Effects of arginine vasopressin on human anxiety and associations with sex, dose, and V1a-receptor genotype.

RATIONALE: Arginine vasopressin (AVP) has dose- and sex-specific effects on social behavior, and variation in social responses is related to variation in the V1a receptor gene in animals. Whether such complexity also characterizes AVP effects on anxiety in humans, or whether V1a genotype is related to anxiety and/or AVP's ability to affect it, remains to be determined. OBJECTIVE: To test if AVP has dose-dependent effects on anxiety in men and/or women and if a particular allele within the RS3 promoter region of the V1a receptor gene is associated with anxiety and/or AVP effects on anxiety. METHOD: Men and women self-administered 20 IU or 40 IU intranasal arginine vasopressin (AVP) and placebo in a double-blind, within-subjects design, and State (SA) and Trait (TA) anxiety were measured 60 min later. PCR was used to identify allelic variation within the RS3 region of the V1a receptor gene. RESULTS: AVP decreased SA in men across both doses, whereas only the lower dose had the same effect, across sexes, in individuals who carry at least one copy of a previously identified "risk" allele in the RS3 promoter of the V1a receptor gene. Additionally, after placebo, women who carried a copy of the allele displayed lower TA than women who did not, and AVP acutely increased TA scores in those women. CONCLUSIONS: Exogenous AVP has modest sex- and dose-dependent effects on anxiety/affect in humans. Further, allelic variation in the V1a promoter appears associated with responsiveness to AVP's effects and, at least in women, to stable levels of anxiety/affect.

Tumour response 3 months after neoadjuvant single-fraction radiotherapy for low-risk breast cancer.

Introduction: Standard treatment for early-stage invasive breast cancer (bca) consists of breast-conserving surgery and several weeks of adjuvant radiotherapy (rt). Neoadjuvant single-fraction rt is a novel approach for early-stage bca. We sought to investigate the effect of delaying surgery after neoadjuvant rt with respect to the rate of pathologic response (pr). Methods: Women 65 years of age or older with a new diagnosis of stage i luminal A bca were eligible for inclusion. A single 20 Gy dose to the primary breast tumour was given, followed by breast-conserving surgery 3 months later. The primary endpoint was the pr rate assessed by microscopic evaluation using the Miller-Payne system. Results: To date, 10 patients have been successfully treated. Median age of the patients was 72 years (range: 65-84 years). In 8 patients, neoadjuvant rt resulted in a tumour pr with median residual cellularity of 3%. No immediate rt complications other than mild dermatitis were noted. Conclusions: This study demonstrates a method for delivering single-fraction rt that can lead to a high level of pr in most patients. Continued accrual to this study and subsequent trials are needed to determine the feasibility, safety, and role of this novel technique in the management of early-stage bca.

Rationale for the administration of systemic 5-FU in combination with heated intraperitonal oxaliplatin.

BACKGROUND: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) with oxaliplatin (OX) is the standard of care for selected patients with peritoneal carcinomatosis of colorectal origin. Because 5-FU is mandatory to improve efficacy of OX when used by systemic route, several teams now empirically combine intravenous (IV) 5-FU with HIPEC OX, but this practice has yet to be supported by preclinical data. Using a murine model, we studied the impact of IV 5-FU on peritoneal absorption of HIPEC OX. METHODS: Under general anesthesia, 24 Sprague-Dawley rats were submitted to 4 different doses of IV 5-FU (0, 100, 400 and 800 mg/m2) and a fixed dose of HIPEC OX (460 mg/m2) perfused at 40 °C during 25 min. At 25 min, samples in different compartments were harvested (peritoneum, portal vein and systemic blood) and the concentrations of 5-FU and OX were measured by high performance liquid chromatography. RESULTS: Peritoneal absorption of OX was significantly higher (17.0, 20.1, 34.9 and 38.1 nmol/g, p < 0.0001) with increasing doses of 5-FU (0, 100, 400 and 800 mg/m2, respectively). Peritoneal absorption of OX reached a plateau between 400 and 800 mg/m2 of IV 5-FU. CONCLUSION: IV 5-FU enhances peritoneal absorption of HIPEC OX. The most efficient dose of IV 5-FU to be used in combination with HIPEC OX seems to be 400 mg/m2.

Differential effects of high fat diet and diet-induced obesity on skeletal acquisition in female C57BL/6J vs. FVB/NJ Mice.

