Oral mucosal melanoma in situ: a case report and review of the literature.

Oral mucosal melanoma is a rare presentation of malignant melanoma with a 5-year survival rate of only 15%. Oral mucosal melanoma in situ (OMMIS) is its assumed precursor. This report describes one of only 20 documented cases of OMMIS and outlines how early clinical recognition resulted in prompt histopathological diagnosis and subsequent complete surgical excision. A literature review of existing reported cases, their management, and latest outcomes was also performed, highlighting this rare condition for consideration in the differential diagnosis of pigmented oral pathologies.

Complete spontaneous regression of a metastatic melanoma of the mandible: a case report and follow-up recommendations.

Regression of metastatic melanoma is very rare and occurs in only 0.23% of cases. Metastasis to the oral cavity is particularly uncommon and accounts for only 1-3% of all oral malignancies. This report presents a case of spontaneous and complete regression of a metastatic melanoma in the mandibular ramus. The patient remains asymptomatic more than 2 years after diagnosis. The patient was followed up regularly. It is recommended that further surveillance imaging be performed in asymptomatic patients following discussion with the surgical and oncological teams. This type of surveillance, together with new systemic treatments, is advocated due to its potential to increase long-term survival even after relapse.

Changes in mediators of inflammation and pro-thrombosis after 12 months of dietary modification in adults with metabolic syndrome.

OBJECTIVE: This study evaluated the effects of a 12-month dietary modification on indices of inflammation and pro-thrombosis in adults with metabolic syndrome (MS). MATERIALS AND METHODS: This longitudinal study involved 252 adults with MS recruited from the Bodija market, Ibadan and its environs. Participants were placed on 20%, 30% and 50% calories obtained from protein, total fat and carbohydrate respectively and were followed up monthly for 12 months. Anthropometry and blood pressure were measured using standard methods. Fasting plasma glucose (FPG), total cholesterol (TC), triglycerides (TG), high density lipoprotein-cholesterol (HDL-C), fibrinogen, plasminogen activator inhibitor-1 (PAI-1)], interleukin-6 (IL-6) and interleukin-10 (IL-10) were measured using spectrophotometric methods and ELISA as appropriate. Data was analysed using ANCOVA, Student's t-test, Mann-Whitney U and Wilcoxon signed-rank tests. P-values less than 0.05 were considered significant. RESULTS: After 6 months of dietary modification, there was a significant reduction in waist circumference (WC), while the levels of HDL-C, fibrinogen and PAI-1 were significantly increased when compared with the corresponding baseline values. However, WC and fibrinogen reduced significantly, while HDL-C and IL-10 significantly increased after 12 months of dietary modification as compared with the respective baseline values. CONCLUSION: Long-term regular dietary modification may be beneficial in ameliorating inflammation and pro-thrombosis in metabolic syndrome.

Anatomy of the vasculature of the lower leg and harvest of a fibular flap: a systematic review.

The fibular free flap (FFF) is based on the peroneal artery, which has a consistent anatomy and makes a minimal contribution to the pedal circulation. However, certain anatomical variations in the vasculature of the leg might leave the peroneal artery with a major role in the perfusion of the foot, and to raise a FFF could lead to ischaemic complications. Our aim was to review the implications of anatomical variants on planning and harvest of a FFF. We systematically reviewed all relevant publications, and included 28 cases that described a dominant peroneal artery and FFF. Most of the patients had clinically normal pulses, and the dominant peroneal artery was diagnosed by preoperative vascular mapping. Variants of the peronea arteria magna were the most common. Bilateral anatomical variations were reported in 10 cases. The surgical plan to harvest the fibula was altered in 21 patients with vascular aberrations. In 17 of the 21, the leg with the anatomical variant was not used. The opposite fibula was used in 10 cases. In four of the 21, the FFF was harvested from the leg with a dominant peroneal artery, after the technique of harvest had been modified. The FFF was successfully harvested without any modification in only five cases. Two patients who had not had preoperative vascular mapping developed acute ischaemia of the limb after harvest of the FFF because of an existing peronea arteria magna. Preoperative vascular mapping is a valuable way to assess that perfusion of the foot is adequate, and it provides accurate information about the vascular anatomy, cutaneous perforators, and the fibular blood supply, with minimal or no added cost or risks.

