CD4 lymphocytes in the blood of HIV(+) individuals migrate rapidly to lymph nodes and bone marrow: support for homing theory of CD4 cell depletion

Recent studies have provided evidence that macrophages from Th1-prone mouse strains respond with an M1 profile, and macrophages from Th2-prone mouse strains respond with an M2 profile, characterized by the dominant production of NO or TGF-beta 1, respectively. We have shown that peritoneal macrophages from IL-12p40 gene knockout mice have a bias toward the M2 profile, spontaneously secreting large amounts of TGF-beta 1 and responding to rIFN-gamma with weak NO production. Moreover, IL-12p40KO macrophages are more permissive to Trypanosoma cruzi replication than their wild-type littermate cells. Prolonged incubation with rIL-12 fails to reverse the M2 polarization of IL-12p40KO macrophages. However, TGF-beta 1 is directly implicated in sustaining the M2 profile because its inhibition increases NO release from IL-12p40KO macrophages. IFN-gamma deficiency is apparently not the reason for TGF-beta 1 up-regulation, because rIFN-gamma KO macrophages produce normal amounts of this cytokine. These findings raise the possibility that IL-12 has a central role in driving macrophage polarization, regulating their intrinsic ability to respond against intracellular parasites.     

Increasing access to medical education for students from medically underserved communities: one program's success.

The Premedical Honors College (PHC) is an eight-year, BS-MD program created in 1994 by Baylor College of Medicine (BCM) and The University of Texas-Pan American (UT-PA) to increase the number of physicians addressing the health care needs of underserved populations in Texas. The PHC targets South Texas, a 13-county, medically underserved area with a population that is 82% Hispanic. To date, the PHC has had 159 matriculants and 71 graduates, of whom 60 (84.5%) have matriculated into medical school. These results are significant considering that in 1996, only four students from all five South Texas colleges (combined enrollment of 30000 students) were accepted to medical school. An outcomes study comparing PHC matriculants with students of similar academic ability, ethnicity, and interest in medicine revealed that the odds of medical school matriculation were seven times higher for PHC students than for non-PHC students. The PHC's initial success has been acknowledged by the Texas legislature, which recently passed a bill to promote the PHC's replication. In addition, the number of PHC students-of whom 95% are Mexican American-who matriculate into medical school annually is significant nationally. In 2001, only 386 U.S. medical school matriculants (2.3% of all matriculants) were Mexican American; 17 of these students (4.4%) were PHC graduates. If current trends continue, the PHC could significantly expand the number of physicians serving minority and medically underserved populations in Texas and the nation. Also, the PHC provides an opportunity for research on programs designed to create pathways from high school to medical school.     

Elevated amyloid beta protein (Abeta42) and late onset Alzheimer's disease are associated with single nucleotide polymorphisms in the urokinase-type plasminogen activator gene

Plasma amyloid beta protein (Abeta42) levels and late onset Alzheimer's disease (LOAD) have been linked to the same region on chromosome 10q. The PLAU gene within this region encodes urokinase-type plasminogen activator, which converts plasminogen to plasmin. Abeta aggregates induce PLAU expression thereby increasing plasmin, which degrades both aggregated and non-aggregated forms of Abeta. We evaluated single nucleotide polymorphisms (SNPs) in PLAU for association with Abeta42 and LOAD. PLAU SNP compound genotypes composed of haplotype pairs showed significant association with AD in three independent case-control series. PLAU SNP haplotypes associated significantly with plasma Abeta42 in 10 extended LOAD families. One of the SNPs analyzed was a missense C/T polymorphism in exon 6 of PLAU (PLAU_1=rs2227564), which causes a proline to leucine change (P141L). We analyzed PLAU_1 for association with AD in six case-control series and 24 extended LOAD families. The CT and TT PLAU_1 genotypes showed association (P=0.05) with an overall estimated odds ratio of 1.2 (1.0-1.5). The CT and TT genotypes of PLAU_1 were also associated with significant age-dependent elevation of plasma Abeta42 in 24 extended LOAD families (P=0.0006). In knockout mice lacking the PLAU gene, plasma--but not brain--Abeta42 as well as Abeta40 was significantly elevated, also in an age-dependent manner. The PLAU_1 associations were independent of the associations we found among plasma Abeta42, LOAD and variants in the IDE or VR22 region. These results provide strong evidence that PLAU or a nearby gene is involved in the development of LOAD. PLAU_1 is a plausible pathogenic mutation that could act by increasing Abeta42, but additional biological experiments are required to show this definitively.     

