Diagnostic prostate biopsy performed in a non-academic center increases the risk of re-classification at confirmatory biopsy for men considering active surveillance for prostate cancer.

BACKGROUND: To examine whether diagnostic biopsy (B1), for patients on active surveillance (AS) for prostate cancer, performed at an outside referral centre (external) compared with our in-house tertiary center (internal), increased the risk of re-classification on the second (confirmatory) biopsy (B2). METHODS: Patients on AS were identified from our tertiary center database (1997-2012) with PSA<10, Gleason sum (GS) ⩽6, clinical stage ⩽cT2, ⩽3 positive cores, <50% of single core involved, age ⩽75 years and having a B2. Patients who had <10 cores at B1 and delay in B2 >24 mo were excluded. Depending on center where B1 was performed, men were dichotomized to internal or external groups. All B2 were performed internally. Multivariate logistic regression examined if external B1 was a predictor of re-classification at B2. RESULTS: A total of 375 patients were divided into external (n=71, 18.9%) and internal groups (n=304, 81.1%). At B2, more men in the external group re-classified (26.8%) compared with the internal group (13.8%) (P=0.008). On multivariate analysis, external B1 predicted grade-related re-classification (odds ratio (OR) 4.14, confidence interval (CI) 2.01-8.54, P<0.001) and volume-related re-classification (OR 3.43, CI 1.87-6.25, P<0.001). Other significant predictors for grade-related re-classification were age (OR 2.13 per decade, CI 1.32-3.57, P<0.001), PSA density (OR 2.56 per unit, CI 1.44-4.73, P<0.001), maximum % core involvement (OR 1.04 per percentage point, CI 1.01-1.09, P=0.02) and time between B1 and B2 (OR 1.43 per 6 months, CI 1.21-1.71, P<0.001). CONCLUSION: At our institution, patients on AS who had their initial B1 performed externally were more likely to have adverse pathological features and re-classify on internal B2.

Should follow-up biopsies for men on active surveillance for prostate cancer be restricted to limited templates?

OBJECTIVE: To investigate if prostate biopsy templates with fewer cores can be used during active surveillance (AS) for prostate cancer. METHODS: At present, we use an AS protocol template (ASPT) consisting of 13-17 cores. We hypothesize in the setting of known cancer, sextant (6 cores) or standard extended (10-12 cores) templates, could be used with similar effect. We identified patients in our referral institution database (1997-2009) with entry prostate-specific antigen <10 ng/mL, stage ≤cT2, Gleason sum ≤6, ≤3 cores positive for cancer, <50% of single core involved, and age ≤75 years (N = 272). Patients fulfilling standard criteria for pathologic reclassification (N = 94) at any follow-up biopsy were selected for evaluation. By mapping tumor location on the pathologic reclassification determining biopsy, hypothetical scenarios of sextant or standard extended templates (SET) were compared with our ASPT and examined for frequency of cancer detection and pathologic reclassification. RESULTS: For the 94 patients analyzed, the median number of cores taken was 9.7 (6-22) at baseline and 15 (14-17) for the reclassification biopsy. The median time between baseline and the pathologic reclassification determining biopsy was 15.4 months. Analysis of subgroupings showed that sextant template would identify 84% of cancers and 47.9% of the reclassification events, whereas SET detected 99% of cancers and 81.9% of patients who pathologically reclassified. When only considering Gleason sum ≥7 related progression events, SET found 16.2% less (n = 57) compared with ASPT (n = 68). CONCLUSION: When monitoring patients on AS, a 13-17 core template detects more pathologic reclassification than standard sextant (18.1%) or extended (52.1%) biopsy templates.

A systematic review/meta-analysis of primary research investigating swine, pork or pork products as a source of zoonotic hepatitis E virus.

The objectives of our study were to identify and categorize primary research investigating swine/pork as a source of zoonotic hepatitis E virus (HEV) using the relatively new technique of scoping study, and to investigate the potential association between human exposure to swine/pork and HEV infection quantitatively using systematic review/meta-analysis methodology. From 1890 initially identified abstracts, 327 were considered for the review. Five study design types (cross-sectional, prevalence, genotyping, case-report and experimental transmission studies) were identified. A significant association between occupational exposure to swine and human HEV IgG seropositivity was reported in 10/13 cross-sectional studies. The association reported between pork consumption and HEV IgG seropositivity was inconsistent. The quantification of viral load in swine and retail pork, viral load required for infection in primates, cohort and case-control studies in humans, and formal risk assessment are recommended before specific public-health policy actions are taken.

