The nasal hinge.

It is generally agreed that rhinoplasty is the most challenging procedure performed by the facial plastic surgeon. Mastery of nasal tip maneuvers to alter tip projection, rotation, and lobule refinement is intrinsic to successful rhinoplasty technique. The nasal hinge region comprises the most lateral aspect of the lower lateral cartilage.

Acute pancreatitis after ifosfamide therapy.

Acute pancreatitis is an uncommon but serious complication of cancer chemotherapy. A 16-year-old girl with metastatic osteosarcoma experienced recurrent bouts of symptomatic pancreatitis 24 hours after treatment with ifosfamide administered as a single agent. To the authors' knowledge, this is the first report of an association between ifosfamide and pancreatitis.

Unexpected interaction between beta-adrenergic blockade and heart rate variability before and after myocardial infarction. A longitudinal study in dogs at high and low risk for sudden death.

Background: Heart rate (HR) variability is a marker of tonic cardiac autonomic activity and contributes in assessing risk for sudden death after myocardial infarction. Recent clinical observations have indicated that attenuation of HR variability, which occurs after myocardial infarction, may be transient. This study addresses the issue of whether autonomic control of heart rate recovers at different rates after myocardial infarction in subjects at high and low risk for ventricular fibrillation (VF).

Vertical dome division in open rhinoplasty. An update on indications, techniques, and results.

Objective: A new modification of vertical dome division (VDD) in rhinoplasty using cartilage overlap and suturing to reestablish the integrity of the alar cartilages is analyzed and compared with the more standard technique of cartilage resection and suturing.

Design: Retrospective before-and-after trial.

Setting: Private patients of one of the authors (P.

Baroreflex sensitivity: methods, mechanisms, and prognostic value.

A large bulk of data collected over the last 25 years links reflex autonomic activation during acute myocardial ischemia with risk of developing lethal arrhythmias. Specifically, evidence obtained in an experimental preparation in chronically infarcted dogs supported the concept that sympathetic hyperactivity enhances likelihood for ventricular tachyarrhythmias, vagal activation exerts protective effects. Based on this knowledge, it was first proposed by our group that analysis of autonomic control of heart rate could provide information relevant to risk stratification in post-myocardial infarction individuals.

Exercise training confers anticipatory protection from sudden death during acute myocardial ischemia.

Seven conscious dogs documented to be at high risk by the occurrence of ventricular fibrillation (VF) during acute myocardial ischemia were randomly assigned to 6 weeks of either daily exercise training or cage rest followed by exercise training. After 6 weeks of daily treadmill training, heart rate variability, a marker of vagal tone, increased by 74% (P < .001); baroreflex sensitivity, a marker of the capability to reflexly augment vagal activity, increased by 69% (P < .

The Kirschner wire guide.

The Kirschner wire guide is a useful means of introducing K-wires into the facial skeleton. It can be easily constructed in the maxillofacial laboratory and its use allows accurate positioning of K-wires, especially in fractures of the zygomatic complex.

Clinical and pharmacokinetic studies of all-trans-retinoic acid in pediatric patients with cancer.

This review will summarize the rationale for pursuing investigations into the use of retinoids for pediatric patients with cancer, describe the phase I results of all-trans-retinoic acid (ATRA) in children, and discuss the results of a series of preclinical and clinical pharmacokinetic studies of ATRA. The prognosis for children with advanced stage neuroblastoma, the most common extracranial solid tumor of childhood, has remained poor despite significant increases in the intensity of multi-modality therapy. Observations that neuroblastoma has the potential in vivo to differentiate into the more mature neuronal phenotype of a ganglioneuroma or to spontaneously regress, combined with the ability of ATRA to induce differentiation of neuroblastoma cell lines in vitro, suggests that neuroblastoma may be a prime candidate for a retinoid-based approach to differentiation therapy.

Desulfuration of 6-mercaptopurine. The basis for the paradoxical cytotoxicity of thiopurines in cultured human leukemic cells.

The thiopurines have a wide array of effects on purine metabolism, but the primary mechanism of cytotoxicity for both 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) appears to be incorporation of drug into DNA following conversion to the thioguanylate form. In murine leukemic cell lines exposed to a range of thiopurine concentrations in vitro, cell survival curves have displayed a phenomenon termed paradoxical cytotoxicity, defined as a decrease in cytotoxicity with increasing drug concentration. The paradoxical cytotoxicity of thiopurines has usually been attributed to concentration-dependent perturbations in the cell cycle.

Pertussis toxin-induced ADP ribosylation of inhibitor G proteins alters vagal control of heart rate in vivo.

Prior studies have shown that in vivo systemic administration of pertussis toxin in conscious dogs catalyzes ADP ribosylation of Gi and G(o) proteins, which attenuates intracellular transduction of muscarinic receptor activation. We tested the hypothesis that this impairment may result in the alteration of the following indexes of cardiac vagal activity: baroreflex sensitivity and heart rate variability. Heart rates during submaximal exercise were also determined.

Cellular responses regulated by rho-related small GTP-binding proteins.

Rho-related proteins are members of the ras superfamily of small GTP-binding proteins. Their function in fibroblasts has been analysed using microinjection of living cells. Rho appears to link plasma membrane receptors to the assembly of focal adhesions and actin stress fibres.

