The value of baseline 18F-sodium fluoride and 18F-choline PET activity for identifying responders to radium-223 treatment in castration-resistant prostate cancer bone metastases.

OBJECTIVES: To investigate whether baseline 18F-sodium fluoride (NaF) and 18F-choline PET activity is associated with metastatic castration-resistant prostate cancer (mCRPC) global and individual bone metastases' DWI MR imaging response to radium-223 treatment. METHODS: Thirty-six bone-only mCRPC patients were prospectively recruited from three centers. Whole-body (WB)-MRI with DWI and 18F-NaF and 18F-choline PET/CT were performed at therapy baseline and 8-week intervals. In each patient, bone disease median global (g)ADC change between baseline and follow-up was calculated. Additionally, up to five bone target lesions per patient were delineated and individual median ADC change recorded. An ADC increase > 30% defined response per-patient and per-lesion. For the same targets, baseline 18F-NaF and 18F-choline PET SUVmax were recorded. Mean SUVmax across patient targets was correlated with gADC change and lesion SUVmax with per-lesion ADC change. RESULTS: A total of 133 lesions in 36 patients (14 responders) were analyzed. 18F-NaF PET per-patient mean SUVmax was significantly higher in responders (median = 56.0 versus 38.7 in non-responders; p = 0.008), with positive correlation between SUVmax and gADC increase (rho = 0.42; p = 0.015). A 48.7 SUVmax threshold identified responders with 77% sensitivity and 75% specificity. Baseline 18F-NaF PET per-lesion SUVmax was higher in responding metastases (median = 51.6 versus 31.8 in non-responding metastases; p = 0.001), with positive correlation between baseline lesion SUVmax and ADC increase (rho = 0.39; p < 0.001). A 36.8 SUVmax threshold yielded 72% sensitivity and 63% specificity. No significant association was found between baseline 18F-choline PET SUVmax and ADC response on a per-patient (p = 0.164) or per-lesion basis (p = 0.921). CONCLUSION: 18F-NaF PET baseline SUVmax of target mCRPC bone disease showed significant association with response to radium-223 defined by ADC change. CLINICAL RELEVANCE STATEMENT: 18F-sodium fluoride PET/CT baseline maximum SUV of castration-resistant prostate cancer bone metastases could be used as a predictive biomarker for response to radium-223 therapy. KEY POINTS: • 18F-sodium fluoride PET baseline SUVmax of castration-resistant prostate cancer bone metastases showed significant association with response to radium-223. • Baseline 18F-sodium fluoride PET can improve patient selection for radium-223 therapy. • Change in whole-body DWI parameters can be used for response correlation with baseline 18F-sodium fluoride PET SUVmax in castration-resistant prostate cancer bone metastases

Mitochondrial DNA Copy Number Is Associated with Breast Cancer Risk

Mitochondrial DNA (mtDNA) copy number in peripheral blood is associated with increased risk of several cancers. However, data from prospective studies on mtDNA copy number and breast cancer risk are lacking. We evaluated the association between mtDNA copy number in peripheral blood and breast cancer risk in a nested case-control study of 183 breast cancer cases with pre-diagnostic blood samples and 529 individually matched controls among participants of the Singapore Chinese Health Study. The mtDNA copy number was measured using real time PCR. Conditional logistic regression analyses showed that there was an overall positive association between mtDNA copy number and breast cancer risk (Ptrend = 0.01). The elevated risk for higher mtDNA copy numbers was primarily seen for women with <3 years between blood draw and cancer diagnosis; ORs (95% CIs) for 2nd, 3rd, 4th, and 5th quintile of mtDNA copy number were 1.52 (0.61, 3.82), 2.52 (1.03, 6.12), 3.12 (1.31, 7.43), and 3.06 (1.25, 7.47), respectively, compared with the 1st quintile (Ptrend = 0.004). There was no association between mtDNA copy number and breast cancer risk among women who donated a blood sample ≥3 years before breast cancer diagnosis (Ptrend = 0.41). This study supports a prospective association between increased mtDNA copy number and breast cancer risk that is dependent on the time interval between blood collection and breast cancer diagnosis. Future studies are warranted to confirm these findings and to elucidate the biological role of mtDNA copy number in breast cancer risk. © 2013 Thyagarajan et al

Otalgia and eschar in the external auditory canal in scrub typhus complicated by acute respiratory distress syndrome and multiple organ failure

<p>Abstract</p> <p>Background</p> <p>Scrub typhus, a mite-transmitted zoonosis caused by <it>Orientia tsutsugamushi</it>, is an endemic disease in Taiwan and may be potentially fatal if diagnosis is delayed.</p> <p>Case presentations</p> <p>We encountered a 23-year-old previously healthy Taiwanese male soldier presenting with the right ear pain after training in the jungle and an eleven-day history of intermittent high fever up to 39°C. Amoxicillin/clavulanate was prescribed for otitis media at a local clinic. Skin rash over whole body and abdominal cramping pain with watery diarrhea appeared on the sixth day of fever. He was referred due to progressive dyspnea and cough for 4 days prior to admission in our institution. On physical examination, there were cardiopulmonary distress, icteric sclera, an eschar in the right external auditory canal and bilateral basal rales. Laboratory evaluation revealed thrombocytopenia, elevation of liver function and acute renal failure. Chest x-ray revealed bilateral diffuse infiltration. Doxycycline was prescribed for scrub typhus with acute respiratory distress syndrome and multiple organ failure. Fever subsided dramatically the next day and he was discharged on day 7 with oral tetracycline for 7 days.</p> <p>Conclusion</p> <p>Scrub typhus should be considered in acutely febrile patients with multiple organ involvement, particularly if there is an eschar or a history of environmental exposure in endemic areas. Rapid and accurate diagnosis, timely administration of antibiotics and intensive supportive care are necessary to decrease mortality of serious complications of scrub typhus.</p

