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1.  The Sinonasal Tract: Another Potential “Hot Spot” for Carcinomas with Transcriptionally-Active Human Papillomavirus 
Head and Neck Pathology  2013;8(3):241-249.
While high risk human papillomavirus (HPV) is well established as causative and clinically important for squamous cell carcinoma (SCC) of the oropharynx, its role in non-oropharyngeal head and neck SCC is much less clearly elucidated. In the sinonasal region, in particular, although it is a relatively uncommon site for SCC, as many as 20 % of SCC harbor transcriptionally-active high risk HPV. These tumors almost always have a nonkeratinizing morphology and may have a better prognosis. In addition, specific variants of SCC as well as other rare carcinoma types, when arising in the sinonasal tract, can harbor transcriptionally-active HPV. This article reviews the current literature on HPV in sinonasal carcinomas, attempts to more clearly demonstrate what tumors have it and how this relates to possible precursor lesions like inverted papilloma, and discusses the possible clinical ramifications of the presence of the virus.
PMCID: PMC4126925  PMID: 24338611
Human papillomavirus; Sinonasal; Nonkeratinizing; Squamous cell carcinoma; p16
2.  Kinin B2 Receptor Mediates Induction of Cyclooxygenase-2 and Is Over-Expressed In Head and Neck Squamous Cell Carcinomas 
Molecular cancer research : MCR  2008;6(12):1946-1956.
Bradykinin (BK) has been shown to promote growth and migration of head and neck squamous cell carcinoma (HNSCC) cells via epidermal growth factor receptor (EGFR) transactivation. It has also been reported that BK can cause the induction of cyclooxygenase-2 (COX-2), a pro-tumorigenic enzyme, via the MAPK (Mitogen-Activated Protein Kinase) pathway in human airway cells. To determine whether COX-2 is up-regulated by BK in HNSCC, the current study investigated BK- induced EGFR transactivation, MAPK activation, and cyclooxygenase-2 (COX-2) expression in human HNSCC cells. BK induced a concentration- and time-dependent induction of COX-2 protein in HNSCC, which was preceded by phosphorylation of EGFR and MAPK. These effects were abolished by the B2 receptor (B2R) antagonist Hoe 140 but not the B1 receptor (B1R) antagonist, Lys-[Leu8]des-Arg9-BK. COX-2 induction was accompanied by increased release of PGE2. No effect of a B1R agonist (des-Arg9-BK) on p-MAPK or COX-2 expression was observed. B2R protein was found to be expressed in all four head and neck cell lines tested. Immunohistochemical analysis and immunoblot analysis revealed that B2R, but not B1R, was significantly over-expressed in HNSCC tumors compared to levels in normal mucosa from the same patient. In HNSCC cells, the BK-induced expression of COX-2 was inhibited by the EGFR kinase inhibitor gefitinib or mitogen activated protein kinase kinases (MEK) inhibitors (PD98059 or U0126). These results suggest that EGFR and MAPK are required for COX-2 induction by BK. Up-regulation of the B2R in head and neck cancers suggests this pathway is involved in HNSCC tumorigenesis.
PMCID: PMC3575100  PMID: 19074839
Bradykinin; B2 receptor; EGFR; MAPK; cyclooxygenase-2; head and neck cancer
3.  Influence of Panax ginseng on Cytochrome P450 (CYP)3A and P-glycoprotein (Pgp) Activity in Healthy Subjects 
Journal of clinical pharmacology  2011;52(6):10.1177/0091270011407194.
