Human leukocyte antigen-DR expression on peripheral blood monocytes and the risk of pneumonia in pediatric lung transplant recipients.

BACKGROUND: Pneumonia is the leading cause of morbidity and mortality after living lobar lung transplantation (LT). Low levels of human leukocyte antigen-DR (HLA-DR) expression on peripheral blood monocytes, have been demonstrated to correlate with risk of infection in surgical, trauma, and adult transplant patients. In addition, interleukin (IL)-10 has been shown to be a negative regulator of HLA-DR expression. This study investigates whether HLA-DR expression and serum IL-10 levels correlate with the development of pneumonia after pediatric LT. METHODS: Thirteen LT recipients were prospectively monitored with blood samples obtained pre-LT (baseline) and post-LT weeks 1-4. Mean fluorescence intensity (MFI) of HLA-DR on CD14+ monocytes was measured by flow cytometry. IL-10 levels were determined by ELISA from frozen serum collected at the same time points as monocyte HLA-DR expression. Correlates of pneumonia were abstracted from the medical record. RESULTS: Monocyte HLA-DR expression declined in 11 of 13 patients in the first week post-LT. Two patients without an initial decline and four others whose HLA-DR expression recovered by week 2 post-LT, did not develop pneumonia or other infection or rejection. Pneumonia was observed in seven patients, six of whom failed to recover their monocyte HLA-DR expression by 2 weeks post-LT. Six of seven patients with pneumonia recovered, and one patient died of aspergillosis. During weeks 1-4, a statistically significant difference was seen in the profile of mean monocyte HLA-DR expression levels, analyzed as percent of baseline, between the patients with and without pneumonia (P=0.002). The greatest difference between groups over time was seen from post-LT weeks 1-2 (P=0.003). In addition, when comparing the values at each week, a significant difference was seen between the two groups at post-LT week 2 (P=0.006) and week 4 (P=0.05). Analysis of IL-10 concentrations revealed that the overall difference between the groups (patients with and without pneumonia) was statistically significant (P=0.014), with a paradoxical positive correlation between HLA-DR expression at post-LT week 4 and IL-10 concentrations. CONCLUSIONS: Persistent low monocyte HLA-DR expression was associated with the risk of post-LT pneumonia in these patients. This measurement may be useful for monitoring risk of infection and stratifying patients into higher and lower risk groups. Increased IL-10 levels may be protective for infection in this group of patients. At present it is unknown whether the predictive power of HLA-DR expression is indicative of a global defect in monocytic function or a specific abnormality.

Elevated visual motion detection thresholds in adults with acquired ophthalmoplegia.

AIMS: To test the hypothesis that in patients with acquired chronic bilateral ophthalmoplegia, abnormal retinal image slippage during head movements would result in abnormal thresholds for visual perception of motion. METHODS: Five patients (two males and three females) with ophthalmoplegia were included in the study. The average age was 44 years (range 30-69 years). The aetiology of ophthalmoplegia was myasthenia gravis (MG; n=2), chronic progressive external ophthalmoplegia (CPEO; n=2), and chronic idiopathic orbital inflammation. Visual motion detection thresholds were assessed using horizontal and vertical gratings (spatial frequency) set at thresholds for visibility. The grating was then accelerated at 0.09 deg/s(2). The subject's task was to detect the drift direction of the stimulus. RESULTS: Visual motion detection thresholds were raised to a mean of 0.434 deg/s (SD 0.09) (mean normal value 0.287 deg/s (SD 0.08)) for horizontal motion; and to a mean of 0.425 deg/s (SD 0.1) (mean normal value 0.252 deg/s (SD 0.08)) for vertical motion. The difference in values for both horizontal and vertical motion detection were statistically significant when compared with age matched controls; p <0.023 for horizontal motion and p<0.07 for vertical motion (two tailed t test). CONCLUSION: Abnormally raised visual motion thresholds were found in patients with ophthalmoplegia. This may represent a centrally mediated adaptive mechanism to ignore excessive retinal slip and thus avoid oscillopsia during head movements.

Adenoviral infections and a prospective trial of cidofovir in pediatric hematopoietic stem cell transplantation.

