Effects of nociceptin/orphanin FQ receptor (NOP) agonist, Ro64-6198, on reactivity to acute pain in mice: comparison to morphine

The aim of the present study was to clarify the role of nociceptin system in pain modulation. The effects of the synthetic nociceptin (NOP) receptor agonist, Ro64-6198 ((1S,3aS)-8-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one), on reactivity to acute noxious stimuli were assessed in C57BL/6N (B6) mice in tail-flick, hot-plate and shock threshold tests. The mu receptor agonist, morphine, was used in each study for comparison. In the tail-flick test, morphine (4 and 8 mg/kg, i.p.) produced analgesia, while Ro64-6198 (0.3, 1 and 3 mg/kg, i.p.) increased pain sensitivity. The effects of Ro64-6198 were seen in na?ve but not in mice previously habituated to testing conditions, indicating that increased pain sensitivity may be due to inhibition of stress-induced analgesia. In the hot-plate and the shock threshold tests, Ro64-6198 produced analgesia in B6 mice, like morphine. These effects were reproduced in wild-type but not in NOP receptor knockout mice. Finally, when injected conjointly at subthreshold doses, Ro64-6198 (1 mg/kg) and morphine (1 mg/kg) acted in additive manner to reduce pain sensitivity in the hot-plate test. Together these results show that systemic activation of NOP receptors produced bidirectional changes in pain sensitivity depending on the experimental conditions. They also suggest that central NOP and mu receptors may inhibit reactivity to acute noxious stimuli via independent neural mechanisms.     

Piper cubeba targets multiple aspects of the androgen-signalling pathway. A potential phytotherapy against prostate cancer growth?

Despite the high prevalence of prostate cancer (PC) in the Western world, there is a dearth of effective medication. Since the androgen-signalling pathway is very much involved in PC growth and development, we investigated the potential of Piper cubeba L. extract, P9605, in targeting multiple events simultaneously within this pathway. This may be more effective compared to an antiandrogen monotherapy. Our results indicated that P9605 inhibited proliferation in androgen-dependent LNCaP human prostate cancer cells by reducing DNA synthesis and inducing apoptosis. This antigrowth effect was less pronounced in androgen-independent PC-3 prostate cancer cell lines. P9605 potently inhibited 5 alpha-reductase II activity, which is responsible for converting testosterone to its active form, dihydrotestosterone (DHT), in the prostate. It also acted as an antagonist at recombinant wild-type androgen receptors (AR). P9605 suppressed cell growth and prostate-specific antigen (PSA) secretion stimulated by physiological concentrations of DHT in LNCaP cells. Interestingly, it down-regulated AR levels. In conclusion, our findings suggest that P9605 may potentially retard the growth of androgen-dependent PC via several mechanisms.     

Numeracy of multiple sclerosis patients: A comparison of patients from the PERCEPT study to a German probabilistic sample

Objective

A shared decision-making approach is suggested for multiple sclerosis (MS) patients. To properly evaluate benefits and risks of different treatment options accordingly, MS patients require sufficient numeracy – the ability to understand quantitative information. It is unknown whether MS affects numeracy. Therefore, we investigated whether patients’ numeracy was impaired compared to a probabilistic national sample.

Men with family history of prostate cancer have a higher risk of disease recurrence after radical prostatectomy

Purpose

We aimed to determine if family history (FH) of prostate cancer (PC) influenced cancer control after radical prostatectomy (RP).

Methods

Patients were evaluated in a prospectively-collected PC family database: The focus was on hereditary prostate cancer (HPC) defined by Johns Hopkins criteria and sporadic prostate cancer (SPC), rigorously defined by absence of prostate cancer in ≥ 2 brothers aged ≥ 60 years. Additionally, patients with first-degree (FPC) and non-first-degree PC (non-FPC) were assessed. Endpoints were biochemical recurrence-free survival (BRFS) and prostate cancer-specific survival (CSS). Finally, clinico-pathological characteristics were compared and multiple proportional hazards regression was used to identify prognostic factors.

