Efficacy, safety and tolerability of topical terbinafine nail solution in patients with mild-to-moderate toenail onychomycosis: results from three randomized studies using double-blind vehicle-controlled and open-label active-controlled designs.

BACKGROUND: Terbinafine nail solution (TNS) was developed for the treatment of onychomycosis. OBJECTIVE: To assess the efficacy of TNS vs. vehicle and amorolfine 5% nail lacquer. METHODS: Subjects with mild-to-moderate toe onychomycosis (25% to ≤75% nail-involvement, matrix uninvolved) were randomized to receive either TNS or vehicle in two double-blind studies, and to TNS or amorolfine in an active-controlled, open-label study. Primary endpoint was complete cure (no residual clinical involvement and negative mycology) at week 52. Secondary endpoints were mycological cure (negative mycology defined as negative KOH microscopy and negative culture) and clinical effectiveness (≤10% residual-involvement and negative mycology) at week 52. RESULTS: Complete cure was not different between TNS vs. vehicle and amorolfine. Mycological cure was higher with TNS vs. vehicle, as was clinical effectiveness with TNS vs. vehicle, and TNS and amorolfine were not different for secondary efficacy endpoints. Patients achieving mycological cure had a better clinical outcome, and efficacy was improved in subjects with milder disease. Post hoc analysis suggests that nail thickness is an important prognostic factor. Moreover, mycological cure may require 6 months of treatment regimen while complete cure and clinical effectiveness may be achievable only after 10 months. A simulation study suggests that longer treatment duration would have resulted in higher complete cure with TNS vs. vehicle. Study treatments were well-tolerated. CONCLUSION: Primary efficacy objectives were not met in the studies reported herein. Possible reasons for failure to achieve significant outcomes include insufficient length of treatment; stringency of primary endpoint and severity of nail involvement of study population.

Efficacy and safety of secukinumab in the treatment of moderate-to-severe plaque psoriasis: a randomized, double-blind, placebo-controlled phase II dose-ranging study.

BACKGROUND: Conventional systemic therapies for plaque psoriasis have not fully met the needs of patients, and although current biologic treatments are generally well tolerated, concerns exist with respect to long-term safety. Interleukin (IL)-17A is believed to be an important effector cytokine in the pathogenesis of psoriasis and is produced by Th17 cells, a class of helper T cells that act outside the established Th1/Th2 paradigm for regulation of innate and adaptive immunity. OBJECTIVES: To assess the efficacy and safety of different doses of secukinumab, a fully human anti-IL-17A IgG1κ monoclonal antibody, in patients with moderate-to-severe plaque psoriasis. METHODS: Patients (n = 125) were randomized 1 : 1 : 1 : 1 : 1 to receive subcutaneous doses of placebo (n = 22) or secukinumab [1 × 25 mg (n = 29), 3 × 25 mg (n = 26), 3 × 75 mg (n = 21) or 3 × 150 mg (n = 27)] at weeks 0, 4 and 8. After the 12-week treatment period, patients entered a follow-up period of 24 weeks. The primary efficacy outcome was at least 75% improvement from baseline in the Psoriasis Area and Severity Index score (PASI 75); secondary outcomes included the Investigator's Global Assessment (IGA) and PASI 90 and 50 response rates. RESULTS: After 12 weeks of treatment, secukinumab 3 × 150 mg and 3 × 75 mg resulted in significantly higher PASI 75 response rates vs. placebo (82% and 57% vs. 9%; P < 0·001 and P = 0·002, respectively). Higher PASI 75 response rates compared with placebo were maintained throughout the follow-up period with these dosages [week 36, 26% (n = 7) and 19% (n = 4) vs. 4% (n = 1), respectively], with a gradual decline of PASI 75 response over time after the dosing period. IGA response rates were significantly higher in the 3 × 150 mg group vs. placebo at week 12 (48% vs. 9%; P = 0·005) and were consistently higher for the 3 × 150 mg and 3 × 75 mg groups vs. placebo at all time points from week 4 onward. The PASI 90 response rate was significantly higher in the 3 × 150 mg group vs. placebo (52% vs. 5%) at week 12 and remained higher during the follow-up period. Secukinumab was well tolerated. Two cases of neutropenia (≤ grade 2) were reported in the 3 × 150 mg cohort. CONCLUSIONS: Treatment with subcutaneous secukinumab 3 × 75 mg and 3 × 150 mg met the primary outcome of PASI 75 response achievement after 12 weeks, demonstrating efficacy in moderate-to-severe psoriasis.

Factors contributing to the amount of vehicular damage resulting from collisions between four-wheel drive vehicles and passenger cars.

