A preventive registry for hereditary nonpolyposis colorectal cancer

Hereditary nonpolyposis colorectal cancer (HNPCC) is a genetic disorder characterized by a strong family history of colorectal and extracolonic cancers, usually at a young age. This article presents a new provincial service for families with HNPCC. The Steve Atanas Stavro Familial Gastrointestinal Cancer Registry at Mount Sinai Hospital is accruing patients that meet a set of criteria establishing a putative diagnosis of HNPCC. The objectives of the Registry are to develop and assess patient pedigrees, to coordinate screening procedures for at-risk persons, to maintain a prospective database of patient information, to provide education and support for families and to contribute to research. To date, surgeons and patients are the most common referral sources, while oncologists and geneticists are the least common. The ultimate goal of the HNPCC service is the secondary prevention of cancer and a corresponding decrease in mortality for HNPCC family members.     

Laparoscopic esophagomyotomy and antireflux procedure with intraoperative manometry

We have been routinely performing laparoscopic cholecystectomy and antireflux procedures. Having this experience, we decided to assess the feasibility and safety of performing a laparoscopic esophagomyotomy and antireflux procedure. Here we present a case of a 37-year-old man with a history of progressive dysphagia and a diagnosis of achalasia, made on the basis of clinical, endoscopic, and manometric studies. Preoperative manometry reported a pressure of 52 mm Hg (normal, 15-25 mm Hg) for 4.5 cm (normal, > 3 cm). Laparoscopic esophagomyotomy and anterior fundoplication were performed. The esophagomyotomy included a 6-cm segment of distal esophagus and 2 cm of stomach; postoperative manometry was 18 mm Hg for 3 cm. Eight months postoperatively, a barium swallow demonstrated no reflux. Laparoscopic esophagomyotomy and antireflux procedure can be performed with efficacy and safety, with the advantage of a shorter hospitalization and an early recovery compared with the traditional procedure. Also, we emphasize the importance of the intraoperative manometry in the relevance of a concomitant antireflux procedure.     

Polysomnographic sleep measures in patients with uremic and idiopathic restless legs syndrome

In the present study, the nocturnal electroencephalographic sleep pattern, the number of periodic leg movements (PLM) during sleep and wakefulness, and the subjective sleep parameters of patients with uremic (n = 10) and idiopathic (n = 17) restless legs syndrome (RLS) were compared. The main finding was that the total number of PLM (p = 0.019), the PLM index (p = 0.018), and the PLM index while awake (p = 0.003) were significantly higher in patients with uremic RLS compared with patients who had idiopathic RLS. Additionally, both groups showed a distinct time-of-night pattern of PLM activity. Polysomnographic measures of sleep continuity (total sleep time, sleep efficiency, sleep onset latency, time awake) and sleep architecture (amount of nonrapid eye movement sleep stages 1, 2, 3, and 4 and the amount of rapid eye movement sleep) did not differ between uremic and idiopathic RLS patients. With regard to subjective parameters, sleep quality was estimated to be worse in uremic RLS (p = 0.033), whereas other parameters (for example, severity of RLS, quality of life) did not differ between the two groups. It is suggested that uremia itself worsens the motor symptoms of RLS, probably as a result of increased excitability.     

Synergistic anticancer effects of ganciclovir/thymidine kinase and 5-fluorocytosine/cytosine deaminase gene therapies

BACKGROUND: A bacterial enzyme, Escherichia coli cytosine deaminase, which converts the prodrug 5-fluorocytosine into the toxic drug 5-fluorouracil, and a viral enzyme, herpes simplex virus thymidine kinase, which converts ganciclovir from an inactive prodrug to a cytotoxic agent by phosphorylation, are being actively investigated for use in gene therapy for cancer. The purpose of this study was to determine whether combining these prodrug-activating gene therapies might result in enhanced anticancer effects. METHODS: Rat 9L gliosarcoma cells were transfected with plasmids containing the E. coli cytosine deaminase gene (9L/CD cells), with plasmids containing the herpes simplex virus thymidine kinase gene (9L/TK cells), or with both expression plasmids (9L/CD-TK cells). The drug sensitivities of the cell lines were evaluated; in addition, the sensitivities of 9L and 9L/CD-TK cells mixed in varied proportions were measured. The effects of prodrug treatment on 9L/CD-TK tumor growth (i.e., size and volume) in nude mice were monitored. The isobologram method of Loewe and the multiple drug-effect analysis method of Chou-Talalay were used to measure the interaction between the two prodrug-activating gene therapies. To elucidate the mechanism of interaction, the phosphorylation of ganciclovir in 9L/CD-TK cells after varying prodrug treatments was studied. RESULTS AND CONCLUSIONS: The presence of transfected cytosine deaminase and thymidine kinase genes in 9L gliosarcoma cells reduced cell survival, both in vitro and in vivo, following treatment with the relevant prodrugs; the effects of the two components appeared to be synergistic and related mechanistically to the enhancement of ganciclovir phosphorylation by thymidine kinase following 5-fluorouracil treatment.     