Role of surgery in high-risk localized prostate cancer.

Men with high-risk localized prostate cancer (PCa) remain a challenge for clinicians. Until recently, surgery was not the preferred approach, in part because risk of subclinical metastatic disease, elevated rates of positive surgical margins, absence of randomized studies, and suboptimal cancer control did not justify the morbidity of surgery. No randomized data comparing surgery with radiation therapy are yet available. Data for and comparisons between treatment options should therefore be analyzed with extreme caution.When selecting the best treatment for patients with clinically localized high-risk PCa, considerations should include the life expectancy of the patient, the natural history of PCa, the curability of the disease, and the morbidity of treatment. High-grade PCa managed with noncurative intent greatly reduces life expectancy, but overall, it must also be remembered that radical prostatectomy (RP) and radiotherapy (RT) appear to have similar effects on quality of life. In this population, RP necessitates an extended pelvic lymph node dissection (PLND), but in selected cases, nerve-sparing is a therapeutic possibility and may offer a significant advantage over rt in terms of local control and-although absolutely not yet proved-maybe even in survival. One clear advantage is the ease of administering adjuvant or salvage external-beam rt (EBRT) after rp; conversely, salvage rp after failed EBRT is an exceedingly difficult surgery, with major complications. Surgery therefore has its place, but must be considered in the context of multimodality treatment and the risk of micrometastatic disease. Awaited trial results will help to further refine management in this group of patients.

Etiology of infantile autism: a review of recent advances in genetic and neurobiological research.

The etiology of autism is complex, and in most cases the underlying pathologic mechanisms are unknown. Autism is a hetereogeneous disorder, diagnosed subjectively on the basis of a large number of criteria. Recent research has investigated genetics, in utero insults and brain function as well as neurochemical and immunological factors. On the basis of family and twin studies, there appears to be a genetic basis for a wide "autistic syndrome." About a quarter of cases of autism are associated with genetic disorders such as fragile X syndrome or with infectious diseases such as congenital rubella. Genetic studies have shown an association between autism markers of brain development such as 3 markers of the c-Harvey-ros oncogene and the homeobox gene EN2. In some cases, autism is associated with insults early in gestation, including thalidomide embryopathy. Autism may arise from abnormal central nervous system functioning, since most autistic patients have indications of brain dysfunction, and about half of them have abnormal electroencephalograms. Similarly, the pattern of evoked response potentials and conduction time is altered in autistic children. There is substantial evidence from neuroimaging studies that dysfunctions in the cerebellum and possibly the temporal lobe and association cortex occur in autistic symptoms. Neurochemical studies have investigated the role of serotonin, epinephrine and norepinephrine, since levels of these neurotransmitters are altered in autism, although other hypotheses implicate overactive brain opioid systems and changes in oxytocin neurotransmission. Autoimmunity may also play a role; antibodies against myelin basic protein are often found in children with autism, who also have increased eosinophil and basophil response to IgE-mediated reactions. In summary, the prevailing view is that autism is caused by a pathophysiologic process arising from the interaction of an early environmental insult and a genetic predisposition.

Cyclic GMP-dependent and cyclic GMP-independent actions of nitric oxide on the renal afferent arteriole.

1. The effects of exogenous NO and endothelial-derived NO (EDNO) on the afferent arteriole were investigated in the in vitro perfused hydronephrotic rat kidney. Vessels were pre-constricted with angiotensin II (0.1-0.3 nM) or KCl (30 mM). NO was infused directly into the renal artery at concentrations ranging from 30-9000 nM. ODQ (10, 30 microM) was administered to examine the effects of guanylyl cyclase inhibition. Kidneys were treated with ibuprofen (10 microM) to avoid actions of prostaglandins. 2. During angiotensin II-induced vasoconstriction, NO elicited vasodilation at concentrations of 30 900 nM (EC50=200 nM) and ODQ caused a 10 fold shift in NO-sensitivity (EC50 1600 nM). During KCl-induced vasoconstriction, NO elicited a maximal dilation of 82+9% at 9000 nM (EC50 2000 nM) and ODQ had no effect. Thus in the presence of ODQ, the NO concentration-response curves for KCI- and angiotensin II-induced vasoconstriction were identical (P>0.2). 3. To assess the possible role of cyclic GMP-independent mechanisms in the actions of EDNO, we compared the effects of L-NAME, ODQ and ODQ+L-NAME on acetylcholine-induced vasodilation. Angiotensin II reduced afferent arteriolar diameters from 16.7+/-0.5 to 8.1+/-0.8 microns and acetylcholine fully reversed this effect (16.9+/-0.5 microns). ODQ restored the angiotensin II response in the presence of acetylcholine (7.1+/-0.6 microns) and the subsequent addition of L-NAME had no further effect (6.8+/-0.7 microns). Similarly, L-NAME alone, fully reversed the actions of acetylcholine. 4. Our findings indicate that exogenous NO is capable of eliciting renal afferent arteriolar vasodilation through both cyclic GMP-dependent and cyclic GMP-independent mechanisms. The cyclic GMP-independent action of NO did not require K+ channel activation, as it could be elicited in the presence of 30 mM KCl. Finally, although cyclic GMP-independent effects of exogenous NO could be demonstrated in our model, EDNO appears to act exclusively through cyclic GMP.

