H.H.M. de Boer

Does nifedipine suppress atherogenesis in WHHL rabbits

The effects of the calcium antagonist, nifedipine, on atherogenesis were investigated in WHHL rabbits, a unique animal model for human familial hypercholesterolemia. Nifedipine, in a daily dose of 40 mg, was fed orally to 9 rabbits over a period of 26 weeks, resulting in serum concentrations of between 740 and 1370 ng/ml. Rabbits were killed at an age of 40 weeks and atherosclerotic plaque formation in various aortic segments was quantified. Atherosclerosis was most pronounced in the aortic arch and the thoracic aorta, plaques covering, respectively, 59 +/- 17% and 17 +/- 9% of total vessel area. These results are similar to those observed in a control group, which received the same diet and no nifedipine and displayed lesions on 62 +/- 19% and 21 +/- 13% of total area of aortic arch and thoracic aorta, respectively. Although variations in plaque area between WHHL rabbits are large and thus preclude the observation of small effects, the efficacy of nifedipine as an anti-atherogenic agent in rabbits with hereditary hypercholesterolemia appears questionable.

The influence of NSAIDs on experimental intestinal anastomoses.

Limiting degradation of collagen during the initial phase of wound healing is expected to improve postoperative intestinal strength and thereby decrease chances for anastomotic dehiscence. We studied the influence of four nonsteroid anti-inflammatory drugs on the healing of intestinal anastomoses in rats, with special regard to changes of collagen levels around the anastomoses. Four experimental groups of 20 rats each received daily oral doses of piroxicam, ibuprofen, aspirin, or indomethacin and were compared with a control group. Animals were sacrificed 3 or 7 days after operation. Both morbidity and mortality rate in the experimental groups were high. Collagen, measured as hydroxyproline, levels in anastomotic and adjoining 1-cm intestinal segments were compared with concentrations in control segments resected during operation. After an initial decrease on day 3, hydroxyproline concentrations increased on day 7. In the colon the lowering of hydroxyproline concentrations, which was more pronounced than in the ileum, was significantly reduced by administration of piroxicam and ibuprofen, both in the anastomosis and its proximal segment. On day 7, the increase of hydroxyproline concentrations in the ileum was inhibited by administration of anti-inflammatory drugs. It is concluded that nonsteroidal anti-inflammatory drugs may limit postoperative degradation of collagen in colonic anastomoses, but at the same time may increase the rats susceptibility to surgical infections.

Loss of collagen from experimental intestinal anastomoses: Early events

Collagen lysis, which always occurs to some extent in the wound area, is thought to be the underlying cause for breakdown of intestinal anastomoses. Therefore, we have studied the loss of collagen around ileal and colonic anastomoses in New Zealand White rabbits during the first 48 hr after operation. In the ileum, significant lysis of collagen in the anastomotic area, as represented by a decreased level of hydroxyproline, occurs from 12 hr postoperatively onward. Maximal loss of hydroxyproline, as compared to preoperative values, is 27% measured 24 hr after operation. In the colon, significant lysis of collagen occurs after 3 hr. The lowest level of hydroxyproline measured during the experimental period is found 48 hr after operation, where the concentration is decreased by 38%. Changes in ileum are restricted to the anastomotic area, while in the colon the decrease in hydroxyproline extends along the intestinal wall, particularly in a proximal direction. The fact that total protein concentrations do not vary significantly indicates that the lowered hydroxyproline levels are specific. Microscopic examination of the wound area shows that the cellular response during the first 24 hr after wounding is restricted to granulocytes. It is suggested that granulocyte collagenase is mainly responsible for the observed lysis of collagen after intestinal anastomosis.

Morphometric analysis of the effects of antineoplastic drugs on mucosa of normal ileum and ileal anastomoses in rats

Antineoplastic agents affect the healing of intestinal anastomoses. They often induce anorexia and diarrhea, possibly caused by morphological changes in the small intestinal mucosa. These changes were evaluated in the rat ileum. Animals in group I underwent only intestinal surgery while those in groups II and III underwent surgery on the third day of a 5-day course with cisplatin (in two different doses), bleomycin, and 5-fluorouracil. The parameters were: number of mitoses in crypts, crypt depth, villus height, width, and contour length, measured in the mucosa of primarily resected segments of the ileum and of the anastomotic area. Surgery yields an increased crypt depth and villus length in the anastomotic area without changing villus width. The changes in intestinal crypts precede those in villi. Antineoplastic drugs decrease crypt mitotic rate, villus height, width, and contour length. After cessation of antineoplastic chemotherapy mitotic activity increases. The shallower and shorter villi increase in width and length resulting in an increased villus contour length and area. A linear relation exists between villus contour length and villus height and width. Thus, antineoplastic polychemotherapy, dose-dependently, reduces and surgical trauma increases intestinal proliferative activity. However, the morphologic changes do not unequivocally explain possible metabolic disturbances causing retarded intestinal wound healing.