Results

In total 11,654 patients were included (807 HPC, 2251 FPC, 8072 non-FPC and 524 SPC). Familial imposition (HPC/FPC) was associated with a younger age at diagnosis. Thus, HPC patients were diagnosed 2.9 years earlier than SPC patients with more locally advanced tumors (≥ pT3). With a median follow up of 6.2 years (range 0–31.5) BRFS was significantly different when stratified by FH. In pairwise analyses BRFS differed significantly for HPC compared to SPC (HR = 1.27). Consecutively FH was identified as prognostic factor for BRFS (p = 0.021) together with age, PSA, pathologic characteristics and adjuvant androgen deprivation. Analyses of CSS did not show a difference.

Conclusion

Patients with FH of PC are likely to be diagnosed earlier and present a higher proportion of locally advanced disease. In addition, men with FH are at higher risk of biochemical recurrence after surgery but reveal similar outcomes regarding prostate cancer-specific survival.

     

Model-based segmentation in orbital volume measurement with cone beam computed tomography and evaluation against current concepts

Purpose

Objective determination of the orbital volume is important in the diagnostic process and in evaluating the efficacy of medical and/or surgical treatment of orbital diseases. Tools designed to measure orbital volume with computed tomography (CT) often cannot be used with cone beam CT (CBCT) because of inferior tissue representation, although CBCT has the benefit of greater availability and lower patient radiation exposure. Therefore, a model-based segmentation technique is presented as a new method for measuring orbital volume and compared to alternative techniques.

Methods

Both eyes from thirty subjects with no known orbital pathology who had undergone CBCT as a part of routine care were evaluated (\(n = 60\) eyes). Orbital volume was measured with manual, atlas-based, and model-based segmentation methods. Volume measurements, volume determination time, and usability were compared between the three methods. Differences in means were tested for statistical significance using two-tailed Student’s t tests.

Results

Neither atlas-based \((26.63 \pm 3.15\,\hbox {mm}^{3})\) nor model-based \((26.87 \pm 2.99\,\hbox {mm}^{3})\) measurements were significantly different from manual volume measurements \((26.65 \pm 4.0\,\hbox {mm}^{3})\). However, the time required to determine orbital volume was significantly longer for manual measurements (\(10.24 \pm 1.21\) min) than for atlas-based (\(6.96 \pm 2.62\) min, \(p < 0.001\)) or model-based (\(5.73 \pm 1.12\) min, \(p < 0.001\)) measurements.

Conclusion

All three orbital volume measurement methods examined can accurately measure orbital volume, although atlas-based and model-based methods seem to be more user-friendly and less time-consuming. The new model-based technique achieves fully automated segmentation results, whereas all atlas-based segmentations at least required manipulations to the anterior closing. Additionally, model-based segmentation can provide reliable orbital volume measurements when CT image quality is poor.

     

Spontaneous large volume adipose tissue generation from a vascularized pedicled fat flap inside a chamber space

A novel method of spontaneous generation of new adipose tissue from an existing fat flap is described. A defined volume of fat flap based on the superficial inferior epigastric vascular pedicle in the rat was elevated and inset into a hollow plastic chamber implanted subcutaneously in the groin of the rat. The chamber walls were either perforated or solid and the chambers either contained poly(D,L-lactic-co-glycolic acid) (PLGA) sponge matrix or not. The contents were analyzed after being in situ for 6 weeks. The total volume of the flap tissue in all groups except the control groups, where the flap was not inserted into the chambers, increased significantly, especially in the perforated chambers (0.08 +/- 0.007 mL baseline compared to 1.2 +/- 0.08 mL in the intact ones). Volume analysis of individual component tissues within the flaps revealed that the adipocyte volume increased and was at a maximum in the chambers without PLGA, where it expanded from 0.04 +/- 0.003 mL at insertion to 0.5 +/- 0.08 mL (1250% increase) in the perforated chambers and to 0.16 +/- 0.03 mL (400% increase) in the intact chambers. Addition of PLGA scaffolds resulted in less fat growth. Histomorphometric analysis rather than simple hypertrophy documented an increased number of adipocytes. The new tissue was highly vascularized and no fat necrosis or atypical changes were observed.