Medication compliance is one of the foremost problems affecting neuroleptic efficacy in psychiatric patients. To date, compliancy has most commonly been assessed with the Drug Attitude Inventory (DAI) developed by Hogan et al. (Hogan, T.P., Awad, A.G., Eastwood, R., 1983. A self-report scale predictive of drug compliance in schizophrenics: reliability and discriminative validity. Psychol. Med. 13, 177-183). The present study identified several deficiencies in the DAI. Using the partial credit version of the Item Response Theory measurement model, the DAI was refined with the aim of greater validity and clinical utility. The new inventory was administered to 66 patients, the majority of whom were diagnosed with schizophrenia. When available, lithium levels and carer ratings of compliance were also recorded and used to verify compliancy. The new inventory appears to be a valid and reliable measure of compliancy for psychoactive medications.

Octanol-to-water solvation free energies of acetyl amino amides (Ac-X-amides) [Fauchère, J.L., & Pliska, V. (1983) Eur. J. Med. Chem. --Chim. Ther. 18,369] form the basis for computational comparisons of protein stabilities by means of the atomic solvation parameter formalism of Eisenberg and McLachlan [(1986) Nature 319, 199]. In order to explore this approach for more complex systems, we have determined by octanol-to-water partitioning the solvation energies of (1) the guest (X) side chains in the host-guest pentapeptides AcWL-X-LL, (2) the carboxy terminus of the pentapeptides, and (3) the peptide bonds of the homologous series of peptides AcWLm (m = 1-6). Solvation parameters were derived from the solvation energies using estimates of the solvent-accessible surface areas (ASA) obtained from hard-sphere Monte Carlo simulations. The measurements lead to a side chain solvation-energy scale for the pentapeptides and suggest the need for modifying the Asp, Glu, and Cys values of the "Fauchère-Pliska" solvation-energy scale fro the Ac-X-amides. We find that the unfavorable solvation energy of nonpolar residues can be calculated accurately by a solvation parameter of 22.8 +/- 0.8 cal/mol/A2, which agrees satisfactorily with the AC-X-amide data and thereby validates the Monte Carlo ASA results. Unlike the Ac-X-amide data, the apparent solvation energies of the uncharged polar residues are also largely unfavorable. This unexpected finding probably results, primarily, from differences in conformation and hydrogen bonding in octanol and buffer but may also be due to the additional flaking peptide bonds of the pentapeptides. The atomic solvation parameter (ASP) for the peptide bond is comparable to the ASP of the charged carboxy terminus which is an order of magnitude larger than the ASP of the uncharged polar side chains of the Ac-X-amides. The very large peptide bond ASP, -96 +/- 6 cal/mol/A2, profoundly affects the results of computational comparisons of protein stability which use ASPs derived from octanol-water partitioning data.

Although the potential for genomics to contribute to clinical care has long been anticipated, the pace of defining the risks and benefits of incorporating genomic findings into medical practice has been relatively slow. Several institutions have recently begun genomic medicine programs, encountering many of the same obstacles and developing the same solutions, often independently. Recognizing that successful early experiences can inform subsequent efforts, the National Human Genome Research Institute brought together a number of these groups to describe their ongoing projects and challenges, identify common infrastructure and research needs, and outline an implementation framework for investigating and introducing similar programs elsewhere. Chief among the challenges were limited evidence and consensus on which genomic variants were medically relevant; lack of reimbursement for genomically driven interventions; and burden to patients and clinicians of assaying, reporting, intervening, and following up genomic findings. Key infrastructure needs included an openly accessible knowledge base capturing sequence variants and their phenotypic associations and a framework for defining and cataloging clinically actionable variants. Multiple institutions are actively engaged in using genomic information in clinical care. Much of this work is being done in isolation and would benefit from more structured collaboration and sharing of best practices.Genet Med 2013:15(4):258-267.

BACKGROUND

While pervasive racial and ethnic inequalities in access to care and health status have been documented, potential underlying causes, such as patients' perceptions of their physicians, have not been explored as thoroughly.

OBJECTIVE

To assess whether a person's race or ethnicity is associated with low trust in the physician.

METHODS

Data were obtained from the 1996 through 1997 Community Tracking Survey, a nationally representative sample. Adults who identified a physician as their regular provider and had at least 1 physician visit in the preceding 12 months were included (N = 32,929).

