologic evidence of composite B- and T-cell lymphomas. A report of three cases developing in follicular center cell lymphomas

Composite lymphoma (CL) may be defined as two lymphomas, differing as to their cell of origin, that occur simultaneously in the same tissue specimen. While CL usually is indicated histopathologically by at least two morphologically distinct lymphomatous proliferations, the proof that these proliferations are separate and distinct neoplasms requires immunologic analysis. Many so-called cases of CL actually represent the well-known phenomenon of lymphoid transformation, in which there is a small cell and a large cell component in the same specimen. Immunologic studies in these cases have shown that the cytologically distinct neoplastic cells represent different stages in the same cell line. While studying a large series of follicular center cell (FCC) lymphomas, the authors recognized three cases in which there was both morphologic and immunologic evidence of a true CL. Following an initial diagnosis of a nodular FCC lymphoma, rebiopsies from 21 to 62 months later showed the coexistence of a nodular FCC (B-cell) component and a diffuse large cell (T-cell) component.     

T-cell lymphomas of the stomach: Morphological and immunological studies characterizing two cases of T-cell lymphoma

Summary Using cytochemical, electron microscopic and immunohistochemical techniques in 20 primary malignant lymphomas of the stomach, we found 18 B-cell and 2 T-cell lymphomas. Primary T-cell lymphoma in the stomach has not been previously reported. The T cells in both cases were reminiscent of T immunoblasts with prominent nucleoli and a basophilic cytoplasm. Case 1 showed a cytological relationship to pleomorphic T-cell lymphoma, large cell type. Case 2 contained in addition some cells not previously described in T-cell lymphomas, resembling immature plasma cells with abundant rough endoplasmic reticulum. Focal positivity to acid phosphatase and dipeptidylaminopeptidase IV suggests the T-cell nature of both lymphomas. In both cases the tumour cells were OKT 11 and OKT 4 positive, and negative for OKT 8. Thus, both cases represent high-grade malignant T-cell lymphomas which correspond phenotypically to T-helper cell lymphoma. Case 2 revealed a further immunohistochemical peculiarity: atypical immunoblasts reacted positively with Ki-1 antibody. Thus, it is a Ki-1 lymphoma of T-cell type.     

Follicular dendritic cells are a major reservoir for human immunodeficiency virus type 1 in lymphoid tissues facilitating infection of CD4+ T-helper cells.

Human immunodeficiency virus type 1 (HIV-1) infection causes progressive depletion of CD4/HIV-receptor-positive T helper lymphocytes, ultimately leading to AIDS. The major HIV reservoir and site of T-helper cell infection in lymphoid tissues, however, has remained poorly defined. The authors used in situ hybridization in combination with immunohistologic labeling techniques to identify the phenotype of HIV-infected cells in lymph nodes from patients at different stages of HIV-infection. The number of HIV-infected macrophages, widely considered the major site of HIV replication, was extremely low. There was no evidence for HIV-infection of endothelial and interdigitating reticulum cells. However, HIV RNA was found in small but consistent proportions of CD45RO-positive T cells and in the vast majority of follicular dendritic cells (FDC) in a pattern suggestive of active infection in addition to HIV-immunocomplex trapping on cell membranes. FDC may therefore be a major HIV reservoir and since T-helper cells travel through the FDC meshwork during their migration within lymphoreticular tissues, it appears likely that HIV-replicating T cells may infect FDC, which then infect new T cells, thus causing a gradual dissemination of the virus to all FDC and thereby a steadily increasing infection of T-helper/memory cells within germinal centers. This results in CD4+ T cell depletion, and ultimately, in immunodeficiency.     

Well-being and life satisfaction in generalized anxiety disorder: comparison to major depressive disorder in a community sample

BACKGROUND: In most settings, generalized anxiety disorder (GAD) is highly comorbid with major depressive disorder (MDD). This raises uncertainty about the clinical relevance of GAD as a distinct diagnostic entity. The demonstration of functional impairment attached to GAD, independent of that attributable to MDD, would support the importance of GAD as a separate diagnostic category. METHODS: The Ontario Health Survey Mental Health Supplement, a survey of more than 8000 residents aged 15-64 of the Canadian province of Ontario, used the University of Michigan Composite International Interview Schedule (also used in the US National Comorbidity Survey) to assign DSM-III-R diagnoses. Several indicators of disability and quality of life were included. Our analytic strategy was to compare these indices in persons with and without GAD, stratified by MDD comorbidity, and adjusting for the effects of relevant sociodemographic factors (e.g., social class, age, gender) and dysthymia. Odds ratios (ORs) are reported; SUDAAN was used to adjust for the sampling framework. RESULTS: GAD was highly comorbid with MDD on both a lifetime and past-year basis. Both past-year and lifetime MDD and GAD were associated with an increased likelihood of low overall perceived well-being. Both lifetime MDD and GAD were associated with dissatisfaction in one's main activity and with family relationships. LIMITATIONS: Other comorbid Axis I or II conditions might be confounders with impairment; a lower rate of GAD than in some prior surveys bears consideration. CONCLUSIONS: These observations confirm that GAD is associated with an increased likelihood of poor global well-being and life satisfaction, beyond that associated with MDD. Given the chronicity of GAD relative to the more often episodic course of MDD, the long-term functional benefits of treating GAD may be substantial.     

Randomized controlled trial assessing the effect of vitamin A supplementation on maternal morbidity during pregnancy and postpartum among HIV-infected women

OBJECTIVE: To determine whether low-cost treatment of HIV using vitamin A would be beneficial, we examined the effect of vitamin A supplementation on morbidity of HIV-1 infected women. METHODS: We conducted a randomized, double blind placebo-controlled trial at King Edward VIII Hospital, in Durban, South Africa. In total, 312 HIV-seropositive pregnant women between 28 and 32 weeks' gestation were recruited into this trial. Patients were randomized to receive placebo or 5,000 IU retinyl palmitate and 30 mg beta-carotene daily. At delivery of their children, patients received placebo or 200,000 IU retinyl palmitate. The main outcome measures were pre- and postnatal report of HIV-related symptoms. RESULTS: Vitamin A did not confer any significant beneficial effect on the report of either HIV or pregnancy-related symptoms during the pre- or postnatal period. CONCLUSION: In this study of HIV-infected pregnant women, vitamin A supplementation given in doses designed to decrease mother-to-infant transmission did not result in significant beneficial effect on reported symptoms pre- or postnatally. Further investigation with larger number of participants, tailoring supplementation for specific clinical conditions, outside the context of pregnancy, is required to help clarify the possible clinical benefits of vitamin A.