Biomedical subjects

Mark Foster

Publications and source records attributed to Mark Foster.

16 recordsLinked to original sources

PubMed2025

Abnormal mitochondrial structure and function in brown adipose tissue of SLC35A4-MP knockout mice.

Uncovering the role of upstream open reading frames (uORFs) challenges conventional views of one protein per messenger RNA and reveals the capacity of some uORFs to encode microproteins that contribute to cellular biology and physiology. This study explores the functional role of a recently identified mitochondrial microprotein, SLC35A4-MP, in the brown adipose tissue of mice. Our findings reveal dynamic regulation of SLC35A4-MP expression during primary brown adipocyte differentiation in vitro and during cold exposure or high-fat diet (HFD)-induced obesity in mice. Using a knockout mouse model, we show that loss of SLC35A4-MP disrupts mitochondrial lipid composition, decreasing cardiolipins and phosphatidylethanolamine in brown adipose tissue from HFD-fed mice. SLC35A4-MP deficiency also impairs mitochondrial activity, alters mitochondrial number and morphology, and promotes inflammation. Knockout mice accumulate acylcarnitines during cold exposure, indicating defective fatty acid oxidation. These findings reveal SLC35A4-MP as a previously unrecognized microprotein in regulating mitochondrial function and tissue lipid metabolism, adding to the growing list of functional endogenous microproteins.

Animals↗

PubMed2007

Mandatory protocol for treating adult patients with diabetic ketoacidosis decreases intensive care unit and hospital lengths of stay: results of a nonrandomized trial.

OBJECTIVE: To determine the effect of a mandatory protocol for treating diabetic ketoacidosis. DESIGN: Chart review of patients treated before and after protocol implementation. SETTING: University-affiliated U.S. public teaching hospital. PATIENTS: A total of 241 consecutive nonpregnant patients >18 yrs old admitted to a medical intensive care unit for diabetic ketoacidosis between January 2000 and January 2005. INTERVENTION: Implementation of a mandatory treatment protocol in May 2003. MEASUREMENTS: Intensive care unit and hospital lengths of stay, time to correction of anion gap and ketone clearance, and hypoglycemic episodes. RESULTS: Before protocol implementation, the mean +/- sd intensive care unit and hospital lengths of stay were 44 +/- 28 hrs and 91 +/- 73 hrs, respectively. After implementation, intensive care unit and hospital lengths of stay decreased 23% and 30%, to 34 +/- 18 hrs and 64 +/- 41 hrs, respectively (both p < .007). Time to anion gap closure and ketone clearance also decreased (both p < .05). No difference in the number of hypoglycemic episodes was observed. CONCLUSION: Implementing a mandatory protocol for treating adult patients with diabetic ketoacidosis decreases intensive care and hospital lengths of stay and time to anion gap closure and ketone clearance, without increasing the rate of hypoglycemia.

Acid-Base Equilibrium↗

PubMed2005

Novel cell-penetrating alpha-keto-amide calpain inhibitors as potential treatment for muscular dystrophy.

Dipeptide-derived alpha-keto-amide compounds with potent calpain inhibitory activity have been identified. These reversible covalent inhibitors have IC(50) values down to 25nM and exhibit greatly improved activity in muscle cells compared to the reference compound MDL28170. Several novel calpain inhibitors have shown positive effects on histological parameters in an animal model of Duchenne muscular dystrophy demonstrating their potential as a treatment option for this fatal disease.

Amides↗

PubMed2004

Seroepidemiology of infection with human papillomavirus 16, in men and women attending sexually transmitted disease clinics in the United States.

