This review describes the clinical status (based on available information) of experimental drugs that inhibit enzymes called proteases, or more precisely a sub-class of proteases called peptidases that catalyse the hydrolysis of polypeptide main chain amide bonds. These peptidases are classified by the key catalytic residue in the active site of the enzyme that effects hydrolysis, namely aspartic, serine, cysteine, metallo or threonine proteases. In this review we show structures for 108 inhibitors of these enzymes and update the clinical disposition of over 100 inhibitors that have been considered worthy enough by pharmaceutical, biotechnology or academic researchers and their financial backers to be trialed in humans as prospective medicines. We outline some of their chemical and pharmacological characteristics and compare the current status of protease inhibitors in the clinic with what was observed about 5 years ago (Leung et al, J. Med. Chem. 2000, 43, 305-341). We assess the progress of protease inhibitors into man, predict their futures, and outline some of the hurdles that have been overcome and that still remain for this promising class of new therapeutic agents.

The purpose of this study was to investigate the effects on leg muscular performance from whole-body vibration exercise. Literature search was performed on the databases Pubmed, Cinahl, ISI web of science (Sci-expanded, SSCI) and Embase (Rehab & Physical Med). Rating of 19 relevant studies was performed (14 on long-term exercise and five on short-term exercise) using a score system for the methodological quality. Several randomized-controlled trial studies of high to moderate quality show similar improvements from long-term regimen on muscular performance in the legs after a period of whole-body vibration exercise. As there were few studies on short-term exercise and as they had no control groups, the same convincing improvements regarding muscular performance were not achieved. Preliminarily, there is strong to moderate evidence that long-term whole-body vibration exercise can have positive effects on the leg muscular performance among untrained people and elderly women. There is no clear evidence for effects on muscular performance after short-term vibration stimuli.

The intervertebral disk is routinely subjected to compressive loads that alter with posture and muscle activity and can produce pressures>> 2 MPa in human lumbar disks in vivo (A. Nachemson and G. Elfstrom. Scand. J. Rehabil. Med. 2, Suppl. 1:1-40, 1979; A. Nachemson and J. M. Morris. J. Bone Jt. Surg. Am. Vol. 46A: 1077-1092, 1964). We measured the effect of load on hydrostatic pressures in bovine caudal disks. With increase in applied load, pressure increased linearly in the nucleus and inner annulus. The resting pressure measured after slaughter (0.19 +/- 0.05 MPa) and the pressure at failure (34 MPa, estimated from the vertebrae/disk segment failure load of 7,430 +/- 590 N) define the limits that can occur in vivo. Because hydrostatic pressure influences matrix synthesis in articular cartilage, we have examined the effects of pressures in the range 1-10 MPa applied for 20 s or 2 h on proteoglycan synthesis in bovine caudal and human lumbar intervertebral disks in vitro. In the nucleus pulposus and inner annulus of bovine disks, application of hydrostatic pressure in the range of 1-7.5 MPa for only 20 s stimulated matrix synthesis over the following 2 h at atmospheric pressure. The maximum stimulation in the bovine disks was seen in the inner annulus after application of 2.5 MPa, where proteoglycan synthesis rates doubled. Exposure to 2.5 MPa also stimulated synthesis in the nucleus pulposus of human disks taken at surgery, whereas 7.5 MPa inhibited synthesis in five out of six specimens. With 2-h continuous exposure to the same levels of pressure, no stimulation was seen in the nucleus of bovine disks, and significant stimulation was only observed at 5.0 MPa in the inner annulus. Exposure to 10 MPa for either 20 s or 2 h inhibited proteoglycan synthesis in these regions of the disks. In contrast, in the outer annulus, where loading does not lead to a rise in hydrostatic pressure in vivo, there was no significant response to hydrostatic pressure over the range of 1-10 MPa in bovine or human disks.

