Analgesic doses of fentanyl impair oxidative metabolism of neonatal hepatocytes

BACKGROUND/PURPOSE: Studies in human surgical neonates have shown that intraoperative fentanyl analgesia results in greater fall in perioperative body core temperature compared with morphine analgesia. The aim of the study was to compare in a neonatal animal model the biochemical effect of fentanyl and morphine on hepatocyte oxidative metabolism. METHODS: Hepatocytes were isolated from suckling rats and the oxygen consumption from palmitate was measured polarographically. In experiment A, fentanyl and morphine within the respective analgesic serum ranges were added to hepatocytes to assess the effect on oxygen consumption. In experiment B, fentanyl was added to hepatocytes in the presence of inhibitors of mitochondrial respiration to investigate its site of action. In experiment C, hepatocytes were incubated with either fentanyl or morphine, centrifuged, and then examined ultrastructurally by electron microscopy. RESULTS: In experiment A, fentanyl inhibited oxygen consumption by up to 40% (P < .01). Morphine inhibited oxygen consumption to a maximum of 25% (P < .01). In experiment B, in the presence of oligomycin, fentanyl increased the inhibition of oxygen consumption; however, in the presence of myxothiazol, no further inhibition by fentanyl occurred. In experiment C, mild ultrastructural alterations to hepatocytes were observed after incubation with fentanyl but not with morphine. CONCLUSIONS: This study demonstrates that therapeutic doses of two commonly used analgesic drugs impair neonatal hepatic oxidative metabolism. Fentanyl exerts a greater effect than morphine by diminishing liver oxygen consumption by up to 40%. The inhibitory effect of fentanyl occurs directly on the mitochondrial respiratory chain, either on substrate oxidation or on the thermogenic proton leak. The findings of this study are relevant to the perioperative management of surgical neonates.     

Adjuvant and neoadjuvant chemoradiation therapy for primary colorectal cancer

The management of rectal cancer presents substantial challenges. Patients with T3 and/or node-positive rectal cancers are at high risk for local failure and distant metastases (DM). Adjuvant radiation has been shown to decrease local recurrence (LR) rates; however, this local therapy has not been demonstrated to improve survival when compared to surgery alone. In several prospective randomized trials adjuvant chemoradiation with 5-fluorouracil-(5-FU)-based chemotherapy improved LR rates, DM rates, and overall survival (OS). The optimal chemotherapeutic regimen has not been determined; however, studies comparing standard IV bolus 5-FU administration with continuous infusion (CI) 5-FU demonstrated that CI administration was superior. Preoperative therapy has potential advantages over adjuvant therapy such as less acute bowel toxicity and improved sphincter preservation. Preoperative chemoradiation has been shown in several studies to improve LR rates and OS when compared to surgery alone. Our current approach to patients with resectable T3 or N1 cancer in the distal two-thirds of the rectum on preoperative staging is preoperative chemoradiation with planned postoperative chemotherapy. This regimen offers the best chance for local control and disease-free survival while potentially downstaging the tumor and improving sphincter preservation.     

Untersuchung zur Kategorisierung des mandibulären Wachstumspotentials von Petrovic,Lavergne und Stutzmann

Zusammenassung In der vorliegenden Studie sollte untersucht werden, ob die vonPetrovic, Lavergne undStutzmann vorgeschlagene Kategorisierung des mandibulären Wachstumspotentials für die Behandlung mit dem Funktionsregler Geltung hat. Dazu wurden die Fernröntgenaufnahmen von 140 Patienten der Angle-Klasse II nach zirka zweijähriger Behandlung mit Funktionsreglern analysiert. Im Vergleich zu 133 unbehandelten Kindern mit Angle-Klasse II trat in fast allen Rotationsgruppen eine signifikant größere Zunahme der Unterkiefergesamtlänge ein. Zwischen der Kategorie 2 mit niedrigem Wachstumpotential und Kategorie 5 mit hohem Wachstumspotential wurden keine signifikant unterschiedlichen Zunahmen der Unterkieferlänge festgestellt.

