Feasibility of completing an accelerated vaccine series for homeless adults.

Homeless adults are at high risk for hepatitis B virus (HBV) infection. In addition to culturally sensitive programmes designed to enhance vaccination compliance, accelerated HBV vaccination (three doses over 21 days) have also been suggested to improve compliance among high-risk groups. In this paper, we examined predictors of completers of two of three doses of a HAV/HBV vaccine series, normally delivered over a 6-month period, to simulate compliance with an accelerated series, dosed over 4 weeks. A convenience sample of 865 homeless adults was randomized into a nurse case-managed approach (NCMIT) vs standard programmes with (SIT) and without tracking (SI). Each group was assessed for completion of two of the three dose HAV/HBV vaccine series as well as the full three dose vaccine series. Sixty-eight percent of the NCMIT participants completed the three dose vaccination series at 6 months compared to 61% of SIT participants and 54% of SI participants. Eighty-one percent of the NCMIT participants completed two of the vaccinations compared to 78% of SIT participants and 73% of SI participants. The NCMIT approach resulted in greater numbers of completers of two of three doses and of the full three dose vaccine series. Predictors of completers of two doses and the full three dose vaccine series are provided. A greater number of homeless persons completed two doses across the three groups compared to the three dose vaccine series. The use of nurse case-management and tracking, coupled with an accelerated HAV/HBV vaccination schedule, may optimize vaccination compliance in homeless adults.

Periodicity of sleep states is altered in infants at risk for the sudden infant death syndrome.

The normal succession of sleep and waking states through a night is disturbed in infants at risk for the sudden infant death syndrome. Compared with normal infants, siblings of the sudden infant death syndrome victims have longer intervals between active sleep epochs at particular times during the night in the newborn period and a decreased tendency to enter short waking periods at 2 and 3 months of age. The latter finding is interpreted as an increased tendency to remain asleep, or a relative failure to arouse from sleep in infants at risk.

Naringin is a major and selective clinical inhibitor of organic anion-transporting polypeptide 1A2 (OATP1A2) in grapefruit juice.

We showed previously that grapefruit and orange juices inhibited human enteric organic anion-transporting polypeptide (OATP)1A2 in vitro and lowered oral fexofenadine bioavailability clinically. Inhibition of OATP1A2 transport by flavonoids in grapefruit (naringin) and orange (hesperidin) was conducted in vitro. Two randomized, crossover, pharmacokinetic studies were performed clinically. In one study, 120 mg of fexofenadine was ingested with 300 ml grapefruit juice, an aqueous solution of naringin at the same juice concentration (1,200 microM), or water. In the other study, fexofenadine was administered with grapefruit juice, with or 2 h before aqueous suspension of the particulate fraction of juice containing known clinical inhibitors of enteric CYP3A4, but relatively low naringin concentration (34 microM), or with water. Naringin and hesperidin's half-maximal inhibitions were 3.6 and 2.7 microM, respectively. Fexofenadine area under the plasma drug concentration-time curves (AUCs) with grapefruit juice and naringin solution were 55% (P<0.001) and 75% (P<0.05) of that with water, respectively. Fexofenadine AUCs with grapefruit juice and particulate fractions were 57% (P<0.001), 96% (not significant (NS)), and 97% (NS) of that with water, respectively. Individuals tested in both studies (n=9 of 12) had highly reproducible fexofenadine AUC with water (r(2)=0.85, P<0.001) and extent of reduction of it with grapefruit juice (r(2)=0.72, P<0.01). Naringin most probably directly inhibited enteric OATP1A2 to decrease oral fexofenadine bioavailability. Inactivation of enteric CYP3A4 was probably not involved. Naringin appears to have sufficient safety, specificity, and sensitivity to be a clinical OATP1A2 inhibitor probe. Inherent OATP1A2 activity may be influenced by genetic factors. This appears to be the first report of a single dietary constituent clinically modulating drug transport.

Intestinal drug transporter expression and the impact of grapefruit juice in humans.

