The evidence behind the level of a random urine protein:creatinine in the diagnosis of preeclampsia: A systematic review

Objective. To determine the accuracy of the urine protein:creatinine ratio (pr:cr) in predicting 300 mg of protein in 24-hour urine collection in pregnant patients with suspected preeclampsia. ^ Methods. A systematic review was performed. Articles were identified through electronic databases and the relevant citations were hand searching of textbooks and review articles. Included studies evaluated patients for suspected preeclampsia with a 24-hour urine sample and a pr:cr. Only English language articles were included. The studies that had patients with chronic illness such as chronic hypertension, diabetes mellitus or renal impairment were excluded from the review. Two researchers extracted accuracy data for pr:cr relative to a gold standard of 300 mg of protein in 24-hour sample as well as population and study characteristics. The data was analyzed and summarized in tabular and graphical form. ^ Results. Sixteen studies were identified and only three studies met our inclusion criteria with 510 total patients. The studies evaluated different cut-points for positivity of pr:cr from 130 mg/g to 700 mg/g. Sensitivities and specificities for pr:cr of 130mg/g -150 mg/g were 90-93% and 33-65%, respectively; for a pr:cr of 300 mg/g were 81-95% and 52-80%, respectively; for a pr:cr of 600-700mg/g were 85-87% and 96-97%, respectively. ^ Conclusion. The value of a random pr:cr to exclude pre-eclampsia is limited because even low levels of pr:cr (130-150 mg/g) may miss up to 10% of patients with significant proteinuria. A pr:cr of more than 600 mg/g may obviate a 24-hour collection.^

Pre-employment drug testing among job applicants at a Texas tertiary level pediatric hospital: 1992--2006

This study is a retrospective longitudinal study at Texas Children's Hospital, a 350-bed tertiary level pediatric teaching hospital in Houston, Texas, for the period 1990 to 2006. It measured the incidence and trends of positive pre-employment drug tests among new job applicants At TCH. ^ Over the study period, 16,219 job applicants underwent pre-employment drug screening at TCH. Of these, 330 applicants (2%) tested positive on both the EMIT and GC/MS. After review by the medical review officer, the number of true drug test positive applicants decreased to 126 (0.78%). ^ According to the overall annual positive drug test incidence rates, the highest overall incidence was in 2002 (14.71 per 1000 tests) and the lowest in 2004 (3.17 per 1000 tests). Despite a marked increase in 2002, over the 15-year study period the overall incidence tended to decrease. Incidence rates and trends of other illegal drugs are further discussed in the study. And in general, these incidence rates also decline in the study period. In addition to that, we found the overall, positive drug tests were more common in females than in males (55.5% versus 44.4%). ^

The nonsteroidal anti-inflammatory drug indomethacin induces heterogeneity in lipid membranes: potential implication for its diverse biological action.

BACKGROUND: The nonsteroidal anti-inflammatory drug (NSAID), indomethacin (Indo), has a large number of divergent biological effects, the molecular mechanism(s) for which have yet to be fully elucidated. Interestingly, Indo is highly amphiphilic and associates strongly with lipid membranes, which influence localization, structure and function of membrane-associating proteins and actively regulate cell signaling events. Thus, it is possible that Indo regulates diverse cell functions by altering micro-environments within the membrane. Here we explored the effect of Indo on the nature of the segregated domains in a mixed model membrane composed of dipalmitoyl phosphatidyl-choline (di16:0 PC, or DPPC) and dioleoyl phosphatidyl-choline (di18:1 PC or DOPC) and cholesterol that mimics biomembranes. METHODOLOGY/PRINCIPAL FINDINGS: Using a series of fluorescent probes in a fluorescence resonance energy transfer (FRET) study, we found that Indo induced separation between gel domains and fluid domains in the mixed model membrane, possibly by enhancing the formation of gel-phase domains. This effect originated from the ability of Indo to specifically target the ordered domains in the mixed membrane. These findings were further confirmed by measuring the ability of Indo to affect the fluidity-dependent fluorescence quenching and the level of detergent resistance of membranes. CONCLUSION/SIGNIFICANCE: Because the tested lipids are the main lipid constituents in cell membranes, the observed formation of gel phase domains induced by Indo potentially occurs in biomembranes. This marked Indo-induced change in phase behavior potentially alters membrane protein functions, which contribute to the wide variety of biological activities of Indo and other NSAIDs.

