Paradoxical effects of N-cyanoalkyl substituents upon the activities of several classes of opioids.

The pharmacological effect of the N-(beta-cyanoethyl) moiety is dependent on the opioid on which it is substituted. It caused a large increase in antinociceptive potency, in (--)-3-hydroxymorphinan and (--)-normetazocine, as compared with the N-methyl opioid. These cyanoethyl compounds do not substitute for morphine in morphine-dependent monkeys. This moiety also appears to greatly increase the ability of the opiate receptor to differentiate enantiomers. An ca. 100,000-fold difference in binding was noted between the epimeric N-(beta-cyanoethyl)-3-hydroxymorphinans and the normetazocines. The levo enantiomers have little acute toxicity and showed excellent therapeutic ratios. In contrast, the N-(beta-cyanoethyl) moiety on normorphine, norcodeine, and noroxymorphone did not appear to improve their pharmacological properties. Homologous N-cyanoalkyl opioids were less potent antinociceptives.     

Prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in young women: a randomised double-blind placebo-controlled multicentre phase II efficacy trial

BACKGROUND: A randomised double-blind placebo-controlled phase II study was done to assess the efficacy of a prophylactic quadrivalent vaccine targeting the human papillomavirus (HPV) types associated with 70% of cervical cancers (types 16 and 18) and with 90% of genital warts (types 6 and 11). METHODS: 277 young women (mean age 20.2 years [SD 1.7]) were randomly assigned to quadrivalent HPV (20 microg type 6, 40 microg type 11, 40 microg type 16, and 20 microg type 18) L1 virus-like-particle (VLP) vaccine and 275 (mean age 20.0 years [1.7]) to one of two placebo preparations at day 1, month 2, and month 6. For 36 months, participants underwent regular gynaecological examinations, cervicovaginal sampling for HPV DNA, testing for serum antibodies to HPV, and Pap testing. The primary endpoint was the combined incidence of infection with HPV 6, 11, 16, or 18, or cervical or external genital disease (ie, persistent HPV infection, HPV detection at the last recorded visit, cervical intraepithelial neoplasia, cervical cancer, or external genital lesions caused by the HPV types in the vaccine). Main analyses were done per protocol. FINDINGS: Combined incidence of persistent infection or disease with HPV 6, 11, 16, or 18 fell by 90% (95% CI 71-97, p<0.0001) in those assigned vaccine compared with those assigned placebo. INTERPRETATION: A vaccine targeting HPV types 6, 11, 16, 18 could substantially reduce the acquisition of infection and clinical disease caused by common HPV types.     

Natural History and Outcome of Hepatic Vascular Malformations in a Large Cohort of Patients with Hereditary Hemorrhagic Teleangiectasia

Background

Hereditary hemorrhagic telangiectasia is a genetic disease characterized by teleangiectasias involving virtually every organ. There are limited data in the literature regarding the natural history of liver vascular malformations in hemorrhagic telangiectasia and their associated morbidity and mortality.

Aim

This prospective cohort study sought to assess the outcome of liver involvement in hereditary hemorrhagic telangiectasia patients.

Methods

We analyzed 16 years of surveillance data from a tertiary hereditary hemorrhagic telangiectasia referral center in Italy. We considered for inclusion in this study 502 consecutive Italian patients at risk of hereditary hemorrhagic telangiectasia who presented at the hereditary hemorrhagic telangiectasia referral center and underwent a multidisciplinary screening protocol for the diagnosis of hereditary hemorrhagic telangiectasia. Of the 502 individuals assessed in the center, 154 had hepatic vascular malformations and were the subject of the study; 198 patients with hereditary hemorrhagic telangiectasia and without hepatic vascular malformations were the controls. Additionally, we report the response to treatment of patients with complicated hepatic vascular malformations.

Results

The 154 patients were included and followed for a median period of 44 months (range 12?C181); of these, eight (5.2%) died from VM-related complications and 39 (25.3%) experienced complications. The average incidence rates of death and complications were 1.1 and 3.6 per 100 person-years, respectively. The median overall survival and event-free survival after diagnosis were 175 and 90 months, respectively. The rate of complete response to therapy was 63%.

Conclusions

This study shows that substantial morbidity and mortality are associated with liver vascular malformations in hereditary hemorrhagic telangiectasia patients.     