The effects of obesity on bone metabolism are complex, and may be mediated by consumption of a high fat diet and/or by obesity-induced metabolic dysregulation. To test the hypothesis that both high fat (HF) diet and diet-induced metabolic disease independently decrease skeletal acquisition, we compared effects of HF diet on bone mass and microarchitecture in two mouse strains: diet-induced obesity (DIO)-susceptible C57BL/6J (B6) and DIO-resistant FVB/NJ (FVB). At 3 wks of age we weaned 120 female FVB and B6 mice onto normal (N, 10% Kcal/fat) or HF diet (45% Kcal/fat) and euthanized them at 6, 12 and 20 weeks of age (N = 10/grp). Outcomes included body mass; percent fat and whole-body bone mineral density (WBBMD, g/cm2) via DXA; cortical and trabecular bone architecture at the midshaft and distal femur via µCT; and marrow adiposity via histomorphometry. In FVB HF, body mass, percent body fat, WBBMD and marrow adiposity did not differ vs. N, but trabecular bone mass was lower at 6 wks of age only (p < 0.05), cortical bone geometric properties were lower at 12 wks only, and bone strength was lower at 20 wks of age only in HF vs. N (p < 0.05). In contrast, B6 HF had higher body mass, percent body fat, and leptin vs. N. B6 HF also had higher WBBMD (p < 0.05) at 9 and 12 wks of age but lower distal femur trabecular bone mass at 12 wks of age, and lower body mass-adjusted cortical bone properties at 20 wks of age compared to N (p < 0.05). Marrow adiposity was also markedly higher in B6 HF vs. N. Overall, HF diet negatively affected bone mass in both strains, but was more deleterious to trabecular bone microarchitecture and marrow adiposity in B6 than in FVB mice. These data suggest that in addition to fat consumption itself, the metabolic response to high fat diet independently alters skeletal acquisition in obesity.

Sclerostin antibody inhibits skeletal deterioration in mice exposed to partial weight-bearing.

Whereas much is known regarding the musculoskeletal responses to full unloading, little is known about the physiological effects and response to pharmacological agents in partial unloading (e.g. Moon and Mars) environments. To address this, we used a previously developed ground-based model of partial weight-bearing (PWB) that allows chronic exposure to reduced weight-bearing in mice to determine the effects of murine sclerostin antibody (SclAbII) on bone microstructure and strength across different levels of mechanical unloading. We hypothesize that treatment with SclAbII would improve bone mass, microarchitecture and strength in all loading conditions, but that there would be a greater skeletal response in the normally loaded mice than in partially unloaded mice suggesting the importance of combined countermeasures for exploration-class long duration spaceflight missions. Eleven-week-old female mice were assigned to one of four loading groups: normal weight-bearing controls (CON) or weight-bearing at 20% (PWB20), 40% (PWB40) or 70% (PWB70) of normal. Mice in each group received either SclAbII (25mg/kg) or vehicle (VEH) via twice weekly subcutaneous injection for 3 weeks. In partially-unloaded VEH-treated groups, leg BMD decreased -5 to -10% in a load-dependent manner. SclAbII treatment completely inhibited bone deterioration due to PWB, with bone properties in SclAbII-treated groups being equal to or greater than those of CON, VEH-treated mice. SclAbII treatment increased leg BMD from +14 to +18% in the PWB groups and 30 ± 3% in CON (p< 0.0001 for all). Trabecular bone volume, assessed by µCT at the distal femur, was lower in all partially unloaded VEH-treated groups vs. CON-VEH (p< 0.05), and was 2-3 fold higher in SclAbII-treated groups (p< 0.001). Midshaft femoral strength was also significantly higher in SclAbII vs. VEH-groups in all-loading conditions. These results suggest that greater weight bearing leads to greater benefits of SclAbII on bone mass, particularly in the trabecular compartment. Altogether, these results demonstrate the efficacy of sclerostin antibody therapy in preventing astronaut bone loss during terrestrial solar system exploration.

Second-look surgery plus HIPEC for patients with colorectal cancer at high risk of peritoneal carcinomatosis: Should we resect the initial anastomosis? An observational study.