Increased fat intake during lactation modifies hypothalamic-pituitary-adrenal responsiveness in developing rat pups: a possible role for leptin.

High fat feeding reportedly enhances hypothalamus-pituitary-adrenal (HPA) responses to stress in adult rats. The present study tested whether elevated fat intake during suckling could have short and/or long lasting consequences on HPA regulation in the offspring. Mothers were fed either a control (C; 5% fat) or high fat (HF; 20% fat) diet during the last week of gestation and throughout lactation. After weaning (day 21), pups from C and HF mothers were fed a chow diet. Offspring from both C- and HF-fed mothers were tested for ACTH and corticosterone responses to stress on postnatal days 10 and 35. We found that HF feeding produced higher lipid levels in the milk of HF compared with C lactating rat dams and that offspring of these mothers had significantly increased retroperitoneal fat pad weight and relative adipose mass on day 21 as well as elevated plasma leptin levels on days 10 and 21 of age. After weaning, pups from the HF mothers had lower plasma leptin levels than those from C mothers. Maternal dietary fat affected HPA responsiveness in the offspring in an age-related manner. Neonatal pups (day 10) from the HF mothers exhibited a reduction in the ACTH and corticosterone responses to ether stress. However, in 35-day-old offspring from HF-fed dams, stress-induced ACTH secretion was increased compared with that in pups from the C-fed mothers. These results demonstrate that maternal diet and increased fat intake through the milk are important regulators of HPA responsiveness in neonates and prepubertal rats. During neonatal life, the blunted stress responsiveness seen with elevated fat intake and the resulting high leptin levels might protect the pups from excessive HPA activation. After removal of the maternal dietary influence and reduced leptin levels, enhanced ACTH stress responses are observed as in adult rats fed a HF diet. Because of the inverse relationship between plasma levels of leptin and HPA responses in pups, the possibility exists that the effects of the HF diet on stress responsiveness are mediated by changes in leptin exposure during development.

Membrane potential measurements in renal afferent and efferent arterioles: actions of angiotensin II.

An adaptation of the in vitro perfused hydronephrotic rat kidney model allowing in situ measurement of arteriolar membrane potentials is described. At a renal perfusion pressure of 80 mmHg, resting membrane potentials of interlobular arteries (22 +/- 2 microns) and afferent (14 +/- 1 microns) and efferent arterioles (12 +/- 1 microns) were -40 +/- 2 (n = 8), -40 +/- 1 (n = 45), and -38 +/- 2 mV (n = 22), respectively (P = 0.75). Using a dual-pipette system to stabilize the impalement site, we measured afferent and efferent arteriolar membrane potentials during angiotensin II (ANG II)-induced vasoconstriction. ANG II (0.1 nM) reduced afferent arteriolar diameters from 13 +/- 1 to 8 +/- 1 microns (n = 8, P = 0.005) and membrane potentials from -40 +/- 2 to -29 +/- mV (P = 0.012). ANG II elicited a similar vasoconstriction in efferent arterioles, decreasing diameters from 13 +/- 1 to 8 +/- 1 microns (n = 8, P = 0.004), but failed to elicit a significant depolarization (-39 +/- 2 for control; -36 +/- 3 mV for ANG II; P = 0.27). Our findings thus indicate that resting membrane potentials of pre- and postglomerular arterioles are similar and lie near the threshold activation potential for L-type Ca channels. ANG II-induced vasoconstriction appears to be closely coupled to membrane depolarization in the afferent arteriole, whereas mechanical and electrical responses appear to be dissociated in the efferent arteriole.