A number of herbal preparations have been shown to interact with prescription medications secondary to modulation of cytochrome P450 (CYP) and/or P-glycoprotein (P-gp). The purpose of this study was to determine the influence of Panax ginseng on CYP3A and P-gp function using the probe substrates midazolam and fexofenadine, respectively. Twelve healthy subjects (8 males) completed this open label, single sequence pharmacokinetic study. Healthy volunteers received single oral doses of midazolam 8 mg and fexofenadine 120 mg, before and after 28 days of P. ginseng 500 mg twice daily. Midazolam and fexofenadine pharmacokinetic parameter values were calculated and compared pre-and post P. ginseng administration. Geometric mean ratios (post-ginseng/pre-ginseng) for midazolam area under the concentration vs. time curve from zero to infinity (AUC0-∞), half life (T1/2), and maximum concentration (Cmax) were significantly reduced at 0.66 (0.55 – 0.78), 0.71 (0.53 – 0.90), and 0.74 (0.56 – 0.93), respectively. Conversely, fexofenadine pharmacokinetics were unaltered by P. ginseng administration. Based on these results, Panax ginseng appeared to induce CYP3A activity in the liver and possibly the gastrointestinal tract. Patients taking Panax ginseng in combination with CYP3A substrates with narrow therapeutic ranges should be monitored closely for adequate therapeutic response to the substrate medication.
PMCID: PMC3523324  PMID: 21646440
HIV; Panax ginseng; cytochrome P450; drug interaction; midazolam; herb
4.  Antenatal and Postnatal Diagnosis of Coxsackie B4 Infection: Case Series 
AJP Reports  2011;2(1):1-6.
Enteroviruses are a common cause of neonatal infection. In particular, Coxsackie B viruses are often associated with severe, fatal disease. The antenatal diagnosis of Coxsackie B viral infections is uncommon. We present a unique case of Coxsackie B4 virus ventriculitis and myocarditis causing fetal hydrops at 22 weeks gestation. Transmission was inferred by viral isolation from the amniotic fluid and by placental pathology. We also describe two additional cases of fatal neonatal Coxsackie B4 infection complicated by myocarditis and encephalitis with cerebral necrosis in a 4-day-old female and by myocarditis, spinal leptomeningitis, and hepatitis in a 4-day-old male. Transplacental acquisition of infection carries a poor prognosis. We propose that Coxsackie B virus should be considered in the investigation of nonimmune hydrops, particularly in the presence of cardiac dysfunction.
PMCID: PMC3653513  PMID: 23946895
coxsackie B virus; hydrops; myocarditis; cerebritis; ventriculitis
5.  Variation in apoptosis mechanisms employed by malaria parasites: the roles of inducers, dose dependence and parasite stages 
Malaria Journal  2012;11:297.
Plasmodium berghei ookinetes exhibit an apoptotic phenotype when developing within the mosquito midgut lumen or when cultured in vitro. Markers of apoptosis increase when they are exposed to nitric oxide or reactive oxygen species but high concentrations of hydrogen peroxide cause death without observable signs of apoptosis. Chloroquine and other drugs have been used to induce apoptosis in erythrocytic stages of Plasmodium falciparum and to formulate a putative pathway involving cysteine protease activation and mitochondrial membrane permeabilization; initiated, at least in the case of chloroquine, after its accumulation in the digestive vacuole causes leakage of the vacuole contents. The lack of a digestive vacuole in ookinetes prompted the investigation of the effect of chloroquine and staurosporine on this stage of the life cycle. Finally, the suggestion that apoptosis may have evolved as a strategy employed by ookinetes to increase the fitness of surviving parasites was explored by determining whether increasing the ecological triggers parasite density and nutrient depletion induced apoptosis.
Ookinetes were grown in culture then either exposed to hydrogen peroxide, chloroquine or staurosporine, or incubated at different densities and in different media. The proportion of ookinetes displaying positive markers for apoptosis in treated samples was compared with controls and results were analyzed using analysis of variance followed by a Turkey’s test, or a Kruskal-Wallis test as appropriate.
Hydrogen peroxide below 50 μM triggered apoptosis but cell membranes were rapidly compromised by higher concentrations, and the mode of death could not be defined. Both chloroquine and staurosporine cause a significant increase in ookinetes with condensed chromatin, caspase-like activity and, in the case of chloroquine, phosphatidylserine translocation and DNA fragmentation (not investigated for staurosporine). However, mitochondrial membrane potential remained intact. No relationship between ookinete density and apoptosis was detected but nutrient depletion significantly increased the proportion of ookinetes with chromatin condensation in four hours.
It is proposed that both a mitochondrial and an amitochondrial apoptotic pathway may be involved, dependent upon the trigger that induces apoptosis, and that pathways may differ between erythrocytic stages and ookinetes, or between rodent and human malaria parasites.