Neuroprotective effects of kolaviron against psycho-emotional stress induced oxidative brain injury in rats: The whisker removal model.

BACKGROUND: The study investigated the neuroprotective potentials of kolaviron (a biflavonoid complex of Garcinia kola) against psycho-emotional stress induced oxidative brain injury in Wistar rats. METHODS: Twenty-four adult Wistar rats (180-220g) randomly divided into four groups (1-1V,n=6) were used for the study . Group 1 served as control (non stressed), group 11 consisted of stressed rats induced by complete removal' of the whiskers around the mouth and the nose without anaesthesia. The rats in group 111 were pre- treated with 200mg/kg kolaviron per oral (p.o), daily for seven days before being subjected to the stress procedure' while group 1V rats also had 200mg/kg oral kolaviron alone without being stressed. The animals were later euthanized by cervical dislocation, cerebellum and frontal cortex removed and then subjected to biochemical and histopathological analysis. RESULTS: Whisker removal significantly(p<0.05) increased lipid peroxidation (U/mg protein) in the cerebellum (3.82±0.22 vs 6.50±0.41) and the cerebral cortex (14.57±2.50 vs 30.11± 4.70) compared with their controls, it also produced significant reductions 'in catalase activities (U/min/mg protein) in cerebellum (169.65±11.02 vs 87.72, p <0.001) and the cerebral cortex (264.5 ± 40.57 vs 122.71 ± 15.70,p< 0.001). Glutathione levels (U/mg protein) were similarly significantly (P<0.001) reduced in both cerebellum (132.40 ± 4.81 vs 37.60 ± 1.50) and the cerebral cortex (370.42 ±20.51 vs 120.51± 25.35) compared with their corresponding controls. There were also histological abnormalities like cellular degeneration and necrosis in both the frontal cortex and the cerebellum of the stressed rats. Pre- treatment with kolaviron not only reversed these biochemical alterations but also significantly attenuated these observed histopathological changes. CONCLUSION: The present study demonstrated the neuroprotective potential of kolaviron against psycho-emotional stress-induced oxidative brain injury through the inhibition of oxidative stress.

WITHDRAWN: Can depth of invasion of pT1 carcinoma of the oral tongue predict occult metastases in the neck? A retrospective study.

This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.

Population pharmacokinetics-pharmacodynamics of vedolizumab in patients with ulcerative colitis and Crohn's disease.

BACKGROUND: Vedolizumab, an anti-α(4)ß(7) integrin monoclonal antibody (mAb), is indicated for treating patients with moderately to severely active ulcerative colitis (UC) and Crohn's disease (CD). As higher therapeutic mAb concentrations have been associated with greater efficacy in inflammatory bowel disease, understanding determinants of vedolizumab clearance may help to optimise dosing. AIMS: To characterise vedolizumab pharmacokinetics in patients with UC and CD, to identify clinically relevant determinants of vedolizumab clearance, and to describe the pharmacokinetic-pharmacodynamic relationship using population modelling. METHODS: Data from a phase 1 healthy volunteer study, a phase 2 UC study, and 3 phase 3 UC/CD studies were included. Population pharmacokinetic analysis for repeated measures was conducted using nonlinear mixed effects modelling. Results from the base model, developed using extensive phase 1 and 2 data, were used to develop the full covariate model, which was fit to sparse phase 3 data. RESULTS: Vedolizumab pharmacokinetics was described by a 2-compartment model with parallel linear and nonlinear elimination. Using reference covariate values, linear elimination half-life of vedolizumab was 25.5 days; linear clearance (CL(L)) was 0.159 L/day for UC and 0.155 L/day for CD; central compartment volume of distribution (V(c)) was 3.19 L; and peripheral compartment volume of distribution was 1.66 L. Interindividual variabilities (%CV) were 35% for CLL and 19% for V(c); residual variance was 24%. Only extreme albumin and body weight values were identified as potential clinically important predictors of CL(L). CONCLUSIONS: Population pharmacokinetic parameters were similar in patients with moderately to severely active UC and CD. This analysis supports use of vedolizumab fixed dosing in these patients. Clinicaltrials.gov Identifiers: NCT01177228; NCT00783718 (GEMINI 1); NCT00783692 (GEMINI 2); NCT01224171 (GEMINI 3).