METHODS

Patients' ratings of their satisfaction with the style of their physician and their trust in physicians. The Satisfaction With Physician Style Scale measured respondents' perceptions of their physicians' listening skills, explanations, and thoroughness. The Trust in Physician Scale measured respondents' perceptions that their physicians placed the patients' needs above other considerations, referred the patient when needed, performed unnecessary tests or procedures, and were influenced by insurance rules.

RESULTS

After adjustment for socioeconomic and other factors, minority group members reported less positive perceptions of physicians than whites on these 2 conceptually distinct scales. Minority group members who lacked physician continuity on repeat clinic visits reported even less positive perceptions of their physicians on these 2 scales than whites.

CONCLUSIONS

Patients from racial and ethnic minority groups have less positive perceptions of their physicians on at least 2 important dimensions. The reasons for these differences should be explored and addressed. Arch Fam Med. 2000;9:1156-1163

We describe methods for the production, purification, and characterization of clinical grade (cGMP) exosomes derived from antigen presenting cells (APCs). Exosomes have been shown to have immunotherapeutic properties through their presentation of biologically relevant antigens [Nat. Med. 4 (1998) 594] and are being developed as an alternative to cellular therapies. Exosomes are 50-90-nm-diameter vesicles secreted from multivesicular bodies (MVBs) found in a variety of both hematopoietic and tumor cells. These particles contain antigen presenting molecules (MHC class I, MHC class II, and CD1), tetraspan molecules (CD9, CD63, CD81), adhesion molecules (CD11b and CD54), and costimulatory molecules (CD86); hence, providing them the necessary machinery required for generating a potent immune response [J. Biol. Chem. 273 (1998) 20121; J. Cell. Sci. 113 (2000) 3365; J. Immunol. Methods 247 (2001) 163; J. Immunol. 166 (2001) 7309]. Exosomes from monocyte-derived dendritic cells (MDDCs) were rapidly purified (e.g. 4-6 h of a 2-3 l culture) based on their unique size and density. Ultrafiltration of the clarified supernatant through a 500-kDa membrane and ultracentrifugation into a 30% sucrose/deuterium oxide (D2O) (98%) cushion (density 1.210 g/cm3) reduced the volume and protein concentration approximately 200- and 1000-fold, respectively. The percentage recovery of exosomes ranged from 40% to 50% based on the exosome MHC class II concentration of the starting clarified supernatant. This methodology was extended to a miniscale process with comparable results. Conversely, the classical differential centrifugation technique is a more lengthy and variable process resulting in exosomes being contaminated with media proteins and containing only 5-25% of the starting exosome MHC class II concentration; hence, making it difficult for their use in clinical development. Lastly, we developed the following quality control assays to standardize the exosome vaccine: quantity (concentration of MHC class II) and protein characterization (FACS). The combination of a rapid and reproducible purification method and quality control assays for exosomes has allowed for its evaluation as a cancer vaccine in clinical trials [Proc. Am. Soc. Oncol. 21 (2002) 11a].

OBJECTIVE

To identify, localize, and determine M1/M2 polarization of epidydimal adipose tissue (eAT) macrophages (Phis) during high-fat diet (HFD)-induced obesity.

METHODS

Male C57BL/6 mice were fed an HFD (60% fat kcal) or low-fat diet (LFD) (10% fat kcal) for 8 or 12 weeks. eATMPhis (F4/80(+) cells) were characterized by in vivo fluorescent labeling, immunohistochemistry, fluorescence-activated cell sorting, and quantitative PCR.