BACKGROUND: The study sought to characterize the seroprevalence, seropersistence, and seroincidence of human papillomavirus (HPV)-16 antibody, as well as the behavioral risk factors for HPV-16 seropositivity. METHODS: Serologic data at baseline and at 6- and 12-month follow-up visits were used to examine the seroprevalence, seropersistence, and seroincidence of HPV-16 antibody in 1595 patients attending United States clinics treating sexually transmitted disease. Testing for antibody to HPV-16 was performed by capture enzyme-linked immunosorbent assay (ELISA) using viruslike particles. RESULTS: The seroprevalence of HPV-16 antibody was 24.5% overall and was higher in women than in men (30.2% vs. 18.7%, respectively). In those who were HPV-16 seropositive at baseline, antibody response persisted to 12 months in 72.5% of women and in 45.6% of men. The seroincidence of HPV-16 antibody was 20.2/100 person-years (py) overall, 25.4/100 py in women, and 15.7/100 py in men. In multivariate analysis, the seroprevalence of HPV-16 antibody was significantly associated with female sex, age >20 years, and the number of episodes of sex with occasional partners during the preceding 3 months, whereas the seroincidence of HPV-16 antibody was significantly associated with female sex, age >20 years, baseline negative ELISA result greater than the median value, and the number of episodes of unprotected sex with occasional partners during the preceding 3 months. CONCLUSION: Sex- and age-related differences in both the seropositivity and seroincidence of HPV-16 antibody persisted after adjustment for behavioral and sociodemographic risk factors, and behavioral risk factors during the preceding 3 months were stronger predictors of the seroprevalence and seroincidence of HPV-16 antibody than was lifetime sexual behavior.

Adolescent↗

PubMed2004

Incidence of herpes simplex virus type 2 infection in 5 sexually transmitted disease (STD) clinics and the effect of HIV/STD risk-reduction counseling.

The seroincidence of herpes simplex virus type 2 (HSV-2) infection was determined among 1766 patients attending sexually transmitted disease (STD) clinics and enrolled in a randomized, controlled trial of human immunodeficiency virus (HIV)/STD risk-reduction counseling (RRC). Arm 1 received enhanced RRC (4 sessions); arm 2, brief RRC (2 sessions); and arm 3, the control arm, brief informational messages. The overall incidence rate was 11.7 cases/100 person-years (py). Independent predictors of incidence of HSV-2 infection included female sex; black race; residence in Newark, New Jersey; <50% condom use with an occasional partner; and, in females, incident trichomoniasis and bacterial vaginosis. Only 10.8% of new HSV-2 infections were diagnosed clinically. Incidence rates were 12.9 cases/100 py in the control arm, 11.8 cases/100 py in arm 2, and 10.3 cases/100 py in arm 1 (hazard ratio, 0.8 [95% confidence interval, 0.6-1.1], vs. controls). The possible benefit of RRC in preventing acquisition of HSV-2 infection offers encouragement that interventions more specifically tailored to genital herpes may be useful and should be an important focus of future studies.

Adolescent↗

PubMed2004

Myelomonocytic cells are sufficient for therapeutic cell fusion in liver.

Liver repopulation with bone marrow-derived hepatocytes (BMHs) can cure the genetic liver disease fumarylacetoacetate hydrolase (Fah) deficiency. BMHs emerge from fusion between donor bone marrow-derived cells and host hepatocytes. To use such in vivo cell fusion efficiently for therapy requires knowing the nature of the hematopoietic cells that fuse with hepatocytes. Here we show that the transplantation into Fah(-/-) mice of hematopoietic stem cells (HSCs) from lymphocyte-deficient Rag1(-/-) mice, lineage-committed granulocyte-macrophage progenitors (GMPs) or bone marrow-derived macrophages (BMMs) results in the robust production of BMHs. These results provide direct evidence that committed myelomonocytic cells such as macrophages can produce functional epithelial cells by in vivo fusion. Because stable bone marrow engraftment or HSCs are not required for this process, macrophages or their highly proliferative progenitors provide potential for targeted and well-tolerated cell therapy aimed at organ regeneration.

Animals↗

PubMed2004

Histological parameters for the quantitative assessment of muscular dystrophy in the mdx-mouse.

Duchenne muscular dystrophy is a severe X-linked hereditary disease caused by the absence of functional dystrophin. The dystrophin-deficient mdx-mouse strain is a widely used animal model for dystrophin-deficiency. Several therapeutic approaches for muscular dystrophy have been proposed by different laboratories. In order to compare the efficacy of these therapies in the mdx-mouse, it is essential to implement standardized protocols for the assessment of functional and histological parameters in this mouse model. Here, we determine that the minimal 'Feret's diameter' is a geometrical parameter that allows for reliable measure of muscle fiber cross-sectional size. Using this geometrical parameter we calculate variance coefficients of the muscle fiber size and provide reference values for the quantitative assessment of dystrophic symptoms in frequently investigated muscles of wild-type and mdx-mouse. In addition, we compare the variance coefficients of the muscle fiber size with the percentage of muscle fibers with centralized nuclei; another histological hallmark of muscular dystrophy.

