Acute cardiovascular and sympathetic effects of nicotine replacement therapy

Sympathetic overactivity is implicated in the increased cardiovascular risk of cigarette smokers. Excitatory nicotinic receptors are present on peripheral chemoreceptor cells. Chemoreceptors located in the carotid and aortic bodies increase ventilation (Ve), blood pressure (BP), heart rate (HR), and sympathetic nerve activity to muscle circulation (MSNA) in response to hypoxia. We tested the hypothesis that nicotine replacement therapy (NRT) increases MSNA and chemoreceptor sensitivity to hypoxia. Sixteen young healthy smokers were included in the study (8 women). After a randomized and blinded sublingual administration of a 4-mg tablet of nicotine or placebo, we measured minute Ve, HR, mean BP, and MSNA during normoxia and 5 minutes of isocapnic hypoxia. Maximal voluntary end-expiratory apneas were performed at baseline and at the end of the fifth minute of hypoxia. Nicotine increased HR by 7+/-3 bpm, mean BP by 5+/-2 mm Hg, and MSNA by 4+/-1 bursts/min, whereas subjects breathed room air (all P<0.05). During hypoxia, nicotine also raised HR by 8+/-2 bpm, mean BP by 2+/-1 mm Hg, and MSNA by 7+/-2 bursts/min (all P<0.05). Nicotine increased MSNA during the apneas performed in normoxia and hypoxia (P<0.05). Nicotine also raised the product of systolic BP and HR, a marker of cardiac oxygen consumption, during normoxia, hypoxia, and the apneas (P<0.05). Ve, apnea duration, and O2 saturation during hypoxia and the apneas remained unaffected. In conclusion, sympathoexcitatory effects of NRT are not because of an increased chemoreflex sensitivity to hypoxia. NRT increases myocardial oxygen consumption in periods of reduced oxygen availability.     

Portal vein embolization effect on colorectal cancer liver metastasis progression: Lessons learned

Colorectal liver metastasis (CRLM) is the major cause of death in patients diagnosed with colorectal cancer. The gold standard treatment of CRLM is surgical resection. Yet, in the past, more than half of these patients were deemed unresectable due to the inadequate future liver remnant (FLR). The introduction of efficient portal vein embolization (PVE) preoperatively allowed more resections of metastasis in CRLM patients by stimulating adequate liver hypertrophy. However, several experimental and clinical studies reported tumor progression after PVE which critically influences the subsequent management of these patients. The underlying pathophysiological mechanism of tumor progression post-PVE is still not fully understood. In spite of the adverse effects of PVE, it remains a potentially curative procedure in patients who would remain otherwise unresectable because of the insufficient FLR. Currently, the challenge is to halt tumor proliferation following PVE in patients who require this technique. This could potentially be achieved by either attempting to suppress the underlying oncologic stimulus or by inhibiting tumor growth once observed after PVE, without jeopardizing liver regeneration. More research is still required to better identify patients at risk of experiencing tumor growth post-PVE.     

Clusters of cancer mortality in New Jersey municipalities; with special reference to chemical toxic waste disposal sites and per capita income

The state of New Jersey (NJ), USA, has been thought to have an unusually high cancer mortality rate; this assumption has been based on 1950-1969 mortality data for NJ counties. This study presents an analysis of mortality from major cancers for NJ municipalities during 1968-1977, and correlates cancer mortality rates with several potentially relevant variables. Age-adjusted mortality rates for 13 major cancer sites for 194 municipalities of 10 000 or more people in 21 NJ counties were compared with cancer mortality in the US. Municipality rates were correlated with: distribution of chemical toxic waste disposal sites (CTWDS); annual per capita income; the rates of low birth weight, birth defects and infant mortality of NJ municipalities. Clusters of cancer mortality were observed in 23 municipalities in 10 counties in which a total of 98 age-adjusted cancer death rates were at least 50% above the national rate, and each of these municipalities had at least two race-sex-specific cancers in which the observed number of cancer deaths was greater than the expected number of deaths at the p less than 0.0005 level. Of these 98 excessive cancer death rates, 72% involved the gastrointestinal tract. Most of the municipalities are located in the highly industrialized densely populated northeastern part of the State. Correlation analyses showed a consistent and significant (p less than 0.05) negative correlation between income and cancer mortality in 11 of 12 cancers studied. These analyses also showed a significant positive association between 8 of 12 cancers studied and CTWDS in one or more subgroup populations and lesser associations with birth defects, low birth weight and infant mortality.     

International comparison of medical students' perceptions of HIV infection and AIDS.

This analysis compared medical students'' perceptions of human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS) in two cities in two countries with different cultural and educational backgrounds. A total of 292 first- and second-year medical students (45% sample) were surveyed from New Jersey Medical School and from Benin Medical School, Nigeria. Compared with the Benin students, the Newark medical students were significantly more knowledgeable and had more positive attitudes and behaviors regarding HIV infection and AIDS. Misperceptions regarding certain modes of transmission of HIV were significantly higher among the Benin students than the Newark students. Compared with the Benin students, the Newark students had more frequent sexual intercourse and used condoms more frequently, but the Benin students had more sex partners. Perception of personal risk and concern of contracting AIDS was significantly higher among the Newark students than the Benin students. These results indicate it is important that medical educators in medical schools convey accurate information to improve medical students'' perception regarding HIV infection and AIDS.     