Bilateral ankylosis of the jaw treated with total alloplastic replacement using the TMJ concepts system in a patient with ankylosing spondylitis.

Minimal documentation exists regarding bilateral temporomandibular joint (TMJ) involvement in ankylosing spondylitis (AS) and surgical management of this specific manifestation. Use of TMJ concepts prostheses in AS patients has not been previously described. This case demonstrates that TMJ replacement with prosthetic joints in AS is technically possible and appropriate.

Quinacrine induces cytochrome c-dependent apoptotic signaling in human cervical carcinoma cells.

Quinacrine (QU), a phospholipase-A2 (PLA-2) inhibitor has been used clinically as a chemotherapeutic adjuvant. To understand the mechanisms leading to its chemotherapeutic effect, we have investigated QU-induced apoptotic signaling pathways in human cervical squamous carcinoma HeLa cells. In this study, we found that QU induced cytochrome c-dependent apoptotic signaling. The release of pro-apoptotic cytochrome c was QU concentration- and time-dependent, and preceded activation of caspase-9 and -3. Flow cytometric FACScan analysis using fluorescence intensities of DiOC6 demonstrated that QU-induced cytochrome c release was independent of mitochondrial permeability transition (MPT), since the concentrations of QU that induced cytochrome c release did not alter mitochondrial membrane potential (delta pai(m)). Moreover, kinetic analysis of caspase activities showed that cytochrome c release led to the activation of caspase-9 and downstream death effector, caspase-3. Caspase-3 inhibitor (Ac-DEVD-CHO) partially blocked QU-induced apoptosis, suggesting the importance of caspase-3 in this apoptotic signaling mechanism. Supplementation with arachidonic acid (AA) sustained caspase-3 activation induced by QU. Using inhibitors against cellular arachidonate metabolism of lipooxygenase (Nordihydroxyguaiaretic Acid, NDGA) and cyclooxygenase (5,8,11,14-Eicosatetraynoic Acid, ETYA) demonstrated that QU-induced apoptotic signaling may be dependent on its role as a PLA-2 inhibitor. Interestingly, NDGA attenuated QU-induced cytochrome c release, caspase activity as well as apoptotic cell death. The blockade of cytochrome c release by NDGA was much more effective than that attained with cyclosporin A (CsA), a MPT inhibitor. ETYA was not effective in blocking cytochrome c release, except under very high concentrations. Caspase inhibitor z-VAD blocked the release of cytochrome c suggesting that this signaling event is caspase dependent, and caspase-8 activation may be upstream of the mitochondrial events. In summary, we report that QU induced cytochrome c-dependent apoptotic signaling cascade, which may be dependent on its role as a PLA-2 inhibitor. This apoptotic mechanism induced by QU may contribute to its known chemotherapeutic effects.

Ameloblastoma--a diagnostic problem.

A 50-year-old female was referred by her dental practitioner. She had a periapical radiolucency associated with the lower right second premolar tooth. The tooth was root treated and subsequently apicected. Tissue curetted at the time of surgery was shown to be a solid ameloblastoma which was managed initially by marginal excision. Histopathological examination of the resection specimen demonstrated tumour at the inferior margin. A segmental resection of the mandible with an immediate reconstruction using a free tissue transfer of the iliac crest was therefore performed. The case shows the need for vigilance in dealing with periapical pathology and underlines the importance of sending all tissue specimens for histopathological analysis.

Effects of adrenoceptor blockers on the glycemic response to nicotine in thyroidectomised rats.

The effect of adrenoceptor blockers on nicotine induced hyperglycemia were studied in fasted normal and thyroidectomised rats. Blood glucose was estimated using the modified glucose oxidase method. The control experiments consisted of sham operated rats with intact thyroid glands. Pre-treatment of the rats with either the alpha adrenoceptor blocker prazosin or the beta adrenoceptor blocker propranolol before intravenous injection of nicotine (50 micrograms/kg) significantly reduced the hyperglycemia induced by nicotine in normal rats, while a combination of propranolol and prazosin abolished nicotine induced hyperglycemia. In the thyroidectomised group, nicotine also caused hyperglycemia. However, the basal glucose level and peak of glycemic response were lowered compared to that in the control group. The results therefore seem to suggest that both alpha and beta adrenoceptors are involved in nicotine-induced hyperglycemia in the rat.