This study examines the vehicular damage resulting from motor vehicle crashes involving four-wheel drive vehicles and passenger cars in the state of Oklahoma. In particular, the focus of the analysis is on differences in vehicular damage to passenger cars and four-wheel drive vehicles. Results indicate that passenger cars sustain significantly greater vehicular damage than four-wheel drive vehicles. In addition, several other factors significantly influence the level of damage resulting from collisions between four-wheel drive vehicles and passenger cars. Driver behavior or unsafe acts, represented by the rate of travel prior to the collision, failure to yield, failure to obey a stoplight or a stop sign, the consumption of alcohol and the use of drugs, also contributed to the amount of vehicular damage. In addition, results also indicate that the level of damage was influenced significantly by environmental factors, represented by a reduced intensity of light, wet or slippery roadways and the type of collision. The findings reinforce the importance of a number of policy initiatives that may reduce the vehicular damage resulting from collisions involving four-wheel drive vehicles and passenger cars. For example, the study indicates a need to initiate legislation that lowers the speed limit during dark and twilight hours, commits additional resources to road maintenance to reduce unsafe road conditions, and stimulates improvements in automotive design that provide better lateral protection to vehicles.

Substance abuse and mental illness: unaddressed public health issues for women.

Although women have been disproportionately affected by substance abuse and mental illness, these issues have received little attention. Women with substance abuse and mental disorders tend to experience more severe environmental, health, social, and economic consequences and require more costly care. The Substance Abuse and Mental Health Services Administration is responsible for strengthening the nation's health care delivery system for prevention and treatment of substance abuse and mental illness and addresses women's issues through its Women, Children, and Families Team (WCFT). The WCFT is concerned with the public health risks associated with substance abuse and mental disorders in women, including physical and sexual abuse/violence, human immunodeficiency virus and acquired immune deficiency syndrome, criminal justice, welfare reform, and child welfare.

Magnetic resonance imaging of breast cancer: clinical indications and breast MRI reporting system.

Magnetic resonance imaging (MRI) is well suited to the investigation of breast cancer by virtue of its noninvasive nature and its multiplanar imaging abilities. MRI investigations showed high sensitivity but modest specificity for breast cancer detection and diagnosis. Most early studies tested the ability of MRI to evaluate and diagnose findings in the breast discovered by other imaging tests or by breast physical examination (1-4). When it was discovered that MRI identified small breast cancers undetected by mammography or breast ultrasound, MRI was used to estimate breast cancer extent in known cancer cases for surgical planning (5,6). These investigations led to the use of MRI in a multitude of breast imaging applications, raising further questions about the use of MRI in everyday practice: What are the indications for breast MRI in general practice? What is its role in light of other imaging tests? What are its benefits and limitations in each setting? How do I report these studies? The purpose of this article is to review the clinical background regarding indications for the use of MRI and relevant cases in which MRI can impact patient management in breast disease, and to describe new developments in reporting breast MRI studies. J. Magn. Reson. Imaging 2000;12:975-983.

An analysis of factors associated with seat belt use: prevention opportunities for the medical community.

Motor vehicle collisions are a significant cause of morbidity and mortality in the Oklahoma population. The cost associated with this morbidity and mortality is exacerbated by the failure of individuals to use seat belts. Numerous organizations believe that seat belt compliance can be improved through physician counseling. This would allow medical resources to be redirected towards other health problems. Analysis was performed using the Oklahoma Department of Public Safety (ODPS) crash file and the hospital in-patient data discharge file from the Oklahoma State Department of Health (OSDH). These provide a profile of Oklahoma drivers who do not use seat belts. This analysis allows physicians to pinpoint and advise those individuals most likely to not utilize seat belts about the benefits of seat belt use. The results of the analysis show that non-seat belt-users tend to be young and male. Significant predictors of seat belt use are age, gender, alcohol use, time of day (day versus night), driver location (urban versus rural), vehicle type (pick up versus passenger car), and decreased hospital charges. These results show that increased seat belt use can lead to significant decreases in fatalities related to motor vehicle crashes and a decline in associated hospital charges for those who survive. Physicians should encourage seat belt use by their patients and inform them of the risks associated with failure to use seat belts.

Misrepresentation of publications by radiology residency applicants.