The clinical pharmacokinetics and in vitro inhibition of digoxin were examined to predict the P-glycoprotein (P-gp) component of drug-drug interactions. Coadministered drugs (co-<em>meds</em>) in clinical trials (N = 123) resulted in a small, <or=100% increase in digoxin pharmacokinetics. Digoxin is likely to show the highest perturbation, via inhibition of P-gp, because of the absence of metabolic clearance. In vitro inhibitory potency data (concentration of inhibitor to inhibit 50% P-gp activity; IC(50)) were generated using Caco-2 cells for 19 P-gp inhibitors. Maximum steady-state inhibitor systemic concentration [I], [I]/IC(50) ratios, hypothetical gut concentration ([I(2)], dose/250 ml), and [I(2)]/IC(50) ratios were calculated to simulate systemic and gut-based interactions and were compared with peak plasma concentration (C(max))(,i,ss)/C(max,ss) and area under the curve (AUC)(i)/AUC ratios from the clinical trials. [I]/IC(50) < 0.1 shows high false-negative rates (24% AUC, 41% C(max)); however, to a limited extent, [I(2)]/IC(50) < 10 is predictive of negative digoxin interaction for AUC, and [I]/IC(50)>> 0.1 is predictive of clinical digoxin interactions (AUC and C(max)).

Fabry disease is a lysosomal storage disorder caused by deficient lysosomal alpha-galactosidase A (alpha-Gal A) activity. Deficiency of the enzyme activity results in progressive deposition of neutral glycosphingolipids with terminal alpha-galactosyl residue in vascular endothelial cells. We recently proposed a chemical chaperone therapy for this disease by administration of 1-deoxygalactonojirimycin, a potent inhibitor of the enzyme, at subinhibitory intracellular concentrations [Fan, J.-Q., Ishii, S., Asano, N. and Suzuki, Y. (1999) Nat. Med. 5, 112-115]. 1-Deoxygalactonojirimycin served as a specific chaperone for those mutant enzymes that failed to maintain their proper conformation to avoid excessive degradation. In order to establish a correlation between in vitro inhibitory activity and intracellular enhancement activity of the specific chemical chaperone, a series of 1-deoxygalactonojirimycin derivatives were tested for activity with both alpha-Gal A and Fabry lymphoblasts. 1-Deoxygalactonojirimycin was the most potent inhibitor of alpha-Gal A with an IC50 value of 0.04 microM. alpha-Galacto-homonojirimycin, alpha-allo-homonojirimycin and beta-1-C-butyl-deoxygalactonojirimycin were effective inhibitors with IC50 values of 0.21, 4.3 and 16 microM, respectively. N-Alkylation, deoxygenation at C-2 and epimerization at C-3 of 1-deoxygalactonojirimycin markedly lowered or abolished its inhibition toward alpha-Gal A. Inclusion of 1-deoxygalactonojirimycin, alpha-galacto-homonojirimycin, alpha-allo-homonojirimycin and beta-1-C-butyl-deoxygalactonojirimycin at 100 microM in culture medium of Fabry lymphoblasts increased the intracellular alpha-Gal A activity by 14-fold, 5.2-fold, 2.4-fold and 2.3-fold, respectively. Weaker inhibitors showed only a minimum enhancement effect. These results suggest that more potent inhibitors act as more effective specific chemical chaperones for the mutant enzyme, and the potent competitive inhibitors of alpha-Gal A are effective specific chemical chaperones for Fabry disease.

During blast crisis of chronic myelogenous leukemia (CML), abnormal granulocyte macrophage progenitors (GMP) with nuclear beta-catenin acquire self-renewal potential and may function as leukemic stem cells (Jamieson et al. N Engl J Med, 2004). To develop a mouse model for CML-initiating GMP, we expressed p210(BCR-ABL) in an established line of E2A-knockout mouse BM cells that retain pluripotency in ex vivo culture. Expression of BCR-ABL in these cells reproducibly stimulated myeloid expansion in culture and generated leukemia-initiating cells specifically in the GMP compartment. The leukemogenic GMP displayed higher levels of beta-catenin activity than either the nontransformed GMP or the transformed nonGMP, both in culture and in transplanted mouse BM. Although E2A-deficiency may have contributed to the formation of leukemogenic GMP, restoration of E2A-function did not reverse BCR-ABL-induced transformation. These results provide further evidence that BCR-ABL-transformed GMP with abnormal beta-catenin activity can function as leukemic stem cells.

