Effect of zileuton and celecoxib on urinary LTE4 and PGE-M levels in smokers.

COX-2 and 5-lipoxygenase (5-LO) use arachidonic acid for the synthesis of eicosanoids that have been implicated in carcinogenesis and cardiovascular disease. The ability of celecoxib, a selective COX-2 inhibitor, to redirect arachidonic acid into the 5-LO pathway can potentially reduce its efficacy as a chemopreventive agent and increase the risk of cardiovascular complications. Levels of urinary prostaglandin E metabolite (PGE-M) and leukotriene E4 (LTE4), biomarkers of the COX and 5-LO pathways, are elevated in smokers. Here, we investigated the effects of zileuton, a 5-LO inhibitor, versus zileuton and celecoxib for 6 ± 1 days on urinary PGE-M and LTE4 levels in smokers. Treatment with zileuton led to an 18% decrease in PGE-M levels (P = 0.03); the combination of zileuton and celecoxib led to a 62% reduction in PGE-M levels (P < 0.001). Levels of LTE4 decreased by 61% in subjects treated with zileuton alone (P < 0.001) and were unaffected by the addition of celecoxib. Although zileuton use was associated with a small overall decrease in PGE-M levels, increased PGE-M levels were found in a subset (19 of 52) of subjects. Notably, the addition of celecoxib to the 5-LO inhibitor protected against the increase in urinary PGE-M levels (P = 0.03). In conclusion, zileuton was an effective inhibitor of 5-LO activity resulting in marked suppression of urinary LTE4 levels and possible redirection of arachidonic acid into the COX-2 pathway in a subset of subjects. Combining celecoxib and zileuton was associated with inhibition of both the COX-2 and 5-LO pathways manifested as reduced levels of urinary PGE-M and LTE4.

Parathyroid carcinoma: challenges in diagnosis and treatment.

Parathyroid carcinoma is a malignant neoplasm affecting 0.5% to 5.0% of all patients with primary hyperparathyroidism. Since it was first described by De Quervain in 1904 to this day, it continues to defy diagnosis and treatment because of its rarity, overlapping features with benign parathyroid disease, and lack of distinct characteristics. En bloc surgical extirpation of the tumor with clear margins remains the best curative treatment. Although prolonged survival is possible with recurrent or metastatic disease, cure is rarely achievable. Efficacy of adjuvant therapies, such as radiotherapy and chemotherapy, in management of persistent, recurrent, or metastatic disease has been disappointing.

A web-based screening and accrual strategy for a cancer prevention clinical trial in healthy smokers.

Screening and recruitment of qualified subjects for clinical trials is an essential component of translational research, and it can be quite challenging if the most efficient recruitment method is not utilized. In this report, we describe a successful web-based screening and accrual method used in a randomized prospective chemoprevention clinical trial with urinary biomarker endpoints. The targeted study population was a group of at-risk healthy current smokers with no evidence of lung disease. Craigslist was used as the sole recruitment modality for this study. All interested subjects were directed to a pre-screening website, in which subject questionnaire responses were linked to the study coordinator's secure e-mail account. Of the 429 initial inquiries, 189 individuals were initially eligible based on the questionnaire response. One hundred twenty-two people were telephone-screened, of whom 98 subjects were consented, 84 were randomized and 77 subjects completed the study successfully. Utilizing this single web-based advertising strategy, accrual for the trial was completed 7 months prior to the projected date. Craigslist is a cost effective and efficient web-based resource that can be utilized in accruing subjects to some chemoprevention trials.

Carnosol, a constituent of Zyflamend, inhibits aryl hydrocarbon receptor-mediated activation of CYP1A1 and CYP1B1 transcription and mutagenesis.

