In VivoStudies of Adenovirus-Based p53 Gene Therapy for Ovarian Cancer

Objectives.To test the safety, efficacy, and toxicity of gene therapy using wild-type p53-expressing adenovirus (Ad-CMV-p53) in a nude mouse model with intraperitoneal (ip) 2774 human ovarian cancer cell line that contains a p53 mutation.Study design.An initial study of adenovirus tolerance was determined in nude mice by a single ip injection of increasing doses of Ad-CMV-p53. Nude mice were implanted with an LD₁₀₀dose of 1 × 10⁷cells. To study the efficacy and specificity of Ad-CMV-p53 treatment, the mice received treatment with different adenovirus constructs. One group received Ad-CMV-p53 and another group received a control adenovirus construct, Ad-CMV-βgal. To study the treatment response to Ad-CMV-p53, the mice were divided into groups and received various treatment schedules of 1 × 10⁸pfu of Ad-CMV-p53.Results.The mice tolerated Ad-CMV-p53 without adverse effects at doses of 1 × 10⁸pfu. The response to Ad-CMV-p53 showed significant survival duration in each dose regimen, with a survival time greater than that of untreated animals (P= 0.0173). However, no statistically significant survival advantage was observed between Ad-CMV-p53- and Ad-CMV-βgal-treated mice.Conclusions.These studies show that at the adenovirus dose and administration regimen used, there is effective but not specific 2774 tumor growth inhibitionin vivo.Efficient introduction of biologically active genes into tumor cells would greatly facilitate cancer therapy. Thus, although promising, these results caution that much effort will be required to realize the potential for clinical application of adenovirus-based ovarian cancer gene therapy.     

Radiotherapy in the treatment of low-grade astrocytomas

Between 1954 and 1986 inclusive, 160 children in the North West Region of England were registered with histologically proven lowgrade astrocytomas (grade 1 or 2). Ten died before receiving any treatment, and a further seven died within 28 days of surgery, leaving 143 children whose survival in relation to treatment modality is the subject of this paper. Low-grade astrocytomas are responsive to radiation therapy. This treatment has no clear benefit to offer children with superficial tumours that can be resected completely or nearly so, but significantly improves survival rates when tumours are deep-seated and not amenable to excision.     

Venous disease: investigation and treatment,fact or fiction?

This review looks at some clinical and experimental methods and treatments used in venous disease, and attempts to dispel some myths which have been associated with it. Over the last century numerous techniques have been introduced to aid the understanding of the physiology of normal legs and the pathophysiology of those with venous disease. Tourniquet testing along with clinical examination remains the only method of venous assessment in most hospitals. Venous ulceration in the past has been associated with deep vein incompetence, but the newer, non-invasive techniques of Doppler ultrasound and duplex examination are now identifying patients with leg ulceration who have superficial venous insufficiency and therefore a surgically correctable condition. Perforating veins and their possible role in the aetiology of venous ulceration along with invasive and non-invasive methods for their detection is reviewed. Some of the conservative compression treatments and dressings available for the treatment of venous ulceration are discussed. It is concluded that adherence to sound surgical principles remains the mainstay of the successful management of patients with venous disease.     

Ocular molecules and cells that regulate immune responses in situ

Regulation of T cell-dependent immune responses is mediated in part by bone marrow-derived antigen presenting cells (APC) that (a) process and present antigens which engage the T cell receptor and (b) secrete cytokines that influence the threshold of T cell activation. The anterior chamber of the eye is lined by the corneal endothelium (which rests on a stroma and epithelium that is devoid of class II MHC + APC) and iris/ciliary body (which contain significant numbers of bone marrow-derived cells, one third of which are class II MHC +). When tested in vitro, these potential APCs fail to present antigens in a form that activates T cells. Moreover, iris/ciliary body cells actually suppress activation of T cells exposed to antigens on conventional APC. In addition, aqueous humor under normal circumstances contains factors (one of which is TGF_B) that are potent inhibitors of antigen-driven T cell activation, but spare other aspects of T cell function. Evidence suggests that the bone marrow-derived cells in iris/ciliary body are the source of this factor. Thus, the anterior chamber contains powerful forces that can prevent induction and can suppress expression of T cell mediated immunity. It is proposed that these forces are responsible for immunologic privilege and anterior chamber associated immune deviation, and for suppressing pathologic proliferation and inflammation in the anterior segment of the eye.     

The prevalence of autonomic neuropathy in the primary glaucomas

The results of systemic autonomic nerve function studies in patients with closed-angle glaucoma and ocular hypertension are reviewed. Autonomic neuropathy has been demonstrated in 58% of patients with closed-angle glaucoma and 42% of ocular hypertensive subjects, with significantly increased prevalence in ocular hypertensives with narrow iridocorneal angles. The implications are discussed, with particular reference to the pathogenesis of raised intraocular pressure.     