The non-communicating children's pain checklist (NCCPC) has displayed preliminary validity and reliability for measuring pain in children with severe cognitive impairments (Dev Med Child Neurol 42 (2000) 609). This study provides evidence of the psychometric properties of a revised NCCPC (NCCPC-R) with a larger cohort of children. Caregivers of 71 children with severe cognitive impairments (aged 3-18) conducted observations of their children using the NCCPC-R during a time of pain and a time without pain. Fifty-five caregivers completed a second set of observations. The score results on the NCCPC-R were: internally consistent, significantly related to pain intensity ratings provided by caregivers, consistent over time, sensitive to pain, and specific to pain. Analyses of children's individual scores indicated up to 95% of their scores were consistent. Receiver operating characteristic curves suggest a score of 7 or greater on the NCCPC-R as indicative of pain in children with cognitive impairments, with 84% sensitivity and up to 77% specificity. These results provide evidence of NCCPC-R having excellent psychometric properties.

Free fatty acids (FFAs) provide an important energy source and also act as signaling molecules. FFAs are known to exert a variety of physiological responses via their G protein-coupled receptors (GPCRs), such as the GPR40 family. Recently, we identified a novel FFA receptor, GPR120, that promotes secretion of glucagon-like peptide-1 (Hirasawa, A., Tsumaya, K., Awaji, T., Katsuma, S., Adachi, T., Yamada, M., Sugimoto, Y., Miyazaki, S., and Tsujimoto, G. (2005) Nat. Med. 11, 90-94). Here we showed that FFAs inhibit serum deprivation-induced apoptosis of murine enteroendocrine STC-1 cells, which express two types of GPCRs, GPR120 and GPR40, for unsaturated long chain FFA. We first found that linolenic acid potently activated ERK and Akt/protein kinase B (Akt) in STC-1 cells. ERK kinase inhibitors significantly reduced the anti-apoptotic effects of linolenic acid. Inhibitors for phosphatidylinositol 3-kinase (PI3K), a major target of which is Akt, significantly reduced the anti-apoptotic effects. Transfection of STC-1 cells with the dominant-negative form of Akt also inhibited the anti-apoptotic effect. These results suggested that the activation of ERK and PI3K-Akt pathways is required for FFA-induced anti-apoptotic effects on STC-1 cells. Transient transfection of STC-1 cells with GPR120 cDNA, but not GPR40 cDNA, enhanced inhibition of caspase-3 activation. RNA interference experiments showed that reduced expression of GPR120, but not GPR40, resulted in reduced ERK activation and reduced effects of FFAs on caspase-3 inhibition. Collectively, these results demonstrated that FFAs promote the activation of ERK and PI3K-Akt pathways mainly via GPR120, leading to the anti-apoptotic effect of STC-1 cells.

OBJECTIVE

A systematic review of the literature was undertaken to estimate the differences in length of hospital stay, morbidity, mortality and long-term survival between staged and simultaneous resection of synchronous liver metastases from colorectal cancer to determine the level of evidence for recommendations of a treatment strategy.

METHODS

A Pub-med search was undertaken for studies comparing patients with synchronous liver metastases, who either had a combined or staged resection of metastases. Twenty-six were considered and 16 were included based on Newcastle Ottawa Quality Assessment Scale. All studies were retrospective and had a general bias, because the staged procedure was significantly more often undertaken in patients with left-sided primary tumours and larger, more numerous and bi-lobar metastases. Analyses of primary outcomes were performed using the random effects model.

RESULTS

For the reason of the heterogeneity of the observational studies, no odds ratios were calculated. In 11 studies, there was a tendency towards a shorter hospital stay in the synchronous resection group. Fourteen studies compared total perioperative morbidity and lower morbidity was observed in favour of a combined resection. Fifteen studies compared perioperative mortality, which seemed to be lower with the staged approach. Eleven studies compared 5-year survival, which seemed to be similar in the two groups.

CONCLUSIONS

No randomized controlled trials were identified, and hence a meta-analysis was not performed. The evidence level is II to III with grade C recommendations. Synchronous resections can be undertaken in selected patients, provided that surgeons specialized in colorectal and hepatobiliary surgery are available.