RATIONALE AND OBJECTIVES: The authors' purpose was to determine the extent of misrepresentation of research publications by radiology resident applicants. MATERIALS AND METHODS: The authors reviewed 379 consecutive applications, including curricula vitae, for a radiology residency program in 1996. All reported publications and "in-press" articles were checked by means of a MEDLINE search. RESULTS: Of the 379 applicants, 108 were from medical schools in the United States, and 271 were from international medical schools. Seventy-three applicants listed articles published or in press on their applications (24 U.S., 49 international applicants). Of 286 separate citations in the applications, 105 were found with the MEDLINE search, and 181 were not found. Of the latter, 168 cited journals were not indexed in MEDLINE or the applicants did not include sufficient information to verify their existence. Thirteen citations (from eight applicants; three U.S., five international) were not found even though they cited journals indexed by MEDLINE. CONCLUSION: Of all applicants reporting publications, 11% likely misrepresented them on their applications. A large percentage of citations, however, could not be verified because of insufficient information in the citation or claimed publication in a journal not available on MEDLINE. Radiology residency program directors should be aware of this uncommon, but important, problem.

Magnetic resonance imaging of occult breast cancer.

Magnetic resonance imaging (MRI) findings in a case of clinically and mammographically occult breast cancer are presented. Breast MRI allows detection of the site of primary cancer with high sensitivity in patients with occult neoplasms and should be considered as a routine test in these patients.

Single-system ureteroceles in infants and children: imaging features.

PURPOSE: The purpose of this manuscript is to describe the clinical and imaging findings in children who have single-system ureteroceles. MATERIALS AND METHODS: We reviewed the urology records and imaging studies in 32 consecutive infants and children who were diagnosed in our department with single-system ureteroceles. RESULTS: There were 35 ureteroceles in the 32 patients-- 29 were unilateral (14 right-sided, 15 left-sided) and 3 were bilateral. Twenty-five patients were boys (78 %) and 7 girls. Mean age at presentation was 0.7 years (0-9.2 years). Prenatally detected hydronephrosis or cystic renal dysplasia was the most common presentation (24 patients). Four presented with urinary infection, 2 with abdominal mass, 1 had myelomeningocele, and 1 had hypospadias. Three patients also had multiple non-urologic, congenital anomalies. Thirty-three ureteroceles were intravesical, and 2 were ectopic to the bladder neck. Twenty-four ureteroceles were associated with ipsilateral hydroureteronephrosis and 10 with ipsilateral multicystic dysplastic kidney. One patient had a normal ipsilateral kidney and a contralateral multicystic dysplastic kidney. The ureterocele was identified on at least one imaging study in each patient. Sixteen ureteroceles (47%) everted at VCUG, mimicking paraureteral diverticula. Other variations included ureterocele prolapse and inadvertent ureterocele catheterization (1 each). CONCLUSIONS: Single-system ureterocele is an important, although uncommon cause of hydronephrosis and renal dysplasia in infants and children. Single-system ureterocele is distinguished clinically from the more common duplex-system ureterocele by its frequent occurrence in boys and its association with multicystic dysplastic kidney. Because these ureteroceles are frequently small and have a propensity to evert at VCUG, they can be mistaken for paraureteral diverticula.

Pathogenicity of an enterotoxigenic Escherichia coli hemolysin (hlyA) mutant in gnotobiotic piglets.

Pigs infected with hemolytic F4(+) strains of enterotoxigenic Escherichia coli often develop septicemia secondary to intestinal infection. We tested the hypothesis that inactivation of hemolysin would reduce the ability of F4(+) enterotoxigenic E. coli to cause septicemia in swine following oral inoculation. Inactivation of the hemolysin structural gene (hlyA) did not decrease the incidence of septicemia in the gnotobiotic piglet model.

Expression of mucin-type glycoprotein K88 receptors strongly correlates with piglet susceptibility to K88(+) enterotoxigenic Escherichia coli, but adhesion of this bacterium to brush borders does not.

