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"Elliott, D. J."
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Longitudinal assessment of urinary PCA3 for predicting prostate cancer grade reclassification in favorable-risk men during active surveillance
Background:
To assess the utility of urinary prostate cancer antigen 3 (PCA3) as both a one-time and longitudinal measure in men on active surveillance (AS).
Methods:
The Johns Hopkins AS program monitors men with favorable-risk prostate cancer with serial PSA, digital rectal examination (DRE), prostate magnetic resonance imaging and prostate biopsy. Since 2007, post-DRE urinary specimens have also been routinely obtained. Men with multiple PCA3 measures obtained over ⩾3 years of monitoring were included. Utility of first PCA3 score (fPCA3), subsequent PCA3 (sPCA3) and change in PCA3 were assessed for prediction of Gleason grade reclassification (GR, Gleason score >6) during follow-up.
Results:
In total, 260 men met study criteria. Median time from enrollment to fPCA3 was 2 years (interquartile range (IQR) 1–3) and from fPCA3 to sPCA3 was 5 years (IQR 4–6). During median follow-up of 6 years (IQR 5–8), 28 men (11%) underwent GR. Men with GR had higher median fPCA3 (48.0 vs 24.5,
P
=0.007) and sPCA3 (63.5 vs 36.0,
P
=0.002) than those without GR, while longitudinal change in PCA3 did not differ by GR status (log-normalized rate 0.07 vs 0.06,
P
=0.53). In a multivariable model including age, risk classification and PSA density, fPCA3 remained significantly associated with GR (log(fPCA3) odds ratio=1.77,
P
=0.04).
Conclusions:
PCA3 scores obtained during AS were higher in men who underwent GR, but the rate of change in PCA3 over time did not differ by GR status. PCA3 was a significant predictor of GR in a multivariable model including conventional risk factors, suggesting that PCA3 provides incremental prognostic information in the AS setting.
Journal Article
Mutations at the mitochondrial DNA polymerase (POLG) locus associated with male infertility
Human mitochondrial DNA polymerase, encoded by
POLG
, contains a polyglutamine tract encoded by a CAG microsatellite repeat
1
,
2
. Analysis of
POLG
genotypes in different populations identified an association between absence of the common, ten-repeat allele and male infertility typified by a range of sperm quality defects but excluding azoospermia.
Journal Article
Expression of RBM in the Nuclei of Human Germ Cells is Dependent on a Critical Region of the Y Chromosome Long Arm
The association of abnormal spermatogenesis in men with Y chromosome deletions suggests that genes important for spermatogenesis have been removed from these individuals. Recently, genes encoding two putative RNA-binding proteins (RBM and DAZ/SPGY) have been mapped to two different regions of the human Y chromosome. Both of these genes encode proteins that contain a single RNA recognition motif and a (different) internally repeating sequence. Y-linked RBM homologues are found in all mammalian species. We have raised an antiserum to RBM and used it to show that RBM is a nuclear protein expressed in fetal, prepubertal, and adult male germ cells. The distribution of RBM protein in the adult correlates with the pattern of transcriptional activity in spermatogenesis, suggesting that RBM is involved in the nuclear metabolism of newly synthesized RNA. RBM sequences are found on both arms of the Y chromosome making genotype-phenotype correlations difficult for this gene family. To address the location of the functional genes and the consequences of their deletion, we examined a panel of men with Y chromosome deletions and known testicular pathologies using this antiserum. This approach enabled us to map a region of the Y chromosome essential for RBM expression. In the absence of detectable RBM expression we see stages of germ cell development up to early meiosis, but not past this point into the haploid phase of spermatogenesis.
Journal Article
Managing hypertension in urban underserved subjects using telemedicine—A clinical trial
We evaluated an Internet- and telephone-based telemedicine system for reducing blood pressure (BP) in underserved subjects with hypertension.
A total of 241 patients with systolic BP ≥140 mm Hg were randomized to usual care (C; n = 121) or telemedicine (T; n = 120). The T group reported BP, heart rate, weight, steps/day, and tobacco use twice weekly. The primary outcome was BP control at 6 months.
Average age was 59.6 years, average body mass index was 33.7 kg/m2, 79% were female, 81% were African American, 15% were white, 53% were at or below the federal poverty level, 18% were smokers, and 32% had diabetes. Six-month follow-up was achieved in 206 subjects (C: 107, T: 99). Goal BP was achieved in 52.3% in C and 54.5% in T (P = .43). Systolic BP change (C: −13.9 mm Hg, T: −18.2; P = .118) was similar in both groups. Subjects in the T group reported BP 7.7 ± 6.9 d/mo. Results were not affected by age, sex, ethnicity, education, or income. In nondiabetic T subjects, goal BP was achieved in 58.2% compared with 45.2% of diabetic T subjects (P = .024). Nondiabetic T subjects demonstrated a greater reduction in systolic BP (T: −19 ± 20 mm Hg, C: −12 ± 19 mm Hg; P = .037). No difference in BP response between C and T was noted in patients with diabetes.