BACKGROUND: Cytoreductive surgery (CCRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) improves the overall survival in selected cases of peritoneal carcinomatosis (PC) of colorectal origin. Second-look surgery in asymptomatic patients at high risk of developing PC has shown encouraging results. This study aims at identifying cases in which initial anastomosis should be resected. METHODS: Patients treated by second-look surgery and HIPEC were identified from a prospective database. High-risk was defined as synchronous resected and minimal PC, ovarian metastasis or perforated primary tumor. Patients were divided in two groups based on intra-operative evaluation of the anastomosis: possibly-invaded (PI) and unlikely-invaded (UI). PI was defined as 1) PC away from the anastomosis, 2) nodules resting on the anastomosis 3) anastomotic stenosis or anastomotic thickening. Anastomosis in the PI group were resected. RESULTS: Forty patients were included: 12 in the PI group and 28 in the UI group. Incidence of pathological anastomotic invasion was 42% (5 on 12 patients) in the PI group. In the UI group, 2 patients had anastomotic recurrence, both associated with peritoneal recurrence. Morbidity and mortality was not influenced by anastomosis resection. The presence of suspicious nodules on the anastomosis had a sensitivity of 100% and a specificity of 89% in predicting anastomotic invasion. CONCLUSION: In second-look surgery and HIPEC for colorectal cancer at high-risk of PC, anastomosis should be resected when overlying PC nodules are found. This attitude is supported by high sensitivity of this finding for anastomotic invasion and low morbidity related to anastomotic resection.

Jet injection of a monoclonal antibody: A preliminary study.

Monoclonal antibodies (mAbs) represent a major group of biotherapeutics. The high concentration and volume of drug administered together with a shift to administration via the subcutaneous route have generated interest in alternative delivery technologies. The feasibility of using a novel, highly controllable jet injection technology to deliver a mAb is presented. The effect of delivery parameters on protein structure were evaluated and compared with delivery using a conventional needle and syringe. Injection of mAb into a rat model showed that jet injection using the device resulted in more rapid absorption and longer duration of exposure.

Modified selection criteria for complete cytoreductive surgery plus HIPEC based on peritoneal cancer index and small bowel involvement for peritoneal carcinomatosis of colorectal origin.

BACKGROUND: Complete cytoreductive surgery (CCRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) is on the verge of becoming the gold standard treatment for selected patients presenting peritoneal metastases (PM) of colorectal origin. PM is scored with the peritoneal cancer index (PCI), which is the main prognostic factor. However, small bowel (SB) involvement could exert an independent prognostic impact. AIM: To define an adequate cut-off for the PCI and to appraise whether SB involvement exerts an impact on this cut-off. PATIENTS AND METHODS: Patients (n = 139) treated with CCRS plus HIPEC were prospectively verified and retrospectively analyzed. One hundred presented with SB involvement of different extents and at different locations. RESULTS: All the patients with a PCI ≥ 15 exhibited SB involvement. Five-year overall survival was 48% when the PCI was <15 vs 12% when it was ≥ 15 (p < 0.0001. The multivariate analysis retained two prognostic factors: PCI ≥ 15 (p = 0.02, HR = 1.8), and the involvement of area 12 (lower ileum) (p = 0.001, HR = 3.1). When area 12 was invaded, it significantly worsened the prognosis: 5-year overall survival of patients with a PCI <15 and area 12 involved was 15%, close to that of patients with a PCI ≥ 15 (12%) and far lower than that of patients with a PCI <15 and no area 12 involvement (70%). CONCLUSION: A PCI greater than 15 appears to be a relative contraindication for treatment of colorectal PM with CCRS + HIPEC. Involvement of the lower ileum is also a negative prognostic factor to be taken into consideration.

Maternal perinatal diet induces developmental programming of bone architecture.

Maternal high-fat (HF) diet can alter offspring metabolism via perinatal developmental programming. This study tests the hypothesis that maternal HF diet also induces perinatal programming of offspring bone mass and strength. We compared skeletal acquisition in pups from C57Bl/6J mice fed HF or normal diet from preconception through lactation. Three-week-old male and female pups from HF (HF-N) and normal mothers (N-N) were weaned onto normal diet. Outcomes at 14 and 26 weeks of age included body mass, body composition, whole-body bone mineral content (WBBMC) via peripheral dual-energy X-ray absorptiometry, femoral cortical and trabecular architecture via microcomputed tomography, and glucose tolerance. Female HF-N had normal body mass and glucose tolerance, with lower body fat (%) but higher serum leptin at 14 weeks vs. N-N (P<0.05 for both). WBBMC was 12% lower at 14 weeks and 5% lower at 26 weeks, but trabecular bone volume fraction was 20% higher at 14 weeks in female HF-N vs. N-N (P<0.05 for all). Male HF-N had normal body mass and mildly impaired glucose tolerance, with lower body fat (%) at 14 weeks and lower serum leptin at 26 weeks vs. N-N (P<0.05 for both). Serum insulin was higher at 14 weeks and lower at 26 weeks in HF-N vs. N-N (P<0.05). Trabecular BV/TV was 34% higher and cortical bone area was 6% higher at 14 weeks vs. N-N (P<0.05 for both). These data suggest that maternal HF diet has complex effects on offspring bone, supporting the hypothesis that maternal diet alters postnatal skeletal homeostasis.