Erythrocyte osmotic fragility in hypertension and during diuretic therapy.

To determine the effect of diuretic therapy on osmotic fragility of red blood cells of hypertensive patients, 25 hypertensive and 15 normotensive subjects were followed up for 12 weeks. Osmotic fragility of erythrocytes of the hypertensive subjects were determined before treatment and at 6 weeks and 12 weeks after the start of diuretic therapy. The red cell size was larger in hypertensive subjects than in normal controls. With treatment, however, the red cell size was similar in the two groups of subjects. Osmotic fragility was higher in hypertensive subjects than in normotensive subjects. The osmotic fragility also became similar in the two groups with control of blood pressure in the hypertensive group. Osmotic fragility of red blood cells may be determined as a screening tool for hypertensive patients who will benefit from diuretic therapy.

Phase II trial of paclitaxel and topotecan with granulocyte colony-stimulating factor support in stage IV breast cancer.

PURPOSE: This multicenter phase II trial investigated the efficacy and safety of a combination of paclitaxel and topotecan in patients with pretreated metastatic breast cancer. Plasma levels of paclitaxel and topotecan were obtained during cycle 1 to correlate pharmacokinetic parameters with toxicity. PATIENTS AND METHODS: Paclitaxel was administered intravenously (i.v.) at 230 mg/m2 over 3 hours on day 1 followed by topotecan 1.0 mg/m2 i.v. over 30 minutes on days 1 to 5. Patients received an abbreviated premedication regimen that consisted of ranitidine 50 mg, diphenhydramine 50 mg, and a single 20-mg dose of dexamethasone, all administered i.v. 30 minutes before paclitaxel. Granulocyte colony-stimulating factor (GCSF) was administered at 5 micrograms/kg/d subcutaneously starting on day 6 and continuing until the absolute granulocyte count (AGC) was greater than 10,000/microL. Plasma paclitaxel and topotecan concentrations were assessed during the first cycle using limited-sampling strategies. RESULTS: Seventeen patients were treated. The majority had visceral metastases. Four patients experienced neutropenic fever and one had mild bronchospasm. Only one partial response (PR) was observed. Nadir AGC correlated strongly with both duration of paclitaxel levels greater than 0.05 mumol/L and maximum concentration (Cmax) of paclitaxel. CONCLUSION: This regimen does not produce a response rate superior to that expected with single-agent paclitaxel at doses that do not require growth factor support.

O6-benzylguanine in humans: metabolic, pharmacokinetic, and pharmacodynamic findings.

PURPOSE: O6-Benzylguanine is a potent inactivator of the DNA-repair protein, O6-alkylguanine-DNA alkyl-transferase (AGT), that enhances sensitivity to nitrosoureas in tumor-cell lines and tumor-bearing animals. The objective of this study was to determine the pharmacokinetics and metabolic fate of O6-Benzylguanine in humans and its effect on AGT activity in peripheral-blood mononuclear cells (PBMCs). PATIENTS AND METHODS: Twenty-five cancer patients were treated with O6-Benzylguanine at a dose level of 10, 20, 40, and 80 mg/m2 intravenously (IV) over 1 hour. Plasma and urine samples were collected and analyzed for O6-Benzylguanine and O6-Benzyl-8-oxoguanine concentrations. AGT activity in PBMCs was determined up to 2 weeks postinfusion. RESULTS: There was no toxicity attributable to O6-Benzylguanine alone at all doses tested. O6-Benzylguanine rapidly disappeared from plasma and was converted to a major metabolite, O6-Benzyl-8-oxoguanine. The half-life of O6-Benzyl-8-oxoguanine increased with dose from 2.8 to 9.2 hours at doses of 10 and 80 mg/m2, respectively. The maximum concentration Cmax and area under the concentration-time curve (AUC) for O6-Benzyl-8-oxoguanine were, respectively, 2.2- and 12- to 29-fold greater than those of O6-Benzylguanine. At all doses, depletion of AGT activity was observed in lymphocytes with a return to baseline by 1 week posttreatment. CONCLUSION: This study demonstrates that administration of O6-Benzylguanine to humans results in a rapid conversion to O6-Benzyl-8-oxoguanine, which follows nonlinear kinetics. Both compounds contribute to an effective depletion of AGT activity in lymphocytes; however, prolonged depletion of AGT activity is likely due primarily to the effect of O6-Benzyl-8-oxoguanine.

