Transport,Uptake, and Metabolism of the Bis(pivaloyloxymethyl)-Ester Prodrug of 9-(2- Phosphonylmethoxyethyl)Adenine in an In Vitro Cell Culture System of the Intestinal Mucosa (Caco-2)

Purpose. To evaluate intestinal transport, uptake and metabolism characteristics of the bis(pivaloyloxymethyl)-ester [bis(POM)-ester] of the antiviral agent 9-(2-phosphonylmethoxyethyl)adenine [PMEA]. Methods. Intestinal transport, uptake and metabolism of bis(POM)-PMEA were studied using an in vitro cell culture system of the intestinal mucosa (Caco-2 monolayers). Concentrations of bis(POM)-PMEA and its metabolites mono(POM)-PMEA and PMEA were determined using a reversed-phase HPLC method. Enzymatic stability of bis(POM)-PMEA was evaluated by incubation with purified liver carboxylesterase, homogenates of Caco-2 cells and scraped pig small intestinal mucosa. Results. The use of bis(POM)-PMEA as a prodrug of PMEA resulted in a significant increase in transport of total PMEA [bis(POM)-PMEA, mono(POM)-PMEA and PMEA] across Caco-2 monolayers. While transepithelial transport of PMEA (500 M) was lower than 0.1% during a 3 hr incubation period, transport of total PMEA after addition of bis(POM)-PMEA (100 M) amounted to 8.8% over the same incubation period. Only 23% of the amount transported appeared as intact bis-ester at the basolateral side, while 33% of this amount was free PMEA and 44% was mono(POM)-PMEA, suggesting susceptibility of the prodrug to chemical and enzymatic degradation. Uptake studies revealed that only negligible amounts of bis(POM)-PMEA (< 0.2%) were present inside the cells. Very high intracellular concentrations of PMEA were found 1.2 mM, after a 3 hr incubation with 50 M bis(POM)-PMEA), which suggests that PMEA was trapped inside the cells probably due to its negative charge. This explains that efflux of PMEA was relatively slow (25% of the intracellular amount in 3 hr). Enzymatic degradation of the prodrug by carboxylesterase was confirmed by incubation of bis(POM)-PMEA with purified enzyme (K_m = 87 M and V_max = 9.5 M/min). Incubation of bis(POM)-PMEA (10 M) with cell homogenate of Caco-2 monolayers and pig small intestinal mucosa produced similar degradation profiles. Conclusions. The use of the bis(POM)-prodrug significantly enhances the intestinal permeability of PMEA. Intracellular trapping of PMEA in the intestinal mucosa may result in slow release of PMEA to the circulation after oral administration of bis(POM)-PMEA.     

'She thinks this is the Queen's Castle': women patients' perceptions of an Ontario psychiatric hospital

Drawing on the detailed information contained in patient case files, this study explores women patients' perceptions of the Ontario Hospital, Cobourg, a psychiatric facility for women which operated from 1920 to 1974. The paper concludes that, while twentieth-century psychiatry promoted an image of asylums as modern medical facilities, women patients continued to view these institutions as 'crazy houses', 'havens' and 'prisons'. It was not until the 1950s and 1960s, the eve of the decline of the authority of scientific psychiatry, that some women patients began to conceive of psychiatric hospitals as 'medical' facilities where therapeutic care could be sought.     

Nutrition education and oral health

At present, reduction of the consumption of fat is the main issue in nutritional education. However, this can lead to an increased consumption of mono- and disaccharides and, as a result, to increased dental caries. Individual variations in the susceptibility of caries make it necessary to differentiate the advice for the consumption of snacks between meals. Generally, consumption of complex carbohydrates, such as bread or bread products, can be advised as an alternative for fat and sugar containing snacks. Sugar-free products can also be advised, but not unlimited because of the laxative effect of sorbitol. To prevent tooth erosion the frequent consumption of fruits and fruit juices should be discouraged.     