PET images of cerebral blood flow (CBF) in an activation study are usually smoothed to a resolution much poorer than the intrinsic resolution of the PET camera. This is done to reduce noise and to overcome problems caused by neuroanatomic variability among different subjects undertaking the same experimental task. In many studies the choice of this smoothing is arbitrarily fixed at about 20 mm FWHM, and the resulting statistical field or parametric map is searched for local maxima. Poline and Mazoyer [(1994): J Cereb Blood Flow Metab 14:690-699; (1994): IEEE Trans Med Imaging 13(4):702-710] have proposed a 4-D search over smoothing kernel widths as well as the usual three spatial dimensions. If the peaks are well separated then this makes it possible to estimate the size of regions of activation as well as their location. One of the main problems identified by Poline and Mazoyer is how to assess the significance of scale space peaks. In this paper we provide a solution for the case of pooled-variance Z-statistic images (Gaussian fields). Our main result is a unified P value for the 4-D local maxima that is accurate for searches over regions of any shape or size. Our results apply equally well to any Gaussian statistical field, such as those resulting from fMRI.

Knowledge representation involves enumeration of conceptual symbols and arrangement of these symbols into some meaningful structure. Medical knowledge representation has traditionally focused more on the structure than the symbols. Several significant efforts are under way, at local, national, and international levels, to address the representation of the symbols though the creation of high-quality terminologies that are themselves knowledge based. This paper reviews these efforts, including the Medical Entities Dictionary (MED) in use at Columbia University and the New York Presbyterian Hospital. A decade's experience with the MED is summarized to serve as a proof-of-concept that knowledge-based terminologies can support the use of coded patient data for a variety of knowledge-based activities, including the improved understanding of patient data, the access of information sources relevant to specific patient care problems, the application of expert systems directly to the care of patients, and the discovery of new medical knowledge. The terminological knowledge in the MED has also been used successfully to support clinical application development and maintenance, including that of the MED itself. On the basis of this experience, current efforts to create standard knowledge-based terminologies appear to be justified.

Controversy persists about the etiology of Parkinson's disease (PD). Pesticides, herbicides, well-water consumption, head injury, and a family history of PD have been reported as risk factors for PD. The purpose of this study was to (1) investigate the impact of environmental factors on PD risk (2) estimate the chronology, frequency, and duration of those exposures associated with PD; and (3) investigate the effects of family history on PD risk. One-hundred and forty PD cases were recruited from Boston University Medical Center. The control group was composed of 147 friends and in-laws of PD patients. Environmental, medical, and family history data were obtained by structured interview from each participant for events recalled prior to PD onset for cases, or corresponding censoring age for controls (mean age = 56 years of age for each group). A traditional stratified analysis, adjusting for birth cohort and sex, was employed. Four factors were associated with increased risk for PD: (1) head injury (OR=6.23, confidence interval [CI]: 2.58-15.07); (2) family history of PD (OR=6.08, CI: 2.35-15. 58); (3) family history of tremor (OR=3.97, CI: 1.17-13.50); and (4) history of depression (OR=3.01, CI: 1.32-6.88). A mean latency of 36. 5 (SE=2.81) years passed between the age of first reported head injury and PD onset. A mean latency of 22 (SE=2.66) years passed between the onset of the first reported symptoms of depression and onset of PD. Years of education, smoking, and well-water intake were inversely associated with PD risk. PD was not associated with exposure to pesticides or herbicides. These findings support the role of both environmental and genetic factors in the etiology in PD. The results are consistent with a multifactorial model. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:742-749, 1999.

Autistic disorder (AD) is a neurodevelopmental disorder characterized by abnormalities in behavior, communication, and social interactions and functioning. Recently, Cook et al. reported significant linkage disequilibrium with an AD susceptibility locus and a marker, GABRB3 155CA-2, in the gamma-aminobutyric acid(A) (GABA(A)) receptor beta3-subunit gene on chromosome 15q11-q13. This linkage disequilibrium was detected using a multiallelic version of the transmission/disequilibrium test (TDT) in a sample of nuclear families having at least one child with autistic disorder. In an attempt to replicate this finding we tested for linkage disequilibrium with this marker, as well as with three additional markers in and around the GABA(A) receptor beta3-subunit gene, in an independent, clinically comparable set of AD families. Unlike Cook et al., we failed to detect significant linkage disequilibrium between GABRB3 155CA-2 and AD in our sample. We did, however, find suggestive evidence for linkage disequilibrium with a marker, GABRB3, approximately 60 kb beyond the 3' end of beta3-subunit gene. This finding lends support for previous reports implicating the involvement of genes in this region with AD. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:43-48, 2000

