Health consequences of androgenic anabolic steroid use.

BACKGROUND: The lifetime prevalence of androgenic anabolic steroid abuse is estimated to be around 6% for men, but there is limited knowledge about the side effects of these drugs. OBJECTIVE: To investigate mortality and morbidity amongst users of androgenic anabolic steroids (AAS). METHODS: In this retrospective matched cohort study, 545 male subjects tested positive for AAS in Danish fitness centres during the period 3 January 2006 to 1 March 2018. Subjects were matched with 5450 male controls. In addition, 644 men who were sanctioned because they refused to submit to a doping test and 6440 controls were included as a replication cohort. RESULTS: Mortality was three times higher amongst users of AAS than amongst nonuser controls (hazard ratio 3.0, 95% CI 1.3-7.0). The median annual number of hospital contacts was 0.81 in the cohort of AAS users and 0.36 in the control cohort (P < 0.0001). Acne, gynaecomastia and erectile dysfunction affected more than 10% of the androgenic anabolic steroid users, and the prevalence of these disorders was significantly higher than in the control group (P < 0.0001). The results could be replicated in a similar cohort. CONCLUSION: Androgenic anabolic steroid users have an increased risk of dying and significantly more hospital admissions than their nonuser peers. Side effects of AAS and their metabolites were highly prevalent. Given the high rate of androgenic anabolic steroid abuse, these side effects are of public health concern.

Inclusion of an IgG1-Fc spacer abrogates efficacy of CD19 CAR T cells in a xenograft mouse model.

Cancer therapy with T cells expressing chimeric antigen receptors (CARs) has produced remarkable clinical responses in recent trials, but also severe side effects. Whereas most protocols use permanently reprogrammed T cells, we have developed a platform for transient CAR expression by mRNA electroporation. This approach may be useful for safe clinical testing of novel receptors, or when a temporary treatment period is desirable. Herein, we investigated therapy with transiently redirected T cells in vitro and in a xenograft mouse model. We constructed a series of CD19-specific CARs with different spacers and co-stimulatory domains (CD28, OX40 or CD28-OX40). The CAR constructs all conferred T cells with potent CD19-specific activity in vitro. Unexpectedly, the constructs incorporating a commonly used IgG1-CH2CH3 spacer showed lack of anti-leukemia activity in vivo and induced severe, partly CD19-independent toxicity. By contrast, identical CAR constructs without the CH2-domain eradicated leukemia in vivo, without notable toxicity. Follow-up studies demonstrated that the CH2CH3-spacer bound soluble mouse Fcγ-receptor I and mediated off-target T-cell activation towards murine macrophages. Our findings highlight the importance of non-signalling CAR elements and of in vivo studies. Finally, the results show that transiently redirected T cells control leukemia in mice and support the rationale for developing an mRNA-CAR platform.

Trimethoprim use in early pregnancy and the risk of miscarriage: a register-based nationwide cohort study.

The antibiotic trimethoprim acts as a folate antagonist. Since trophoblasts are very sensitive to drugs that interfere with the folic acid cycle and thereby inhibit DNA synthesis, use of trimethoprim during the first trimester could be associated with miscarriage. A nationwide cohort study including all women in Denmark with a registered pregnancy between 1997 and 2005 was conducted. We used nationwide registers to identify all women giving birth, having a record of miscarriage or induced abortion. Data on exposure to trimethoprim were obtained from the National Prescription Register. Cox proportional hazard regression analysis with exposure to trimethoprim as a time-dependent variable was used to estimate the risk of miscarriage. The adjusted hazard ratio of having a miscarriage after exposure to trimethoprim in the first trimester compared to non-exposure was 2∙04 (95% confidence interval 1∙43-2∙91). Our results indicate that trimethoprim exposure in the first trimester is associated with a doubling of the hazard of miscarriage.

A markerless motion capture system can reliably determine peak trunk flexion while squatting with and without a weighted vest.