Adenoviral (ADV) infections are increasingly recognized as a cause of morbidity and mortality in pediatric hematopoietic stem cell transplantation (HSCT). We reviewed our experience with ADV infections in HSCT patients hospitalized for transplantation at Childrens Hospital Los Angeles January 1998 through December 1998. ADV was detected in 47% of patients, with recipients of HSCT from alternative donors (matched unrelated, unrelated cord, and mismatched related donors) being more frequently culture positive than recipients of HSCT from matched siblings (62% versus 27%, P = .04). Detection of ADV from 2 or more sites was associated with organ injury, eg, hemorrhagic cystitis, enteritis, and hepatitis. Because of the high incidence of ADV culture-positive patients and the lack of effective anti-ADV therapy, we initiated a prospective trial to evaluate cidofovir (CDV) in the treatment of ADV infections in HSCT recipients. Eight patients were enrolled on a dosage schedule of 1 mg/kg 3 times weekly. AD of these patients eventually achieved long-term viral suppression and clinical improvement, although 6 patients needed prolonged CDV therapy for up to 8 months before CDV could be stopped without ADV recurrence. We did not observe dose-limiting nephrotoxicity, and the discontinuation of the drug was not required in any patients. Prospective controlled trials to further define the role of CDV in the treatment of ADV infections in HSCT patients are warranted.

Escherichia coli K1 purA and sorC are preferentially expressed upon association with human brain microvascular endothelial cells.

In order to better understand the events that allow Escherichia coli K1 to cross the blood-brain barrier we used differential fluorescence induction to identify bacterial genes that are preferentially expressed when associated with human brain microvascular endothelial cells (HBMEC), which comprise the blood-brain barrier. Random gene fusions of E. coli K1 DNA were created in a promoterless gfp vector and gene fusion libraries were incubated with and without HBMEC. The cells were subjected to a series of fluorescence-activated cell sorting screens to identify promoter fusions which lead to fluorescence when bacteria were associated with HBMEC, yet not fluorescent when grown in media alone. Two genes were identified, purA (encodes adenylosuccinate synthetase) and a sorC homologue (encodes a member of the sorC family of transcriptional regulators), whose expression were preferentially induced when bacteria were associated with eukaryotic cells. Individual gene disruption mutants of E. coli K1 purA and sorC demonstrated significantly decreased HBMEC invasion phenotype in vitro, when compared to the wild-type strain, and could be complemented when the respective wild-type sequences were supplied in trans. The purA and sorC mutants were deficient in their ability to grow in defined minimal media, without adenine, and with sorbose as sole carbon source, respectively, yet capable of normal growth in complex media. We have identified novel phenotypes associated with E. coli K1 purA and sorC, which provide evidence that these genes contribute to the invasion of HBMEC.

New federal regulations for improving quality in opioid treatment programs.

The U.S. Food and Drug Administration (FDA) has enforced federal requirements related to the use of methadone since 1972; regulations essentially have not changed for nearly 30 years. With Congress' recently released federal regulations for opioid treatment programs (OTPs), however, oversight of OTPs has shifted from the FDA to the Substance Abuse and Mental Health Services Administration (SAMHSA). SAMHSA's Center for Substance Abuse Treatment developed guidelines for accreditation agencies such as the Joint Commission on Accreditation of Healthcare Organizations and The, Rehabilitation Accreditation Commission...CARF to develop standards for OTPs. Preliminary findings show that OTPs are indeed able to meet these accreditation standards. This article reviews the need for the changes, the history of methadone treatment oversight, the development of accreditation requirements, stakeholders' initial response to the proposed regulations, and performance domains of importance to OTPs.

Escherichia coli K1 aslA contributes to invasion of brain microvascular endothelial cells in vitro and in vivo.

Neonatal Escherichia coli meningitis remains a devastating disease, with unacceptably high morbidity and mortality despite advances in supportive care measures and bactericidal antibiotics. To further our ability to improve the outcome of affected neonates, a better understanding of the pathogenesis of the disease is necessary. To identify potential bacterial genes which contribute to E. coli invasion of the blood-brain barrier, a cerebrospinal fluid isolate of E. coli K1 was mutagenized with TnphoA. TnphoA mutant 27A-6 was found to have a significantly decreased ability to invade brain microvascular endothelial cells compared to the wild type. In vivo, 32% of the animals infected with mutant 27A-6 developed meningitis, compared to 82% of those infected with the parent strain, despite similar levels of bacteremia. The DNA flanking the TnphoA insertion in 27A-6 was cloned and sequenced and determined to be homologous to E. coli K-12 aslA (arylsulfatase-like gene). The deduced amino acid sequence of the E. coli K1 aslA gene product shows homology to a well-characterized arylsulfatase family of enzymes found in eukaryotes, as well as prokaryotes. Two additional aslA mutants were constructed by targeted gene disruption and internal gene deletion. Both of these mutants demonstrated decreased invasion phenotypes, similar to that of TnphoA mutant 27A-6. Complementation of the decreased-invasion phenotypes of these mutants was achieved when aslA was supplied in trans. This is the first demonstration that this locus contributes to invasion of the blood-brain barrier by E. coli K1.