RESULTS

Recruited interstitial macrophage galactose-type C-type lectin (MGL)1(+)/CD11c(-) and crown-like structure-associated MGL1(-)/CD11c(+) and MGL1(med)/CD11c(+) eATMPhis were identified after 8 weeks of HFD. MGL1(med)/CD11c(+) cells comprised approximately 65% of CD11c(+) eATMPhis. CD11c(+) eATMPhis expressed a mixed M1/M2 profile, with some M1 transcripts upregulated (IL-12p40 and IL-1beta), others downregulated (iNOS, caspase-1, MCP-1, and CD86), and multiple M2 and matrix remodeling transcripts upregulated (arginase-1, IL-1Ra, MMP-12, ADAM8, VEGF, and Clec-7a). At HFD week 12, each eATMPhi subtype displayed an enhanced M2 phenotype as compared with HFD week 8. CD11c(+) subtypes downregulated IL-1beta and genes mediating antigen presentation (I-a, CD80) and upregulated the M2 hallmark Ym-1 and genes promoting oxidative metabolism (PGC-1alpha) and adipogenesis (MMP-2). MGL1(med)/CD11c(+) eATMPhis upregulated additional M2 genes (IL-13, SPHK1, CD163, LYVE-1, and PPAR-alpha). MGL1(med)/CD11c(+) ATMPhis expressing elevated PGC-1alpha, PPAR-alpha, and Ym-1 transcripts were selectively enriched in eAT of obese mice fed pioglitazone for 6 days, confirming the M2 features of the MGL1(med)/CD11c(+) eATMPhi transcriptional profile and implicating PPAR activation in its elicitation.

CONCLUSIONS

These results 1) redefine the phenotypic potential of CD11c(+) eATMPhis and 2) suggest previously unappreciated phenotypic and functional commonality between murine and human ATMPhis in the development of obesity and its complications.

Antigen transport from the airway mucosa to the thoracic lymph nodes (TLNs) was studied in vivo by intratracheal instillation of fluorescein isothiocyanate (FITC)-conjugated macromolecules. After instillation, FITC(+) cells with stellate morphology were found deep in the TLN T cell area. Using flow cytometry, an FITC signal was exclusively detected in CD11c(med-hi)/major histocompatibility complex class II (MHCII)(hi) cells, representing migratory airway-derived lymph node dendritic cells (AW-LNDCs). No FITC signal accumulated in lymphocytes and in a CD11c(hi)MHCII(med) DC group containing a CD8 alpha(hi) subset (non-airway-derived [NAW]-LNDCs). Sorted AW-LNDCs showed long MHCII(bright) cytoplasmic processes and intracytoplasmatic FITC(+) granules. The fraction of FITC(+) AW-LNDCs peaked after 24 h and had reached baseline by day 7. AW-LNDCs were depleted by 7 d of ganciclovir treatment in thymidine kinase transgenic mice, resulting in a strong reduction of FITC-macromolecule transport into the TLNs. Compared with intrapulmonary DCs, AW-LNDCs had a mature phenotype and upregulated levels of MHCII, B7-2, CD40, and intracellular adhesion molecule (ICAM)-1. In addition, sorted AW-LNDCs from FITC-ovalbumin (OVA)-instilled animals strongly presented OVA to OVA-TCR transgenic T cells. These results validate the unique sentinel role of airway DCs, picking up antigen in the airways and delivering it in an immunogenic form to the T cells in the TLNs.

BACKGROUND

Systemic sclerosis (SSc) is a multisystem autoimmune disease, which is classified into a diffuse cutaneous (dcSSc) and a limited cutaneous (lcSSc) subset according to the skin involvement. In order to better understand the vascular, immunological and fibrotic processes of SSc and to guide its treatment, the EULAR Scleroderma Trials And Research (EUSTAR) group was formed in June 2004.

OBJECTIVE

EUSTAR collects prospectively the Minimal Essential Data Set (MEDS) on all sequential patients fulfilling the American College of Rheumatology diagnostic criteria in participating centres. We aimed to characterise demographic, clinical and laboratory characteristics of disease presentation in SSc and analysed EUSTAR baseline visits.

RESULTS

In April 2006, a total of 3656 patients (1349 with dcSSc and 2101 with lcSSc) were enrolled in 102 centres and 30 countries. 1330 individuals had autoantibodies against Scl70 and 1106 against anticentromere antibodies. 87% of patients were women. On multivariate analysis, scleroderma subsets (dcSSc vs lcSSc), antibody status and age at onset of Raynaud's phenomenon, but not gender, were found to be independently associated with the prevalence of organ manifestations. Autoantibody status in this analysis was more closely associated with clinical manifestations than were SSc subsets.

CONCLUSIONS

dcSSc and lcSSc subsets are associated with particular organ manifestations, but in this analysis the clinical distinction seemed to be superseded by an antibody-based classification in predicting some scleroderma complications. The EUSTAR MEDS database facilitates the analysis of clinical patterns in SSc, and contributes to the standardised assessment and monitoring of SSc internationally.

