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Biomedical subjects

L Knowles

Publications and source records attributed to L Knowles.

At least 19 recordsLinked to original sources
PubMed2006

Activation of extracellular signal-regulated protein kinase 5 downregulates FasL upon osmotic stress.

Extracellular signal-regulated protein kinase (ERK) 5 is a mitogen-activated protein kinase (MAPK) that is activated by dual phosphorylation via a unique MAPK/ERK kinase 5, MEK5. The physiological importance of this signaling cascade is underscored by the early embryonic death caused by the targeted deletion of the erk5 or the mek5 genes in mice. Here, we have found that ERK5 is required for mediating the survival of fibroblasts under basal conditions and in response to sorbitol treatment. Increased Fas ligand (FasL) expression acts as a positive feedback loop to enhance apoptosis of ERK5- or MEK5-deficient cells under conditions of osmotic stress. Compared to wild-type cells, erk5-/- and mek5-/- fibroblasts treated with sorbitol display a reduced protein kinase B (PKB) activity associated with increased Forkhead box O3a (Foxo3a) activity. Based on these results, we conclude that the ERK5 signaling pathway promotes cell survival by downregulating FasL expression via a mechanism that implicates PKB-dependent inhibition of Foxo3a downstream of phosphoinositide 3 kinase.

Animals↗
PubMed2005

Incorporating a social networking approach to enhance contact tracing in a heterosexual outbreak of syphilis.

OBJECTIVE: This report describes the outcomes of a social networking approach (SNA) in a heterosexually transmitted syphilis epidemic by street nurses in British Columbia, Canada. METHODS: Street nurses used SNA interviewing cues, environmental observation, peer outreach, serial interviewing, conducted blood tests, and offered treatment on the street. Rates of cases of syphilis identified by outreach nurses and cases linked to another case were compared before and after adoption of an SNA. RESULTS: SNA resulted in a significantly increased proportion of cases identified by the street nurses (p = 0.01) and increased the percentage of cases linked to a previous case (p = 0.03). CONCLUSION: This preliminary study confirms that SNA can increase the number of cases and contacts identified in an epidemic of a sexually transmitted disease in a vulnerable, hard to reach population.

British Columbia↗
PubMed2004

Law and policy in the era of reproductive genetics.

The extent to which society utilises the law to enforce its moral judgments remains a dominant issue in this era of embryonic stem cell research, preimplantation genetic diagnosis, and human reproductive cloning. Balancing the potential health benefits and diverse moral values of society can be a tremendous challenge. In this context, governments often adopt legislative bans and prohibitions and rely on the inflexible and often inappropriate tool of criminal law. Legal prohibitions in the field of reproductive genetics are not likely to reflect adequately the depth and diversity of competing stakeholder positions. Rather, a comprehensive and readily responsive regulatory policy is required. Such a policy must attend to the evolving scientific developments and ethical considerations. We outline a proposal for effective, responsive, and coherent oversight of new reproductive genetic technologies.

Attitude to Health↗
PubMed2003

Ovarian stimulation of marmoset monkeys (Callithrix jacchus) using recombinant human follicle stimulating hormone.

To reduce the number of animals required for controlled studies of marmoset oocytes and early embryos, a superovulation protocol was developed for the common marmoset. Females were given up to 50 i.u./day recombinant human follicle stimulating hormone (FSH)--(r-hFSH) for 6 days. Ovaries were visualized by a modified laparoscopic technique and follicular aspiration was performed using a needle and suction apparatus inserted directly through an otoscope speculum. The number of follicles + ovulation points (+/- S.E.) was 2.9 (+/- 0.2) in controls and 14.1 (+/- 1.6; P < or = 0.001) in the 50 i.u. r-hFSH per day animals. Oocytes, typically at the germinal vesicle stage at collection, extruded a first polar body within 26 hours. In vitro fertilization was performed and embryos developed to the hatched blastocyst stage (34%). With many high quality oocytes and the ability to synchronize cycles, the marmoset is a valuable primate model for examining nuclear reprograming and early embryonic events.

Animals↗
PubMed2001

Pregnancy and live birth from nonsurgical transfer of in vivo- and in vitro-produced blastocysts in the rhesus monkey.

Embryo transfer in the rhesus monkey has been historically limited to transfer of cleavage stage embryos. In order to allow genetic manipulation of rhesus embryos in vitro, without using invasive surgical techniques, it is important to explore the transfer of morula and blastocyst stage embryos. Embryos were produced by in vitro fertilization from gonadotropin-stimulated monkeys, or were obtained by nonsurgical uterine flushing of naturally mated or artificially inseminated females. Nonsurgical transfer was accomplished by inserting a metal guide through the cervix into the uterus, after which a hollow cell sampler was inserted over the guide. The guide was removed and a catheter was inserted containing one to five embryos. Several pregnancies resulted from in vitro- and in vivo-derived blastocysts, and two pregnancies were carried to term resulting in one live birth. Blood samples were collected regularly to monitor plasma levels of chorionic gonadotropin, luteinizing hormone, and progesterone. The recipients received progesterone as a subcutaneous implant or daily injections from the day of transfer. The approach described in this study provides the opportunity to explore transgenic and chimeric models in the monkey by the development of noninvasive methods to transfer late-stage embryos that have been manipulated in vitro.