In hypertensive subjects, engagement in a system of care with or without telemedicine resulted in significant BP reduction. Telemedicine for nondiabetic patients resulted in a greater reduction in systolic BP compared with usual care. Telemedicine may be a useful tool for managing hypertension particularly among nondiabetic subjects.
Journal Article
Prostate involvement during sexually transmitted infections as measured by prostate-specific antigen concentration
Background:
We investigated prostate involvement during sexually transmitted infections by measuring serum prostate-specific antigen (PSA) as a marker of prostate infection, inflammation, and/or cell damage in young, male US military members.
Methods:
We measured PSA before and during infection for 299 chlamydia, 112 gonorrhoea, and 59 non-chlamydial, non-gonococcal urethritis (NCNGU) cases, and 256 controls.
Results:
Chlamydia and gonorrhoea, but not NCNGU, cases were more likely to have a large rise (⩾40%) in PSA than controls (33.6%, 19.1%, and 8.2%
vs
8.8%,
P
<0.0001, 0.021, and 0.92, respectively).
Conclusion:
Chlamydia and gonorrhoea may infect the prostate of some infected men.
Journal Article
The tumour-suppressor protein ASPP1 is nuclear in human germ cells and can modulate ratios of CD44 exon V5 spliced isoforms in vivo
The ASPP1 (Apoptosis Stimulating Protein of p53) protein is an important tumour-suppressor. We have detected a novel protein interaction between the human ASPP1 (hASPP1) protein and the predominantly nuclear adaptor protein SAM68. In the human testis, full-length endogenous hASPP1 protein is located in the nucleus like SAM68, predominantly within meiotic and postmeiotic cells. Mouse ASPP1 (mASPP1) protein is mainly expressed in the brain and testis. The interaction with nuclear SAM68 is likely to be restricted to human germ cells, since endogenous mASPP1 protein is exclusively cytoplasmic. The C-terminal region of hASPP1 efficiently targeted a fused GFP molecule to the nucleus, whereas the N-terminus of hASPP1 targeted GFP to the cytoplasm. In the context of the full-length molecule this cytoplasmic targeting sequence is dominant in HEK293 and Saos-2 cells, since full-length hASPP1-GFP is almost exclusively cytoplasmic. Despite its predominantly cytoplasmic location, we show that ASPP1-GFP expression in HEK293 cells can regulate the ratio of alternative spliced isoforms derived from a pre-mRNA regulated downstream of cytoplasmic signalling pathways, and our data suggest that ASPP1 may operate in this case downstream or parallel to RAS signalling pathways.
Journal Article
Hepatitis C virus replication in mice with chimeric human livers
Lack of a small animal model of the human hepatitis C virus (HCV) has impeded development of antiviral therapies against this epidemic infection. By transplanting normal human hepatocytes into SCID mice carrying a plasminogen activator transgene (
Alb-uPA
), we generated mice with chimeric human livers. Homozygosity of
Alb-uPA
was associated with significantly higher levels of human hepatocyte engraftment, and these mice developed prolonged HCV infections with high viral titers after inoculation with infected human serum. Initial increases in total viral load were up to 1950-fold, with replication confirmed by detection of negative-strand viral RNA in transplanted livers. HCV viral proteins were localized to human hepatocyte nodules, and infection was serially passaged through three generations of mice confirming both synthesis and release of infectious viral particles. These chimeric mice represent the first murine model suitable for studying the human hepatitis C virus
in vivo
.
Journal Article
Denitrification of groundwater using acetic acid as a carbon source
A pilot scale rotating biological contactor was used to investigate the ability to remove nitrate from groundwater using acetic acid as a carbon source under various operating conditions. The reactor achieved a nitrate removal efficiency of 99 to 83 percent at loading rates of 76 and 490 mg/m2.hr respectively with a flow rate of 2.5 1/min at 20±2°C. The nitrate removal rate was found to be dependent on the influent acetic acid loading rate. The optimum acetic acid to nitrate-nitrogen (A/N) ratio was found to be 4.3:1. Under optimum conditions the effluent nitrate, nitrite-nitrogen and residual acetic acid concentrations were 0.43, 0.03 and 4.4 mg/1. The process generally produced low nitrite intermediate production for up to 100 mg/1 influent nitrate-nitrogen. The results of this study show that an anoxic RBC using acetic acid as a carbon source is a convenient and reliable process for the removal of nitrate from water supply. Pseudomonas were found to be the dominant bacterial species with species being Ps. stutzen and Ps. fluorescence.
Journal Article
Variable photosynthetic characteristics in waste stabilisation ponds
Algae play several key roles in waste stabilisation ponds. A model has been developed to predict algal concentration in waste stabilisation ponds, in which the relationship between photosynthesis and underwater light availability is central. One equation was selected from several alternative expressions that describe this relationship. The selected equation consisted of four photosynthetic parameters. A field sampling programme was designed to investigate the relationships between the photosynthetic parameters and the pond environment. Although initial regression analyses were unsuccessful, distinct diurnal variations were revealed in two key photosynthetic parameters, related to an inverse variation in chlorophyll a concentration. This led to the derivation of a dynamic feedback hypothesis which challenges the classic assumption in algal modelling of constant photosynthetic parameters.
Journal Article