The goals of this study were to assess the extent of human intestinal drug transporter expression, determine the subcellular localization of the drug uptake transporter OATP1A2, and then to assess the effect of grapefruit juice consumption on OATP1A2 expression relative to cytochrome P450 3A4 and MDR1. Expression of drug uptake and efflux transporters was assessed using human duodenal biopsy samples. Fexofenadine uptake by different transporters was measured in a transporter-transfected cell line. We investigated the influence of grapefruit juice on pharmacokinetics of orally administered fexofenadine. The effect of grapefruit juice on the expression of intestinal transporters was determined using real-time polymerase chain reaction and Western blot analysis. In the duodenum of healthy volunteers, an array of CYP enzymes as well as uptake and efflux transporters was expressed. Importantly, uptake transporters thought to be liver-specific, such as OATP1B1 and 1B3, as well as OATP2B1 and 1A2 were expressed in the intestine. However, among OATP transporters, only OATP1A2 was capable of fexofenadine uptake when assessed in vitro. OATP1A2 colocalized with MDR1 to the brush border domain of enterocytes. Consumption of grapefruit juice concomitantly or 2 h before fexofenadine administration was associated with reduced oral fexofenadine plasma exposure, whereas intestinal expression of either OATP1A2 or MDR1 remained unaffected. In conclusion, an array of drug uptake and efflux transporters are expressed in the human intestine. OATP1A2 is likely the key intestinal uptake transporter for fexofenadine absorption whose inhibition results in the grapefruit juice effect. Although short-term grapefruit juice ingestion was associated with reduced fexofenadine availability, OATP1A2 or MDR1 expression was unaffected.

The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors.

Currently available HIV-1 protease inhibitors are potent agents in the therapy of HIV-1 infection. However, limited oral absorption and variable tissue distribution, both of which are largely unexplained, complicate their use. We tested the hypothesis that P-glycoprotein is an important transporter for these agents. We studied the vectorial transport characteristics of indinavir, nelfinavir, and saquinavir in vitro using the model P-glycoprotein expressing cell lines L-MDR1 and Caco-2 cells, and in vivo after intravenous and oral administration of these agents to mice with a disrupted mdr1a gene. All three compounds were found to be transported by P-glycoprotein in vitro. After oral administration, plasma concentrations were elevated 2-5-fold in mdr1a (-/-) mice and with intravenous administration, brain concentrations were elevated 7-36-fold. These data demonstrate that P-glycoprotein limits the oral bioavailability and penetration of these agents into the brain. This raises the possibility that higher HIV-1 protease inhibitor concentrations may be obtained by targeted pharmacologic inhibition of P-glycoprotein transport activity.

A randomized controlled trial of two treatment programs for homeless adults with latent tuberculosis infection.

SETTING: Few studies have examined strategies for optimizing adherence to latent tuberculosis infection (LTBI) treatment programs in homeless populations. OBJECTIVES: 1) To compare the effectiveness of an intervention program employing nurse case management and incentives (NCMI) vs. a control program with standard care and incentives on completion of LTBI treatment; and 2) to compare the impact of the two programs on tuberculosis (TB) knowledge among participants. DESIGN: A prospective, two-group site-randomized design conducted among 520 homeless adults residing in the Skid Row region of Los Angeles from 1998 to 2003, assessing completion rates of a 6-month isoniazid (INH) treatment program and change in TB knowledge. RESULTS: Using intent-to-treat analysis, 62% of participants in the intervention program, compared with 39% of controls, completed the full 6-month course of LTBI treatment with INH. Logistic regression modeling revealed that intervention participants had three times greater odds of completing INH treatment than controls. TB knowledge improved in both programs, but the increase was greater among the intervention participants (P < 0.001). CONCLUSIONS: Nurse case management combined with education, incentives, and tracking dramatically improves both adherence to LTBI treatment and TB knowledge in homeless persons compared to a standard approach of outreach and incentives.

Human MRP3 transporter: identification of the 5'-flanking region, genomic organization and alternative splice variants.

In humans, at least six members of the multidrug resistance-associated protein (MRP) family are thought to exist. Here we report the molecular cloning of two splice variants of MRP3 from human liver. In addition, MRP3 genomic organization including the 5'-flanking region and a major portion of the MRP3 intron-exon organization are identified and characterized.

Effect of physician specialty on use of necessary coronary angiography.