Markerless motion capture has improved physical screening efficiency in sport and occupational settings; however, reliability of kinematic measurements from commercial systems must be established. Further, the impact of torso-borne equipment on these measurements is unclear. The purpose of this study was to evaluate the reliability of HumanTrak, a markerless motion capture system, for estimating peak trunk flexion in squat movements with and without a weighted vest. Eighteen participants completed body weight squats (BWSQ) and overhead squats (OHSQ) to their maximum depth (unrestricted-range) and to a plyometric box (fixed-range) while wearing no body armour (NBA) or 9 kg body armour (BA9). Peak trunk flexion was measured using HumanTrak. Testing was performed in two sessions on one day (intra-day) and one session on a separate day (inter-day) to assess reliability. HumanTrak had a standard error of measurement < 3.74° across all movements and conditions. Reliability was good to excellent (ICC = 0.82-0.96) with very large to nearly perfect Pearson correlations (r > 0.80) for all comparisons except unrestricted-range BWSQ with BA9 (ICC = 0.60-0.71, r = 0.71). HumanTrak was more reliable for intra- than inter-day, but reliability was still excellent for almost all inter-day comparisons (ICC > 0.82). HumanTrak is reliable for detecting differences in peak trunk flexion > 8.5° when body armour is not worn and > 10.5° when body armour is worn. Practitioners can assess meaningful changes in sagittal plane trunk motion when screening squat movements regardless of whether body armour is worn.

Exposure to mebendazole and pyrvinium during pregnancy: a Danish nationwide cohort study.

PURPOSE: Families with children are frequently exposed to pinworm infection and treatment involves the whole family. Information on consequences of exposure during, pregnancy is limited. The aim of this study was to investigate the exposure to pyrvinium and mebendazole before, during, and after pregnancy in a Danish nationwide cohort. METHODS: From nationwide administrative registers, we identified 718,900 births in Denmark between January 1997 and December 2007 as well as maternal prescription data of anthelmintics and maternal characteristics. Redemption of a prescription for pyrvinium or mebendazole was used to identify exposure. RESULTS: 4715 women redeemed a prescription for pyrvinium or mebendazole during pregnancy; 1606 for pyrvinium, 2575 for mebendazole, and 534 for both drugs. Having >2 children compared to having no previous children was associated with exposure to pyrvinium (OR: 7.1, 95% CI: 5.8-8.7) and mebendazole (OR: 20.8, 95% CI: 17.3-24.9). CONCLUSION: 4715 pregnant women redeemed a prescription for either mebendazole or pyrvinium. We believe the exposure to be even higher since pyrvinium is also sold over-the-counter. Limited information on birth outcomes is available at present time, and considering the number of exposed pregnancies, we recommend that studies are to be undertaken to assess the safety of pyrvinium and mebendazole during pregnancy.

Blocking FcRn in humans reduces circulating IgG levels and inhibits IgG immune complex-mediated immune responses.

The neonatal crystallizable fragment receptor (FcRn) functions as an intracellular protection receptor for immunoglobulin G (IgG). Recently, several clinical studies have reported the lowering of circulating monomeric IgG levels through FcRn blockade for the potential treatment of autoimmune diseases. Many autoimmune diseases, however, are derived from the effects of IgG immune complexes (ICs). We generated, characterized, and assessed the effects of SYNT001, a FcRn-blocking monoclonal antibody, in mice, nonhuman primates (NHPs), and humans. SYNT001 decreased all IgG subtypes and IgG ICs in the circulation of humans, as we show in a first-in-human phase 1, single ascending dose study. In addition, IgG IC induction of inflammatory pathways was dependent on FcRn and inhibited by SYNT001. These studies expand the role of FcRn in humans by showing that it controls not only IgG protection from catabolism but also inflammatory pathways associated with IgG ICs involved in a variety of autoimmune diseases.

Characterization of an FcgammaRI-binding peptide selected by phage display.

