Photodynamic Therapy Is an Effective Adjuvant Therapy for Image-Guided Surgery in Prostate Cancer.

Local and metastatic relapses of prostate cancer often occur following attempted curative resection of the primary tumor, and up to 66% of local recurrences are associated with positive margins. Therefore, technologies that can improve the visualization of tumor margins and adjuvant therapies to ablate remaining tumor tissues are needed during surgical resection of prostate adenocarcinoma. Photodynamic agents have the potential to combine both fluorescence for image-guided surgery (IGS) and photodynamic therapy (PDT) to resect and ablate cancer cells. The objective of this study was to determine the utility of a targeted PDT agent for IGS and adjuvant PDT. Using a previously developed prostate-specific membrane antigen (PSMA)-targeted PDT agent, PSMA-1-Pc413, we showed that PSMA-1-Pc413 selectively highlighted PSMA-expressing tumors, allowing IGS and more complete tumor resection compared with white light surgery. Subsequent PDT further reduced tumor recurrence and extended animal survival significantly. This approach also enabled identification of tumor cells in lymph nodes. In summary, this study presents a potential new treatment option for patients with prostate cancer undergoing surgery, which improves tumor visualization and discrimination during surgery, including identification of cancer in lymph nodes. SIGNIFICANCE: These findings present a photodynamic agent that can be used for both photodynamic therapy and image-guided surgery, allowing better visualization of tumor margins and elimination of residual tumor tissues.

Mechanical evaluation of gradient electrospun scaffolds with 3D printed ring reinforcements for tracheal defect repair.

Tracheal stenosis can become a fatal condition, and current treatments include augmentation of the airway with autologous tissue. A tissue-engineered approach would not require a donor source, while providing an implant that meets both surgeons' and patients' needs. A fibrous, polymeric scaffold organized in gradient bilayers of polycaprolactone (PCL) and poly-lactic-co-glycolic acid (PLGA) with 3D printed structural ring supports, inspired by the native trachea rings, could meet this need. The purpose of the current study was to characterize the tracheal scaffolds with mechanical testing models to determine the design most suitable for maintaining a patent airway. Degradation over 12 weeks revealed that scaffolds with the 3D printed rings had superior properties in tensile and radial compression, with at least a three fold improvement and 8.5-fold improvement, respectively, relative to the other scaffold groups. The ringed scaffolds produced tensile moduli, radial compressive forces, and burst pressures similar to or exceeding physiological forces and native tissue data. Scaffolds with a thicker PCL component had better suture retention and tube flattening recovery properties, with the monolayer of PCL (PCL-only group) exhibiting a 2.3-fold increase in suture retention strength (SRS). Tracheal scaffolds with ring reinforcements have improved mechanical properties, while the fibrous component increased porosity and cell infiltration potential. These scaffolds may be used to treat various trachea defects (patch or circumferential) and have the potential to be employed in other tissue engineering applications.

Neonatal maternal separation increases susceptibility to experimental colitis and acute stress exposure in male mice.

Experiencing early life stress can result in maladjusted stress response via dysregulation of the hypothalamic-pituitary-adrenal axis and serves as a risk factor for developing chronic pelvic pain disorders. We investigated whether neonatal maternal separation (NMS) would increase susceptibility to experimental colitis or exposure to acute or chronic stress. Male mice underwent NMS from postnatal day 1-21 and as adults were assessed for open field behavior, hindpaw sensitivity, and visceromotor response (VMR) to colorectal distension (CRD). VMR was also measured before and after treatment with intracolonic trinitrobenzene sulfonic acid (TNBS) or exposure to acute or chronic water avoidance stress (WAS). Myeloperoxidase (MPO) activity, proinflammatory gene and corticotropin-releasing factor (CRF) receptor expression were measured in distal colon. Baseline VMR was not affected by NMS, but undergoing CRD increased anxiety-like behaviors and mechanical hindpaw sensitivity of NMS mice. Treatment with TNBS dose-dependently decreased body weight and survival only in NMS mice. Following TNBS treatment, IL-6 and artemin mRNA levels were decreased in the distal colon of NMS mice, despite increased MPO activity. A single WAS exposure increased VMR during CRD in NMS mice and increased IL-6 mRNA and CRF2 protein levels in the distal colon of naïve mice, whereas CRF2 protein levels were heightened in NMS colon both at baseline and post-WAS exposure. Taken together, these results suggest that NMS in mice disrupts inflammatory- and stress-induced gene expression in the colon, potentially contributing towards an exaggerated response to specific stressors later in life.

Study protocol for a randomised trial of nicotine-free cigarettes as an adjunct to usual NRT-based cessation practice, in people who wish to stop smoking.