The aryl hydrocarbon receptor (AhR), a ligand-activated member of the basic helix-loop-helix family of transcription factors, plays a significant role in polycyclic aromatic hydrocarbon (PAH)-induced carcinogenesis. In the upper aerodigestive tract of humans, tobacco smoke, a source of PAHs, activates the AhR leading to increased expression of CYP1A1 and CYP1B1, which encode proteins that convert PAHs to genotoxic metabolites. Inhibitors of Hsp90 ATPase cause a rapid decrease in levels of AhR, an Hsp90 client protein, and thereby block PAH-mediated induction of CYP1A1 and CYP1B1. The main objective of this study was to determine whether Zyflamend, a polyherbal preparation, suppressed PAH-mediated induction of CYP1A1 and CYP1B1 and inhibited DNA adduct formation and mutagenesis. We also investigated whether carnosol, one of multiple phenolic antioxidants in Zyflamend, had similar inhibitory effects. Treatment of cell lines derived from oral leukoplakia (MSK-Leuk1) and skin (HaCaT) with benzo[a]pyrene (B[a]P), a prototypic PAH, induced CYP1A1 and CYP1B1 transcription, resulting in enhanced levels of message and protein. Both Zyflamend and carnosol suppressed these effects of B[a]P. Notably, both Zyflamend and carnosol inhibited Hsp90 ATPase activity and caused a rapid reduction in AhR levels. The formation of B[a]P-induced DNA adducts and mutagenesis was also inhibited by Zyflamend and carnosol. Collectively, these results show that Zyflamend and carnosol inhibit Hsp90 ATPase leading to reduced levels of AhR, suppression of B[a]P-mediated induction of CYP1A1 and CYP1B1, and inhibition of mutagenesis. Carnosol-mediated inhibition of Hsp90 ATPase activity can help explain the chemopreventive activity of herbs such as Rosemary, which contain this phenolic antioxidant.

Imaging techniques in parathyroid surgery for primary hyperparathyroidism.

As more patients present with the incidental diagnosis of primary hyperparathyroidism due to biochemical screening, treatment guidelines have been developed for the treatment of hyperparathyroidism. Management of primary hyperparathyroidism has evolved in recent years, with considerable interest in minimally invasive approaches. Successful localization of the diseased gland(s) by nuclear imaging and anatomical studies, along with rapid intraoperative parathyroid hormone assay, has allowed for focused and minimally invasive surgical approaches. Patients in whom the localization studies have identified single-gland adenoma or unilateral disease are candidates for such focused approaches instead of the traditional approach of bilateral exploration. These imaging techniques have also been critical in the successful management of patients with persistent or recurrent disease.

UV radiation inhibits 15-hydroxyprostaglandin dehydrogenase levels in human skin: evidence of transcriptional suppression.

Elevated levels of prostaglandins (PG) have been detected in the skin following UV radiation (UVR). PGs play an important role in mediating both the acute and the chronic consequences of UVR exposure. UVR-mediated induction of cyclooxygenase-2 (COX-2) contributes to increased PG synthesis. In theory, reduced catabolism might also contribute to increased PG levels. 15-Hydroxyprostaglandin deyhdrogenase (15-PGDH), a tumor suppressor gene, plays a major role in PG catabolism. In this study, we investigated whether UVR exposure suppressed 15-PGDH while inducing COX-2 in keratinocytes and in human skin. UVR exposure caused dose-dependent induction of COX-2, suppression of 15-PGDH, and increased prostaglandin E(2) (PGE(2)) production in HaCaT cells. Exposure to UVR suppressed the transcription of 15-PGDH, resulting in reduced 15-PGDH mRNA, protein, and enzyme activities. UVR exposure induced Slug, a repressive transcription factor that bound to the 15-PGDH promoter. Silencing Slug blocked UVR-mediated downregulation of 15-PGDH. The effects of UVR were also evaluated in the EpiDerm skin model, a three-dimensional model of human epidermis. Here too, COX-2 levels were induced and 15-PGDH levels suppressed following UVR exposure. Next, the effects of UVR were evaluated in human subjects. UVR treatment induced COX-2 while suppressing 15-PGDH mRNA in the skin of 9 of 10 subjects. Collectively, these data suggest that reduced expression of 15-PGDH contributes to the elevated levels of PGs found in the skin following UVR exposure. Possibly, agents that prevent UVR-mediated downregulation of 15-PGDH will affect the acute or the long-term consequences of UVR exposure, including nonmelanoma skin cancer.