OBJECTIVES: This study sought to determine whether having a cardiologist as a regular source of care influences likelihood of undergoing necessary coronary angiography. BACKGROUND: An important element of the current health policy debate is the respective roles of primary care and specialist physicians. However, there are few data on interspecialty differences in quality of care for patients with ischemic heart disease. METHODS: We contacted 243 patients by telephone (response rate 72%) who had positive (or very positive) exercise stress test results and met additional clinical criteria for necessary coronary angiography. Study patients were randomly sampled from those undergoing exercise stress testing at one university and three public hospitals in Los Angeles between January 1, 1990 and June 30, 1991. Patients were asked whether they had a regular source of care during the time after their exercise stress test and, if so, whether that provider was a cardiologist or cardiology clinic. RESULTS: Among survey responders, 47% underwent necessary coronary angiography within 3 months of exercise testing and 61% within 12 months. After adjustment for sociodemographics and clinical presentation, patients with a cardiologist as a regular source of care were more likely than all other patients to have undergone necessary angiography within 3 months (52% vs. 38%, p = 0.05) and within 12 months (74% vs. 44%, p = 0.0001) of the exercise test. At 3 months, there was a trend toward a more pronounced effect of ongoing cardiologic care within the public hospitals compared with the private hospital (p = 0.09 for interaction between hospital types). CONCLUSIONS: Patients with a cardiologist as a regular source of care were more likely than all other patients to undergo clinically necessary coronary angiography within both 3 and 12 months of exercise stress testing.

Faculty development in general internal medicine. Perceptions concerning academic survival.

To understand the educational needs of faculty general internists in academic hospital environments, surveys of general internal medicine division chiefs, department of medicine chairmen, and members of the Society for Research and Education in Primary Care Internal Medicine were undertaken. Results indicated considerable interest in faculty development activities among all physicians sampled. Division chiefs and department chairmen viewed such activities as feasible, potentially effective, and were willing to assume considerable responsibility in providing educational opportunities to their faculty. Although some physicians viewed self-learning as a potentially effective educational method, the vast majority preferred learning in a small group taught by an expert. Specific content areas for faculty development were assessed, as were the skills thought to be essential for personal job satisfaction, academic promotion, and organizational effectiveness.

Recent sexual behaviors among homosexual men seeking primary medical care.

We studied the sociodemographic characteristics, knowledge, and beliefs about acquired immunodeficiency syndrome transmission and sexual practices of 823 gay or bisexual men seeking primary care. During the previous 2 months, 64% had engaged in at least one sexual behavior considered unsafe. These patients compared with those having safer sex, were younger, of lower socioeconomic status, and from a racial minority, especially Latino. The unsafe group also had more sexual partners, engaged in sexual acts more often, felt less in control over their sexual behavior, used recreational drugs more frequently, and were less likely to talk about safe sex with partners. The unsafe group had less adequate knowledge about human immunodeficiency virus transmission but felt safer from the risk of acquired immunodeficiency syndrome even when engaging in unsafe sex. Educational programs dealing more directly with belief systems and the potential addiction to recreational drugs and sexual behaviors need to be developed for primary care settings.

Effect of tetrodotoxin on the inward ionic current of the guinea pig atrium.

The inward ionic current in the atrium has been measured by electronic differentiation of the voltage, time signal, on the assumption that the single cell penetrated by the micro-electrode shows cable-like properties. The method exploits fully information contained in the upstroke of the action potential, and an internally consistent set of parameters can be derived. Tetrodotoxin was found to reduce the fast inward ionic current, and to shift the voltage of maximum current flow to more negative values. TTX augmented the effects of high stimulation rates but did not alter the refractory period of the atrium. It is suggested that TTX interacts with the Na+ channel so as to reduce activation of the Na+ current and hence unit conductance. The present results are consistent with the apparent voltage-dependence of TTX action, since activation and inactivation of the Na+ current are both voltage-sensitive phenomena.

Identification of functionally variant MDR1 alleles among European Americans and African Americans.

MDR1 (P-glycoprotein) is an important factor in the disposition of many drugs, and the involved processes often exhibit considerable interindividual variability that may be genetically determined. Single-strand conformational polymorphism analysis and direct sequencing of exonic MDR1 deoxyribonucleic acid from 37 healthy European American and 23 healthy African American subjects identified 10 single nucleotide polymorphisms (SNPs), including 6 nonsynonymous variants, occurring in various allelic combinations. Population frequencies of the 15 identified alleles varied according to racial background. Two synonymous SNPs (C1236T in exon 12 and C3435T in exon 26) and a nonsynonymous SNP (G2677T, Ala893Ser) in exon 21 were found to be linked (MDR1*2 ) and occurred in 62% of European Americans and 13% of African Americans. In vitro expression of MDR1 encoding Ala893 (MDR1*1 ) or a site-directed Ser893 mutation (MDR1*2 ) indicated enhanced efflux of digoxin by cells expressing the MDR1-Ser893 variant. In vivo functional relevance of this SNP was assessed with the known P-glycoprotein drug substrate fexofenadine as a probe of the transporter's activity. In humans, MDR1*1 and MDR1*2 variants were associated with differences in fexofenadine levels, consistent with the in vitro data, with the area under the plasma level-time curve being almost 40% greater in the *1/*1 genotype compared with the *2/*2 and the *1/*2 heterozygotes having an intermediate value, suggesting enhanced in vivo P-glycoprotein activity among subjects with the MDR1*2 allele. Thus allelic variation in MDR1 is more common than previously recognized and involves multiple SNPs whose allelic frequencies vary between populations, and some of these SNPs are associated with altered P-glycoprotein function.