Epidemiological, serological and in vitro phagocytosis experiments provide evidence that the newly discovered type 5 and type 8 capsular polysaccharides (CPs) are both virulence factors and protective antigens for bacteremia caused by Staphylococcus aureus. Neither type 5 nor type 8 CP elicited serum antibodies when injected into mice. These two CPs were bound to Pseudomonas aeruginosa exotoxin A (ETA) to form conjugates by using the synthetic scheme devised for the CP (Vi) of Salmonella typhi and of pneumococcus type 12F (A. Fattom, W. F. Vann, S. C. Szu, A. Sutton, X. Li, D. Bryla, G. Schiffman, J. B. Robbins, and R. Schneerson, Infect. Immun. 56:2292-2298, 1988; S. C. Szu, A. L. Stone, J. D. Robbins, R. Schneerson, and J. B. Robbins, J. Exp. Med. 166:1510-1524, 1987). Both S. aureus CP-ETA conjugates elicited a rise in CP antibodies. As components of conjugates, both S. aureus CPs acquired T-cell-dependent properties, as shown by their ability to respond to carrier priming and to stimulate booster responses. The conjugate-induced antibodies facilitated type-specific opsonization of S. aureus by human polymorphonuclear leukocytes. The conjugates also induced ETA antibodies which neutralized the native toxin in vitro. Clinical studies of these two conjugates for active or passive immunization of patients at risk for S. aureus bacteremia are planned.

POP-1, a Tcf/Lef-1-like target of the convergent Wnt and MAP kinase (MAPK) signaling pathways, functions throughout Caenorhabditis elegans development to generate unequal daughters during asymmetric cell divisions. A particularly prominent such asymmetric division occurs when the EMS blastomere divides to produce MS, a mesoderm precursor, and E, the sole endoderm progenitor. POP-1 allows mesoderm development in the MS lineage by repressing the endoderm-promoting end-1 and end-3 genes. This repression is relieved in the E lineage by Wnt/MAPK signaling, which results in phosphorylation and export of POP-1 from the E nucleus. Here, we report that, in addition to repressing E development in MS, POP-1 also functions positively in endoderm development, in conjunction with the well-characterized endoderm-promoting SKN-1->>MED regulatory cascade. While removal of POP-1 alone results in derepression of endoderm development in the MS lineage, mutations in several genes that result in impenetrant loss of endoderm are strongly enhanced by loss of pop-1 function. A Lef-1-like binding site is essential for activation of an end-1 promoter fusion, suggesting that POP-1 may act directly on end-1. Thus, POP-1 may generate developmental asymmetry during many cell divisions in C. elegans by reiteratively switching from repressive and activating states. Furthermore, we report that the Caudal-like homeodomain protein PAL-1, whose role in early embryogenesis was thought to be exclusive specification of mesectodermal development in the lineage of the C blastomere, can act with POP-1 to activate endoderm specification in the absence of the SKN-1->>MED transcriptional input, accounting for the impenetrance of mutants lacking SKN-1 or MED-1,2 activity. We conclude that the combined action of several separate transcriptional regulatory inputs, including SKN-1, the MEDs, PAL-1, and the Wnt/MAPK-activated form of POP-1, are responsible for activating end gene transcription and endoderm development.

The FAS receptor-ligand system plays a key role in regulating apoptotic cell death, and corruption of this signaling pathway has been shown to participate in tumor-immune escape and carcinogenesis. We have recently demonstrated (Sun, T., X. Miao, X. Zhang, W. Tan, P. Xiong, and D. Lin. 2004. J. Natl. Cancer Inst. 96:1030-1036; Zhang, X., X. Miao, T. Sun, W. Tan, S. Qu, P. Xiong, Y. Zhou, and D. Lin. 2005. J. Med. Genet. 42:479-484) that functional polymorphisms in FAS and FAS ligand (FASL) are associated with susceptibility to lung cancer and esophageal cancer; however, the mechanisms underlying this association have not been elucidated. We show that the FAS -1377G, FAS -670A, and FASL -844T variants are expressed more highly on ex vivo-stimulated T cells than the FAS -1377A, FAS -670G, and FASL -844C variants. Moreover, activation-induced cell death (AICD) of T cells carrying the FASL -844C allele was increased. We also found a threefold increased risk of cervical cancer among subjects with the FASL -844CC genotype compared with those with the -844TT genotype in a case-control study in Chinese women. Together, these observations suggest that genetic polymorphisms in the FAS-FASL pathway confer host susceptibility to cervical cancers, which might be caused by immune escape of tumor cells because of enhanced AICD of tumor-specific T cells.