Neonatal oxygen exposure leads to increased aortic wall stiffness in adult rats: a Doppler ultrasound study.

We have previously shown that neonatal high oxygen (O2) exposure in rats leads to hypertension and vascular dysfunction in adulthood. Pulse-wave velocity (PWV), an indirect measure of vascular biophysical properties (arterial stiffness or distensibility), is a sensitive marker of cardiovascular health. Its measurement in rats is mostly based on invasive hemodynamics measurements, prohibiting longitudinal studies particularly relevant in models of developmental programming of cardiovascular dysfunctions. With this study, we sought (1) to verify the feasibility and validity of measuring of aortic PWV in Sprague-Dawley rats by ultrasound; (2) to use the technique to compare aortic PWV in adult rats exposed to O2 as newborns (80% day 3-10 of life) v. controls; and (3) to develop an algorithm to calculate PWV in a non-invasive manner. We calculated aortic PWV using standard echocardiography and electrocardiogram, and validated the measures with PWV obtained by intraaortic catheters. Aortic full length was measured at sacrifice. PWV was significantly increased in O2 exposed (505 ± 18 cm/s) v. control animals (421 ± 17 cm/s, P < 0.01). With regard to weight, femur length and distance from the manubrium to the anal margin (MA length), the latter showed the best correlation (R = 0.84, P < 0.0001) with full aorta length derived from (L) = 0.339 × (MA length) + 4.281. The current data using echo-Doppler method demonstrated increased aortic stiffness in adult rats exposed to hyperoxia as newborns and suggests that non-invasive longitudinal studies of aortic PWV can be performed using the proposed algorithm for estimation of the full aorta length.

Advanced breast cancer: recent developments in hormonal therapy.

OBJECTIVES: To review recent developments in hormonal therapy for metastatic breast cancer. DATA SOURCES: Published books and articles. CONCLUSIONS: Newer hormonal agents are offering women alternatives for sequential therapy of metastatic disease that provide benefit with less risk. IMPLICATIONS FOR NURSING PRACTICE: A thorough understanding of the relationship between hormonal influences and breast cancer will assist nurses to better appreciate the variety of agents now available and their specific indications, outcomes, and effects. Common side effects include weight gain, hot flashes, nausea, and skin and vaginal changes. Nursing efforts focus on the areas of body image disturbance, side effect management, and fostering healthy relationships.

Meeting the challenge of unscheduled outpatient visits.

Cancer patients receive multimodal therapy and treatments on an ongoing basis in free-standing cancer centers, infusion centers, and oncology offices and at home. To serve those who require unscheduled evaluation for treatment effects, one hospital developed a program to receive those visits on an inpatient cancer unit.

Evolution of fetal ventricular aneurysms and diverticula of the heart: an echocardiographic study.

Due to the rarity of congenital ventricular diverticula and aneurysms, their natural history remains unclear. An excellent prognosis has been suggested for those cases diagnosed during fetal life: From October 1992 to January 1996 seven fetuses were diagnosed with ventricular diverticula or aneurysms. Gestational age ranged from 18 to 36 weeks. The indications for fetal echocardiogram were cardiomegaly, abnormal four-chamber view, a large pericardial effusion, and hydrothorax. Echocardiography revealed a moderate sized apical left ventricular aneurysm (2), a small subvalvular right ventricular diverticulum (1), small apical right ventricular diverticulum (2), a large submitral left ventricular aneurysm (1), and a large diverticulum arising from the lateral free wall of the left ventricle (1). Decreased left ventricular function was detected in three fetuses with left ventricular aneurysms. Two fetuses with large lesions, developed hydrops and died in utero. Postnatal echocardiograms confirmed prenatal findings in all survivors. All infants remained asymptomatic, with age on follow-up from 8 to 24 months. An accurate diagnosis of ventricular diverticula and aneurysms is feasible prenatally. Outcome depends on the size and progression of the lesion. The presence of a large pericardial effusion in three cases with a diverticula was noted.