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Summary The results of the study show whether the classification of mandibular growth potential, as proposed by Petrovic, Lavergne and Stutzmann has any influence on the treatment with a function regulator. X-rays of 140 class II patients were analysed after a treatment time of approximately 2 years. In comparison with 133 class II children without any treatment, a significant increase of the overall mandibular length was observed in almost all children treated. There was no significant difference in the increase of mandibular length between category 2 (low growth potential) and category 5 (high growth potential).

     

Deletions in chromosome arms 3p and 11q are new prognostic markers in localized and 4s neuroblastoma.

PURPOSE: To find new nonrandom chromosomal changes in neuroblastoma (NB) with a potential to forecast the patient's outcome, alterations in chromosome arms 3p and 11q were investigated. EXPERIMENTAL DESIGN: Frequency and prognostic potential of 3p and 11q alterations in 144 NBs were analyzed using interphase fluorescence in situ hybridization with DNA probes for 3p26 and 11q23. Aberrations were defined as deletion (monosomy of a specific region) or imbalance (at least two intact and additional 3p26- or 11q23-deleted chromosomes). RESULTS: Forty-two of 144 cases (29%) displayed 11q alterations (21% deletions, 8% imbalances). Most aberrations were associated with stage 4 disease (28 of 59, 47%) but were also present in localized and 4s tumors (14 of 85, 16%; P = 0.007). Patients with 11q deletion/imbalance were significantly older at diagnosis (P < 0.001). Changes in 3p were detected in 26 of 144 (18%) samples (15% deletions, 3% imbalances). These alterations were also associated with stage 4 [20 of 59 (34%) versus 6 of 85 (7%) in stages 1-3 and 4s, P = 0.007], and the median age was increased (P < 0.001). Aberrations in both chromosomes were highly associated with each other (P < 0.001). MYCN amplification (MNA) was detected in 10% and 12% of tumors with 11q and 3p alterations, and changes in 1p36 occurred in 13% and 26% of the 3p- and 11q-aberrant tumors. MYCN amplification and 11q deletion/imbalance tended to show an inverse correlation (P = 0.07) as well as 1p and 3p deletion/imbalance (P = 0.07). Patients with 3p and 11q abnormalities in localized/4s tumors showed an inferior outcome compared with those without these alterations (P = 0.002 and P = 0.0027, respectively), in particular in MYCN single copy tumors (P < 0.0001 and P = 0.0006, respectively). CONCLUSION: Alterations in 3p and 11q are frequent nonrandom aberrations in NB and define a new high-risk subgroup in MYCN single copy stage 1-3 and 4s disease.     

Dietary folate intake and lung cancer risk in former smokers: a case-control analysis.

No studies have focused on the role of dietary folate intake in risk of lung cancer in former smokers, in whom dietary folate intake is less likely confounded with current smoking. Therefore, we evaluated the association between dietary folate intake and risk of lung cancer in a population of 470 histopathologically confirmed incident lung cancer cases from M. D. Anderson Cancer Center and 472 cancer-free controls from enrollees at a community-based multispecialty physician practice, frequency-matched on age (5 years), sex, and ethnicity. Dietary folate intake levels were estimated from a National Cancer Institute standard food frequency questionnaire. Unconditional logistic regression analyses were used to calculate the crude and adjusted ORs and their 95% CIs. Dietary folate intake from natural food was significantly higher among the controls than among the cases (P < 0.001), and folate intake above the control median value was associated with a 40% decreased risk of lung cancer (adjusted OR, 0.60; 95% CI, 0.45-0.79). A significant inverse dose-response relationship between increasing dietary folate and decreasing risk of lung cancer was also evident (adjusted OR, 1.02; 95% CI, 0.71-1.47; OR, 0.67; 95% CI, 0.46-0.99; and OR, 0.53; 95% CI, 0.35-0.80 for the second, third, and fourth quartiles of average folate intake, respectively; P for trend <0.001). A more pronounced inverse association between dietary folate intake and lung cancer risk was observed among subjects who drank alcohol, had smoked relatively more, those who did not take supplemental folate, and those who reported a family history of lung cancer. Our data suggest that there is a possible protective role of dietary folate in lung carcinogenesis, a finding which may have implications in public health and cancer prevention.     