BACKGROUND

The intriguing differences in the natural course, transmissibility, and epidemiological characteristics of human immunodeficiency virus type 1 (HIV-1) and HIV-2 are still insufficiently explained. Differences in plasma viral load are an obvious possibility, but this has been difficult to investigate because of the lack of tests for HIV-2 RNA.

OBJECTIVE

To compare plasma HIV RNA load between individuals infected with HIV-1 and HIV-2 in Guinea-Bissau, a West African country with high prevalence and incidence of HIV-1 and HIV-2 infection.

METHODS

A total of 102 participants were recruited from ongoing prospective cohort studies. These included 19 HIV-1 and 29 HIV-2 seroincident cases tested at a median of less than 2 years after seroconversion as well as seroprevalent cases with single (9 HIV-1 cases and 31 HIV-2 cases) or dual (n = 14) infections. Plasma HIV RNA levels were determined by a commercial HIV-1 assay and an experimental HIV-2 assay based on the same principles.

RESULTS

The viral set point, ie, the semi-equilibrium reached after seronconversion, was 28-fold lower in recent HIV-2 seroconverters than in recent HIV-1 seroconverters (median, 2500 and 70,000 RNA copies per milliliter, respectively; P<. 001). This difference appeared to persist to symptomatic stages of the diseases. Dually infected individuals had lower plasma HIV-1 RNA levels than singly infected individuals.

CONCLUSIONS

The differences between HIV-1 and HIV-2 infection are likely to be caused by differences in plasma viral set point and load, but the mechanisms through which HIV-2 infection is contained to a higher degree than HIV-1 remain to be identified. Arch Intern Med. 2000;160:3286-3293.

BACKGROUND

The cancer risk of low-grade dysplasia (LGD) in chronic ulcerative colitis is variable and its management remain contentious.

OBJECTIVE

To determine the risk of cancer or any advanced lesion once LGD is diagnosed.

METHODS

A MEDLINE, EMBASE and Pub Med search was conducted using the key words 'surveillance', 'colorectal cancer', 'low-grade dysplasia' and 'ulcerative colitis'. A random effects model of meta-analysis was used.

RESULTS

Twenty surveillance studies had 508 flat LGD or LGD with dysplasia-associated lesion or mass. An average of 4.3 colonoscopies was performed/patient post-LGD diagnosis (range: 3-7.6). An average of 18 biopsies taken per colonoscopy (range: 9-24) detected 73 advanced lesions (cancer or high-grade dysplasia) pre-operatively. The cancer incidence was 14 of 1000 (95% CI: 5.0-34) person years duration (pyd) and the incidence of any advanced lesion was 30 of 1000 pyd (95% CI: 12-76). When LGD is detected on surveillance there is a ninefold risk of developing cancer (OR: 9.0, 95% CI: 4.0-20.5) and 12-fold risk of developing any advanced lesion (OR: 11.9, 95% CI: 5.2-27).

CONCLUSIONS

The risk of developing cancer in patients with LGD is high. These estimates are valuable for decision-making when LGD is encountered on surveillance.

OBJECTIVE

To examine which atherosclerotic risk factors are determinants for peripheral arterial disease (PAD), we performed a population-based study in 6450 subjects (40% men, 60% women) aged 55 years and older.

METHODS

The presence of PAD was assessed by measuring the ankle-arm systolic blood pressure index (AAI); PAD was considered present if the AAI was lower than 0.90 in either leg. In addition, a threshold AAI of 0.70 in either leg defined severe PAD.