BACKGROUND

Although minimally invasive surgery has been accepted for a variety of disorders, laparoscopic resection of colorectal cancer is performed by few. Concern about oncological radicality and long term outcome has limited the adoption of laparoscopic surgery for colorectal cancer.

OBJECTIVE

To determine long-term outcome after laparoscopically-assisted versus open surgery for non-metastasised colorectal cancer.

METHODS

The Cochrane library, EMBASE, Pub med and Cancer Lit were searched for published and unpublished randomised controlled trials.

METHODS

Randomised clinical trials comparing laparoscopically-assisted and open surgery for non-metastasised colorectal cancer were included. Studies that did not report any long-term outcomes were excluded.

METHODS

Two reviewers independently assessed the studies and extracted data. RevMan 4.2 was used for statistical analysis.

RESULTS

Thirty-three randomised clinical trials (RCT) comparing laparoscopically-assisted versus open surgery for colorectal cancer were identified. Twelve of these trials, involving 3346 patients, reported long-term outcome and were included in the current analysis. No significant differences in the occurrence of incisional hernia, reoperations for incisional hernia or reoperations for adhesions were found between laparoscopically assisted and open surgery (2 RCT, 474 pts, 7.9% vs 10.9%;P = 0.32 and 2 RCT, 474 pts, 4.0% vs 2.8%; P = 0.42 and 1 RCT, 391 pts, 1.1% vs 2.5%;P = 0.30, respectively). Rates of recurrence at the site of the primary tumor were similar (colon cancer: 4 RCT, 938 pts, 5.2% vs 5.6%; OR (fixed) 0.84 (95% CI 0.47 to 1.52)(P = 0.57); rectal cancer: 4 RCT, 714 pts, 7.2% vs 7.7%; OR (fixed) 0.81 (95% CI 0.45 to 1.43) (P = 0.46). No differences in the occurrence of port-site/wound recurrences were observed (P=0.16). Similar cancer-related mortality was found after laparoscopic surgery compared to open surgery ( colon cancer: 5 RCT, 1575 pts, 14.6% vs 16.4%; OR (fixed) 0.80 (95% CI 0.61 to 1.06) (P=0.15); rectal cancer: 3 RCT, 578 pts, 9.2% vs 10.0%; OR (fixed) 0.66 (95% CI 0.37 to 1.19) (P=0.16). Four studies were included in the meta-analyses on hazard ratios for tumour recurrence in laparoscopic colorectal cancer surgery. No significant difference in recurrence rate was observed between laparoscopic and open surgery (hazard ratio for tumour recurrence in the laparoscopic group 0.92; 95% CI 0.76-1.13). No significant difference in tumour recurrence between laparoscopic and open surgery for colon cancer was observed (hazard ratio for tumour recurrence in the laparoscopic group 0.86; 95% CI 0.70-1.08).

CONCLUSIONS

Laparoscopic resection of carcinoma of the colon is associated with a long term outcome no different from that of open colectomy. Further studies are required to determine whether the incidence of incisional hernias and adhesions is affected by method of approach. Laparoscopic surgery for cancer of the upper rectum is feasible, but more randomised trials need to be conducted to assess long term outcome.

The aim of this study was to investigate whether apparent diffusion coefficients (ADCs) could be used as measures of cell density and necrotic fraction of tumors. Tumors of four human melanoma xenograft lines were subjected to diffusion-weighted magnetic resonance imaging (DWI). ADCs were calculated from the images and related to cell density and necrotic fraction, as determined from histological sections. A significant correlation was found between the ADC of the viable tissue and cell density, regardless of whether tumors of different lines or different regions within individual tumors were considered. Necrosis was found in two of the lines. A single region of massive necrosis that could be differentiated from the viable tissue in ADC maps was found in one line, whereas a number of smaller necrotic regions that could not be identified in ADC maps were found in the other line. Tumor ADC was significantly correlated with the necrotic fraction of the former, but not of the latter line. Our results suggest that ADCs can be used as measures of cell density and necrotic fraction of some but not of all tumors, depending on whether the individual necrotic regions are large enough to be differentiated from the viable tissue with the obtained spatial resolution of the DW images. Magn Reson Med 43:828-836, 2000.