Current risks of occupational blood-borne viral infection.

BACKGROUND: Human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), and other viruses remain occupational risks for both surgeons and patients in the operating room environment. In the past, this concern attracted great attention, but recently, this subject has been given much less attention. METHODS: Review of the literature over the past 50 years on occupational risks of viral infection in the operating room. RESULTS: Transmission of HIV still looms as a potential pathogen in the operating room, but no case has been documented in the United States. Infection with HBV can be prevented by a safe and effective vaccine. Chronic HCV infection is present in more than three million U.S. residents and remains a risk that can be managed only by adhering to strict infection control practices and avoiding blood exposure. CONCLUSIONS: The risks of viral infection in the operating room remain the same as a decade ago even though attention to this issue has waned. The avoidance of blood exposure to prevent transmission of both known and unknown blood-borne pathogens continues to be a goal for all surgeons.

Extended left-sided pancreatectomy with spleen preservation.

BACKGROUND: Distal pancreatectomy (DP) is frequently performed with splenectomy, although splenectomy can be linked to various untoward effects, and sparing of the main splenic vessels (SVs) is not necessary for successful spleen preservation (SP). METHODS: We reviewed all DPs in a single-surgeon practice to assess feasibility and outcomes of SP. RESULTS: Between 1997 and 2007, 41 of 177 pancreatic resections involved a DP (23%). There were 14 men (34%) and 27 women (66%), with a median age of 60 years (range: 34-86). Four procedures were en bloc resections, two total pancreatectomies, while eight of the remaining 35 DPs were performed laparoscopically. SP was accomplished in 33 of 34 possible cases (SP rate 97%), despite SV resection in 27 of these (82%). The postoperative complication rate was 24%, without death. Pancreatic fistulae occurred in two patients (5% of patients at risk), and one SPDP led to splenic infarct. No other clinically relevant problems specific to SP have become apparent. CONCLUSIONS: Pancreatic fistula rate and other outcomes in this small DP experience compare favorably to other DP series. Few spleen-specific complications and the radicality of resection support the liberal use of SP with SV resection, irrespective of an open or laparoscopic approach.

Ziprasidone-induced priapism requiring surgical treatment.

Both typical and atypical antipsychotic psychotropics have been reported to cause ischemic priapism presumptively secondary to alpha1-adrenergic blockade. This condition is a urologic emergency for if not evaluated and treated appropriately, long-term sequelae include erectile dysfunction and impotence. This paper addresses the first reported case of priapism requiring surgical intervention presumed to be secondary to ziprasidone. Increased clinician and patient education regarding priapism is required in order to minimize this adverse event and to maximize immediate treatment.

Resolution of hemiballism after carotid endarterectomy: case report.

A 74-year-old man presented with a 3-week history of involuntary left-sided upper and lower extremity shaking without any focal neurologic deficit. Bilateral carotid artery duplex demonstrated severe stenosis of the right internal carotid artery and moderate stenosis of the left internal carotid artery. A right carotid endarterectomy was performed without complications and resulted in elimination of the left-sided involuntary movements postoperatively.

Pseudoseizures and hysterical stridor.

Differentiation of pseudoseizures from epileptic seizures and hysterical stridor from asthma is key to the treatment of patients. Both pseudoseizures and hysterical stridor are associated commonly with sexual abuse, eating disorders, depression, substance abuse, anxiety disorders, and personality disorders. Failure to reach an appropriate diagnosis results in inappropriate medical care including recurrent intubations, antiepileptic drugs, and excessive hospitalizations. This case represents the first instance of reported pseudoseizures in a patient with hysterical stridor secondary to childhood sexual abuse.