Current attitudes in the management of obstructive biliary tract disease

The current attitudes of surgeons towards the management of obstructive biliary tract disease were assessed by analyzing the responses of general surgeons to a 20-item questionnaire. The responses indicate that ultrasound is the most favored initial diagnostic test for suspected choledocolithiasis. Ninety-nine per cent of the respondents always or almost always insert a T-tube following exploration of the common bile duct for stones. For patients with stone impacted at the ampulla of Vater, sphincterotomy with or without sphincteroplasty is recommended by 86 per cent of surgeons. However, differences are noted in the approach to management of malignant lesions in the biliary tract. For carcinoma of the head of the pancreas, at laparotomy, if the lesion is resectable, 59 per cent of the surgeons will perform a Whipple procedure, nine per cent a total pancreatectomy, and 28 per cent recommend bypass only. For unresectable carcinoma of the head of the pancreas, 73 per cent perform cholecystojejunostomy, and 26 per cent prefer choledocojejunostomy. In addition to the biliary bypass, only 57 per cent perform a gastric bypass routinely. The favored treatment (62%) for unresectable common bile duct tumors is an internal bypass. However, following bypass, only 45 per cent recommend further treatment with radiation and/or chemotherapy. Therefore, it appears that there is agreement on the treatment of biliary obstruction due to stones. Differences are noted, however, in the approach to the management of malignant disease.     

Sympathoexcitation increases the QT/RR slope in healthy men: differential effects of hypoxia, dobutamine, and phenylephrine

Introduction: Dynamic ventricular repolarization assessed by QT/RR slopes studies the effects of modifications in cardiac repolarization independently of variations in RR interval (RR). The effects of changes in sympathetic and vagal activity on the QT/RR slope are controversial. We tested the hypothesis that sympathoexcitation is an important determinant of the QT/RR slope.
Methods and Results: We compared the effects of a reflex sympathetic activation in response to hypoxia, to the direct effects of the infusion of the beta-adrenergic agent dobutamine, on the QTa (apex) and QTe (end)/RR slopes. Dobutamine was titrated to obtain similar increases in cardiac output than with hypoxia. Cardiac vagal activity was estimated by rMSSD and pNN50. In a second group of healthy subjects, we assessed the effect of a reflex cardiac vagal activation in response to phenylephrine infusion on the same variables. We observed a similar increase in QTa and QTe slopes during hypoxia and dobutamine (both P < 0.017 vs. normoxia), despite divergent changes in cardiac vagal activity, as rMSSD and pNN50 decreased with hypoxia compared to normoxia (P < 0.001) but increased during dobutamine infusion compared to hypoxia (P < 0.017). In contrast, these slopes did not change during the rises in rMSSD and pNN50 elicited by phenylephrine (P > 0.7).
Conclusion: Beta-adrenergic stimulation induces comparable increases in the QT/RR slopes than hypoxia, but in the presence of a larger cardiac vagal activity. Vagal cardiac activation by phenylephrine does not change the QT slopes. This reveals that the sympathetic system is an important determinant of QT/RR dynamicity in healthy men.     

Perioperative chemotherapy with bevacizumab and liver resection for colorectal cancer liver metastasis

Background:

Surgery remains the only curative option for patients with colorectal cancer liver metastases (CRLM). Perioperative chemotherapeutic strategies have become increasingly popular in the treatment of CRLM. Although the role of bevacizumab (Bev) in this setting remains unclear, its widespread use has raised concerns about the use of Bev as part of perioperative chemotherapy.

Methods:

We retrospectively reviewed all patients who received Bev and underwent liver resection between July 2004 and July 2008 at the McGill University Health Center. Chemotherapy-related toxicity, response to chemotherapy, surgical morbidity and mortality, liver function and survival data were assessed.

Results:

A total of 35 patients were identified. Of these, 26 (74.3%) patients received oxaliplatin-based cytotoxic chemotherapy, six (17.1%) received irinotecan-based therapy and the remainder received both agents. A total of 17 patients (48.6%) underwent portal vein embolization prior to resection and 12 (34.3%) underwent staged resection for extensive bilobar disease. A median of six cycles of preoperative Bev were administered. Nine patients (25.7%) experienced grade 3 or higher chemotherapy-related toxicities. Four events were deemed to be related to Bev. The overall response rate was 65.7% (complete and partial response). One patient progressed on therapy, but this did not prevent R0 resection. The incidence of postoperative morbidity was 42.3%. A total of 21.7% of complications were Clavien grade 3 or higher. There were no perioperative mortalities. There were no cases of severe sinusoidal injury or steatohepatitis. The Kaplan–Meier estimate of 4-year survival was 52.5%.

Conclusions:

These data confirm the safety of chemotherapy regimens which include Bev in the perioperative setting and demonstrate that such perioperative chemotherapy in patients with CRLM does not adversely affect patient outcome. There was no increase in perioperative morbidity compared with published rates. The addition of Bev to standard chemotherapy may improve response rates, which may, in turn, impact favourably on patient survival.