Three antigenic variants of the K88 fimbrial adhesin exist in nature, K88ab, K88ac, and K88ad. Enterotoxigenic Escherichia coli (ETEC) strains that produce these fimbriae cause life-threatening diarrhea in some but not all young pigs. The susceptibility of pigs to these organisms has been correlated with the adherence of bacteria to isolated enterocyte brush borders. Whether that correlation holds for multiple K88 variants and over a broad genetic base of pigs is unknown and was the impetus for this study. We also desired to examine the correlation of the expression of a porcine intestinal brush border mucin-type glycoprotein (IMTGP) which binds K88ab and K88ac with the susceptibility of piglets to K88(+) ETEC. Of 31 neonatal gnotobiotic pigs inoculated with K88ab+ or K88ac+ ETEC, 13 developed severe diarrhea, became dehydrated, and died or became moribund. Another pig became severely lethargic but not dehydrated. In vitro brush border adherence analysis was not possible for 10 of the severely ill pigs due to colonization by challenge strains. However, of the 17 pigs that did not become severely ill, 8 (47%) had brush borders that supported the adherence of K88ab+ and K88ac+ bacteria in vitro, suggesting a poor correlation between in vitro brush border adherence and piglet susceptibility to K88(+) ETEC. By contrast, the expression of IMTGP was highly correlated with susceptibility to K88(+) ETEC. Of the 12 pigs that produced IMTGP, 11 developed severe diarrhea. The other pig that produced IMTGP became lethargic but not severely diarrheic. Only 2 of 18 pigs that did not produce IMTGP became severely diarrheic. Colonizing bacteria were observed in histologic sections of intestines from all pigs that expressed IMTGP except for the one that did not develop severe diarrhea. However, colonizing bacteria were observed in histologic sections from only one pig that did not produce IMTGP. The bacterial concentration in the jejuna and ilea of pigs expressing IMTGP was significantly greater (P < 0.005) than that in pigs not expressing IMTGP. These observations suggest the IMTGP is a biologically relevant receptor for K88ab+ and K88ac+ E. coli or a correlate for expression for such a receptor.

Optometric management of patients with Alzheimer's disease.

BACKGROUND: The earliest symptoms of Alzheimer's disease (AD) may be visual. AD is an age-related, progressive dementia. At least 7% of Americans over 65 years of age are afflicted, and it ranks as the fourth leading cause of death in the United States. A review of the literature was performed to delineate the visual manifestations of Alzheimer's disease. RESULTS: Abnormal visual perception and visuospatial processing are common among patients with AD Visual acuity, pupillary light reflexes, and the ocular fundus do not appear to be specifically affected by AD. Whether AD impairs color vision is controversial. Stereopsis may also be affected. True visual-field defects are rarely found. Although not universally reported, some studies of contrast sensitivity functions show abnormal sensitivity possibly at low spatial frequencies. The electroretinogram is normal, while the visual evoked response is frequently abnormal. CONCLUSIONS: As primary eye care providers, optometrists must properly identify and refer individuals with suspected Alzheimer's disease to the appropriate specialist, as well as manage their visual welfare.

Distribution of K88 Escherichia coli-adhesive and nonadhesive phenotypes among pigs of four breeds.

Enterotoxigenic Escherichia coli expressing K88 fimbrial adhesins often cause diarrhea in young pigs. However, some pigs are inherently resistant to colibacillosis, because they lack receptors on their epithelial cell brush borders to which the fimbriae bind. Phenotypic diversity with respect to the binding of E. coli expressing K88 of the three variant types (K88ab, K88ac, and K88ad) was reported by Bijlsma et al. (1982), and binding specificities for each phenotype were described: A (adhesive to all three variants), B (adhesive to K88ab and K88ac), C (adhesive to K88ab and K88ad), D (adhesive to K88ad) and E (nonadhesive). Because brush border adhesiveness has been correlated with disease susceptibility, swine K88 adhesive phenotypes are of significance in the control of enteric disease. To determine the prevalence of the various K88 adhesive phenotypes in the swine population in the Midwestern United States, we tested epithelial cell brush borders of 24 purebred pigs from each of four breeds (Chester White, Duroc, Hampshire and Yorkshire) for adhesiveness to each of the K88 variants. Four, 4-week-old pigs (the largest and smallest healthy female littermates from two litters) were collected from each of 24 farms. Brush border vesicles from the pigs were tested for ability to bind E. coli expressing each K88 variant. The five brush border adherence patterns described for phenotypes A-E were observed. In addition, brush borders from some pigs only bound K88ab + bacteria. Nearly three quarters of the pigs whose brush borders tested, were found to be phenotype A (43%) or phenotype E (28%). These were the most common phenotypes in each breed, except Hampshire, in which case phenotypes C (17%) and D (25%) were more common than E (8%). There appeared to be no relationship between the phenotype of a pig and its weight relative to its littermate.

Variation in virulence in the gnotobiotic pig model of O157:H7 Escherichia coli strains of bovine and human origin.

Escherichia coli strains of serotype O157:H7 have been incriminated in outbreaks and sporadic cases of food-borne illness, including diarrhea, hemorrhagic colitis, hemolytic uremic syndrome and thrombotic thrombocytopenic purpura. Food-producing animals, particularly cattle, are believed to be reservoirs of the organism. Whether all strains of bovine origin pose human health risk is unknown and was the impetus for this investigation. We compared the virulence of ten SLT-I, SLT-II, and eae DNA probe-positive O157:H7 strains from cattle to 10 like strains associated with human diarrheal disease outbreaks for virulence in one day-old gnotobiotic pigs. All strains caused diarrhea, and only four pigs inoculated with either of two bovine strains failed to develop that condition. Signs of central nervous system disease, death, debilitation requiring euthanasia before the end of an eight day observation period, and/or encephalomalacia occurred in 32/42 pigs inoculated with the strains isolated from human beings, 13/39 pigs inoculated with strains from cattle, and 7/7 pigs inoculated with a positive control strain. More strains of human origin (9/10) than bovine origin (5/10) caused these effects. The results of this study indicate considerable variability in virulence of O157:H7 strains possessing the same known virulence determinants, and suggest that disease outbreaks tend to be caused by the more virulent of these strains.