The high-affinity IgG receptor, Fcgamma receptor I (FcgammaRI), is expressed exclusively on myeloid cells, and there is a great interest in the targeting of vaccine antigens to FcgammaRI using anti-human FcgammaRI antibodies or fragments derived from such molecules. In order to reduce the size and complexity of the targeting reagent, we have searched for FcgammaRI binding peptides in peptide libraries displayed on phage. The human monocytic cell line U937 was used as target. Phages that displayed the consensus peptide CLRSGXGC were selected and revealed increased binding to IFN-gamma stimulated versus non-stimulated U937 cells as well as to FcgammaRI transfected versus non-transfected IIA1.6 cells. Furthermore, they bound the extracellular domains of soluble FcgammaRI, but neither FcgammaRIIA, FcgammaRIIB nor FcgammaRIIIB. Binding was inhibited by a synthetic version of the peptide, whereas neither human IgG nor the FcgammaRI-specific monoclonal antibodies (mAb) mAb22 and 32.2 interfered. Flow-cytometry analysis and internalization studies showed that a synthetic biotin-conjugated peptide ADGACLRSGRGCGAAK-bio was able to target U937 cells and FcgammaRI transfected IIA1.6 cells, and further to promote internalization and vesicular degradation of streptavidin coupled to 1 microm magnetic beads. These peptides may have potential as FcgammaRI targeting reagents.

Early detection of diabetic visceral neuropathy. An electrophysiologic study of bladder and urethral innervation.

The segmental and supraspinal innervation of the detrusor muscle and periurethral striated musculature was studied in 27 patients with diabetes mellitus by gas cystometry, integrated sphincter electromyography, and spinal evoked-response latency measurements. Slowing of neural conduction velocities was a consistent finding in all the patients, even when cystometry did not show abnormalities. Thus, neuropathy in the segmental innervation of the bladder and urethra was documented.

Using inactivated microbial biomass as fertilizer: the fate of antibiotic resistance genes in the environment.

The waste product produced by Novo Nordisk A/S from microbial fermentations is used as agricultural fertilizer in Denmark (NovoGro) after being treated by heat and chemicals to destroy the microorganisms. The fertilizer contains DNA fragments from the genetically modified microorganisms used in industrial production. This DNA contains genes coding for the desired industrial products as well as genes used as genetic selection markers during production strain development. The antibiotic resistance markers used as genetic selection markers are chloramphenicol (Cm), kanamycin (Km) and ampicillin (Ap). The aim of the present study was to examine whether DNA and intact genes were present in NovoGro and whether horizontal transfer of DNA isolated from inactivated production strains occurred either in the laboratory or in the fields treated with NovoGro. DNA isolated from NovoGro was analysed by PCR and intact genes coding for a protease and chloramphenicol resistance were amplified. This isolated DNA was used for in vitro experiments including electroporation and transformation but no transfer of DNA to Escherichia coli or Bacillus subtilis was observed. The antibiotic resistance profile of the indigenous bacterial population in the fields treated with NovoGro compared with fields treated with inorganic fertilizers showed no differences. In addition, DNA isolated directly from the fields treated with NovoGro for up to 7 years was analysed by PCR and no specific production gene constructs could be detected.

One-hour pad-weighing test for objective assessment of female urinary incontinence.

In a 16-month period the one-hour pad-weighing test proposed by the International Continence Society was used in 126 instances for objective assessment of the degree of incontinence in 81 women with urinary incontinence. The present study deals with applicability of the test, patient compliance, reproducibility of the test, and comparison of test results with conventional methods for objective assessment of urinary incontinence. In spite of a rather high mean age (55 years), 73 patients (88%) were able to perform the entire test program. In 85 tests (68%) the patients indicated the result to be in accordance with the daily leakage. The reproducibility of the test was relatively good (r = 0.68; P less than .01), but significantly better (r = 0.93; P less than .0001) when taking into consideration the bladder volume at test start and the diuresis during the test. When compared with the pad-weighing test, the stress test and voiding-cystourethrography gave false negative results in approximately half the cases. The one-hour pad-weighing test was found to be practical and useful in quantifying the degree of leakage in women with urinary incontinence.

Effect of a vaginal device on quality of life with urinary stress incontinence.