BACKGROUND: Current smoking cessation treatments focus on addressing the pharmacological dependence of smokers on nicotine. However, new strategies are needed that address both nicotine dependence and the psychological dependence on cigarettes as the source of nicotine. Evidence from a number of small smoking cessation studies suggests that the use of cigarettes with reduced nicotine content, in combination with nicotine replacement therapy (NRT), may help reduce withdrawal symptoms and increase quit rates. This paper describes the protocol for a large randomised-controlled trial to test the effect of using nicotine-free cigarettes together with NRT on long-term quit rates. METHODS/DESIGN: This single-blind, randomised trial aims to recruit 1,410 participants through the national telephone-based Quitline service in New Zealand. Participants in the treatment arm will be asked to stop smoking nicotine-containing cigarettes on their chosen Quit day and smoke ad libitum nicotine-free (Quest 3) cigarettes for six weeks. At the same time people in this group will be asked to start using NRT patches, gum and/or lozenges (as recommended by Quitline) for eight weeks. Participants in the control arm will be asked to stop smoking completely on their chosen Quit day and start using NRT patches, gum and/or lozenges (as recommended by Quitline) for eight weeks. Data collection will occur at baseline, three and six weeks, and three and six months after Quit day. The primary outcome is the proportion of participants who self-report seven-day point prevalence abstinence at six months since Quit date. DISCUSSION: Smoking prevalence in New Zealand has changed little in recent years (particularly in Maori, the indigenous people of New Zealand) and additional options for smokers who want to quit are needed. Although a variety of methods are available to help, many are expensive, have side effects, and despite their use most quit attempts still fail. This trial will test the balance of benefits and risks of a new strategy for people to overcome nicotine dependence. Since smoking is the leading cause of lost healthy life years in New Zealand, if proven effective this strategy is likely to have substantial public health benefits.

Cardiovascular risk factors after antenatal exposure to betamethasone: 30-year follow-up of a randomised controlled trial.

BACKGROUND: Antenatal betamethasone treatment is widely used for the prevention of neonatal respiratory distress syndrome in preterm infants and substantially reduces neonatal mortality and morbidity. Fetal exposure to excess glucocorticoids has been proposed as one of the core mechanisms of the fetal origins of adult disease hypothesis. We assessed whether antenatal exposure to betamethasone for the prevention of neonatal respiratory distress syndrome affects cardiovascular risk factors at 30 years of age. METHODS: We followed up at age 30 years 534 individuals whose mothers participated in a double-blind, placebo-controlled, randomised trial of antenatal betamethasone for the prevention of neonatal respiratory distress syndrome. Mothers received two doses of betamethasone or placebo given by intramuscular injection 24 h apart. Follow-up assessments included anthropometry; measurement of blood pressure, blood lipids (after overnight fasting), and early morning cortisol levels; and a 75 g oral glucose tolerance test. FINDINGS: There were no differences between those exposed to betamethasone and to placebo in body size, blood lipids, blood pressure, plasma cortisol, prevalence of diabetes, or history of cardiovascular disease. After a 75 g oral glucose tolerance test, participants exposed to betamethasone had higher plasma insulin concentrations at 30 min (60.5 vs 52.0 mIU/L; ratio of geometric means 1.16 [95% CI 1.03 to 1.31], p=0.02) and lower glucose concentrations at 120 min (4.8 vs 5.1 mmol/L; difference -0.26 mmol/L [-0.53 to 0.00], p=0.05) than did those exposed to placebo. INTERPRETATION: Antenatal exposure to betamethasone might result in insulin resistance in adult offspring, but has no clinical effect on cardiovascular risk factors at 30 years of age. Thus, obstetricians should continue to use a single course of antenatal betamethasone for the prevention of neonatal respiratory distress syndrome.

Does capture-recapture analysis provide more reliable estimates of the incidence and prevalence of leg ulcers in the community?

OBJECTIVE: To determine whether capture-recapture analysis provides more reliable estimates of the cumulative incidence and prevalence of leg ulcers in Auckland, New Zealand. METHODS: A population-based, cross-sectional study was conducted in the Central and North Auckland health districts of New Zealand in 1998. Cases were identified through health professional referral and by self-notification. All ages and ulcer types were investigated. Both traditional and capture-recapture methods of analysis were used to estimate the cumulative incidence and prevalence of leg ulcers in the study population. RESULTS: Four hundred and twenty-six people with current leg ulcers were identified during the 12-month study period. Using traditional methods of analysis, the annual cumulative incidence rate of leg ulcers in Auckland was 32 per 100,000, with a point prevalence of 39 per 100,000 and a period prevalence of 79 per 100,000 per year. Results from capture-recapture analysis, however, suggest an annual cumulative incidence rate of 252 per 100,000, with a point prevalence of 248 per 100,000 and a period prevalence of 530 per 100,000 per year. CONCLUSIONS: The traditional method of calculating cumulative incidence and prevalence clearly under-estimates the frequency of leg ulcers in the Auckland region. Capture-recapture analysis provides a more reliable estimate of disease frequency, since cases that remain unidentified in the population are considered.