Deterministic projection by growing cell structure networks for visualization of high-dimensionality datasets

Recent advances in clinical proteomics data acquisition have led to the generation of datasets of high complexity and dimensionality. We present here a visualization method for high-dimensionality datasets that makes use of neuronal vectors of a trained growing cell structure (GCS) network for the projection of data points onto two dimensions. The use of a GCS network enables the generation of the projection matrix deterministically rather than randomly as in random projection. Three datasets were used to benchmark the performance and to demonstrate the use of this deterministic projection approach in real-life scientific applications. Comparisons are made to an existing self-organizing map projection method and random projection. The results suggest that deterministic projection outperforms existing methods and is suitable for the visualization of datasets of very high dimensionality.     

Role of O2-sensitive K and Ca channels in the regulation of the pulmonary circulation: Potential role of caveolae and implications for high altitude pulmonary edema

High altitude pulmonary edema (HAPE) is a potentially fatal complication in response to exposure to low O₂ at high altitudes. Hypoxia, by causing pulmonary vasoconstriction, increases pulmonary vascular resistance and pulmonary arterial pressure, both of which are features in the pathogenesis of HAPE. Uneven hypoxic pulmonary vasoconstriction is thought to be responsible for increased capillary pressure and leakage, resulting in edema. O₂-sensitive ion channels are known to play pivotal roles in determining vascular tone in response to hypoxia. K⁺, Ca²⁺ and Na⁺ channels are ubiquitously expressed in both endothelial and smooth muscle cells of the pulmonary microvasculature, subfamilies of which are regulated by local changes in P_O2. Hypoxia reduces activity of voltage-gated K⁺ channels and down-regulates their expression leading to membrane depolarization, Ca²⁺ influx in pulmonary artery smooth muscle cells (by activating voltage-dependent Ca²⁺ channels) and vasoconstriction. Hypoxia up-regulates transient receptor potential channels (TRPC) leading to enhanced Ca²⁺ entry through receptor- and store-operated Ca²⁺ channels. Altered enrichment of ion channels in membrane microdomains, in particular in caveolae, may play a role in excitation–contraction coupling and perhaps in O₂-sensing in the pulmonary circulation and thereby may contribute to the development of HAPE. We review the role of ion channels, in particular those outlined above, in response to low O₂ on vascular tone and pulmonary edema. Advances in the understanding of ion channels involved in the physiological response to hypoxia should lead to a greater understanding of the pathogenesis of HAPE and perhaps in the identification of new therapies.     

fMRI activation in the human frontal eye field is correlated with saccadic reaction time

Variation in response latency to identical sensory stimuli has been attributed to variation in neural activity mediating preparatory set. Here we report evidence for a relationship between saccadic reaction time (SRT) and set-related brain activity measured with event-related functional magnetic resonance imaging. We measured hemodynamic activation time-courses during a preparatory "gap" period, during which no visual stimulus was present and no saccades were made. The subjects merely anticipated appearance of the target. Saccade direction and latency were recorded during scanning, and trials were sorted according to SRT. Both the frontal (FEF) and supplementary eye fields showed pre-target preparatory activity, but only in the FEF was this activity correlated with SRT. Activation in the intraparietal sulcus did not show any preparatory activity. These data provide evidence that the human FEF plays a central role in saccade initiation; pre-target activity in this region predicts both the type of eye movement (whether the subject will look toward or away from the target) and when a future saccade will occur.     