The human thyroid hormone receptor-associated protein (TRAP) complex, an earlier described coactivator for nuclear receptors, and an SRB- and MED-containing cofactor complex (SMCC) that mediates activation by Gal4-p53 are shown to be virtually the same with respect to specific polypeptide subunits, coactivator functions, and mechanisms of action (activator interactions). In parallel with ligand-dependent interactions of nuclear receptors with the TRAP220 subunit, p53 and VP16 activation domains interact directly with a newly cloned TRAP80 subunit. These results indicate novel pathways for the function of nuclear receptors and other activators (p53 and VP16) through a common coactivator complex that is likely to target RNA polymerase II. Identification of the TRAP230 subunit as a previously predicted gene product also suggests a coactivator-related transcription defect in certain disease states.

Accurate knowledge of the magnetic properties of human blood is required for the precise modeling of functional and vascular flow-related MRI. Herein are reported determinations of the relaxation parameters of blood, employing in vitro samples that are well representative of human blood in situ. The envelope of the blood (1)H(2)O free-induction decay signal magnitude during the first 100 msec following a spin echo at time TE is well- described empirically by an expression of the form, S(t) = S(o). exp[-R(*)(2). (t - TE) - AR*. (t - TE)(2)]. The relaxation parameters AR* and R(*)(2) increase as a function of the square of the susceptibility difference between red blood cell and plasma and depend on the spin-echo time. The Gaussian component, AR*, should be recognized in accurate modeling of MRI phenomena that depend upon the magnetic state of blood. The magnetic susceptibility difference between fully deoxygenated and fully oxygenated red blood cells at 37 degrees C is 0.27 ppm, as determined independently by MR and superconducting quantum interference device (SQUID) measurements. This value agrees well with the 1936 report of Pauling and Coryell (Proc Natl Acad Sci USA 1936;22:210-216), but is substantially larger than that frequently used in MRI literature. Magn Reson Med 45:533-542, 2001.

A genome-wide association (GWA) study with pooled DNA in adult attention-deficit/hyperactivity disorder (ADHD) employing approximately 500K SNP markers identifies novel risk genes and reveals remarkable overlap with findings from recent GWA scans in substance use disorders. Comparison with results from our previously reported high-resolution linkage scan in extended pedigrees confirms several chromosomal loci, including 16q23.1-24.3 which also reached genome-wide significance in a recent meta-analysis of seven linkage studies (Zhou et al. in Am J Med Genet Part B, 2008). The findings provide additional support for a common effect of genes coding for cell adhesion molecules (e.g., CDH13, ASTN2) and regulators of synaptic plasticity (e.g., CTNNA2, KALRN) despite the complex multifactorial etiologies of adult ADHD and addiction vulnerability.

Disclaimer: These recommendations are designed primarily as an educational resource for medical geneticists and other healthcare providers to help them provide quality medical services. Adherence to these recommendations is completely voluntary and does not necessarily assure a successful medical outcome. These recommendations should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed toward obtaining the same results. In determining the propriety of any specific procedure or test, the clinician should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen. Clinicians are encouraged to document the reasons for the use of a particular procedure or test, whether or not it is in conformance with this statement. Clinicians also are advised to take notice of the date this statement was adopted and to consider other medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures.To promote standardized reporting of actionable information from clinical genomic sequencing, in 2013, the American College of Medical Genetics and Genomics (ACMG) published a minimum list of genes to be reported as incidental or secondary findings. The goal was to identify and manage risks for selected highly penetrant genetic disorders through established interventions aimed at preventing or significantly reducing morbidity and mortality. The ACMG subsequently established the Secondary Findings Maintenance Working Group to develop a process for curating and updating the list over time. We describe here the new process for accepting and evaluating nominations for updates to the secondary findings list. We also report outcomes from six nominations received in the initial 15 months after the process was implemented. Applying the new process while upholding the core principles of the original policy statement resulted in the addition of four genes and removal of one gene; one gene did not meet criteria for inclusion. The updated secondary findings minimum list includes 59 medically actionable genes recommended for return in clinical genomic sequencing. We discuss future areas of focus, encourage continued input from the medical community, and call for research on the impact of returning genomic secondary findings.Genet Med 19 2, 249-255.

This November 2011 edition of the IAS-USA drug resistance mutations list updates the figures last published in December 2010 (Johnson VA et al, Top HIV Med, 2010;18:156-163).