PMCID: PMC3489549  PMID: 22929459
Apoptosis; Malaria; Plasmodium berghei; Ookinetes; Chloroquine; Reactive oxygen species; Density
6.  Echinacea Purpurea Significantly Induces Cytochrome P450 3A (CYP3A) but does not alter Lopinavir-Ritonavir Exposure in Healthy Subjects 
Pharmacotherapy  2010;30(8):797-805.
Study Objective
To determine the influence of Echinacea purpurea on the pharmacokinetics of lopinavir-ritonavir, and on CYP3A and P-glycoprotein (P-gp) activity using the probe substrates midazolam, and fexofenadine, respectively.
Open label, single-sequence pharmacokinetic study.
Outpatient clinic in a Federal Government research hospital.
Thirteen (8 males) healthy volunteers (median age: 31 yrs).
Measurements and main results
Healthy volunteers received lopinavir-ritonavir (400/100 mg) twice daily for 30 days. On study day 16, subjects began taking Echinacea purpurea 500 mg three times daily, which they continued for four weeks, the first two weeks in combination with lopinavir-ritonavir. On days 15 and 30 of lopinavir-ritonavir administration (pre and post-Echinacea, respectively), serial blood samples were collected over 12 hrs to determine lopinavir and ritonavir concentrations and subsequent pharmacokinetic parameters using non-compartmental methods. Study subjects also received single doses of midazolam (8 mg orally) and fexofenadine (120 mg orally) before- and after 28 days of Echinacea purpurea to assess CYP3A and P-glycoprotein (P-gp) activity, respectively. Neither lopinavir nor ritonavir pharmacokinetics were significantly altered by 2 weeks of Echinacea coadministration. The geometric mean ratios (GMR, 90% CI) for lopinavir area under the concentration vs. time curve from zero to 12 hrs (AUC0–12) and maximum concentration (post-Echinacea/pre-Echinacea) were 0.96 (0.83, 1.10) and 1.00 (0.88, 1.12), respectively (P > 0.05). Conversely, GMRs (90% CIs) for midazolam AUC from time zero to infinity (AUC0-∞) and oral clearance were 0.73 (0.61, 0.85) (P = 0.008) and 1.37 (1.10, 1.63) (P = 0.02), respectively. Fexofenadine pharmacokinetics did not significantly differ pre- and post-echinacea administration (P > 0.05).
Echinacea purpurea induced CYP3A activity but did not alter lopinavir concentrations, most likely due to the presence of the potent CYP3A inhibitor, ritonavir. Echinacea purpurea is unlikely to alter the pharmacokinetics of ritonavir-boosted protease inhibitors but may cause modest decreases in plasma concentrations of other CYP3A substrates.
PMCID: PMC3407958  PMID: 20653355
HIV; protease inhibitors; lopinavir; ritonavir; Echinacea purpurea; herb; cytochrome P450; P-glycoprotein; drug interaction
7.  Enhanced reporting of deaths among Aboriginal and Torres Strait Islander peoples using linked administrative health datasets 
Aboriginal and Torres Strait Islander peoples are under-reported in administrative health datasets in NSW, Australia. Correct reporting of Aboriginal and Torres Strait Islander peoples is essential to measure the effectiveness of policies and programmes aimed at reducing the health disadvantage experienced by Aboriginal and Torres Strait Islander peoples. This study investigates the potential of record linkage to enhance reporting of deaths among Aboriginal and Torres Strait Islander peoples in NSW, Australia.
Australian Bureau of Statistics death registration data for 2007 were linked with four population health datasets relating to hospitalisations, emergency department attendances and births. Reporting of deaths was enhanced from linked records using two methods, and effects on patterns of demographic characteristics and mortality indicators were examined.
Reporting of deaths increased by 34.5% using an algorithm based on a weight of evidence of a person being Aboriginal or Torres Strait Islander, and by 56.6% using an approach based on 'at least one report' of a person being Aboriginal or Torres Strait Islander. The increase was relatively greater in older persons and those living in less geographically remote areas. Enhancement resulted in a reduction in the urban-remote differential in median age at death and increases in standardised mortality ratios particularly for chronic conditions.