Aggression, impulsivity and serotonin in drug dependence

Aggression, impulsivity, and central serotonergic function were evaluated in two groups of human volunteers; one group having a history of substance dependence (DRUG+) and another group with no drug use history (DRUG$-$). The hypothesis was that DRUG+ subjects would be more aggressive, more impulsive, and have attenuated serotonergic function. Results showed that DRUG+ subjects behaved more aggressively in a computer paradigm of aggression and also reported more aggression on questionnaires than DRUG$-$ subjects. In a computer paradigm of impulsivity, the DRUG+ group showed a lesser ability to delay gratification than the DRUG$-$ group in the last session of testing. The DRUG+ subjects also reported more venturesomeness and problems associated with low impulse control on questionnaires. Serotonergic function was measured through the neuroendocrine and hypothermic response to an orally administered serotonin (5-HT) agonist specific to the 5-HT$\rm\sb{1A}$ receptor subtype (ipsapirone). The neuroendocrine responses did not differ between DRUG$\pm$ groups, indicating no difference in the sensitivity of the presynaptic or postsynaptic 5-HT$\rm\sb{1A}$ receptors. An unexpected result was that the indicator hormone, cortisol, was at a lower baseline level in the DRUG+ group than the DRUG$-$ group. Lowered cortisol levels have been previously noted in children at high risk foul antisociality and future drug use. A principal components analysis including impulsivity, aggression, and serotonergic function measures produced three unique factors. The factors, Antisocial Tendency and Self-Control and Serotonergic Function combined to produce a significant regression equation explaining 36% of variability in the DRUG$\pm$ groups. These factors included measures of aggression, impulsivity, mood, and educational attainment. These results suggest that the current measures of aggression and impulsivity were predictive of a drug dependence disorder but that neuroendocrine function is not yet a useful indicator of drug dependence status. ^

An evaluation of a community-based program for homeless adults with mental disorders and comorbid alcohol drug and mental disorders

Limited research has been conducted evaluating programs that are designed to improve the outcomes of homeless adults with mental disorders and comorbid alcohol, drug and mental disorders. This study conducted such an evaluation in a community-based day treatment setting with clients of the Harris County Mental Health and Mental Retardation Authority's Bristow Clinic. The study population included all clients who received treatment at the clinic for a minimum of six months between January 1, 1995 and August 31, 1996. An electronic database was used to identify clients and to track their program involvement. A profile was developed of the study participants and their level of program involvement included an examination of the amount of time spent in clinical, social and other interventions, the type of interventions encountered and the number of interventions encountered. Results were analyzed to determine whether social, demographic and mental history affected levels of program involvement and the effects of the levels of program involvement on housing status and psychiatric functioning status.^ A total of 101 clients met the inclusion criteria. Of the 101 clients, 96 had a mental disorder, and five had comorbidity. Due to the limited numbers of participants with comorbidity, only those with mental disorders were included in the analysis. The study found the Bristow Clinic population to be primarily single, Black, male, between the ages of 31 and 40 years, and with a gross family income of less than $4,000. There were more persons residing on the streets at entry and at six months following treatment than in any other residential setting. The most prevalent psychiatric diagnoses were depressive disorders and schizophrenia. The Global Assessment of Functioning (GAF) scale which was used to determine the degree of psychiatric functioning revealed a modal GAF score of 31--40 at entry and following six months in treatment. The study found that the majority of clients spent less than 17 hours in treatment, had less than 51 encounters and had clinical, social, and other encounters. In regard to social and demographic factors and levels of program involvement, there were statistically significant associations between gender and ethnicity and the types of interventions encountered as well as the number of interventions encountered. There was also a statistically significant difference between the amount of time spent in clinical interventions and gender. Relative to outcomes measured, the study found female gender to be the only background variable that was significantly associated with improved housing status and the female gender and previous MHMRA involvement to be statistically associated with improvement in GAF score. The total time in other (not clinical or social) interventions and the total number of encounters with other interventions were also significantly associated with improvement in housing outcome. The analysis of previous services and levels of program involvement revealed significant associations between time spent in social and clinical interventions and previous hospitalizations and previous MHMRA involvement.^ Major limitations of this study include the small sample size which may have resulted in very little power to detect differences and the lack of generalizability of findings due to site locations used in the study. Despite these limitations, the study makes an important contribution to the literature by documenting the levels of program involvement and the social and demographic factors necessary to produce outcomes of improved housing status and psychiatric functioning status. ^