Phase I study of concomitant chemoradiotherapy with paclitaxel, fluorouracil, and hydroxyurea with granulocyte colony-stimulating factor support for patients with poor-prognosis cancer of the head and neck.

PURPOSE: We have previously demonstrated high locoregional control rates in patients with poor-prognosis head and neck cancer using fluorouracil (5-FU), hydroxyurea (HU), and concomitant radiotherapy (RT) (FHX). In the trial reported here, we added paclitaxel to the FHX base and used hyperfractionated RT to determine the maximum-tolerated dose (MTD), toxicities, and response rate in a poor-prognosis group of patients. METHODS: Fifty-five patients who had either failed to respond to prior RT (n = 25) or surgery, had a coexistent or prior second malignancy, or who had unresectable or metastatic disease and an expected 2-year survival rate less than 10%, were treated. Chemoradiotherapy consisted of 2 Gy on days 2 to 6 (once-daily RT cohorts) or 1.5 Gy twice a day (hyperfractionated cohorts). Simultaneous HU (500 or 1,000 mg twice per day for 11 doses) and infusional 5-FU (600-800 mg/m2/d for 5 days) were given along with infusional paclitaxel at escalating doses of 5 to 25 mg/m2/d for 5 days. Granulocyte colony-stimulating factor (G-CSF) was administered on days 7 through 13 at 5 microg/kg/d. Cycles were repeated every 14 days until completion of RT. Plasma paclitaxel levels were determined on day 4 of cycle 1. RESULTS: Dose-limiting toxicities (DLTs) consisted of myelosuppression, mucositis, dermatitis, and diarrhea. Plasma concentrations of paclitaxel greater than 10 nmol/L were achieved in 65% of patients at the recommended phase II dose (RPTD) level of paclitaxel. Seventy percent of assessable patients achieved a complete response (CR) to therapy. Twenty patients were treated at the RPTD of HU 500 mg orally twice daily for 11 doses, 5-FU 600 mg/m2/d by continuous infusion for 5 days; and paclitaxel 20 mg/m2/d by continuous infusion for 5 days, with twice-daily RT. CONCLUSION: The addition of infusional paclitaxel and hyperfractionated RT to FHX is feasible. Radiosensitizing levels of paclitaxel are achieved in most patients. The high locoregional control rate of this regimen justifies further investigation in previously untreated patients.

Effects of adrenoceptor blockers on the cardiorespiratory response to nicotine in rats.

Three groups of anaesthetized rats, consisting of 8 rats per group, were studied. Group 1 was the control and received intravenous injection of nicotine, 50 micrograms/kg, only. Groups II and III were pretreated with propranolol, 0.5mg/kg and prazosin, 1mg/kg respectively before 50 micrograms/kg of nicotine was injected i.v. Blood pressure, heart rate, respiratory rate and amplitude of respiratory excursion were monitored continuously before and for 1 hr after the injections. Index of Pulmonary Ventilation Rate was computed as a product of amplitude of respiratory excursion and respiratory rate. The results showed that nicotine caused an initial fall in blood pressure followed by a rise. The initial fall in blood pressure was abolished by prazosin, while propranolol abolished the pressor response. Nicotine had no effect on heart rate in the three groups. Nicotine caused an increase in respiratory rate and this effect was abolished by prazosin. Nicotine also caused an initial increase in pulmonary ventilation which was due mainly to increase in respiratory rate. It was concluded that nicotine exerts most of its cardiorespiratory effect via stimulation of alpha and beta adrenoceptors.

Effects of cows' urine concoction with and without tobacco leaves on plasma glucose concentration in fasted rats.

The effects of a full preparation (FP) and a modified preparation (MP) of cows' urine concoction (CUC) on the level of plasma glucose in fasted male Wistar rats were investigated. The results showed that FP caused significant hyperglycaemia; while the MP and a control injection using 0.9% saline had no effect on plasma glucose. Hexamethonium, prazosin, propranolol and combined prazosin and propranolol did not abolish the hyperglycaemic response to FP. The mechanism of the hyperglcaemic response to FP and the reason why MP did not produce hypoglycaemia are obscure. The result of this study did not agree with the findings of CUC-induced hypoglycaemia reported by earlier workers.