A three-receptor model for the interaction of the K88 fimbrial adhesin variants of Escherichia coli with porcine intestinal epithelial cells.

Four phenotypes of pigs distinguished by the variant(s) of K88 fimbrial adhesin (K88ab, K88ac, K88ad) that bind to their intestinal epithelial cells (I-none of the variants, II-K88ad, III-K88ab and K88ac, and IV-all three variants) have been identified. We hypothesize that the differences between the phenotypes are defined by the presence or absence of K88 adhesin receptors. We propose a three-receptor model to account for the observed phenotypes: 1) Receptor bed which binds all three variants and is found in phenotype IV, 2) Receptor be which binds K88ab and K88ac and is found in phenotype III and IV, and 3) Receptor d which binds K88ad and is found in phenotype II. We have identified the be receptor activity as a pair of mucin-type sialoglycoproteins (210 and 240 kDa). Although neither the bcd nor d receptor has been identified biochemically, their presence has been established using both blocking and receptor localization studies. Blocking studies using phenotype IV brush borders demonstrated that K88ab and K88ac fimbriae block the binding of E. coli expressing any of the K88 variants, but K88ad fimbriae block only K88ad E. coli binding. These results indicate that two receptors (bcd and bc) exist in the phenotype IV animals. Receptor localization studies on intestinal sections from phenotype IV animals showed that K88ab and K88ac adhesin binding is continuous from the crypt to the tip of the villus. The binding of the K88ad adhesin binding is multifocal in phenotype IV pigs, but continuous from crypt to tip of the villus in sections of phenotype II pigs. These studies verify the presence of two receptors (bcd and bc) in phenotype IV animals, and indicate that the K88ad receptor in phenotype IV animals (bcd) is different than in phenotype II animals (d).

Characterization of porcine intestinal receptors for the K88ac fimbrial adhesin of Escherichia coli as mucin-type sialoglycoproteins.

We have previously identified two K88ac adhesion receptors (210 and 240 kDa) which are present in membrane preparations from adhesive but not nonadhesive porcine intestinal brush border cells; these adhesin receptors are postulated to be important determinants of the susceptibility of pigs to K88ac+ enterotoxigenic Escherichia coli infections (A.K. Erickson, J.A. Willgohs, S.Y. McFarland, D.A. Benfield, and D.F. Francis, Infect. Immun. 60:983-988, 1992). We now describe a procedure for the purification of these two receptors. Receptors were solubilized from adhesive intestinal brush border vesicles using deoxycholate and were purified by gel filtration chromatography on Sepharose CL-4B and then by hydroxyapatite chromatography. Amino acid compositional analyses indicated that the two receptors have similar amino acid compositions. The most distinguishing characteristic of both receptors is a high percentage of threonine and proline residues. Neuraminidase treatment caused the K88ac adhesin receptors to migrate with a slower mobility on sodium dodecyl sulfate-polyacrylamide gel electrophoresis gels, indicating that these receptors are sialoglycoproteins. Results from lectin-binding studies indicated that the receptors contain O-linked oligosaccharides composed of galactosyl (beta-1,3)N-acetylgalactosamine, alpha-linked fucose, galactosyl(beta-1,4)N-acetylglucosamine, sialic acid, galactose, and N-acetylgalactosamine. Collectively, these characteristics indicate that the K88ac adhesin receptors are mucin-type sialoglycoproteins.

Prioritization of health services. The Oregon Basic Health Services Act and its implications for dermatologists and patients with dermatologic disease.

The Oregon Basic Health Services Act was passed by the Oregon Legislature in 1989. This act mandates the provision of and payment for health services to Medicaid recipients based on a prioritized list of diseases and treatments. As a result of this legislation, Oregonians with incomes of 100% or less of the federal poverty level are eligible for Medicaid benefits. At present, families with incomes not exceeding 67% of the federal poverty level qualify for Medicaid in Oregon. The definition of prioritized care, how the prioritization was accomplished, and the potential effect of the implementation of this plan for dermatology and patients with dermatologic disease is discussed.