OBJECTIVE: To assess the effect of a vaginal device (Continence Guard) on urine leakage and quality of life. METHODS: Fifty-five women with stress incontinence participated in a 3-month study. They were assessed by the Incontinence Impact Questionnaire, two incontinence-related quality-of-life questions, a generic quality-of-life questionnaire (Short Form-36), two 24-hour home pad weighing tests, a 2-day voiding diary, uroflowmetry, urine cultures, and a questionnaire about subjective effectiveness of the device. RESULTS: Forty-one (74.5%) women completed the study. Estimated on an intent-to-treat basis, the vaginal device was associated with subjective cure in 11 women (20%) and improvement in 27 (49%). The mean 24-hour pad test leakage and leakage episodes in the voiding diary decreased significantly. Fifty-eight percent of the 55 women enrolled wanted to continue using the device after 3 months. The quality of life measured by the Incontinence Impact Questionnaire showed highly significant improvement, and the results of the two incontinence-related quality of life questions also showed significant improvement. Responses to the Short Form-36 general health questionnaire showed no significant changes. Improvement on the Incontinence Impact Questionnaire correlated with improvements in incontinence, whereas the Short Form-36 scores were unchanged. CONCLUSION: Treatment with the Continence Guard significantly decreases leakage and improves quality of life in women with symptoms of urinary stress incontinence. An incontinence-specific, rather than a generic, quality-of-life questionnaire was important in assessing treatment outcomes.

Electromyographic and gas urethral pressure profile.

A new technique for recording urethral pressure profile is described. The method consists of a simultaneous combined electromyographic and gas urethral pressure profile recording. Normal and pathologic patterns are described. The method provides information on the correlation between intraurethral pressure and activity in the periurethral striated musculature and has proved useful in the assessment of neurologic dysfunction of the urethra.

Neurogenic bladder dysfunction in protruded lumbar disk and after laminectomy.

Bladder and urethral innervation was studied in 18 patients with protruded lumbar disk or persistent back pain after laminectomy. A high incidence of neurogenic dysfunction of the detrusor muscle was found, whereas impaired function of the striated external urethral sphincter was rare. The lesions were encountered among the patients with protruded lumbar disk as well as among the patients with sequelae after laminectomy, suggesting that neurogenic bladder dysfunction in cauda equina injury due to protruded disk is often irreversible.

Abnormalities of bladder innervation in diabetes mellitus.

Electrophysiologic evaluation of the neural pathways involved in bladder and urethral function is described in 30 patients with diabetes mellitus. The study showed decreased conduction velocities in patients with the detrusor reflex as well as in detrusor areflexia. The findings indicated that diabetic vesical dysfunction is principally the result of segmental demyelination in the peripheral nerve supply to the detrusor muscle and urethra.

Finasteride significantly reduces acute urinary retention and need for surgery in patients with symptomatic benign prostatic hyperplasia.

OBJECTIVES: A pooled analysis of all available randomized trials with 2-year follow-up data with finasteride and placebo was undertaken to further investigate recent observations that finasteride use may reduce the occurrence of acute urinary retention (AUR) and benign prostatic hyperplasia (BPH)-related surgical intervention. METHODS: Occurrences of AUR and surgical intervention were examined by treatment group in a pooled series of 4222 men with moderately symptomatic BPH. RESULTS: In total, 81 occurrences of AUR were reported, 24 (1.1%) of 2113 in the finasteride group and 57 (2.7%) of 2109 in the placebo group. The hazard ratio was consistent in all three studies, with a 57% decrease in the hazard rate for occurrence of AUR with finasteride compared with that for placebo present in the pooled data set over the 2-year study period (P < 0.001). Additionally, 227 surgical interventions were recorded over the 2-year study period, 89 (4.2%) of 2113 in the finasteride group and 138 (6.5%) of 2109 in the placebo group. The hazard ratio was consistent across the three studies, with a 34% reduction in the hazard rate for occurrence of surgery with finasteride compared with that for placebo (P < 0.002). Overall, there was 35% reduction in the two BPH-related end points (ie, AUR or surgery). CONCLUSIONS: Treatment with finasteride for up to 2 years more than halves the frequency of AUR and reduces surgical intervention by over one third relative to placebo in patients with moderate BPH. This is the first demonstration that long-term medical therapy can reduce clinically significant end points such as AUR or surgery, and these data have important implications for the long-term management of patients with BPH.

Can finasteride reverse the progress of benign prostatic hyperplasia? A two-year placebo-controlled study. The Scandinavian BPH Study Group.