Variability in the oral bioavailability of all-trans-retinoic acid.

Background: Orally administered all-trans-retinoic acid (all-trans-RA) can induce complete remission in a high proportion of patients with acute promyelocytic leukemia. A previous pharmacokinetic study in patients with acute promyelocytic leukemia raised the possibility that the absorption of orally administered all-trans-RA is a saturable process that would have significant clinical impact on dosing strategies.

Purpose: This study was specifically designed to examine the saturability of all-trans-RA absorption by measuring the effect of doubling the oral dose of all-trans-RA on plasma drug concentration in patients receiving long-term oral therapy.

Mechanism of resistance to cyclopentenyl cytosine (CPE-C) in Molt-4 lymphoblasts.

Cyclopentenyl cytosine (CPE-C), a carbocyclic analogue of cytidine, has preclinical antineoplastic activity against ara-C resistant murine leukemias and a broad spectrum of human tumor xenografts. CPE-C is a prodrug and requires intracellular phosphorylation to cyclopentenyl cytosine triphosphate (CPE-CTP) which depletes endogenous CTP pools. The initial step in this activation process is catalyzed by uridine/cytidine kinase.

Open structure rhinoplasty.

Open structure rhinoplasty (OSR) uses the open or external approach via a mid-columellar and bilateral marginal incision. In combination with grafting procedures, such as columellar struts, dorsal grafts and tip grafts, rhinoplasty has developed from a merely reductive procedure to a more graduated approach to the nose. Emphasis is now placed on repositioning, augmentation and restructuring the nasal anatomy to create as natural and functional a nose as possible.

Time course of induction of metabolism of all-trans-retinoic acid and the up-regulation of cellular retinoic acid-binding protein.

A study of chronic i.v. dosing of all-trans-retinoic acid (all-trans-RA) was performed to determine whether induction of the capacity-limited elimination process for all-trans-RA occurred with long-term drug administration.

Phase I and pharmacokinetic evaluation of all-trans-retinoic acid in pediatric patients with cancer.

Purpose: Recent reports of the dramatic antitumor effect of all-trans-retinoic acid (RA) in patients with acute promyelocytic leukemia (APL) have renewed interest in the oncologic indications for retinoids. Furthermore, a variety of pediatric tumors are responsive to RA in vitro, which provides additional rationale for a phase I evaluation of RA in children with cancer that is refractory to standard therapy.

Patients And Methods: A phase I trial of RA administered orally twice daily for 28-day treatment courses was performed.

Intracellular localization of the P21rho proteins.

The three mammalian ras proteins associated specifically with the plasma membrane and this is essential for their biological activity. Two signals encoded within the extreme COOH terminus of the proteins specify this cellular localization; a CAAX box in combination with either a polybasic domain (p21K-rasB) or a palmitoylation site (p21Ha-ras and p21N-ras). All members of the ras-like and rho-like subfamilies of the ras superfamily of small GTP-binding proteins also have CAAX boxes with potential second site sequences resembling either p21K-rasB or P21N-ras/Ha-ras.

Post-translational modifications of p21rho proteins.

Post-translational modifications of the ras proteins, which are required for plasma membrane localization and biological function of the proteins, have been shown to include prenylation and carboxymethylation at the carboxyl terminal cysteine residue of the cysteine-aliphatic amino acid-aliphatic amino acid-any amino acid (CAAX) box. In addition, p21Ha-ras and p21N-ras, but not p21K-ras (B), are palmitoylated. The three mammalian rho proteins (A, B, and C) are also members of the ras superfamily but have distinct biological activities and different intracellular distributions from p21ras.

Dose-dependent pharmacokinetics of all-trans-retinoic acid.

Background: Orally administered all-trans-retinoic acid (all-trans-RA) can induce remission in a high proportion of patients with acute promyelocytic leukemia.

Purpose: To further define the drug's pharmacokinetics, a study of intravenous all-trans-RA was performed in rhesus monkeys.

Methods: A total of nine monkeys received intravenous bolus injections of all-trans-RA.

Methotrexate pharmacokinetics following administration of recombinant carboxypeptidase-G2 in rhesus monkeys.

Purpose: Carboxypeptidase-G2 (CPDG2) is a bacterial enzyme that rapidly hydrolyzes methotrexate (MTX) into inactive metabolites. As an alternative form of rescue after high-dose MTX (HDMTX), CPDG2 has more potential advantages than standard leucovorin (LV) rescue. In this study, the plasma pharmacokinetics of MTX with and without CPDG2 were evaluated in adult rhesus monkeys.

Modulation of the cytotoxic effect of cyclopentenylcytosine by its primary metabolite, cyclopentenyluridine.

Cyclopentenylcytosine (CPE-C), a synthetic cytidine analogue with significant preclinical antitumor activity against both solid tumor xenografts and 1-beta-D-arabinofuranosylcytosine resistant murine leukemia cell lines, will soon enter phase I clinical trials. Unlike 1-beta-D-arabinofuranosylcytosine which is activated by deoxycytidine kinase, the enzyme responsible for the phosphorylation of CPE-C is uridine/cytidine kinase. Preclinical pharmacokinetic studies of CPE-C in nonhuman primates revealed that the primary route of elimination in this species was deamination to cyclopentenyluridine (CPE-U), an inhibitor of uridine/cytidine kinase.