Age Factors↗

PubMed2003

The origin and liver repopulating capacity of murine oval cells.

The appearance of bipotential oval cells in chronic liver injury suggests the existence of hepatocyte progenitor/stem cells. To study the origin and properties of this cell population, oval cell proliferation was induced in adult mouse liver by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) and a method for their isolation was developed. Transplantation into fumarylacetoacetate hydrolase (Fah) deficient mice was used to determine their capacity for liver repopulation. In competitive repopulation experiments, hepatic oval cells were at least as efficient as mature hepatocytes in repopulating the liver. In mice with chimeric livers, the oval cells were not derived from hepatocytes but from liver nonparenchymal cells. This finding supports a model in which intrahepatic progenitors differentiate into hepatocytes irreversibly. To determine whether oval cells originated from stem cells residing in the bone marrow, bone marrow transplanted wild-type mice were treated with DDC for 8 months and oval cells were then serially transferred into Fah mutants. The liver repopulating cells in these secondary transplant recipients lacked the genetic markers of the original bone marrow donor. We conclude that hepatic oval cells do not originate in bone marrow but in the liver itself, and that they have valuable properties for therapeutic liver repopulation.

Animals↗

PubMed2003

Cell fusion is the principal source of bone-marrow-derived hepatocytes.

Evidence suggests that haematopoietic stem cells might have unexpected developmental plasticity, highlighting therapeutic potential. For example, bone-marrow-derived hepatocytes can repopulate the liver of mice with fumarylacetoacetate hydrolase deficiency and correct their liver disease. To determine the underlying mechanism in this murine model, we performed serial transplantation of bone-marrow-derived hepatocytes. Here we show by Southern blot analysis that the repopulating hepatocytes in the liver were heterozygous for alleles unique to the donor marrow, in contrast to the original homozygous donor cells. Furthermore, cytogenetic analysis of hepatocytes transplanted from female donor mice into male recipients demonstrated 80,XXXY (diploid to diploid fusion) and 120,XXXXYY (diploid to tetraploid fusion) karyotypes, indicative of fusion between donor and host cells. We conclude that hepatocytes derived form bone marrow arise from cell fusion and not by differentiation of haematopoietic stem cells.

Alleles↗

PubMed2003

Herpes simplex virus type 2 infection as a risk factor for human immunodeficiency virus acquisition in men who have sex with men.

The association of human immunodeficiency virus (HIV) acquisition with herpes simplex virus type 2 (HSV-2) was assessed among men who have sex with men (MSM) in a nested case-control study of 116 case subjects who seroconverted to HIV during follow-up and 342 control subjects who remained HIV seronegative, frequency-matched by follow-up duration and report of HIV-infected sex partner and unprotected anal sex. The baseline HSV-2 seroprevalence was higher among case (46%) than control (34%) subjects (P=.03); the HSV-2 seroincidence was 7% versus 4% (P=.3). Only 15% of HSV-2-infected MSM reported herpes outbreaks in the past year. HIV acquisition was associated with prior HSV-2 infection (odds ratio [OR], 1.8; 95% confidence interval [CI], 1.1-2.9), reporting >12 sex partners (OR, 2.9; 95% CI, 1.4-6.3), and reporting fewer herpes outbreaks in the past year (OR, 0.3; 95% CI, 0.1-0.8). HSV-2 increases the risk of HIV acquisition, independent of recognized herpes lesions and behaviors reflecting potential HIV exposure. HSV-2 suppression with antiviral therapy should be evaluated as an HIV prevention strategy among MSM.

Case-Control Studies↗

PubMed2003

Self-directed, integrated clinical learning through a sign-up system.

AIM: To help students in a self-directed, problem-based learning (PBL) curriculum learn from a breadth of hospital experience. METHODS: Clinical units were asked to identify what clinical activities they could make available to interested students on a 'first-come, first-served' basis. A centralised, electronic system was developed that allowed students to book a fair, but not excessive, share of those learning opportunities. This web-based programme evolved into a comprehensive timetabling system that managed activities for whole classes of students as well as 'sign-ups' booked by individuals. RESULTS: The sign-up system offered 1792 hours/week, or 6 hours/student/week, to the hospital's 291 students of learning opportunities additional to firm-based teaching and learning. There were sign-ups in all major specialties and they included rounds, clinics, theatre/investigation sessions and conferences. Students accessed the system as commonly from outside the hospital as within it, and used it to view their timetables as well as to book learning opportunities. The system was used particularly heavily when examinations were imminent, indicating that students found it supportive to their learning. CONCLUSIONS: We have developed an innovative way of providing experience that is relevant to problem-based, integrative clinical education. Students, as judged by their heavy use of it, value the system.