RESULTS

Determinants strongly and independently associated with PAD were age of at least 75 years (odds ratio [OR], 1.2; 95% confidence interval [CI], 1.0-1.6), fibrinogen level (OR, 1.5; 95% CI, 1.3-1.7), cigarette smoking (OR, 2.8; 95% CI, 2.3-3.4), diabetes mellitus (OR, 2.0; 95% CI, 1.6-2.5), and systolic blood pressure (OR, 1.2; 95% CI, 1.1-1.2). An inverse relation of high-density lipoprotein cholesterol level with PAD (OR, 0.7; 95% CI, 0.5-0.8) was found. Similar results were demonstrated for severe PAD. Separate analyses for men and women did not demonstrate differences in risk factors for PAD.

CONCLUSIONS

Assessment of a wide range of atherosclerotic risk factors enabled us to quantify the relative importance of each factor as determinant for PAD. In total, 69% of the occurrence of PAD is attributable to cardiovascular risk factors measured in our study; smoking accounted for most (etiologic fraction, 18.1%). The results suggest that preventive management of PAD should be directed at systolic blood pressure, fibrinogen level, smoking, high-density lipoprotein cholesterol level, and diabetes mellitus. Arch Intern Med. 2000;160:2934-2938

BACKGROUND

New rulings nationwide require health services researchers to obtain patient consent before examining personally identifiable data. A selection bias may result if consenting patients differ from those who do not give consent.

OBJECTIVE

To compare patients who consent, refuse, and do not answer.

METHODS

Patients completing an in-office survey were asked for permission to be surveyed at home and for their records to be reviewed. Survey responses and practice billing data were used to compare patients by consent status.

METHODS

Urban family practice center.

METHODS

Of 2046 eligible patients, 1106 were randomly selected for the survey, were approached by staff, and agreed to participate. Approximately 87% of the nonparticipants were eliminated through a randomization process.

METHODS

Consent status.

RESULTS

A total of 33% of patients did not give consent: 25% actively refused, and 8% did not answer. Consenting patients were older, included fewer women and African Americans, and reported poorer physical function than those who did not give consent (P<.05). Patients who did not answer the question were older, included more women and African Americans, and were less educated than those who answered (P<.02). Visits for certain reasons (eg, pelvic infections) were associated with lower consent rates. On multivariate analysis, older age, male sex, and lower functional status were significant predictors of consent.

CONCLUSIONS

Patients who release personal information for health services research differ in important characteristics from those who do not. In this study, older patients and those in poorer health were more likely to grant consent. Quality and health services research restricted to patients who give consent may misrepresent outcomes for the general population. Arch Fam Med. 2000;9:1111-1118

BACKGROUND

Bovine collagen is extensively used for facial soft tissue augmentation but provides only temporary correction and can cause hypersensitivity reactions. Hyaluronic acid derivatives potentially offer improved longevity of correction and a reduced risk of immunogenicity and hypersensitivity.

OBJECTIVE

To compare the efficacy and safety of nonanimal stabilized hyaluronic acid gel (Restylane; Q-Med, Uppsala, Sweden) with that of bovine collagen (Zyplast) for treatment of nasolabial folds.

METHODS

One hundred thirty-eight patients with prominent nasolabial folds were randomized to treatment with hyaluronic acid gel and bovine collagen on contralateral sides of the face. Treatments were repeated at 2-week intervals, as required, to achieve "optimal cosmetic result" (baseline). Outcomes were evaluated by a blinded investigator at 2, 4, and 6 months after baseline.

RESULTS

Less injection volume was required for "optimal cosmetic result" with hyaluronic acid gel than with bovine collagen, and patients and investigators judged hyaluronic acid gel to be more effective in maintaining cosmetic correction. The investigator-based Wrinkle Severity Rating Scale and Global Aesthetic Improvement Scale assessments at 6 months after baseline indicated that hyaluronic acid gel was superior in 56.9% and 62.0% of patients, respectively, whereas bovine collagen was superior in 9.5% and 8.0% of patients, respectively. The frequency, intensity, and duration of local injection-site reactions were similar for the two products.

CONCLUSIONS

Nonanimal stabilized hyaluronic acid provides a more durable aesthetic improvement than bovine collagen and is well tolerated.