A new enzymatic method is presented for the determination of serum choline-containing phospholipids with a combined enzymatic method using phospholipase D (from Streptomyces species), choline oxidase (from Arthrobacter species) and peroxidase. The method is reproducible, and the results correlate well with those obtained by the conventional digestion method (Hoeflmayr, J. and Fried, R. (1966) Med. Ernaehr. 7, 9-10). The method affords better specificity, requires a smaller quantity of the sample and shorter time than those previously reported, and has excellent precision.

The multisubunit Mediator (MED) complex bridges DNA-bound transcriptional regulators to the RNA polymerase II (PolII) initiation machinery. In yeast, the 25 MED subunits are distributed within three core subcomplexes and a separable kinase module composed of Med12, Med13 and the Cdk8-CycC pair thought to control the reversible interaction between MED and PolII by phosphorylating repeated heptapeptides within the Rpb1 carboxyl-terminal domain (CTD). Here, MED conservation has been investigated across the eukaryotic kingdom. Saccharomyces cerevisiae Med2, Med3/Pgd1 and Med5/Nut1 subunits are apparent homologs of metazoan Med29/Intersex, Med27/Crsp34 and Med24/Trap100, respectively, and these and other 30 identified human MED subunits have detectable counterparts in the amoeba Dictyostelium discoideum, indicating that none is specific to metazoans. Indeed, animal/fungal subunits are also conserved in plants, green and red algae, entamoebids, oomycetes, diatoms, apicomplexans, ciliates and the 'deep-branching' protists Trichomonas vaginalis and Giardia lamblia. Surprisingly, although lacking CTD heptads, T. vaginalis displays 44 MED subunit homologs, including several CycC, Med12 and Med13 paralogs. Such observations have allowed the identification of a conserved 17-subunit framework around which peripheral subunits may be assembled, and support a very ancient eukaryotic origin for a large, four-module MED. The implications of this comprehensive work for MED structure-function relationships are discussed.

We examined the incidence and clinical and economic consequences of primary hyperparathyroidism in residents of Rochester, Minn, from 1965 through 1976; 90 cases were found. From January 1, 1965, to June 31, 1974, the average annual incidence was 7.8 +/- 1.2 (mean +/- S.D.) cases per 100,000 population. However, after the introduction of routine measurement of serum calcium, the average annual incidence rose to 51.1 +/- 9.6 cases per 100,000. Even after availability of routine measurement of serum calcium, the annual incidence of primary hyperparathyroidism among persons 39 years of age or younger remained below 10 cases per 100,000. However, the annual incidence increased sharply in persons 40 or more years of age, reaching 188 cases per 100,000 among women 60 years of age and over and 92 cases per 100,000 among men 60 and over. For the last 1.5 years of the study, the average annual age-adjusted incidence of primary hyperparathyroidism was 27.7 +/- 5.8 per 100,000. The frequency of urolithiasis fell from 51 to 4 per cent (P less than 0.001), and the proportion of cases without symptoms or complications of primary hyperparathyroidism rose from 18 to 51 per cent (P less than 0.005). The median charge in 1977 for diagnosis and treatment of primary hyperparathyroidism was $1700. (N Engl J Med 302:189-193, 1980).

The relationship between blood oxygenation level-dependent (BOLD) MRI signals, cerebral blood flow (CBF), and oxygen consumption (CMR(O2)) in the physiological steady state was investigated. A quantitative model, based on flow-dependent dilution of metabolically generated deoxyhemoglobin, was validated by measuring BOLD signals and relative CBF simultaneously in the primary visual cortex (V1) of human subjects (N = 12) during graded hypercapnia at different levels of visual stimulation. BOLD and CBF responses to specific conditions were averaged across subjects and plotted as points in the BOLD-CBF plane, tracing out lines of constant CMR(O2). The quantitative deoxyhemoglobin dilution model could be fit to these measured iso-CMR(O2) contours without significant (P </= 0.05) residual error and yielded MRI-based CMR(O2) measurements that were in agreement with PET results for equivalent stimuli. BOLD and CBF data acquired during graded visual stimulation were then substituted into the model with constant parameters varied over plausible ranges. Relative changes in CBF and CMR(O2) appeared to be coupled in an approximate ratio of approximately 2:1 for all realistic parameter settings. Magn Reson <em>Med</em> 42:849-863, 1999.