Clinical Competence↗

PubMed2003

Initiating contraception in sexually transmitted disease clinic setting: a randomized trial.

OBJECTIVE: Our purpose was to determine the effectiveness of sexually transmitted disease (STD) clinic-initiated contraceptive care. STUDY DESIGN: Nonpregnant women (n=877) attending an urban STD clinic using either no contraception or only condoms were randomly assigned to either an intervention (n=437) or control group (n=440). Both groups received condoms with spermicide and a referral list of primary care providers (PCP) for ongoing reproductive health care, and the intervention group also received enhanced contraceptive counseling, initial provision of contraception, and facilitated referral to a PCP. Outcomes measured at 4-, 8-, and 12-month follow-up were transition to a PCP, effective contraceptive use (ECU), interval pregnancy, and STD. RESULTS: The median time to PCP transition was 79 days for the intervention group versus 115 days for the control group (P=.007). Rates of ECU were higher for the intervention group than for control group at the 4-month visit (50% vs 22%, P<.0001) as well as the 8-month visit, although in the intervention group ECU diminished over the course of the study. During follow-up, pregnancy outcomes were documented for 229 women (26.1%), for an overall pregnancy rate of 38.2 per 100 person-years of follow-up. Of the 159 pregnancies defined by patient self-report, 153 (96.2%) were described as unintended and 32 (20%) resulted in a therapeutic abortion. The pregnancy rate was 15% lower in the intervention (105/437, 24.0%) than the control group (124/440, 28.2%) (P=.16), but this difference was not statistically significant. CONCLUSION: The intervention helped women transition to a PCP and initiate ECU but did not significantly reduce the pregnancy rate. More intensive interventions are needed to prevent unintended pregnancy in this high-risk population.

Abortion, Therapeutic↗

PubMed2002

TROSY-NMR studies of the 91kDa TRAP protein reveal allosteric control of a gene regulatory protein by ligand-altered flexibility.

The tryptophan biosynthesis genes of several Bacilli are controlled through terminator/anti-terminator transcriptional attenuation. This process is regulated by tryptophan-dependent binding of the trp RNA-binding attenuation protein (TRAP) to the leader region of the trp operon mRNA, precluding formation of the antiterminator RNA hairpin, and allowing formation of the less stable terminator hairpin. Crystal structures are available of TRAP in complex with tryptophan and in ternary complex with tryptophan and RNA. However, no structure of TRAP in the absence of tryptophan is available; thus, the mechanism of allostery remains unclear. We have used transverse relaxation optimized spectroscopy (TROSY)-based NMR experiments to study the mechanism of ligand-mediated allosteric regulation in the 90.6kDa 11-mer TRAP. By recording a series of two-dimensional 15N-edited TROSY NMR spectra of TRAP from the thermophile Bacillus stearothermophilus over an extended range of temperatures, we have found tryptophan binding to be temperature-dependent, in agreement with the previously observed temperature-dependent RNA binding. Triple-resonance TROSY-based NMR spectra recorded at 55 degrees C have allowed us to obtain backbone resonance assignments for uniformly 2H,13C,15N-labeled TRAP in the inactive form and in the active form (free and bound to tryptophan). On the basis of ligand-dependent differential line-broadening and chemical shift perturbations, coupled with the results of proteolytic sensitivity measurements, we infer that tryptophan-modulated protein flexibility (dynamics) plays a central role in TRAP function by altering its RNA-binding affinity. Furthermore, because the crystal structures show that the ligand is buried completely in the bound state, we speculate that such dynamic behavior may be important to enable rapid response to changes in intracellular tryptophan levels. Thus, we propose that allosteric control of TRAP is accomplished by ligand-altered protein dynamics.

Bacterial Proteins↗

PubMed2002

Seroprevalence and correlates of herpes simplex virus type 2 infection in five sexually transmitted-disease clinics.