Frequency and intensity of crack use as predictors of women's involvement in HIV-related sexual risk behaviors.

Recent trends in the progression of the AIDS epidemic in the United States indicate that women's rates of acquiring HIV are escalating more rapidly than are men's. Consequently, there has been both an increasing interest in and a need for research targeting substance-abusing women's involvement in HIV risk behaviors. In recent years, strong suggestive evidence has arisen to suggest that women who use crack cocaine are at an elevated risk for acquiring HIV, probably as a result of their involvement in high-risk sexual behaviors. The present study is based on a sample of 1723 women from 22 locales around the United States who used crack cocaine at least once during the previous 30 days but who reported never having injected drugs at any point in their lifetime. Women were divided into four groups based on their frequency and intensity of using crack. In subsequent analyses, this grouping was used to predict the extent to which female crack users engage in five sexual risk behavior measures (number of sexual partners, number of drug-injecting sexual partners, number of times having sexual relations while high on alcohol and/or other drugs, number of times trading sex for drugs and/or money, and proportion of all sexual acts involving the use of protection). The data revealed that the women who used crack with the greatest frequency and the greatest intensity were the most heavily involved in risky sexual behaviors. They differed quite sharply from their lower-intensity and/or lower-frequency crack-using counterparts in terms of their HIV risk behavior involvement and in terms of their actual HIV seroprevalence rates.

Project neighborhoods in action: an HIV-related intervention project targeting drug abusers in Washington, DC.

Project Neighborhoods in Action was a human immunodeficiency virus (HIV) outreach and intervention program that was conducted with injection drug users and crack users in several inner-city neighborhoods in the District of Columbia. Study participants were placed randomly in either a standard intervention or an enhanced intervention condition, with more than 800 persons being assigned to each group. Drug use frequency dropped from 15.2 days to 12.4 for alcohol (P<.0001), 2.1 days to 1.6 for marijuana (P<.003), 13.0 days to 8.8 days for crack (P<.0001), 2.4 days to 1.5 days for cocaine (P<.0001), 19.7 days to 15.6 for heroin (P<.0001), and 5.2 days to 3.4 for speedball (P<.0001). Drug injecting decreased from an average of 90.8 times to 66.9 (P<.0001), with both direct sharing and indirect sharing rates decreasing significantly as well (from 2.4 to 1.1 times for the former [P<.002] and from 12.0 to 8.1 times for the latter [P<.0004]). The number of sexual partners dropped from a mean of 1.6 to 1.1 (P<.0001). The number of drug-injecting sexual partners went from 0.3 to 0.2 (P<.01). Having sex while high decreased from 11.2 times to 7.9 (P<.0001). Trading sex for drugs and/or money declined from 1.9 times to 1.3 (P<.001). Protected sex increased from 29.5% to 63.7% (P<.0001), and the number of unprotected sexual acts dropped from 9.6 to 7.2 (P<.0001). Only a few differences were observed for standard versus enhanced intervention respondents, with no particular pattern formed. We were left with the impression that the standard intervention and enhanced intervention used in this program were about equally effective at reducing the involvement of drug abusers in HIV-related risky behaviors.

The acceptability of the female condom among substance-using women in Washington, DC.

This research is based on structured interviews, semi-structured interviews, and informal firsthand observation of women residents of Washington, DC who used crack and/or injected drugs during the previous 30 days. The study entailed introducing these women to the female condom, exposing them to an HIV risk reduction intervention teaching them how to use it and how to negotiate its use with their sexual partner(s). Women were tested for HIV and asked to return one week later for their results. They were asked to try the female condom within that first week. Upon returning for their tests results, ethnographers discussed with them their experiences with the female condom. They were reinterviewed for follow-up three months later to assess changes in behavior from baseline as well as their longer term experiences with and opinions of the female condom. The data presented in this paper are based on the interviews conducted one week after baseline. Of particular interest and concern to this research were: women's perceptions of the female condom prior to and subsequent to using it, women's partners' perceptions of the female condom after being introduced to it, and potential barriers to use. In all, 131 women, mostly African-American, took part in this study, which was conducted during the winter of 1997-1998.