Chick embryo fibroblast cultures develop fibrinolytic activity after transformation by Rous sarcoma virus (RSV). This fibrinolytic activity is not present in normal cultures, and it does not appear after infection with either nontransforming strains of avian leukosis viruses or cytocidal RNA and DNA viruses. In cultures infected with a temperature sensitive mutant of RSV the onset of fibrinolysis appears after exposure to permissive temperatures and precedes by a short interval the appearance of morphological evidence of transformation. See PDF for Structure The rate of fibrinolysis in transformed cultures depends on the nature of the serum that is present in the growth medium: some sera (e.g., monkey or chicken serum) promote high enzymatic activity, while others (calf, fetal bovine) do not. Some sera contain inhibitors of the fibrinolysin. Based on the effect of a small number of known inhibitors, at least one step of the fibrinolytic process shows specificity resembling that of trypsin. The sera of sarcoma-bearing chickens contain an inhibitor of the fibrinolysin, whereas normal chicken sera do not. For general discussion, conclusions, and summary see the accompanying paper, part II, (J. Exp. Med. 137:112).

The sphingolipid metabolites ceramide (Cer), sphingosine (Sph), and sphingosine-1-phosphate (S1P) play an important role in the regulation of cell proliferation, survival, and cell death. Cer and Sph usually inhibit proliferation and promote apoptosis, while the further metabolite S1P stimulates growth and suppresses apoptosis. Because these metabolites are interconvertible, it has been proposed that it is not the absolute amounts of these metabolites but rather their relative levels that determines cell fate. The relevance of this "sphingolipid rheostat" and its role in regulating cell fate has been borne out by work in many labs using many different cell types and experimental manipulations. A central finding of these studies is that Sph kinase (SphK), the enzyme that phosphorylates Sph to form S1P, is a critical regulator of the sphingolipid rheostat, as it not only produces the pro-growth, anti-apoptotic messenger S1P, but also decreases levels of pro-apoptotic Cer and Sph. Given the role of the sphingolipid rheostat in regulating growth and apoptosis, it is not surprising that sphingolipid metabolism is often found to be disregulated in cancer, a disease characterized by enhanced cell growth, diminished cell death, or both. Anticancer therapeutics targeting SphK are potentially clinically relevant. Indeed, inhibition of SphK has been shown to suppress gastric tumor growth [Cancer Res. 51 (1991) 1613] and conversely, overexpression of SphK increases tumorigenicity [Curr. Biol. 10 (2000) 1527]. Moreover, S1P has also been shown to regulate angiogenesis, or new blood vessel formation [Cell 99 (1999) 301], which is critical for tumor progression. Furthermore, there is intriguing new evidence that S1P can act in an autocrine and/or paracrine fashion [Science 291 (2001) 1800] to regulate blood vessel formation [J. Clin. Invest. 106 (2000) 951]. Thus, SphK may not only protect tumors from apoptosis, it may also increase their vascularization, further enhancing growth. The cytoprotective effects of SphK/S1P may also be important for clinical benefit, as S1P has been shown to protect oocytes from radiation-induced cell death in vivo [Nat. Med. 6 (2000) 1109]. Here we review the growing literature on the regulation of SphK and the role of SphK and its product, S1P, in apoptosis.

BACKGROUND

The Veterans Affairs (VA) health system has been criticized for being inefficient based on comparisons of VA care with non-VA care. Whether such comparisons are biased by differences between the VA patient population and the non-VA patient population is not known. Our objective is to determine if VA patients are different from non-VA patients in terms of health status and medical resource use.

METHODS

We analyzed 128,099 records from the National Health Interview Survey for the years 1993 and 1994. We compared the VA patient population with the general patient population for self report on health status, number of medical conditions, number of outpatient physician visits, number of hospital admissions, and number of hospital days each year.

RESULTS

The VA patient population had poorer health status (odds ratio [OR], 14.7; 95% confidence interval [CI], 10.7-20.2), more medical conditions (OR, 14; 95% CI, 10.5-18.7), and higher medical resource use compared with the general patient population (OR, 3.7 for 3 or more physician visits per year; OR 5.4 for 3 or more hospital admissions per year; OR, 7.7 for 21 or more days spent in a hospital per year). However, after controlling for health and sociodemographic differences, VA patients had similar resource use compared with the general patient population.