Treatment of hypogonadal adolescent boys with long acting subcutaneous testosterone pellets

AIMS: Long acting subcutaneous testosterone pellets are of proved efficacy for the treatment of hypogonadal men, but have not been reported as a treatment modality in adolescent boys. Pharmacodynamic studies of subcutaneous testosterone release have shown prolonged normalisation of testosterone levels for at least four months. Administration of a long acting, safe, effective, and convenient form of treatment is desirable when life-long treatment is indicated. PATIENTS AND METHODS: Eighteen boys (aged 13.9-17.5 years at the start of treatment)-seven with primary hypogonadism, nine with secondary hypogonadism, and two boys being treated with testosterone for tall stature--were given testosterone pellets (8-10 mg/kg) every six months for 18 months. Height, weight, pubertal status, and psychosocial parameters were assessed and follicle stimulating hormone, luteinising hormone, testosterone, prolactin, and lipids were measured at 0, 1, 3, 6, 12, and 18 months. Bone age was measured at 0 and 12 months. RESULTS: In all boys growth velocity continued appropriately for bone age. Puberty continued to progress in all boys and in two boys the amount of virilisation exceeded that seen with previous treatment with intramuscular testosterone. After testosterone administration, follicle stimulating hormone and luteinising hormone suppressed incompletely in the boys with primary hypogonadism. Serum testosterone ranged from 4.3 to 26.7 nmol/l at three months to less than 10 nmol/l at six months after implantation. Prolactin and lipid levels were normal throughout the study. By report, there was an improvement in mood and emotional wellbeing. No pellet extrusions occurred in a total of 156 pellet insertions. CONCLUSIONS: All boys preferred this mode of testosterone administration to intramuscular injections. Long acting subcutaneous testosterone pellets are safe, efficacious, well tolerated, and convenient, and result in normal physical growth and improved psychological outlook in adolescent hypogonadal boys.     

Polymorphisms in the glutathione S-transferase class mu and theta genes interact and increase susceptibility to lung cancer in minority populations (Texas, United States)

The genes coding for separate isoforms of both the human glutathioneS-transferase class mu and class theta enzymes (GSTM1and GSTT1) arepolymorphic with a variable ethnic distribution. These enzymes detoxifyreactive epoxides, including carcinogens produced by tobacco smoke. Becauseof this, the null polymorphism in the GSTM1 gene (coding for the glutathioneS-transferase class mu enzyme) has been studied widely as a possible sourceof inherited susceptibility to smoking-related lung cancer. The more recentlydescribed null polymorphism in the GSTT1 gene also could contribute to anincreased risk of smoking-related lung cancer. As the incidence of lungcancer is known to differ by ethnicity, we have conducted a case-controlstudy in the United States of 108 African-Americans (Blacks) and 60Mexican-Americans (Hispanics) with lung cancer and 132 African-American(Black) and 146 Mexican-American (Hispanic) controls to investigate theassociation of the GSTT1 and GSTM1 polymorphi sms with lung cancer inminority populations. In the unadjusted data, there was a borderlinesignificant association of the GSTM1 null polymorphism with lung cancer inMexican-Americans (odds ratio [OR] = 1.8, 95 percent confidence interval [CI]= 1.0-3.3 ) that was not observed in African-Americans. The GSTT1 nullpolymorphism also had a higher prevalence in cases than controls in bothracial/ethnic groups, but this increase was not statistically significant.When the data were analyzed using logistic regression controlling for age,gender, race, and smoking, no significant association of either trait withlung cancer was observed, with ORs for both traits of approximately 1.3.However, when the prevalence of individuals who were null for bothpolymorphisms was compared by case status, a significant interaction wasobserved. Logistic regression models showed the OR for the association oflung cancer and the presence of both null polymorphisms compared with one(either GSTT1 or GSTM1) or no null genotype to be 2.9 (P < 0.04). Theseresults suggest that there may be carcinogenic intermediates in cigarettesmoke that are substrates for both the GSTT1 and GSTM1 enzymes, and that lungcancer risk is increased more than additively for individuals who have bothGSTT1 and GSTM1 null polymorphisms.     

Median nerve compression in Proteus syndrome

Proteus syndrome is a multi–organ disorder, a prime feature of which is localized gigantism, usually clinically obvious. Symptoms secondary to hypertrophy of nerves has not been previously recognized as a part of the syndrome. Accepted: 16 May 1997