The capsule supports survival but not traversal of Escherichia coli K1 across the blood-brain barrier.

The vast majority of cases of gram-negative meningitis in neonates are caused by K1-encapsulated Escherichia coli. The role of the K1 capsule in the pathogenesis of E. coli meningitis was examined with an in vivo model of experimental hematogenous E. coli K1 meningitis and an in vitro model of the blood-brain barrier. Bacteremia was induced in neonatal rats with the E. coli K1 strain C5 (O18:K1) or its K1(-) derivative, C5ME. Subsequently, blood and cerebrospinal fluid (CSF) were obtained for culture. Viable bacteria were recovered from the CSF of animals infected with E. coli K1 strains only; none of the animals infected with K1(-) strains had positive CSF cultures. However, despite the fact that their cultures were sterile, the presence of O18 E. coli was demonstrated immunocytochemically in the brains of animals infected with K1(-) strains and was seen by staining of CSF samples. In vitro, brain microvascular endothelial cells (BMEC) were incubated with K1(+) and K1(-) E. coli strains. The recovery of viable intracellular organisms of the K1(+) strain was significantly higher than that for the K1(-) strain (P = 0.0005). The recovery of viable intracellular K1(-) E. coli bacteria was increased by cycloheximide treatment of BMEC (P = 0.0059) but was not affected by nitric oxide synthase inhibitors or oxygen radical scavengers. We conclude that the K1 capsule is not necessary for the invasion of bacteria into brain endothelial cells but is responsible for helping to maintain bacterial viability during invasion of the blood-brain barrier.

The effect of entering drug treatment on involvement in HIV-related risk behaviors.

The research described here is based on a sample of 8,241 out-of-drug-treatment users of injected drugs and/or crack, aged 18 or older, recruited from 22 sites across the United States and Puerto Rico. The study divided respondents into three groups-(a) cocaine or crack users who did not also use heroin or speedball (cocaine-only users), (b) heroin injectors who did not also use cocaine or crack or speedball (heroin injectors), and (c) users of cocaine or crack and injected heroin or speedball (dual users)--and compared the efficacy of entering drug treatment for these groups' involvement in HIV-related risk behaviors. The study found that entry into treatment corresponded to greater reductions in substance abusers' frequency of drug use and involvement in risky injection practices compared to those observed in people who did not enter treatment between their baseline and 6-month follow-up interviews. Entry into drug treatment was also associated with reductions in the practice of risky sexual behaviors, but these reductions were less substantial and less consistent than those noted for drug use and injection risk behaviors.

Drug dependence scale in the Millon Clinical Multiaxial inventory.

The Million Clinical Multiaxial Inventory (MCMI versions I, II, and III) includes a scale to assess drug use problems, Scale T-Drug Dependence. Detailed drug use data from a sample of 659 known drug users along with MCMI-II results were examined to determine the operating characteristics of the MCMI-II drug dependence scale. Operating characteristics, sensitivity, specificity, positive predictive power, negative predictive power, and overall diagnostic power were calculated for base rate cutoffs and for the number of prototypic items endorsed to determine the diagnostic efficiency of Scale T-Drug Dependence in identifying regular drug users. Prototypic item cutoffs provided higher levels of diagnostic and positive predictive power than did the standard base rate cutoffs.

The validity of self-reports of drug use at treatment admission and at followup: comparisons with urinalysis and hair assays.

Studies conducted in the 1970s and early 1980s concluded that people will provide valid information about their illicit drug use when research interviews are conducted under appropriate conditions. Recent studies of treated and untreated populations using improved urinalysis techniques as well as hair analysis techniques indicate that the validity of respondents' self-reports of recent drug use may be considerably less than previously reported and may differ according to a number of factors. Results are presented from a study of clients participating in the Washington, DC, Treatment Initiative study who were assessed for drug use by interview, urinalysis, and hair analysis. At intake, almost all clients who tested positive had reported their use of heroin but fewer clients had reported their cocaine use. At posttreatment followup, clients underreported both heroin and cocaine use. Findings from treatment outcome studies that fail to validate and adjust their estimates of self-reported recent drug use should be interpreted with considerable caution.

Characterization of the peptide binding requirements for the cloned human pancreatic polypeptide-preferring receptor.