Prevalence and risk behaviours for HIV infection among inmates of a provincial prison in Quebec City.

OBJECTIVE: To assess HIV prevalence and related risk factors among inmates at the Quebec Detention Centre (QDC). DESIGN: Cross-sectional prevalence study. METHODS: Inmates incarcerated at the QDC in September 1994 were asked to participate in an anonymous survey concerning HIV infection. Volunteers answered a questionnaire and provided a saliva sample during a meeting with an interviewer. RESULTS: The overall participation rate was 95% (618 out of 651). HIV prevalence was 2% (11 out of 499) in men. All HIV-infected men were injecting drug users (IDU) with an HIV prevalence of 9% (11 out of 129) in this group. HIV prevalence was 14% (9/63) among male IDU admitting previous needle-sharing and 3% (two out of 66) among the other IDU (odds ratio, 5.3; P = 0.028). Twelve male inmates admitted injecting drugs during imprisonment, of whom 11 shared needles and three were HIV-positive. HIV prevalence in men reporting sexual intercourse with men prior to incarceration was 10% (five out of 52). Nine of the 119 women were HIV-infected (8%), seven of whom were IDU (prevalence of 16% in female IDU). One of the two non-IDU had sexual contacts with male IDU, and the other with men who had sex with men. Tattooing was not associated with HIV infection in either men or women. CONCLUSIONS: Prisoners constitute a group at high risk of HIV infection mainly because of the high proportion of them who are IDU. Imprisonment offers a good opportunity to provide education and preventive programs to this specific group that might otherwise be difficult to reach.

Dissociation between behavioral and hormonal responses to the forced swim stress in lactating rats.

Retention of immobility in the Porsolt forced swim test is believed to be dependent upon glucocorticoid secretion in male rats. Because lactating females exhibit increased basal glucocorticoid secretion and blunted stress responses, we tested the hypothesis that lactation-induced changes in adrenal glucocorticoid and in circulating estrogen and progesterone levels would improve retention and/or acquisition of immobility. Immobility was recorded during 3 intervals of 5 min on day 1 (acquisition) and one 5 min interval 24 h later (retention). Blood samples were collected before the swim test and at various times after the onset of stress for plasma ACTH and corticosterone (B) determinations. Male rats (young=200 g, old=325 g) were compared to virgin females (V) and to lactating females in early (day 8-10, EL) and late (day 17-19, LL) lactation. Adrenalectomy (ADX) and ovariectomy (OVX) were performed 5 and 10 days prior to testing, respectively. All animals acquired immobility at the end of the 15 min swim on day 1, but only the young male group exhibited a significant retention of immobility on day 2. Total immobility was higher in males than females (V) although basal and stress-induced ACTH and B secretion were comparable on both testing days. Lactational status did not affect immobility in either the acquisition or retention phases. However, stress-induced ACTH secretion was greatly diminished in intact and ADX lactating females (EL and LL) compared to virgins (LL < EL < virgin), demonstrating a clear dissociation between behavioral and neuroendocrine responses. Following ADX, immobility in the retention phase was either decreased in males or increased in lactating females. Finally, OVX decreased immobility in both lactating (EL) and virgin females without significantly altering the magnitude of the ACTH and B responses to stress. In summary, our results demonstrated both sex-related and lactation-related differences in the behavioral and endocrine responses to he forced swim test of Porsolt. Although retention of the immobile response is thought to involve glucocorticoids and/or opioids secreted during the first testing session, we did not find evidence for a direct relationship between basal or stress-induced total corticosterone secretion, the magnitude of ACTH response to stress and behavioral scores in the retention period. However, experimental variables such as body weight, sex and water depth could significantly modify the outcome of behavioral testing and question the validity of glucocorticoid-mediated retention processes. Since the effect of ADX was reversed in lactating females compared to male rats, we hypothesize that glucocorticoid sensitivity of cognitive processes controlling behavioral reactivity is different from that controlling hypothalamic-adrenocortical function. Our results also demonstrated a clear dissociation between behavioral and neuroendocrine responses to the swim test, in particular during lactation. In early and late lactation, blunted responsiveness to stress was not caused by enhanced glucocorticoid feedback but might result from modifications in the inhibitory and/or stimulatory inputs to hypothalamic neurons controlling adrenocortical activity.