Animals↗
PubMed2000

A population-based survey of tuberculosis symptoms: how atypical are atypical presentations?

There is scant information on tuberculosis symptoms from a population-based perspective. We prospectively identified 526 tuberculosis cases reported in Los Angeles County over a 6-month period. Of 313 persons who completed our questionnaire, 72.7% had cough, 48.2% for >2 weeks, and 52.3% had fever, 29.4% for >2 weeks. Among those with pulmonary disease, only 52.4% had cough for >2 weeks. In a multivariate model, persons with significant symptoms typical of tuberculosis disease (defined as cough or fever for >2 weeks, weight loss, or hemoptysis) were associated with lack of medical insurance, negative tuberculin skin test, diagnosis during a process other than screening, and non-Asian race. In summary, classic symptoms of prolonged cough and fever are insensitive predictors of tuberculosis. Our data suggest that Asians may need to be added to the list of persons who present with tuberculosis atypically. We believe that the Infectious Diseases Society of America guidelines for community-acquired pneumonia should emphasize demographic features in addition to clinical symptoms when suggesting which patients require evaluation for Mycobacterium tuberculosis.

Adult↗
PubMed1999

Foci of tuberculosis transmission in central Los Angeles.

To identify sites of tuberculosis transmission and to determine the contribution of HIV-infected patients to tuberculosis morbidity in an urban area, we prospectively evaluated 249 patients with culture-proven tuberculosis in central Los Angeles. Restriction fragment length polymorphism (RFLP) analysis was performed on Mycobacterium tuberculosis isolates to identify patients infected with the same strain. Using RFLP and clinical and epidemiologic data, we identified the most likely source case and site of transmission for 79 patients. Homelessness, birth in the United States and Native American ethnicity were independent predictors of being a source case, but HIV infection was not. Three homeless shelters were sites of tuberculosis transmission for 55 (70%) of the 79 patients. HIV-infected patients constituted 27% (66/249) of the study population, but only 17% (13/79) of patients were infected by an HIV-infected source case. We conclude that transmission of tuberculosis in central Los Angeles was highly focal, and that the major transmission sites were three homeless shelters. HIV- infected tuberculosis patients did not play a major role in spread of tuberculosis. Tuberculosis control measures targeted at specific homeless shelters can reduce tuberculosis morbidity in urban areas where homelessness is common and the incidence of tuberculosis is high.

AIDS-Related Opportunistic Infections↗
PubMed1998

Tuberculosis in homeless patients: potential for case finding in public emergency departments.

STUDY OBJECTIVES: Previous studies have had difficulty evaluating the optimal clinical site for screening homeless patients for active tuberculosis (TB). We hypothesized that homeless patients with TB would not frequently reside in shelters at the time of their diagnosis and would be more likely than other patients with TB to seek care in public hospitals, thus presenting an opportunity for screening radiography. METHODS: This registry-based survey included 743 consecutive patients with confirmed active TB in Los Angeles County. No therapeutic intervention was involved. RESULTS: When compared with patients with TB who were not homeless, homeless patients with TB were more likely to be male (93% versus 63%, P<.001), black (44% versus 15%, P<.001), living in the inner city (55% versus 7%, P<.001), and born in the United States (67% versus 32%, P<.001). They were more infectious than other patients with TB as evidenced by a trend toward more cavitary radiographic lesions (24% versus 16%, P=.11) and significantly more positive sputum smears (56% versus 41%, P=.009). Less than a third lived in congregate facilities such as shelters at the time of their diagnosis. Instead, their disease was diagnosed more often at county hospitals (54% versus 23%, P<.001) than patients with TB who were not homeless. CONCLUSION: Widespread screening for TB in shelters may miss most homeless patients with TB. Because most county-hospital homeless patients with TB initially present to emergency departments and many do not live in shelters, future cost-effectiveness studies should evaluate chest radiograph screening for all homeless ED patients.

Adult↗
PubMed1997

Patterns of tuberculosis transmission in Central Los Angeles.