PHENOTYPIC ASSOCIATION OF GENE AMPLIFICATION WITH MULTIPLE DRUG RESISTANCE IN VINCRISTINE RESISTANT CHINESE HAMSTER OVARY CELLS

Resistance of tumors to pharmacologic agents poses a significant problem in the treatment of human malignancies. This study overviews the scope of clinical resistance and focuses upon current research attempts toward investigation of the phenomenon of multidrug resistance (MDR).^ The objective of this investigation was to determine whether gene amplification had a role in the development of the MDR phenotype in Chinese hamster ovary cells (CHO) primarily selected for resistance to vincristine (VCR). A DNA fragment, previously shown to be amplified in two independently derived Chinese hamster cell lines exhibiting the MDR phenotype, was also amplified in VCR hamster lines. Sequences flanking this fragment were shown to contain coding information for a 4.3 kb transcript overproduced in VCR cells. These sequences were not enriched in double minute DNA preparations isolated from VCR cells. There was an approximately forty-fold increase in both the level of gene amplification and transcript overproduction in the VCR cell lines, independent of the level of primary resistance. This DNA amplification and overproduction of the 4.3 kb transcript was also demonstrated in CHO cells independently selected for resistance to Adriamycin and vinblastine.^ All the DNA sequences of two hamster cDNA clones containing 785 and 932 base pair inserts showed direct homology to the published mouse mdr sequences (about 90%). This sequence conservation held for only portions of the gene when the human mdr1 sequences were compared with those from either the mouse or hamster.^ Somatic cell hybrids, constructed between VCR CHO cells and sensitive murine cells, were used to determine whether there was a functional relationship between the chromosome bearing the amplified sequences and the MDR phenotype. Concordant segregation between vincristine resistance, the MDR phenotype, the presence of MDR-associated amplified sequences, overexpression of the mRNA encoded by these sequences, overexpression of the mRNA encoded by these sequences, and CHO chromosome Z1 was consistent with the hypothesis that there is an amplified gene on chromosome Z1 of the VCR CHO cells which is responsible for MDR in these cells. ^

The effect of alcohol consumption on mortality among idiosyncratic drug induced liver injury (IDILI) patients

Severe liver injury (SLI) due to drugs is a frequent cause of catastrophic illness and hospitalization. Due to significant morbidity, mortality, and excess medical care costs, this poses a challenge as a public health problem. The role of associated risk factors like alcohol consumption in contributing to the high mortality remains to be studied. This study was conducted to assess the impact of alcohol use on mortality in IDILI patients, while adjusting for age, gender, race/ethnicity, and education level. The data from this study indicate only a small excess risk of death among IDILI patients using alcohol, but the difference was not statistically significant. The major contribution of this study to the field of public health is that it excludes a large hazard of alcohol consumption on the mortality among idiosyncratic drug induced liver injury (IDILI) patients. ^