Cholesterol-enriched membrane microdomains are required for inducing host cell cytoskeleton rearrangements in response to attaching-effacing Escherichia coli

The diarrheal pathogens enterohemorrhagic Escherichia coli (EHEC) O157:H7 strain CL56 and enteropathogenic Escherichia coli (EPEC) O127:H6 strain E2348/69 adhere intimately to epithelial cells through attaching-effacing lesions, which are characterized by rearrangements of the host cytoskeleton, intimate adherence, and destruction of microvilli. These cytoskeletal responses require activation of host signal transduction pathways. Lipid rafts are signaling microdomains enriched in sphingolipid and cholesterol in the plasma membrane. The effect of perturbing plasma membrane cholesterol on bacterial intimate adherence was assessed. Infection of both HEp-2 cells and primary skin fibroblasts with strains CL56 and E2348/69 caused characteristic rearrangements of the cytoskeleton at sites of bacterial adhesion. CL56- and E2348/69-induced cytoskeletal rearrangements were inhibited following cholesterol depletion. Addition of exogenous cholesterol to depleted HEp-2 cells restored cholesterol levels and rescued bacterially induced alpha-actinin mobilization. Quantitative bacterial adherence assays showed that EPEC adherence to HEp-2 cells was dramatically reduced following cholesterol depletion, whereas the adherence of EHEC remained high. Cytoskeletal rearrangements on skin fibroblasts obtained from children with Niemann-Pick type C disease were markedly reduced. These findings indicate that host membrane cholesterol contained in lipid rafts is necessary for the cytoskeletal rearrangements following infection with attaching-effacing Escherichia coli. Differences in initial adherence indicate divergent roles for host membrane cholesterol in the pathogenesis of EHEC and EPEC infections.     

Inflammatory Markers in Acute Myocardial Infarction Patients: Preliminary Evidence of a Prospective Association With Depressive Symptoms

Inflammatory activity has been associated with both coronary disease and depressive symptoms. We sought to determine whether inflammatory markers in myocardial infarction (MI) patients are prospectively associated with depressive symptomatology. Participants were a convenience sample of MI patients. Depressive symptoms were assessed soon after the MI and again 7 months postdischarge. Inflammatory markers examined were interleukin-6 (IL-6) and interleukin-1β. Results suggest no significant cross-sectional association between inflammatory markers and depressive symptoms at baseline. However, bivariate and multiple regression analyses revealed a significant positive prospective association between baseline IL-6 and depressive symptoms 7 months later ( β  = .57, p  < .01). The results suggest that temporal considerations are important in understanding relationships between inflammation and depressive symptoms following MI.     

Hepatic angiomyolipoma and hepatic stellate cells share a similar gene expression profile

BACKGROUND AND AIMS: Angiomyolipomas (AMLs) of the liver are rare neoplasms composed of large epithelioid cells with intermixed fat and blood vessels. Hepatic AMLs have no clear normal-cell counterpart in the liver. However, AMLs and stellate cells both are positive for neural crest-derived markers including HMB-45 antigen. METHODS: To further explore the similarities between hepatic AMLs and stellate cells, gene expression of a hepatic AML was studied by cDNA microarray. Real-time polymerase chain reaction was used to confirm gene expression. Hepatic stellate cells can be quiescent, activated, or have a myofibroblastic phenotype depending on their state of activation. Expression of known markers of activated stellate cells was compared between the AML, activated primary mouse stellate cells, and stellate cell lines with activated and myofibroblastic phenotypes. Next, 5 novel genes from the AML were selected because they were not previously known to be markers of stellate cells and mRNA expression measured in the activated mouse stellate cells and in myofibroblastic stellate cell lines. Finally, expression levels of 10 novel genes were determined in 5 cirrhotic and 5 noncirrhotic human livers. RESULTS: Overexpression of known markers of activated stellate cells including transforming growth factor beta (TGF- beta ), smooth muscle actin, and collagen was found in the hepatic AML. Three of 5 novel markers that were identified in the AML, RRAD (Ras-related associated with diabetes), CTSK (cathepsin K), and NIBAN were also found to be overexpressed in activated stellate cells compared with quiescent or myofibroblastic stellate cells. In addition, 9 of 10 novel genes overexpressed in AML were also overexpressed in cirrhotic human livers versus noncirrhotic livers. CONCLUSIONS: Hepatic AMLs share a similar gene expression profile and may differentiate toward activated stellate cells.