The seroprevalence of herpes simplex virus type 2 (HSV-2) infection was studied among 4128 patients from sexually transmitted disease (STD) clinics who were enrolled in a randomized controlled trial of human immunodeficiency virus and STD counseling efficacy. HSV-2 seroprevalence was 40.8% and was higher in women than in men (52.0% vs. 32.4%; P<.0001) and higher in blacks than in nonblacks (48.1% vs. 29.6%; P<.0001). Among 14-19-year-old patients, 36.8% of black women and 25.8% of nonblack women were infected with HSV-2. Independent predictors of HSV-2 seropositivity included female sex, black race, older age, less education, more lifetime sex partners, prior diagnosis of syphilis or gonorrhea, and lack of HSV-1 antibody. The majority of HSV-2-seropositive persons (84.7%) had never received a diagnosis of genital herpes. HSV-2 infection is common in STD clinic attendees in the United States, even among young age groups, especially among women. Efforts to prevent genital herpes should begin at an early age. The high rate of undiagnosed HSV-2 infection likely contributes to ongoing transmission.

Adolescent↗

PubMed2002

Persistence of Chlamydia trachomatis infection detected by polymerase chain reaction in untreated patients.

BACKGROUND: Prior studies have used Chlamydia trachomatis culture methods to demonstrate both persistence and spontaneous clearance of genital C trachomatis infection. OBJECTIVE: To further assess the issue of persistence and spontaneous clearance of C trachomatis infection, untreated men and women were evaluated with repeated polymerase chain reaction (PCR) testing. METHODS: Ninety four untreated patients with a prior positive C trachomatis PCR test returning to the Denver Metro Sexually Transmitted Disease Clinic were retested by PCR. RESULTS: The median and range intervals from initial to follow-up testing were 9.0 (2-112) days for men and 10.0 (2-231) days for women. Repeated PCR tests were positive for 29 of 36 men (80.6%) and 45 of 58 women (77.6%). Persistent PCR positivity did not decrease with a longer testing interval. By multivariate analysis, independent predictors of a persistently positive PCR test included nonwhite ethnicity, an interval of more than 3 days since last sexual encounter before the initial test, and an initial PCR optical density value of greater than or equal to 3.0. CONCLUSIONS: In the absence of treatment, a large majority of patients testing positive for C trachomatis by PCR are likely to remain positive for variable periods of time, increasing the risk of transmission and immune-mediated damage. A low initial optical density value and recent sexual contact may be markers for exposure that does not establish infection.

Adult↗

PubMed2002

Predicting pregnancy risk in women attending an STD clinic.

BACKGROUND: Although sexually transmitted disease (STD) clinics focus mainly on STD treatment and prevention, women attending these clinics are also at high risk for pregnancy. GOAL: To evaluate the relationship between certain demographic and behavioral characteristics and the probability of pregnancy in women attending an urban STD clinic. STUDY DESIGN: Non-contraceptive-using women in an STD clinic-initiated randomized controlled contraception study (n = 877) were interviewed at baseline, and incident pregnancies within 1 year of enrollment were measured. Association between baseline demographic and behavioral characteristics with incident pregnancy was assessed by chi-square analysis, and logistic regression was used to assess factors associated with an incident pregnancy. RESULTS: Among the 673 women (76.7%) for whom follow-up pregnancy information was available, 220 (32.7%) incident pregnancies occurred within 1 year. By logistic regression controlling for study assignment, incident pregnancy was associated with age < or =19 years (odds ratio [OR], 2.8; 95% CI: 1.5-5.2), previous abortion (OR, 3.1; 95% CI: 1.7-5.4), frequency of sexual encounters of at least once a week (OR, 1.8; 95% CI: 1.2-2.6), and having a chlamydial infection at the time of enrollment (OR, 1.8; 95% CI: 1.0-3.2). With a combination of demographic and behavioral characteristics correlated by univariate analysis with incident pregnancy (i.e., age < or =19 years, nonwhite race, high school/general equivalency diploma or less education, previous pregnancy, no use of birth control with last intercourse, sex at least once a week, previous abortion, > or =3 partners within the past month, and <17 years of age at first pregnancy), the cumulative risk of pregnancy with 6 or more of the 9 characteristics was 51%, compared with 25.6% for women with < or =5 characteristics. CONCLUSION: For this STD clinic population, a combination of demographic and behavioral characteristics was useful when combined for identifying a subgroup of women at higher risk for subsequent pregnancy. Targeted intervention by STD care providers should include the provision for both pregnancy and STD prevention counseling.

Adolescent↗