OBJECTIVES: To study if placebo-induced improvement in men with symptomatic benign prostatic hyperplasia (BPH) is maintained over 2 years, and to study the efficacy and safety from intervention with finasteride 5 mg for 24 months. METHODS: This was a multicenter, double-blind, placebo-controlled study involving 707 patients with moderate symptoms of BPH enrolled at 59 centers in five Scandinavian countries. Following enrollment and a 4-week single-blind placebo run-in period, patients were randomized to receive finasteride 5 mg once daily or placebo for 24 months. Urinary symptoms, urinary flow rate, prostate volume, postvoiding residual urinary volume, and serum concentrations of prostate-specific antigen together with laboratory safety parameters were measured at entry and at months 12 and 24. Interim physical and laboratory examinations were performed when indicated clinically. RESULTS: In finasteride-treated patients the total symptom score improved throughout the study, with a significant difference between the two groups at 24 months (P < or = 0.01), whereas in placebo-treated patients, there was an initial improvement in the symptom score but no change from baseline at 24 months. The maximum urinary flow rate decreased in the placebo group, but improved in the finasteride group, resulting in a between-group difference of 1.8 mL/s at 24 months (P < or = 0.01). The mean change in prostate volume was +12% in the placebo group versus -19% in the finasteride-treated group (P < 0.01). Finasteride was generally well tolerated throughout the 2-year study period. CONCLUSIONS: The efficacy of therapy with finasteride 5 mg in improving both symptoms and maximum urinary flow rate and reducing prostate volume has been shown to be maintained during 24 months while patients receiving placebo experienced a return to baseline or deterioration of these parameters during the study. These results demonstrate that finasteride can reverse the natural progression of BPH.

Disturbances of ano-rectal function in multiple sclerosis.

Thirty patients with multiple sclerosis (MS) [18 men and 12 women, mean age 40 years (range 22-50), disease duration 12 years (range 0.5-34), Kurtzke's Expanded Disability Status Score 6.0 (range 4.0-7.5)] were interviewed about bowel symptoms and studied using ano-rectal manometry. The results were compared with findings in healthy controls. Twenty-eight had bowel symptoms: 8 constipation, 10 constipation and infrequent faecal urgency, 4 infrequent faecal incontinence and 6 frequent faecal incontinence. Anal sphincter pressure at rest was significantly reduced in MS patients 69 (SD 17) cm H2O, compared with 92 (SD 15) cm H2O in controls, and the external sphincter contraction force was also significantly reduced. Rectal sensation and rectal compliance were reduced and the ano-rectal inhibition reflex (defaecation reflex) required a higher rectal pressure to be elicited in the patients. Upon rectal filling, an early external sphincter excitation was seen. The presence of faecal incontinence correlated strongly with reduced rectal sensation. The findings suggest that faecal incontinence can at least partly be explained by low anal sphincter pressure and poor rectal sensation. The findings of early sphincter excitation and increased threshold of ano-rectal inhibition reflex may be an important pathophysiological factor for constipation in MS patients.

Alpha 1-blockers vs 5 alpha-reductase inhibitors in benign prostatic hyperplasia. A comparative review.

During recent years, pharmacological treatment of symptomatic benign prostatic hyperplasia (BPH) has become the primary treatment choice for an increasing number of patients. The 2 principal drug classes employed are alpha 1-blockers and 5 alpha-reductase inhibitors. Current information from placebo-controlled double-blind clinical trials is reviewed. The effect of alpha 1-blockers on symptoms and objective parameters for bladder outlet obstruction is well documented. However, alpha 1-blockers carry a small but significant incidence of adverse effects. Parameters for identification of patients who will respond well to alpha 1-blockers have yet to be identified, and data concerning the long term effects of these drugs are not yet available. 5 alpha-Reductase inhibitors have a slow onset of effect, but treatment leads to improvement in symptoms, reduction of the size of the prostate gland and improvement in objective parameters for bladder outflow obstruction. Approximately 30 to 50% of patients will respond to treatment with 5 alpha-reductase inhibitors. The definitive role of pharmacological treatment in symptomatic BPH remains to be established, although it seems that patients unfit or unwilling to undergo surgical resection of the prostate will benefit from such therapy.