Laparoscopic bisegmentectomy 6 and 7 using a Glissonian approach and a half-Pringle maneuver

Background

Despite accumulated experience and advancing techniques for laparoscopic hepatectomy, surgeons still face challenging resections that require specific and innovative intraoperative maneuvers [1–3]. The right posterior sectionectomy presents special concerns about its location, the extensive transection area, and the difficult access to the pedicle [4, 5]. The intrahepatic Glissonian approach allows safe en masse control of the portal structures without prolonged dissection [2]. Its association with the half-Pringle maneuver results in less bleeding during parenchymal transection [1, 6].

Methods

A 34-year-old woman was referred for treatment of an 8-cm hepatocellular adenoma located at segments 6 and 7. She was placed in a semi-supine position, and six ports were located in a distribution that resembled a Makuuchi incision. The right liver was mobilized, and preparation for an anatomic Glissonian approach was performed. A vascular clamp was placed to ensure that full control of the right posterior pedicle was possible. Then a vascular stapler replaced it, with division of the right posterior Glissonian pedicle. A vascular clamp was inserted from the inferior right-flank 5-mm trocar for performance of a half-Pringle maneuver of the right pedicle to minimize blood loss during parenchymal transection. The liver parenchyma was transected with a harmonic scalpel and a vascular stapler. The right hepatic vein was divided intraparenchymally with a vascular stapler. The specimen was extracted through a Pfannenstiel incision.

Results

The total surgical time was 210 min, and the estimated blood loss was 200 ml. No blood transfusion was required. The recovery was uneventful, and hospital discharge occurred on postoperative day 5. Pathology confirmed the diagnosis of an hepatocellular adenoma.

Conclusions

Technical issues initially hindered the development of laparoscopic liver resections [7–10]. Surgeons were concerned about hemostasis, bleeding control, safe and effective parenchymal transection, adequate visualization, and the feasibility of working on deeper regions of the liver. During the past decade, many limitations were overcome, but lesions located on the posterosuperior liver are still considered tough to beat [5, 11]. Large series and extensive reviews [12–14] show that resections located on the posterior segments still are infrequent. Limited access to the portal triad, difficult pedicle control, and a large transection area and its anatomic location, attached to the diaphragm and retroperitoneum and hidden from the surgeon’s view, makes such resections defying. The authors’ team has performed 97 laparoscopic hepatectomies, including resection of 6 lesions in the right posterior sector. In their series, half-pedicle clamping was used for 12 patients, and they adopt such a maneuver as an inflow control when operating on peripheric lesions with difficult vascular control (e.g., enucleations or posterosuperiorly located segmentectomies). This technique is safe and useful because it reduces liver ischemic aggression, a very important issue with diseased livers (e.g., steatosis, steatohepatitis, prolonged chemotherapy, cirrhosis) [6, 15]. In their series, the authors applied the Glissonian intrahepatic approach in 7 cases (2 left hepatectomies and 5 right hepatectomies). They understand that laparoscopy applies perfectly to oddly (posterosuperior) located tumors and that right posterior sectionectomy can be accomplished safely. In fact, they share the opinion of other specialized hepatobiliary centers, believing that this may be the preferred approach [16].     

Cataract surgery complications as a cause of visual impairment in a population aged 50 and over

The purpose of this study was to measure the extent to which complications relating to cataract surgery are a cause of visual impairment in a population aged 50 and over from the city of Campinas, S?o Paulo State, Brazil. An assessment of cataract surgery services was conducted using random cluster sampling, with the sample composed of 60 clusters of 40 people aged 50 years or older. Of the selected sample of 2,400 subjects, 92.67% were examined. Of these 2,224 examined subjects, 75 (3.37%) presented bilateral visual impairment and 164 unilateral, while a total of 314 (7.06%) eyes presented visual impairment. 352 eyes had undergone cataract surgery. The causes of visual impairment after surgery were concurrent eye disease (56%), surgical complications (28.8%) and refractive errors (15.2%). Cataract surgery complications represented the 5th most important cause of visual impairment. The other main causes were cataract, posterior segment disorders, diabetic retinopathy and glaucoma. These results suggest cataract surgery complications are a major cause of visual impairment in this population. Their prevention and treatment must be part of public health care policies.