Record linkage creates a statistical construct that helps to correct under-reporting of deaths and potential bias in mortality statistics for Aboriginal and Torres Strait Islander peoples.
PMCID: PMC3413579  PMID: 22747900
8.  Clear Cell Carcinoma and Clear Cell Odontogenic Carcinoma: a Comparative Clinicopathologic and Immunohistochemical Study 
Head and Neck Pathology  2011;5(2):101-107.
Clear cell carcinoma or hyalinizing clear cell carcinoma (CCC) and clear cell odontogenic carcinoma (CCOC) are rare, low-grade and typically indolent malignancies that can be diagnostically challenging. In this study the clinicopathologic, histologic, and immunohistochemical features of 17 CCCs and 12 CCOCs are examined. The differential diagnosis of clear cell malignancies in the head and neck is discussed. The relationship of CCCs and CCOCs to other clear cell tumors on the basis of their immunohistochemical staining patterns is postulated.
PMCID: PMC3098331  PMID: 21290202
Clear cell carcinoma; Clear cell odontogenic carcinoma; Immunohistochemistry; Histologic
9.  Ewing’s Family of Tumors of the Sinonasal Tract and Maxillary Bone 
Head and Neck Pathology  2010;5(1):8-16.
The Ewing’s family of tumors (EFT) are malignant neoplasms affecting children and young adults. Most cases arise in the long bones or the pelvis. Primary EFT of head and neck is uncommon and primary sinonasal EFT is even rarer. Previous studies have not focused on the sinonasal region specifically, and the published literature on sinonasal EFT consists of sporadic case reports. Fourteen cases of sinonasal EFT were available and had H&Es for review and immunohistochemical stains for CD99, S100, keratins, synaptophysin and desmin. FISH or RT-PCR was performed for EWSR1 abnormalities on 8 cases. The 14 identified patients included 5 males and 9 females, ranging from 7–70 years of age (mean 32.4 years). Tumors involved nasal cavity (5), sinuses (5) or both (4). Five patients had dural, orbital or brain involvement. The majority involved bone radiologically and/or microscopically. All cases were composed of small cells with variable cytoplasmic clearing. Focal or prominent nesting was noted in most cases. All cases were positive for CD99. Keratins (AE1/3 and/or CAM5.2), S100 and synaptophysin were positive in 4, 3 and 5 cases, respectively. All cases were negative for desmin. The 8 cases tested by FISH or RT-PCR were positive for EWSR1 abnormalities. Follow-up in 8 patients ranged from 1–168 months (average 11.3 m) showing 1 death due to metastatic disease, 1 death due to local disease, 1 patient alive with metastases and 5 patients disease-free at last follow-up. Interestingly, however, an analysis of the literature suggests a better prognosis for sinonasal EFT than EFT overall.
PMCID: PMC3037459  PMID: 21107767
Ewing’s family of tumors; Sinonasal; Maxillary bone; Olfactory neuroblastoma
10.  Sheddase Activity of Tumor Necrosis Factor-Alpha Converting Enzyme is Increased and Prognostically Valuable in Head and Neck Cancer 
Tumor necrosis factor alpha converting enzyme (TACE) is a sheddase overexpressed in cancers that generates cancer cell growth and survival factors, and is implicated in carcinogenesis and tumor growth. This indicates that TACE could be a potentially important cancer biomarker. Unexpectedly, TACE expression in cancer tissues does not correlate with cancer stage or invasiveness. Although TACE sheddase activity is a more direct and potentially better indicator of TACE biology and might be a better cancer biomarker than TACE expression, it has not been studied in cancer tissues. In the present study, we developed a reliable specific assay for quantification of TACE sheddase activity, investigated TACE activity and TACE protein expression in head and neck cancer (HNC) tissues, and examined the correlation of the results with HNC clinical stages and likelihood to recur. We found that HNC cell lines and tissues contained remarkably higher quantities of TACE activity and TACE protein than normal keratinocytes or oral mucosa. siRNA silencing of TACE resulted in the inhibition of release of the tumorogenic factors amphiregulin and TGF alpha, and tumor protective factors tumor necrosis factor receptors from HNC cells. Importantly, TACE activity, but not TACE protein expression, was significantly higher in large, T3/T4, primary tumors relative to small, T1/T2, primary tumors, and especially in primary tumors likely to recur relative to those unlikely to recur. These data demonstrate that increased TACE activity in cancer is biologically and clinically relevant, and indicate that TACE activity could be a significant biomarker of cancer prognosis.