The existence of the early-negative blood-oxygenation-level-dependent (BOLD) response is controversial and its practical utility for mapping brain functions with columnar spatial specificity remains questionable. To address these issues, gradient-echo BOLD fMRI studies were performed at 4.7 T and 9.4 T using the well-established orientation column model in the cat visual cortex. A robust transient early-negative BOLD response was consistently observed in anesthetized cat (-0.35 +/- 0.09%, mean +/- SD, n = 8 at 2.9 +/- 0.5 sec poststimulus onset for 4.7 T, TE = 31 ms; -0.29 +/- 0.10%, n = 4 at 3.0 +/- 0.8 sec poststimulus onset for 9.4 T, TE = 12 ms). In addition to its temporal evolution, the BOLD response also evolved dynamically in the spatial domain. The initially spatially localized early-negative signal appeared to dynamically drain from the active sites toward large vessels, followed by a wave of the delayed positive signal, which exhibited similar spatiotemporal dynamics. Only the early-negative BOLD response within 2 sec of the stimulus onset (not the entire dip) yielded columnar layouts without differential subtraction. The functional maps of two orthogonal orientations using the first 2-sec dip were indeed complementary. On the other hand, the delayed positive BOLD response appeared diffused and extended beyond the active sites. It was thus less suitable to resolve columnar layouts. These results have implications for the design and interpretation of the BOLD fMRI at columnar resolution. Magn Reson Med 44:231-242, 2000.

OBJECTIVE

We sought to determine the relationship of greater adherence to Mediterranean diet (MeD) and likelihood of incident cognitive impairment (ICI) and evaluate the interaction of race and vascular risk factors.

METHODS

A prospective, population-based, cohort of individuals enrolled in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study 2003-2007, excluding participants with history of stroke, impaired cognitive status at baseline, and missing data on Food Frequency Questionnaires (FFQ), was evaluated. Adherence to a MeD (scored as 0-9) was computed from FFQ. Cognitive status was evaluated at baseline and annually during a mean follow-up period of 4.0 ± 1.5 years using Six-item-Screener.

RESULTS

ICI was identified in 1,248 (7%) out of 17,478 individuals fulfilling the inclusion criteria. Higher adherence to MeD was associated with lower likelihood of ICI before (odds ratio [lsqb]OR[rsqb] 0.89; 95% confidence interval [lsqb]CI[rsqb] 0.79-1.00) and after adjustment for potential confounders (OR 0.87; 95% CI 0.76-1.00) including demographic characteristics, environmental factors, vascular risk factors, depressive symptoms, and self-reported health status. There was no interaction between race (p = 0.2928) and association of adherence to MeD with cognitive status. However, we identified a strong interaction of diabetes mellitus (p = 0.0134) on the relationship of adherence to MeD with ICI; high adherence to MeD was associated with a lower likelihood of ICI in nondiabetic participants (OR 0.81; 95% CI 0.70-0.94; p = 0.0066) but not in diabetic individuals (OR 1.27; 95% CI 0.95-1.71; p = 0.1063).

CONCLUSIONS

Higher adherence to MeD was associated with a lower likelihood of ICI independent of potential confounders. This association was moderated by presence of diabetes mellitus.

The antioxidant enzyme superoxide dismutase (EC 1.15.1.1) (SOD) catalyzes the conversion of superoxide anion radical (O2.-) to hydrogen peroxide and molecular oxygen. SOD helps prevent tissue damage by O2.- and its metabolites, and augmentation of tissue SOD is a useful therapeutic strategy in certain diseases having an oxidative-injury component. Routine application of direct SOD assays is not technically facile, since the short half-life of the O2.- substrate and its free radical nature necessitate specialized analytical equipment to detect and measure O2.- chemically. Consequently, indirect SOD assays which monitor some change in an indicator substance reacting with O2.- are routinely used, particularly for biological samples. Limitations of indirect test systems utilizing heme-based indicators for the presence of O2.- and/or enzymatic O2.- generators led us to develop a SOD microassay based on spectrophotometric assessment of O2.- mediated nitro blue tetrazolium reduction by an aerobic mixture of NADH and phenazine methosulfate, which produces superoxide chemically at nonacidic pH (Rao, Free Radical Biol. Med. 7, 513-519, 1989). The proposed SOD assay system is formatted for use in an automated 96-well microplate reader and has the virtues of a nonheme indicator, a nonenzymatic O2.- source, physiological pH, and economy of time and materials. The assay has been applied to measure purified and tissue SOD (Cu,Zn- and Mn-types) activity as well as O2.- turnover by small-molecule "SOD mimetics."