Predictors of HIV testing among injection drug users

The current analysis examined the association of several demographic and behavioral variables with prior HIV testing within a population of injection drug users (IDUs) living in Harris County, Texas in 2005 (n=563). After completing the initial univariate analyses of all potential predictors, a multivariable model was created. This model was designed to guide future intervention efforts. Data used in this analysis were collected by the University of Texas School of Public Health in association with the Houston Department of Health and Human Services for the first IDU cycle of the National HIV Behavioral Surveillance System. About 76% of the IDUs reported previously being tested for HIV. Demographic variables that displayed a significant association with prior testing during the univariate analyses include age, race/ethnicity, birth outside the United States, education level, recent arrest, and current health insurance coverage. Several drug-related and sexual behaviors also demonstrated significant associations with prior testing, including age of first injection drug use, heroin use, methamphetamine use, source of needles or syringes, consistent use of new needles, recent visits to a shooting gallery or similar location, previous alcohol or drug treatment, condom use during their most recent sexual encounter, and having sexual partners who also used injection drugs. Additionally, the univariate analyses revealed that recent use of health or HIV prevention services was associated with previously testing for HIV. The final multivariable model included age, race/ethnicity, recent arrest, previous alcohol or drug treatment, and heroin use. ^

Club drug use and unprotected anal intercourse among HIV-seronegative men who have sex with men seeking HIV/STD testing at a local STD clinic in Houston

Objective. To explore (1) the association between "club drug" use and unprotected anal intercourse (UAI) and (2) the association between binge drug use and UAI among HIV seronegative men who have sex with men (MSM) seeking HIV/STD testing at a local clinic in Houston. ^ Study design. A sub-sample of 297 HIV seronegative MSM from a cross-sectional study of drug and sexual behavior in Houston was conducted in 2006. Patients who were seeking HIV/STD testing at a local MSM-identified STD clinic were recruited for an anonymous computer-assisted interview. Analysis of identified secondary data consisted of self-reported information about demographic characteristics, use of drugs, and sexual behaviors. ^ Results. With new and casual sex partners, there was a strong and statistically significant association between use of "club drugs" and UAI. No association between binge drug use and UAI was evident. Men aware of HIV seropositivity or unaware of the HIV serostatus of their primary partner were less likely to report UAI. ^ Conclusion. These data suggest that in the Houston area, HIV-negative MSM club drug users, particularly multiple drug users, are at higher risk of UAI than comparable MSMs who do not use club drugs. Episode-level data regarding binge use of these and other drugs, and UAI should be collected in future studies to explore their relationship. The 'new partner' category should be added to sex partner types to measure sex and drug use behaviors in future studies.^ Keywords. HIV-negative MSM; club drugs; unprotected anal intercourse; binge drug use. ^

Comparison of compliance and immune response of drug users on the standard and accelerated hepatitis B vaccine schedules - Houston, Texas

Despite the availability of hepatitis B vaccine for over two decades, drug users and other high-risk adult populations have experienced low vaccine coverage. Poor compliance has limited efforts to reduce transmission of hepatitis B infection in this population. Evidence suggests that immunological response in drug users is impaired compared to the general population, both in terms of lower seroprotection rates and antibodies levels.^ The current study investigated the effectiveness of the multi-dose hepatitis B vaccine and compared the effect of the standard and accelerated vaccine schedules in a not-in-treatment, drug-using adult population in the city of Houston, USA.^ A population of drug-users from two communities in Houston, susceptible to hepatitis B, was sampled by outreach workers and referral methodology. Subjects were randomized either to the standard hepatitis vaccine schedule (0, 1-, 6-month) or to an accelerated schedule (0, 1-, 2-month). Antibody levels were detected through laboratory analyses at various time-points. The participants were followed for two years and seroconversion rates were calculated to determine immune response.^ A four percent difference in the overall compliance rate was observed between the standard (73%) and accelerated schedules (77%). Logistic regression analyses showed that drug users living on the streets were twice as likely to not complete all three vaccine doses (p=0.028), and current speedball use was also associated with non-completion (p=0.002). Completion of all three vaccinations in the multivariate analysis was also correlated with older age. Drug users on the accelerated schedule were 26% more likely to achieve completion, although this factor was marginally significant (p=0.085).^ Cumulative adequate protective response was gained by 65% of the HBV susceptible subgroup by 12-months and was identical for both the standard and accelerated schedules. Excess protective response (>=100 mIU/mL) occurred with greater frequency at the later period for the standard schedule (36% at 12-months compared to 14% at six months), while the greater proportion of excess protective response for the accelerated schedule occurred earlier (34% at 6 months compared to 18% at 12-months). Seroconversion at the adequate protective response level of 10 mIU/mL was reached by the accelerated schedule group at a quicker rate (62% vs. 49%), and with a higher mean titer (104.8 vs. 64.3 mIU/mL), when measured at six months. Multivariate analyses indicated a 63% increased risk of non-response for older age and confirmed the existence of an accelerating decline in immune response to vaccination manifesting after 40 years (p=0.001). Injecting more than daily was also highly associated with the risk of non-response (p=0.016).^ The substantial increase in the seroprotection rate at six months may be worth the trade-off against the faster antibody titer decrease and is recommended for enhancing compliance and seroconversion. Utilization of the accelerated schedule with the primary objective of increasing compliance and seroconversion rates during the six months after the first dose may confer early protective immunity and reduce the HBV vulnerability of drug users who continue, or have recently initiated, increased high risk drug use and sexual behaviors.^