Src can regulate carboxy terminal interactions with AFAP-110, which influence self-association, cell localization and actin filament integrity

The SH2 and SH3 binding partner AFAP-110 is a tyrosine phosphorylated substrate of Src. AFAP-110 has been hypothesized to link Src to actin filaments, which may contribute to the effects of Src upon actin filament integrity. However, it has been unclear what effect activated Src (Src527F) has upon AFAP-110 structure or function and whether AFAP-110 plays a role in actin filament integrity. We report here that the carboxy terminal 127 amino acids of AFAP-110 are comprised of an alpha-helical region that contains a leucine zipper motif. This indicated the potential of AFAP-110 to self-associate. Expression of the carboxy terminus as a fusion protein (GST-cterm) will permit affinity absorption of cellular AFAP-110. The integrity of the alpha-helical leucine zipper motif in GST-cterm is required for affinity absorption, but binding is not due to a classical leucine zipper interaction. Co-expression of Src527F, unlike cSrc, will abrogate affinity absorption of AFAP-110 with GST-cterm. These data indicate that Src527F has affected a change in the carboxy terminal structure that renders AFAP-110 unavailable for affinity absorption. Superose chromatography demonstrate that AFAP-110 will fractionate as a monomer or multimer, indicating AFAP-110 can be detected in a self-associated form in cell lysates. Co-expression of Src527F resulted in AFAP-110 fractionating with a molecular weight that predicts only a multimeric population. Deletional mutagenesis also indicate a biological role for the carboxy terminus in cellular localization and actin filament integrity. Deletion of the entire carboxy terminal alpha-helix (84 amino acids) will not permit AFAP-110 to efficiently colocalize with actin filaments or the cell membrane. Deletion of only the leucine zipper region of the carboxy terminal alpha-helix (44 amino acids) from AFAP-110 (AFAPAdeltazip) demonstrate that both AFAPdeltalzip and actin filaments are repositioned into rosette-like structures, similar to the effects of Src527F, while co-expression of AFAP-110 with cSrc will not affect actin filaments. These data indicate that AFAP-110 can play an important role in modulating actin filament integrity through carboxy terminal interactions that can be affected by Src527F.     

A role for cAMP in long-term depression at hippocampal mossy fiber synapses

Mossy fiber synapses on hippocampal CA3 pyramidal cells, in addition to expressing an NMDA receptor-independent form of long-term potentiation (LTP), have recently been shown to express a novel presynaptic form of long-term depression (LTD). We have studied the mechanisms underlying mossy fiber LTD and present evidence that it is triggered, at least in part, by a metabotropic glutamate receptor-mediated decrease in adenylyl cyclase activity, which leads to a decrease in the activity of the cAMP-dependent protein kinase (PKA) and a reversal of the presynaptic processes responsible for mossy fiber LTP. The bidirectional control of synaptic strength at mossy fiber synapses by activity therefore appears to be due to modulation of the cAMP-PKA signaling pathway in mossy fiber boutons.     

Role of orlistat in the treatment of obese patients with type 2 diabetes. A 1-year randomized double-blind study

OBJECTIVE: Obesity is an important risk factor for type 2 diabetes. Weight loss in patients with type 2 diabetes is associated with improved glycemic control and reduced cardiovascular disease risk factors, but weight loss is notably difficult to achieve and sustain with caloric restriction and exercise. The purpose of this study was to assess the impact of treatment with orlistat, a pancreatic lipase inhibitor, on weight loss, glycemic control, and serum lipid levels in obese patients with type 2 diabetes on sulfonylurea medications. RESEARCH DESIGN AND METHODS: In a multicenter 57-week randomized double-blind placebo-controlled study, 120 mg orlistat or placebo was administered orally three times a day with a mildly hypocaloric diet to 391 obese men and women with type 2 diabetes who were aged > 18 years, had a BMI of 28-40 kg/m2, and were clinically stable on oral sulfonylureas. Changes in body weight, glycemic control, lipid levels, and drug tolerability were measured. RESULTS: After 1 year of treatment, the orlistat group lost 6.2 +/- 0.45% (mean +/- SEM) of initial body weight vs. 4.3 +/- 0.49% in the placebo group (P < 0.001). Twice as many patients receiving orlistat (49 vs. 23%) lost > or = 5% of initial body weight (P < 0.001). Orlistat treatment plus diet compared with placebo plus diet was associated with significant improvement in glycemic control, as reflected in decreases in HbA1c (P < 0.001) and fasting plasma glucose (P < 0.001) and in dosage reductions of oral sulfonylurea medication (P < 0.01). Orlistat therapy also resulted in significantly greater improvements than placebo in several lipid parameters, namely, greater reductions in total cholesterol, (P < 0.001), LDL cholesterol (P < 0.001), triglycerides (P < 0.05), apolipoprotein B (P < 0.001), and the LDL-to-HDL cholesterol ratio (P < 0.001). Mild to moderate and transient gastrointestinal events were reported with orlistat therapy, although their association with study withdrawal was low. Fat-soluble vitamin levels generally remained within the reference range, and vitamin supplementation was required in only a few patients. CONCLUSIONS: Orlistat is an effective treatment modality in obese patients with type 2 diabetes with respect to clinically meaningful weight loss and maintenance of weight loss, improved glycemic control, and improved lipid profile.     

Anaphylaxis to topical bacitracin zinc ointment

This report describes a case of systemic anaphylaxis to bacitracin zinc ointment in a 24-year-old man who was injured in a motorcycle accident. Extensive abrasions on the patient's extremities were cleaned with Shurclens before application of viscous Xylocaine and bacitracin zinc ointment. Five minutes later, the patient exhibited symptoms of severe anaphylaxis and required the administration of epinephrine, antihistamines, intravenous fluids, and corticosteroids. Two weeks later, he underwent prick/puncture skin testing to Shurclens and bacitracin zinc ointment as well as prick/puncture, intracutaneous, and subcutaneous challenge with Xylocaine. Only the result of the prick test to bacitracin zinc ointment was positive. Although bacitracin is considered to be a safe topical antibiotic, physicians should be aware of the potential not only for delayed hypersensitivity but also for acute IgE-mediated allergic reactions and life-threatening anaphylaxis.