PMCID: PMC2784191  PMID: 19843672
Head and neck cancer; Biomarker; Tumor necrosis factor alpha converting enzyme; protein expression; sheddase activity
11.  Conservative Management of Placenta Accreta in a Multiparous Woman 
Journal of Pregnancy  2010;2010:329618.
Placenta accreta refers to any abnormally invasive placental implantation. Diagnosis is suspected postpartum with failed delivery of a retained placenta. Massive obstetrical hemorrhage is a known complication, often requiring peripartum hysterectomy. We report a case of presumed placenta accreta in a patient following failed manual removal of a retained placenta. We describe an attempt at conservative management with methotrexate in a stable patient desiring future fertility. Treatment was unsuccessful and led to the development of a disseminated intrauterine infection complicated by a bowel obstruction, requiring both a hysterectomy and small bowel resection. In hemodynamically stable patients, conservative management of placenta accreta may involve leaving placental tissue in situ with subsequent administration of methotrexate. However, ongoing close observation is required to identify complications.
PMCID: PMC3065870  PMID: 21490740
12.  Primary Unilateral Multifocal Pleomorphic Adenoma of the Parotid Gland: Molecular Assessment and Literature Review 
Head and Neck Pathology  2008;2(4):339-342.
Multiple separate tumors developing in a single salivary gland is rare in previously untreated patients. Tumors that can be multicentric include Warthin tumor, oncocytoma, basal cell adenoma and acinic cell carcinoma. The incidence of multiple primary unilateral pleomorphic adenomas is extremely rare in patients with no prior history of trauma or surgery. We report two cases of primary multicentric pleomorphic adenoma and review the literature. We also subjected one of our cases to a molecular clonality test. The molecular results suggested that the separate nodules were clonally related, arguing against an independent origin.
PMCID: PMC2807582  PMID: 20614306
Pleomorphic adenoma; Multifocal; Parotid gland
13.  Molecular Diagnosis in Head and Neck: What a Surgical Pathologist Must Know 
Head and Neck Pathology  2008;2(2):99-102.
Molecular alterations in tumors have become interesting targets both for diagnostic and for therapeutic and prognostic applications in tumor pathology. In the head and neck, there are a variety of different alterations, encompassing all the different types of genetic events associated with carcinogenesis. This paper reviews three different types of tumors that display a spectrum of genetic alterations: the translocation in Mucoepidermoid carcinoma, Epstein Barr virus association in nasopharyngeal carcinoma, and the HRPT2 tumor suppressor gene in parathyroid carcinoma. Basic histology is reviewed and the genetic alterations are discussed, along with a brief discussion of potential diagnostic implications.
PMCID: PMC2807553  PMID: 20614331
Tumor markers; Mucoepidermoid carcinoma; Lymphoepithelial carcinoma; Nasopharyngeal carcinoma; Parathyroid carcinoma
16.  Patients with protracted pain: A survey conducted at The London Hospital 
Journal of Medical Ethics  1977;3(2):61-73.
Physical pain has always been part of human experience, and throughout history it is recorded that doctors and wise men and women have sought to ease pain. The attitudes of those suffering pain, however, have varied from stoical acceptance to sullen endurance. Today, most people consciously seek to avoid pain or to have their pain eased, although they do not always expect what in fact appears to be possible. This study of 13 patients with protracted pain was carried out at The London Hospital by a professional group to see how patients regarded their own pain and the efforts of doctors and nurses to relieve it. The attitudes of the doctors and nurses were also studied, and the results, despite the limitations of the survey, suggest that: [List: see text]
PMCID: PMC1154556  PMID: 874980

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