Neuronal Sirt3 Protects against Excitotoxic Injury in Mouse Cortical Neuron Culture

BACKGROUND: Sirtuins (Sirt), a family of nicotinamide adenine nucleotide (NAD) dependent deacetylases, are implicated in energy metabolism and life span. Among the known Sirt isoforms (Sirt1-7), Sirt3 was identified as a stress responsive deacetylase recently shown to play a role in protecting cells under stress conditions. Here, we demonstrated the presence of Sirt3 in neurons, and characterized the role of Sirt3 in neuron survival under NMDA-induced excitotoxicity. METHODOLOGY/PRINCIPAL FINDINGS: To induce excitotoxic injury, we exposed primary cultured mouse cortical neurons to NMDA (30 µM). NMDA induced a rapid decrease of cytoplasmic NAD (but not mitochondrial NAD) in neurons through poly (ADP-ribose) polymerase-1 (PARP-1) activation. Mitochondrial Sirt3 was increased following PARP-1 mediated NAD depletion, which was reversed by either inhibition of PARP-1 or exogenous NAD. We found that massive reactive oxygen species (ROS) produced under this NAD depleted condition mediated the increase in mitochondrial Sirt3. By transfecting primary neurons with a Sirt3 overexpressing plasmid or Sirt3 siRNA, we showed that Sirt3 is required for neuroprotection against excitotoxicity. CONCLUSIONS: This study demonstrated for the first time that mitochondrial Sirt3 acts as a prosurvival factor playing an essential role to protect neurons under excitotoxic injury

Women’s preference for laparoscopic or abdominal hysterectomy

In the present study, women’s preferences on advantages and disadvantages of laparoscopic hysterectomy (LH) and abdominal hysterectomy (AH) have been studied. Patients’ preferences were evaluated in individual, structured interviews in women scheduled for hysterectomy and questionnaires in nurses. Forty-three patients and 39 nurses were included. After general information, 84% of patients and 74% of nurses preferred LH over AH. This preference did not change after supplying more detailed information or after hysterectomy. The avoidance of complications was indicated as the most important factor in the decision. More than half of the women evaluated a difference of 1% as the maximum acceptable risk of major complications. When confronted with scenarios based on current evidence, both patients and nurses prefer LH over AH. This study supports further implementation of LH in clinical practice. The actual major complication rate in hysterectomy, however, is perceived as high

The prevalence and experience of Australian naturopaths and Western herbalists working within community pharmacies

<p>Abstract</p> <p>Background</p> <p>Naturopaths and Western herbal medicine (WHM) practitioners were surveyed to identify their extent, experience and roles within the community pharmacy setting and to explore their attitudes to integration of complementary medicine (CM) practitioners within the pharmacy setting.</p> <p>Method</p> <p>Practising naturopaths and WHM practitioners were invited to participate in an anonymous, self-administered, on-line survey. Participants were recruited using the mailing lists and websites of CM manufacturers and professional associations.</p> <p>Results</p> <p>479 practitioners participated. 24% of respondents (n = 111) reported they had worked in community pharmacy, three-quarters for less than 5 years. Whilst in this role 74% conducted specialist CMs sales, 62% short customer consultations, 52% long consultations in a private room and 51% staff education. This was generally described as a positive learning experience and many appreciated the opportunity to utilise their specialist knowledge in the service of both customers and pharmacy staff. 14% (n = 15) did not enjoy the experience of working in pharmacy at all and suggested pharmacist attitude largely influenced whether the experience was positive or not. Few practitioners were satisfied with the remuneration received. 44% of the total sample provided comment on the issue of integration into pharmacy, with the main concern being the perceived incommensurate paradigms of practice between pharmacy and naturopathy. Of the total sample, 38% reported that they would consider working as a practitioner in retail pharmacy in future.</p> <p>Conclusions</p> <p>The level of integration of CM into pharmacy is extending beyond the mere stocking of supplements. Naturopaths and Western Herbalists are becoming utilised in pharmacies</p

Selective Down-Regulation of Nuclear Poly(ADP-Ribose) Glycohydrolase

The formation of ADP-ribose polymers on target proteins by poly(ADP-ribose) polymerases serves a variety of cell signaling functions. In addition, extensive activation of poly(ADP-ribose) polymerase-1 (PARP-1) is a dominant cause of cell death in ischemia-reperfusion, trauma, and other conditions. Poly(ADP-ribose) glycohydrolase (PARG) degrades the ADP-ribose polymers formed on acceptor proteins by PARP-1 and other PARP family members. PARG exists as multiple isoforms with differing subcellular localizations, but the functional significance of these isoforms is uncertain.Primary mouse astrocytes were treated with an antisense phosphorodiamidate morpholino oligonucleotide (PMO) targeted to exon 1 of full-length PARG to suppress expression of this nuclear-specific PARG isoform. The antisense-treated cells showed down-regulation of both nuclear PARG immunoreactivity and nuclear PARG enzymatic activity, without significant alteration in cytoplasmic PARG activity. When treated with the genotoxic agent MNNG to induced PARP-1 activation, the antisense-treated cells showed a delayed rate of nuclear PAR degradation, reduced nuclear condensation, and reduced cell death.These results support a preferentially nuclear localization for full-length PARG, and suggest a key role for this isoform in the PARP-1 cell death pathway

Inhibition of apoptosis prevents West Nile virus induced cell death

We found that WNV infection induces cell death in the brain-derived tumour cell line T98G by apoptosis under involvement of constituents of the extrinsic as well as the intrinsic apoptotic pathways. Our results illuminate the molecular mechanism of WNV-induced neural cell death