Anxiety disorders in the dental practice. Part 2. Treatment of patients with anxiety

The purpose of the present paper is to provide the dentist with a number of treatment steps that may reduce anxiety and may enhance trust, feelings of control and application of coping skills. A distinction should be made between patients with specific fear for one or more aspects of dental treatment and patients with non-specific, general anxiety. Practical implications for dental treatment of both groups are given. Dentists should be familiar with the signs and symptoms of the various anxiety disorders, in order to be able to properly refer or treat the patient.     

Injuries of the distal radioulnar joint

Injuries of the distal radioulnar (DRU) joint are common. If the joint is unstable or discongruous, attempts should be made to restore anatomic alignment and stability. Although most acute injuries of the DRU joint are easily treated, they are often overlooked or misdiagnosed because they usually occur in association with other major injuries of the upper limb. Acute and chronic abnormalities are described briefly and the treatment for each is discussed. Appropriate diagnosis and management of the acute injury will yield a much higher success rate than reconstructive procedures to correct a chronic disorder. A differentiation should be made between DRU joint dysfunction and ulnar impingement against the carpus; ulnar shortening is the most commonly used technique to treat the latter condition. In an elderly patient, a Darrach procedure is the preferred treatment for a DRU joint dysfunction; in younger patients, the treatment of choice appears to be resection arthroplasty of the DRU joint with preservation of the ulnar length, the ulnar styloid, and the triangular fibrocartilage complex (TFCC). In cases of malunion of the distal radius with involvement of the DRU joint, the recommended treatment is corrective osteotomy and soft tissue reconstruction of the ligamentous support of the joint.     

Follow-up of patients with colorectal cancer. A meta-analysis.

OBJECTIVE: The authors sought to determine whether intensive follow-up improves 5-year survival rates in patients with colorectal cancer who were operated on for cure. SUMMARY BACKGROUND DATA: Intensive follow-up of patients with colorectal cancer is still controversial. The present uncertainty in regard to the value of intensive follow-up could be the result of the absence of prospective randomized studies comparing patients with and without follow-up. METHODS: Studies comparing two follow-up programs of different intensities were identified in the medical literature and were aggregated in a meta-analysis using the "random effects method." Seven nonrandomized studies describing 3283 patients were analyzed. RESULTS: Patients with intensive follow-up did have 9% better 5-year survival rates than did those with minimal or no follow-up, only when intensive follow-up included carcinoembryonic antigen (CEA) assays. In addition, more asymptomatic recurrences were detected and more recurrences were resected in patients with intensive follow-up. CONCLUSIONS: This meta-analysis indicated that intensive follow-up using CEA assays can identify treatable recurrences at a relatively early stage. Treatment of these recurrences appears to be associated with improved 5-year survival rates. However, not all intensive follow-up strategies will be equally effective. Follow-up may yield the best results if diagnostic tests are used only to detect those recurrences that can be operated on with curative intent and when follow-up is "individualized," according to patient characteristics.     

Curative surgery for gastric cancer: Study of 166 consecutive patients

From January 1980 to December 1991 we operated on 295 patients with a gastric carcinoma. In 166 cases (56.3%) surgery was performed with curative intent. In 93 patients (56%) a subtotal gastrectomy was performed, and in 73 cases (44%) a total gastrectomy. In all the cases a D-2 type lymphadenectomy was used. The global morbidity rate was 23%, and in-hospital mortality was 3.6%. The morbidity and mortality rates of these two operations were statistically different. Global 5-year survival estimate for the whole series is 61.3%. Univariate and multivariate analysis according to T and N (TNM classification), the number of positive nodes resected, and the relation of positive per resected nodes, revealed statistically different outcomes. This kind of quantitative classification allowed identification of high risk groups irrespective of site of nodal involvement. Tumors classified as intestinal or diffuse type by the Lauren classification had similar survival curves and 5-year survival estimates (p=0.834). By univariate and multivariate analysis this classification did not reveal a prognostic value in this group of patients. In our opinion, tumor penetration and lymph node involvement are at present the most reliable prognostic factors available.