INACTIVATION OF MUTAGENIC DRUGS AND THEIR METABOLITES IN THE URINE OF PATIENTS ADMINISTERED ANTINEOPLASTIC THERAPY

Urines from patients administered mutagenic antineoplastic drugs were significantly mutagenic in the Ames assay, and hence may pose a genotoxic hazard to hospital personnel or family members caring for the patient. The urines were tested for mutagenicity in several different strains of Salmonella typhimurium that were uvr positive or negative (TA98, TA100, TA102, UTH8413, UTH8414). The urines were fractionated by high pressure liquid chromatography (HPLC) and the fractions assayed for mutagenicity in the strains in which the whole urine was mutagenic. Only fractions of urines containing the parent compound (cisplatin, doxorubicin, or mitomycin) were mutagenic; no other fraction showed significant mutagenicity. However, urine containing cyclophosphamide had two fractions that were mutagenic. One fraction, the fraction containing cyclophosphamide, required metabolic activation for mutagenicity. The other fraction did not require activation for mutagenicity.^ The chemical and mutagenic stability of these urines at room temperature was assayed over a 14 day period. The parent compound degraded within the first seven days, but the urines remained mutagenic. Cis-platinum was chemically stable in the urine; however, the urine decreased in mutagenicity. The decrease was probably the result of stable ligands binding to the platinum.^ Inactivation methods were developed to reduce the genotoxic hazard. Urine containing cisplatin was inactivated by complexing the cisplatin with diethyldithiocarbamate (DDTC). Oxidation with NaOCl of urines containing mitomycin and doxorubicin (sodium thiosulfate must be added to the doxorubicin urine) results in mutagenic inactivation. Inactivation of urine containing cyclophosphamide requires oxidation with alkaline potassium permaganate and trapping of active degradation products with sodium thiosulfate. Urines containing these drugs can be inactivated, but not always by the same method that inactivates the drug alone in solution. Therefore, in the future development of inactivation methods, both chemical and mutagenic assays are necessary to determine effectiveness. Methods of inactivation of mutagenic excreta developed in this study are both effective and practical. ^

Immune response to hepatitis B vaccination in drug using populations: A systematic review and meta-regression analysis