Traditionally, neuropeptide Y (NPY) receptors have been divided into Y1 and Y2 subtypes based on peptide pharmacology and synaptic localization. Other receptor subtypes have been proposed based on preferences for NPY, peptide YY (PYY), or pancreatic polypeptide (PP). Recently, we discovered a novel human member of this receptor family exhibiting high affinity for PP and PYY. In the current study, we expressed a DNA clone encoding this human PP-preferring receptor [hPP1 (or Y4)] in Chinese hamster ovary cells and performed a peptide structure-activity study. [125I]pPYY bound to homogenates of hPP1-Chinese hamster ovary cells with a Kd of 0.064 +/- 0.006 nM and a Bmax of 244 +/- 12 fmol/mg protein. Human PP inhibited binding with a Ki of 0.023 nM, whereas human PYY (Ki = 0.31 nM) and human NPY Ki = 12 nM) were significantly less potent. Rat, porcine, and bovine PP inhibited binding with similar affinities to human PP, whereas avian PP was substantially less potent (Ki = 1 nM). Deletion of the first four amino acids reduced the affinity of bovine PP to 1 nM. Carboxyl-terminal fragments of NPY and PYY also had reduced potency compared with the native peptides. In addition, deletion of Tyr36-amide produced a substantial reduction in affinity. Pro34-substituted NPY and PYY had modestly increased affinity compared with the native peptides, although Gln34-bPP had similar affinity compared with bovine PP. The carboxyl-terminally derived Y1 antagonist 1229U91 was a very potent (Ki = 0.042 nM) inhibitor of binding to hPP1. Thus, the carboxyl-terminal region of PP seems to be the most important part of the peptide for high affinity binding to hPP1. A few key residues (amino acids 2 and 3) in the amino-terminal region of PP contribute to the high affinity of the native peptide. Thus, features required for peptide recognition by the hPP1 receptor seem to be distinct from the Y1 and Y2 receptor.

Profiles of clients in government-funded drug user treatment settings.

This report describes profiles of 535 clients who participated in a federally-funded drug user treatment research demonstration program in Washington, D.C. The majority of clients were African-Americans (92%) and single (60%). These profiles were created to determine which types of clients were enrolled in which modalities and whether there were differences between clients placed in outpatient or residential programs after stratification by primary drug problem: heroin or cocaine. Localities which are involved in developing client placement criteria and/or managed care guidelines for treatment programs may find these profiles helpful in planning to address the multiple needs of drug users.

Psychosocial treatments for cocaine abuse. 12-month treatment outcomes.

The 12-month posttreatment outcome results for a randomized clinical trial that tested the effectiveness of various combinations of 4-month psychosocial treatment interventions are reported for 184 clients who used cocaine. Clients primarily used crack (93%), and the majority were African American (95%). Overall, clients exhibited substantial pre-post treatment gains: reduced regular cocaine use, reduced other drug use, reduced regular alcohol use, and reduced involvement in illegal activities. Logistic regression models produced significant odds ratios showing that those who used cocaine regularly during the year after treatment were more likely to have attended fewer treatment sessions, to be female, to be less educated, to have been regular cocaine users prior to treatment, and to have spent fewer days incarcerated during the 12-months after treatment. It was concluded that treatment positively impacted posttreatment gains, and it was suggested that selective tailoring of additional treatment services may produce additional treatment gains.

Relationship between drug preference and indicators of psychiatric impairment.

This study was conducted to investigate the relationship between the indicators of psychiatric disorders of individuals and their choice of either cocaine or heroin, drugs that differ markedly in their pharmacological effects. Cocaine acts as an intense stimulant, and heroin has profound sedative effects. This investigation examined the relationship between preference for heroin or cocaine and indicators of psychiatric impairment. Data from 282 subjects were grouped according to drug of choice and analyzed. Ninety-three percent of these subjects were African-American, 32% were female, and the average age was 34. Univariate and multivariate statistical analyses, such as discriminant analyses, were used to determine group differences. The results are evaluated and interpreted in relation to both the current empirical findings and to the hypotheses and theories postulated as a result of earlier clinical observations on drug of choice and psychopathology. Discriminant analysis yielded an overall correct classification rate of 75%. The discriminant function suggests that members in the cocaine drug of choice group as contrasted with members in the heroin preference group can be characterized as more socially inhibited and more self-defeating after adjusting for differences in age, duration of use of illicit substances, and marital status. Those who favored cocaine as contrasted with those who favored heroin were more likely to have never married, be younger, and have used illicit substances for a shorter period of time.