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Resumen En el período enero 1980 a diciembre 1991 se operaron 295 pacientes con carcinoma gástrico. En 166 (56.3%), la cirugía fue realizada con intención curativa; en 93 (56%) se realizó gastrectomía subtotal y en 73 (44%) gastrectomía total. En la totalidad de los casos se realizó linfadenectomía D-2. La mortalidad global fue 23% y la mortalidad hospitalaria 3.6%. Las tasas de mortalidad y morbilidad de estas dos operaciones aparecieron significativamente diferentes. La sobrevida global a cinco años estimada para la totalidad de la serie es de 61.3%. Los análisis uni y multivariables de acuerdo con la clasificación TNM, el número de ganglios positivos resecados y la relación positivos/resecados revelaron resultados estadísticamente diferentes. Este tipo de clasificación cuantitativa permitió la identificación de Grupos de alto riesgo independientes del lugar de la invasión ganglionar. Los tumores clasificados como intestinales o difusos (clasificación de Lauren), registraron similares curvas de sobrevida y de sobrevida estimada a cinco años (P=0.834). Mediante el análisis univariable y multivariable esta clasificación no demostró tener valor pronóstico en nuestro Grupo de pacientes. En nuestra opinión, el grado de penetración del tumor y la invasión ganglionar son los factores de pronóstico más confiables.

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Résumé Entre Janvier 1980 et Décembre 1991, nous avons opéré 295 patients ayant un cancer gastrique. Chez 166 (56.3%), l'exérèse a été jugée curative. Chez 93 (56%) des cas, il s'agissait d'une gastrectomie subtotale alors que dans 73 (44%) cas, une gastrectomie totale a été pratiquée. Dans tous les cas une lymphadénectomie du type D-2 lui a été associée. La morbidité globale a été de 23% et la mortalité hospitalière de 3.6%. La morbidité et la mortalité des deux types d'intervention différaient de façon statistiquement significative. La survie à 5 ans de la série en entier a été de 61.3%. Une analyse uni et multifactorielle a pu mettre en évidence une différence statistiquement significative en ce qui concerne la survie par rapport à la classification T-N (TNM), le nombre de ganglions réséqués et le nombre de ganglions envahis/nombre de ganglions enlevés. Cette analyse a permis d'identifier les malades à haut risque, indépendamment du site de l'envahissement lymphatique. La courbe de survie et la survie estimée à 5 ans étaient identiques selon que la tumeur a été classée intestinale ou diffuse selon Lauren. Cette classification n'a pas, pourtant, de valeur pronostique d'après les analyses uni et multifactorielle. A notre avis, la pénétration tumorale et le degré d'envahissement lymphatique sont les deux facteurs pronostiques les plus constants.

     

Amino acid and carnitine supplementation in haemodialysed children

Plasma carnitine, amino acids and lipids levels were studied in ten uraemic children treated with haemodialysis and given amino acid supplementation with and without carnitine. As carnitine is synthesised from lysine and methionine and has a significant influence on lipid metabolism, the relationship between these was examined. Amino acid supplementation (0.25 g/kg body weight) was started with the intention of improving the plasma amino acid pattern in these children and increasing the concentration of lysine, which is the substrate for carnitine synthesis. Amino acids were administered i. v. during dialysis and carnitine (25 mg/kg body weight i. v.) was administered after dialysis three times a week. Concentrations of most essential amino acids were decreased in these patients. The first period of amino acid supplementation did not increase plasma levels of the essential amino acids, with the exception of tyrosine (P<0.01). After the second period of supplementation, methionine was increased (P<0.01), isoleucine was decreased (P<0.01), but tyrosine normalised and was significantly lower than after the first period (P<0.05). Thus overall amino acid supplementation did not improve amino acid levels; it was inconsistently associated with a further decrease in highdensity lipoprotein-cholesterol and an increase in total protein levels. Lysine concentrations after amino acid supplementation remained low. Paradoxically, before carnitine supplementation a positive correlation between free carnitine and triglycerides was observed. The plasma carnitine concentration, initially very low, was excessively high after carnitine supplementation. After carnitine administration no amelioration of any of the other biochemical indices was observed. Carnitine supplementation was associated with a significant reduction of total protein levels (P<0.01). In children with end-stage renal disease on haemodialysis, neither amino acid nor carnitine supplementation appear to result in significant improvements in plasma levels of essential amino acids or lipids.