Hepatitis B virus (HBV) is a significant cause of liver diseases and related complications worldwide. Both injecting and non-injecting drug users are at increased risk of contracting HBV infection. Scientific evidence suggests that drug users have subnormal response to HBV vaccination and the seroprotection rates are lower than that in the general population; potentially due to vaccine factors, host factors, or both. The purpose of this systematic review is to examine the rates of seroprotection following HBV vaccination in drug using populations and to conduct a meta-analysis to identify the factors associated with varying seroprotection rates. Seroprotection is defined as developing an anti-HBs antibody level of ≥ 10 mIU/ml after receiving the HBV vaccine. Original research articles were searched using online databases and reference lists of shortlisted articles. HBV vaccine intervention studies reporting seroprotection rates in drug users and published in English language during or after 1989 were eligible. Out of 235 citations reviewed, 11 studies were included in this review. The reported seroprotection rates ranged from 54.5 – 97.1%. Combination vaccine (HAV and HBV) (Risk ratio 12.91, 95% CI 2.98-55.86, p = 0.003), measurement of anti-HBs with microparticle immunoassay (Risk ratio 3.46, 95% CI 1.11-10.81, p = 0.035) and anti-HBs antibody measurement at 2 months after the last HBV vaccine dose (RR 4.11, 95% CI 1.55-10.89, p = 0.009) were significantly associated with higher seroprotection rates. Although statistically nonsignificant, the variables mean age>30 years, higher prevalence of anti-HBc antibody and anti-HIV antibody in the sample population, and current drug use (not in drug rehabilitation treatment) were strongly associated with decreased seroprotection rates. Proportion of injecting drug users, vaccine dose and accelerated vaccine schedule were not predictors of heterogeneity across studies. Studies examined in this review were significantly heterogeneous (Q = 180.850, p = 0.000) and factors identified should be considered when comparing immune response across studies. The combination vaccine showed promising results; however, its effectiveness compared to standard HBV vaccine needs to be examined systematically. Immune response in DUs can possibly be improved by the use of bivalent vaccines, booster doses, and improving vaccine completion rates through integrated public programs and incentives.^

Design, synthesis and cellular and molecular pharmacology of 2$\sp\prime$-bromo-4$\sp\prime$-epidaunorubicin (WP401): A novel non-cross-resistant anthracycline antibiotic with the intrinsic ability to circumvent P -glycoprotein-mediated drug resistance

We designed and synthesized a novel daunorubicin (DNR) analogue that effectively circumvents P-glycoprotein (P-gp)-mediated drug resistance. The fully protected carbohydrate intermediate 1,2-dibromoacosamine was prepared from acosamine and effectively coupled to daunomycinone in high yield. Deprotection under alkaline conditions yielded 2$\sp\prime$-bromo-4$\sp\prime$-epidaunorubicin (WP401). The in vitro cytotoxicity and cellular and molecular pharmacology of WP401 were compared with those of DNR in a panel of wild-type cell lines (KB-3-1, P388S, and HL60S) and their multidrug-resistant (MDR) counterparts (KB-V1, P388/DOX, and HL60/DOX). Fluorescent spectrophotometry, flow cytometry, and confocal laser scanning microscopy were used to measure intracellular accumulation, retention, and subcellular distribution of these agents. All MDR cell lines exhibited reduced DNR uptake that was restored, upon incubation with either verapamil (VER) or cyclosporin A (CSA), to the level found in sensitive cell lines. In contrast, the uptake of WP401 was essentially the same in the absence or presence of VER or CSA in all tested cell lines. The in vitro cytotoxicity of WP401 was similar to that of DNR in the sensitive cell lines but significantly higher in resistant cell lines (resistance index (RI) of 2-6 for WP401 vs 75-85 for DNR). To ascertain whether drug-mediated cytotoxicity and retention were accompanied by DNA strand breaks, DNA single- and double-strand breaks were assessed by alkaline elution. High levels of such breaks were obtained using 0.1-2 $\mu$g/mL of WP401 in both sensitive and resistant cells. In contrast, DNR caused strand breaks only in sensitive cells and not much in resistant cells. We also compared drug-induced DNA fragmentation similar to that induced by DNR. However, in P-gp-positive cells, WP401 induced 2- to 5-fold more DNA fragmentation than DNR. This increased DNA strand breakage by WP401 was correlated with its increased uptake and cytotoxicity in these cell lines. Overall these results indicate that WP401 is more cytotoxic than DNR in MDR cells and that this phenomenon might be related to the reduced basicity of the amino group and increased lipophilicity of WP401. ^