Aortic valve replacement with pulmonary autograft in children and adults.

Aortic valve replacement with a conventional prosthesis is still flawed with complications, especially in children and young adults. Complex aortic root enlargement (Konno) is often needed because of small aortic diameter. The poor compliance with anticoagulation by teenagers and the risks associated with this made us look at alternative techniques. From November 1990 to June 1994, 70 patients were considered for pulmonary autografts in our institution; 64 underwent the procedure with one death and one failure to implant. Short-term results are excellent, with minimal gradient in 90% and minimal regurgitation in 96% of the patients. The long-term follow-up, hopefully, will confirm the superiority of this procedure over more conventional replacement.

Lobectomy in the treatment of the scimitar syndrome.

The scimitar syndrome is a congenital anomaly that consists mainly of total or partial anomalous venous drainage of the right lung to the inferior vena cava. We report the case of an 8-year-old girl diagnosed at birth as having a scimitar syndrome and who presented with recurrent right lower lung infections. She underwent resection of the lower half of her right lung without diversion of the anomalous venous drainage of the upper portion of the lung. She improved rapidly postoperatively and the shunt fraction diminished.

[Pulmonary autograft as aortic valve replacement in children]. / L'autogreffe pulmonaire comme remplacement aortique chez l'enfant.

The aortic stenosis represents 5% of all congenital cardiac pathology. The conventional treatments often do not give very satisfactory results. Since 1990, as alternative to the traditional aortic valve replacement, we used, in our institution, the Ross procedure (pulmonary autograft). This consists in using the pulmonary valve as an autograft in aortic position to replace the diseased valve. Then, the pulmonary outflow is reconstructed with a cryopreserved homograft. This study includes 15 patients, aged between 16 months and 18 years, treated with this technique since 1990. There has been no mortality. All the patients are alive at the follow-up, and all in NYHA functional class I. No reoperation has been necessary for valvular dysfunction. The post-operative doppler study at aortic level demonstrated those gradients: Mean + SD, 3.8 +/- 8.1 (range 0-23). No regurgitation haemodynamically important has been recorded at aortic level nor in the pulmonary position. Post-operative gradients at pulmonary level were: Mean + SD, 14.6 + 10.6 (range 14-32).

Ocular side effects of chemotherapy: nursing management.

Ocular side effects may be unfamiliar to oncology nurses but are important because of their potentially devastating effects on vision. Presently, more than 20 chemotherapy agents have been reported to cause eye toxicities. Chemotherapy-induced ocular side effects can be manifested on a range of minor, transient irritation to irreversible, complete blindness. This article reviews these ocular complications, their causative agents, their effect on eye structures and function, and nursing management. Oncology nurses can play a vital role in the identification of symptoms and in the management of these eye complications.

[Congestive cardiomyopathies in children. Natural history and studies]. / Les cardiomyopathies congestives chez l'enfant. Histoire naturelle et investigation.

Congestive cardiomyopathies represent a group of diseases having in common an intrinsic abnormality of the myocardial contraction, of which the cause often remains unknown. In children, there is a more marked incidence during the first year of life. At the Cardiology Institute of Quebec, 25 patients have been diagnosed with a congestive cardiomyopathy since January 1967. The mortality remains high at 48 per cent, and the morbidity at 28 per cent. Thus, the chance of total survival at 16 years was 33 percent. The evaluation and the treatment of the cardiac function as well as the search for a specific etiology must be carried out because the etiological treatment is sometimes possible. Biopsy of the skeletal muscle as the study of fatty acids metabolism have become very important since the identification of a carnitine deficiency. On the other hand, biopsy of the endomyocardium remains the only means to make a pathological diagnosis. Since the treatment of persisting myocarditis is feasible, the histological diagnosis is a pre-requisite in children. So, in four patients with congestive cardiomyopathy, biopsy of the endocardium has enabled to demonstrate a chronic inflammation of the myocardium in one patient. In three other cases, two had non specific lesions on histological examination an one had an extensive fibro-elastosis. As the symptomatic treatment is often deceiving, an in-depth investigation is mandatory in a child suffering from a congestive cardiomyopathy in order to identify an etiology. Such an approach will enable to apply a specific treatment, to achieve a better understanding and perhaps modify its natural history.