Conversion of Ouabain-Induced Ventricular Tachycardia in Dogs with Epicardial Lidocaine: Pharmacodynamics and Functional Effects

Epicardial antiarrhythmic drug administration was studied as a therapeutic approach for experimental ventricular tachycardia (VT) in an open-chest dog model. Lidocaine-polyurethane matrices (28%, w/w) were formulated as a model system. Matrices were placed on the left ventricular epicardium in each of 23 anesthetized open-chest dogs with ouabain-induced VT, to evaluate effectiveness in restoring sinus rhythm. Conversion occurred in all animals treated with matrices containing 300 mg or more of lidocaine after 1.5 to 7.0 min. The matrix lidocaine content correlated linearly with the time required for conversion to sinus rhythm (r = 0.75, P = 0.0002); irrespective of matrix size the myocardial/plasma lidocaine ratio was 20.1 ± 4.2 (mean ± SD) at the time of conversion. In a separate series of five dogs without ventricular tachycardia, systolic wall thickening measured with sonomicrometers after 5 min of controlled-release lidocaine administration (500- to 1000-mg matrix lidocaine content, 7.48 ± 3.49-mg/kg dose) was only minimally diminished (–14.1%) and this effect was observed only at the site of matrix placement on the anterior-apical epicardium. In contrast, intracoronary injection of 0.3 or 1.0 mg/kg of lidocaine-HCl resulted in complete elimination of wall thickening or replacement by systolic thinning. Thus epicardial administration of lidocaine from polyurethane matrices was an effective means of treating ouabain-induced ventricular tachycardia. Regional myocardial function in the vicinity of the matrices was modified to a very limited degree, supporting the view that the matrices can be used safely, without serious risk to ventricular contractile performance.     

Symptomatic and Clinical Improvement in Morbidly Obese Patients with Gastroesophageal Reflux Disease Following Roux-en-Y Gastric Bypass

Background: Patients who suffer with gastroesophageal reflux Disease (GERD) endure a worsening of symptoms as their weight increases. When medical treatment of this condition in the morbidly obese patients fails, surgical intervention may be indicated. Choosing a procedure which not only helps achieve weight control but which also relieves symptoms and complications of GERD is the goal. We present a review of patients who have undergone Roux-en-Y Gastric Bypass (RYGBP) and related procedures for this disease. Methods: One hundred eighty-eight patients undergoing surgery for morbid obesity and for GERD in 1992-1996 were contacted by mail or phone. All of these patients had undergone preoperative esophagogastroduodenoscopy to grade the severity of their disease. Their preoperative symptoms were compared to those experienced postoperatively. Results: One hundred thirty patients underwent a RYGBP with modified Hill fundopexy, 22 patients underwent a distal gastrectomy with modified Hill fundopexy, 8 patients underwent distal gastrectomy alone and 28 patients underwent RYGBP alone. There have been no deaths. There were nine surgical complications, eight early and one at 2.5 years postoperation. Follow-up is 4-48 months. The average BMI dropped from 43 to 30.2 kg/m². Whereas all patients were on some form of medical therapy before surgery, only 14 reported the need for medication postoperatively. Conclusions: Surgical intervention for weight control and treatment of GERD has been highly successful in our experience both with respect to weight control and to the reduction of reflux symptoms. Depending upon endoscopic and operative findings a RYGBP with or without an antireflux procedure can provide dramatic improvement. Gastrectomy with antireflux modifications is appropriate in selected cases.     

Neonatal necrotizing enterocolitis

PURPOSE: A retrospective, 12-year review of neonatal necrotizing enterocolitis was undertaken at a county hospital, with emphasis on presentation signs and symptoms. METHODS: Eighty-two patients with presence of intramural air were included in the study. The following signs and symptoms were studied: evidence of respiratory distress, use of umbilical catheters, white blood cell count and temperature at presentation, time interval from birth to diagnosis and time interval from diagnosis to operative intervention, presence of intramural air, air in biliary tree or free air, changes in abdominal girth, and presence of occult or gross blood in stools. Comparison was done among infants who had surgical or medical treatment, premature and full-term infants, and infants who had neonatal necrotizing enterocolitis less than or more than 20 days after birth. RESULTS: Eleven patients had a fatal outcome, with an overall survival of 87 percent. Sixty-four patients were treated medically and 18 had operative treatment. Mortality of the surgically treated group was 44 percent. Neonates who had surgical intervention had a left shift of the white blood cell count more commonly present, and all had documented abdominal distention. There were 62 premature and 20 full-term neonates in the group. Full-term neonates developed neonatal necrotizing enterocolitis earlier after birth (5.3 days compared with 15.3 days in the premature neonate group). Full-term neonates had a better prognosis in our series. Presentation of symptoms more than 20 days after birth did not change outcome. CONCLUSION: Our results reflect the experience of a community-based hospital. Clinical acumen remains the cornerstone of diagnosis and management.