Mental health, alcohol and drug use, and criminal history among homeless adults.

As part of a community-based survey of 529 homeless adults, the authors analyzed factors associated with their use of mental health services. Homeless persons who had had a previous psychiatric hospitalization were the least likely to sleep in an emergency shelter, had been homeless nearly twice as long as the rest of the sample, had the worst mental health status, used alcohol and drugs the most, and were the most involved in criminal activities. The majority had not made an outpatient mental health visit in 5 years. It is suggested that diverse systems of care are needed for homeless persons.

Identifying modifiable risk factors for rehospitalization: a case-control study of seriously mentally ill persons in Mississippi.

OBJECTIVE: The authors sought to identify risk factors for rehospitalization in a seriously mentally ill population, focusing on factors that have the potential to be modified through community-based interventions. METHOD: A case-control design was used in which 101 "case" subjects (recently readmitted psychiatric patients) and a comparison group of 101 subjects living in the community who had been previously hospitalized at the same time as the case subjects, but who in contrast had not been readmitted, were matched on gender, ethnicity, and length of time at risk for rehospitalization. The setting was the Mississippi public mental health system during the first 3 months of 1988, including Mississippi State Hospital and the 10 community mental health regions in its catchment area. The subjects were between the ages of 18 and 55 years, had had at least one previous Mississippi State Hospital admission, and had a primary chart diagnosis of schizophrenia; 197 informants, mostly family members, were also included in the study. Data were collected from structured interviews of subjects and informants, direct observation ratings of subjects, Mississippi State Hospital administrative records, and community mental health center administrative records. RESULTS: Medication noncompliance, comorbid alcohol abuse, and a high level of criticism of subjects by informants were associated with greater risk of rehospitalization, while types and extent of outpatient service use, access to care, quality of life, and demographic variables (other than ethnicity and gender) were not. CONCLUSIONS: These findings imply that interventions aimed at improving medication compliance, reducing alcohol abuse, and helping families cope with their mentally ill relatives could reduce the risk of hospitalization in this population.

Pentoxifylline is not a promising treatment for multiple sclerosis in progression phase.

Fourteen MS patients took pentoxifylline at varying doses for up to 24 months. In vitro production of tumor necrosis factor alpha was reduced in patients taking 2,400 to 3,200 mg/day of pentoxifylline for 12 weeks or more. Twelve of the 14 patients experienced worsening of the disease during the study according to clinical, MRI, or visual evoked potential criteria. These results provide no hint of efficacy for pentoxifylline as a treatment for MS in progression phase.

Developmental patterns of heart rate and heart rate variability during sleep and waking in normal infants and infants at risk for the sudden infant death syndrome.

The developmental sequence of heart rate and heart rate variability was examined during sleep and waking states in 22 normal infants, and 22 siblings of sudden infant death syndrome (SIDS) victims, using 12-h polygraphic recordings at 1 week and at 1, 2, 3, 4, and 6 months of age. Heart rate was higher in siblings of SIDS victims than in normal infants during quiet sleep over the first 6 months of life and was higher in the waking state at 3 months of age. The sibling group also had lower variability at 1 week during quiet sleep. Gender contributed no significant differences to heart rate, but females at risk for SIDS had lower waking cardiac variability than males.

Development of sinus arrhythmia during sleeping and waking states in normal infants.

The development of variability in heart rate (HR) due to respiration (sinus arrhythmia; SA) has been examined in normal infants from birth through the first 6 months of life. Two aspects of HR variation were examined: the absolute variation at the median respiratory frequency, or extent of sinus arrhythmia (XSA), and the degree to which HR follows respiration regardless of the absolute amount of variation, or coherence of sinus arrhythmia (CSA). Extent of sinus arrhythmia tended to be highest in quiet sleep (QS), lower in active or REM sleep (AS), and lowest in waking (AW), especially after 2 months of age. Extent declined at 1 month of age in QS, but rose over the first 6-month period in all states. During this same period, CSA was also highest in QS, lower in AS, and lowest in AW. Coherence in QS also declined at 1 month and rose between 1 and 6 months; however, no age effects were found in other states. Heart rate was negatively correlated with XSA, but less so with CSA. Sleep state appears to have a significant effect on cardiorespiratory coupling, and this coupling undergoes dramatic changes at 1 month in QS.