CONCLUSIONS

Large differences in sociodemographic status, health status, and subsequent resource use exist between the VA and the general patient population. Therefore, comparisons of VA care with non-VA care need to take these differences into account. Furthermore, health care planning and resource allocation within the VA should not be based on data extrapolated from non-VA patient populations. Arch Intern Med. 2000;160:3252-3257.

OBJECTIVE

Develop a knowledge-based representation for a controlled terminology of clinical information to facilitate creation, maintenance, and use of the terminology.

METHODS

The Medical Entities Dictionary (MED) is a semantic network, based on the Unified Medical Language System (UMLS), with a directed acyclic graph to represent multiple hierarchies. Terms from four hospital systems (laboratory, electrocardiography, medical records coding, and pharmacy) were added as nodes in the network. Additional knowledge about terms, added as semantic links, was used to assist in integration, harmonization, and automated classification of disparate terminologies.

RESULTS

The MED contains 32,767 terms and is in active clinical use. Automated classification was successfully applied to terms for laboratory specimens, laboratory tests, and medications. One benefit of the approach has been the automated inclusion of medications into multiple pharmacologic and allergenic classes that were not present in the pharmacy system. Another benefit has been the reduction of maintenance efforts by 90%.

CONCLUSIONS

The MED is a hybrid of terminology and knowledge. It provides domain coverage, synonymy, consistency of views, explicit relationships, and multiple classification while preventing redundancy, ambiguity (homonymy) and misclassification.

Antigen presentation by host dendritic cells (DC) is critical for the initiation of adaptive immune responses. We have previously demonstrated in immunogenic murine tumor models that bone marrow (BM)-derived DC pulsed ex vivo with synthetic tumor-associated peptides, naturally expressed by tumor cells, serve as effective antitumor vaccines, protecting animals against an otherwise lethal tumor challenge (Mayordomo, J.I., T. Zorina, W.J. Storkus, C. Celluzzi, L.D. Falo, C.J. Melief, T. Ildstad, W.M. Kast, A.B. DeLeo, and M.T. Lotze. 1995. Nature Med. 1:1297-1302). However, T cell-defined epitopes have not been identified for most human cancers. To explore the utility of this approach in the treatment of tumors expressing as yet uncharacterized epitopes, syngeneic granulocyte/macrophage colony-stimulating factor-stimulated and BM-derived DC, pulsed with unfractionated acid-eluted tumor peptides (Storkus, W.J., H.J. Zeh III, R.D. Salter, and M.T. Lotze. 1993. J. Immunother. 14:94-103) were used to treat mice bearing spontaneous, established tumors. The adoptive transfer of 5 x 10(5) tumor peptide-pulsed DC dramatically suppressed the growth of weakly immunogenic tumors in day 4 to day 8 established MCA205 (H-2b) and TS/A (H-2d) tumor models, when applied in three biweekly intravenous injections. Using the immunogenic C3 (H-2b) tumor model in B6 mice, tumor peptide-pulsed DC therapy resulted in the erradication of established d14 tumors and long-term survival in 100% of treated animals. The DC-driven antitumor immune response was primarily cell mediated since the transfer of spleen cells, but not sera, from immunized mice efficiently protected sublethally irradiated naive mice against a subsequent tumor challenge. Furthermore, depletion of either CD4+ or CD8+ T cells from tumor-bearing mice before therapy totally suppressed the therapeutic efficacy of DC pulsed with tumor-derived peptides. Costimulation of the host cell-mediated antitumor immunity was critical since inoculation of the chimeric fusion protein CTLA4-Ig virtually abrogated the therapeutic effects of peptide-pulsed DC in vivo. The analysis of the cytokine pattern in the draining lymph nodes and spleens of tumor-bearing mice immunized with DC pulsed with tumor-eluted peptides revealed a marked upregulation of interleukin (IL) 4 and interferon (IFN) gamma production, as compared with mice immunized with DC alone or DC pulsed with irrelevant peptides. DC-induced antitumor effects were completely blocked by coadministration of neutralizing monoclonal antibody directed against T helper cell 1-associated cytokines (such as IL-12, tumor necrosis factor alpha, IFN-gamma), and eventually, but not initially, blocked by anti-mIL-4 mAb. Based on these results, we believe that DC pulsed with acid-eluted peptides derived from autologous tumors represents a novel approach to the treatment of established, weakly immunogenic tumors, and serves as a basis for designing clinical trials in cancer patients.