CONTEXT: Recent studies suggest that many tuberculosis cases in urban areas result from recent transmission. Delineation of the epidemiologic links between patients is important to optimize strategies to reduce tuberculosis transmission. OBJECTIVE: To identify epidemiologic links among recently infected urban patients with tuberculosis. DESIGN: Prospective evaluation of patients with tuberculosis. SETTING: Central Los Angeles, Calif. PATIENTS: A total of 162 patients who had culture-proven tuberculosis. INTERVENTIONS: Patients were prospectively interviewed to identify their contacts and whereabouts. The IS6110-based and pTBN12-based restriction fragment length polymorphism analyses were performed on Mycobacterium tuberculosis isolates. Patients whose isolates had identical or closely related restriction fragment length polymorphism patterns were considered a cluster. Unconditional logistic regression was used to identify independent predictors of clustering. MAIN OUTCOME MEASURES: Relationship of clinical and epidemiologic variables to clustering. RESULTS: A total of 96 (59%) of 162 patients were in 8 clusters. Only 2 of the 96 clustered patients named others in the cluster as contacts. The degree of homelessness was an independent predictor of clustering. Compared with nonclustered patients, patients in 6 clusters were significantly more likely to have spent time at 3 shelters and other locations when at least 1 patient in the cluster was contagious, and these locations were independent predictors of clustering. Among nonhomeless persons, clustered patients were significantly more likely than nonclustered patients to have used daytime services at 3 shelters. CONCLUSIONS: (1) Traditional contact investigation does not reliably identify patients infected with the same M tuberculosis strain, and (2) locations at which the homeless congregate are important sites of tuberculosis transmission for homeless and nonhomeless persons. Measures that reduce tuberculosis transmission should be based on locations rather than on personal contacts.

Adolescent↗
PubMed1996

Relationship of isoniazid resistance to human immunodeficiency virus infection in patients with tuberculosis.

To investigate the relationship between isoniazid resistance and HIV infection in patients with tuberculosis, we evaluated data in the Los Angeles County tuberculosis registry on 1,506 patients for whom drug susceptibility results were available. Among 235 HIV-infected patients, isoniazid resistance was less common than in 1,271 patients who were HIV-seronegative or who had not been tested for HIV, with an unadjusted odds ratio of 0.3. After adjustment for other factors that affect drug resistance (ethnicity, country of birth, prior diagnosis of tuberculosis, and cavitation), the frequency if isoniazid resistance remained lower than that in patients without HIV infection, with an odds ratio of 0.4 (95% confidence interval, 0.2 to 0.8; p = 0.02). We conclude that in Los Angeles, a setting where there is no ongoing outbreak of drug-resistant tuberculosis, isoniazid-resistant tuberculosis is not more common in HIV-infected patients.

Antitubercular Agents↗
PubMed1994

Processes underlying young children's spatial orientation during movement.

Children between 1.5 and 4 years old were tested for their ability to relocate a hidden object after a 180 degrees self-produced movement around an array of four locations. In one task the object's location relative to the other locations could be uniquely defined within one dimension, while in another two dimensions were needed to do this. No differences emerged between conditions, and by 3 years few errors occurred, despite the fact that children were unable to view the array during movement. This indicates either that young children encounter no specific difficulty in coordinating dimensions or that they solved the task without recourse to such a system. An error analysis supports the second possibility. Children apparently tackled the task by a system directly related to body movement, since errors were frequently the result of incomplete compensation for movement around the array. In a second study in which the four containers were placed in contact, children's performance declined and the relation between direction of movement and error was replaced by some evidence for updating on the near-far dimension accompanied by failure to update the left-right dimension. Thus children appear to change strategy when the problem requires more precise specification of target location.

Child, Preschool↗
PubMed1994

Unsatisfactory performance of the leukocyte esterase test of first voided urine for rapid diagnosis of urethritis.

BACKGROUND AND OBJECTIVES: The objective of this study was to determine the performance characteristics of a dipstick test for leukocyte esterase (LE), (Chemstrip 2LN, Boehringer Mannheim) in predicting the presence of urethritis and urethral pathogens in men presenting to a busy sexually transmitted disease clinic and to street outreach facilities. METHODS: Urethral swabs for polymorphonuclear (pmn) cell count, gonorrhoea culture and chlamydia enzyme immunoassay (EIA) as well as 15 ml of first voided urine (FVU) were collected from 737 symptomatic and 726 asymptomatic men. Gonorrhoea cultures and pmn counts were processed according to standard methods. Either Abbott Chlamydiazyme EIA (confirmed) or Syva Microtrak EIA (confirmed) test was employed to detect C trachomatis. The LE test was immediately dipped in FVU, read after 60-120 seconds by the clinician and considered positive if trace, 1+ or 2+. RESULTS: Microscopic evidence of urethritis (> or = = 4 pmn cells per 1000 x field) was found on urethral smear of 782 (53.5%) patients. Chlamydia, gonorrhoea or both were present in 104 (7.1%) patients. Performance characteristics of the LE test were as follows: (table below) CONCLUSION: The LE test did not have adequate sensitivity to be considered a reliable rapid diagnostic test for urethritis or urethral pathogens, particularly in the asymptomatic portion of this STD clinic population.

Adolescent↗
PubMed1991

Faecal incontinence due to perianal cellulitis.

A 4-year-old boy presented with a 6-week history of painful defaecation and faecal incontinence due to streptococcal perianal cellulitis. After treatment with a 10-day course of oral penicillin his symptoms had fully resolved. Early diagnosis and treatment of this under-recognised condition is essential.

Anus Diseases↗