Physician-reported determinants of screening mammography in older women: the impact of physician and practice characteristics.

OBJECTIVE: Despite having markedly higher breast cancer risk, compliance of older women with screening mammography has been poor. This study was undertaken to determine which physician and patient practice characteristics were associated with high self-reported mammography referral rates for older women. METHODS: Primary care physicians (n = 129) from three socioeconomically diverse communities in Los Angeles were surveyed. Agreement with annual screening and self-reported referral rates were assessed for two groups of women, those 65 to 74 years of age and those 75 years and older. Screening outcomes were compared with physician and patient practice characteristics using bivariate and multivariate techniques. RESULTS: Although 73% of physicians agreed with annual screening of women aged 65 to 74 years, only 24% of physicians reported actually screening most women seen in this age group. Similarly, 57% of physicians agreed that women age 75 years and older should be screened annually, but only 21% reported recommending mammograms for most women seen in this age group. In multivariate analysis, white physicians (adjusted OR = 9.1), younger physicians (adjusted OR = 3.85), and those who used the American Cancer Society's low cost mammography projects (adjusted OR = 5.01) were more likely to report screening the majority of women seen. DISCUSSION: This study suggests that although physicians' intentions to screen older women may be relatively high, a gap exists between intentions and what is reported to be accomplished in practice. Race/ethnicity and physician specialty were the two strongest predictors of high self-reported referral rates, suggesting that targeted interventions may be useful.

Physicians' perceptions about increased glove-wearing in response to risk of HIV infection.

Glove-wearing attitudes of 375 physicians, representing 56% of all physicians surveyed, were ascertained. Although the majority were comfortable with their current glove use, 33% preferred wearing them more frequently. The most common reasons for not wearing gloves were a low likelihood of disease transmission and fear of offending patients. Many physicians felt that more frequent glove use in examining human immunodeficiency virus- (HIV)-positive patients might reduce rapport and diminish the adequacy of physical examination procedures, but only 11% felt that increased glove use would compromise overall care of HIV-positive patients. With regard to all patients, 33% felt that increased glove use in examinations would compromise care. Additionally, 56% of physicians stated that they were somewhat concerned about HIV infection. Glove-wearing preferences were significantly associated with greater concern about infection, a younger age and more frequent exposure to blood and body secretions. Contact with high-risk patient groups was not associated with glove-wearing preferences.

Predictors of mortality in older patients following medical intensive care: the importance of functional status.

OBJECTIVE: We examined predictors of hospital and 6-month mortality in older Medical Intensive Care Unit (MICU) patients with particular attention to age and functional status. Age is generally thought to be strongly associated with intensive care outcomes, but this relationship may be confounded by age-related changes. These age-related changes may be approximated by changes in functional status (FS). DESIGN: We conducted a retrospective chart review and collected severity of illness data using the Acute Physiology Score (APS), pre-hospitalization FS dichotomized as limited or not limited, and hospital mortality. County death records were reviewed for 6-month mortality. SETTING: Three community hospital MICUs. PATIENTS: Four-hundred MICU patients aged 50 and older admitted during the study period. RESULTS: Limited FS was found in 42% of the 227 patients who had FS data in the chart. Mortality was significantly associated with APS, age, FS, immunocompromise state, comorbidity, and nursing home residence. In logistic regression analyses, while controlling for important variables, APS (P less than 0.001) and age greater than or equal to 75 with limited FS (P less than 0.05) were associated with hospital mortality. Six-month mortality predictors were APS (P less than 0.001), hospital (P less than 0.05), immunocompromised state (P less than 0.05) and age greater than or equal to 75 with limited FS (P less than 0.05). CONCLUSIONS: We found that among patients without functional limitations, the oldest group was no more likely to die than the youngest group. Age and functional status had a significant interaction: patients older than 75 years with functional limitations were almost six times more likely to die in hospital compared to the reference group of patients between 50-64 years old without functional limitations. We conclude that functional status is an important predictor of outcome in older MICU patients.