Intraperitoneal cytostatics impair healing of experimental intestinal anastomoses.

We investigated the effect of two doses of cytostatics, administered intraperitoneally during 5 consecutive days, on the healing of ileal and colonic anastomoses constructed on the third day. The cytostatics regimen consisted of a combination of 5-fluorouracil, bleomycin and cisplatin at 10, 2 and 0.35 mg kg-1d-1, respectively, or at twice higher doses. The lower dose was similar to that given intravenously in previous experiments. Rats were sacrificed 3 or 7 days after operation. No effects of cytostatics were observed after 3 days, neither on anastomotic bursting pressure nor on hydroxyproline concentration (microgram/mg dry weight) or content (microgram cm-1). Profound effects were seen at 7 days. In the high dose group, bursting pressures in both anastomoses were greatly reduced with respect to the control group. Concurrently, collagen synthesis was severely impaired, as indicated by sustained decreased hydroxyproline concentrations and content. The lower dose of cytostatics showed essentially similar effects on hydroxyproline parameters, but affected anastomotic strength less dramatically. The data indicate that, while intraperitoneal chemotherapy may show less detrimental systemic toxicity and thus allow higher doses, its application as an adjunct to gastrointestinal surgery may be limited because of its severe effects on anastomotic repair.

Anastomotic insufficiency in small bowel surgery —incidence and treatment

ZusammenfassungIn dem Zeitraum 1977–1981 wurden bei 143 Patienten 234 Dünndarmanastomosen angelegt. Acht Anastomosen zeigten eine Nahtleckage (3,4%), bei neun entwickelte sich eine Fistel (3,8%): die Gesamthäufigkeit von Wundheilungsstörungen bei Dünndarmanastomosen war 7,3%. Bei gleichzeitigem Vorliegen intraabdominaler Infektionen betrug die Häufigkeit 14,8%, ohne diese 0,8%. Die Resultate einer Therapie durch Übernähung oder Resektion mit sofort anschließender Reanastomosierung waren enttäuschend. Befriedigendere Ergebnisse wurden durch Aufheben der Anastomosen, Anlage einer ‚split enterostomy’ unter Wiederherstellung der Kontinuität in einer zweiten Sitzung erzielt. Die Mortalität betrug 3/17 (18%). Ein Literaturüberblick wird gegeben.SummaryIn the period 1977–1981 234 small bowel anastomoses were constructed in 143 patients. Eight anastomoses showed leakage (3.4%) and from nine anastomoses a fistula developed (3.8%): a total rate of disturbed healing of small bowel anastomoses (7.3%). In the presence of intra-abdominal infection this rate was 14.8%, in the absence of infection 0.8%. The results of treatment with oversewing and with resection and immediate anastomosis were disappointing. Better results were obtained by dismantling of the anastomosis, establishment of a split-enterostomy and reestablishment of continuity in a second stage. Mortality was 3/17 (18%). The literature is reviewed.

Solubility of tissue hydroxyproline in experimental intestinal anastomoses

Salt and acid solubility of collagen are thought to reflect its degree of crosslinking. In order to examine postoperative changes in crosslinking of intestinal collagen, which are of importance to the stability of the intestinal wall, we have investigated the solubility of hydroxyproline in rabbit ileum and colon, both in unwounded intestine and after construction of an anastomosis. Solubility in salt and dilute acid was increased by a sonication procedure. This way, 9% of total hydroxyproline in the unwounded colonic wall was salt soluble and 65% acid soluble. A similar distribution was observed in ileum. Three days after operation the salt-soluble fraction was significantly elevated in samples from the anastomotic area. In colon, this increase also persisted 7 days postoperatively. Comparison of anastomotic samples collected 3 and 7 days after surgery shows a significant decrease in the acid-soluble and a significant increase in the solid fraction. This phenomenon occurs both in ileum and colon. These results indicate that during the first days after operation the integrity of the intestinal wall is weakened not only by a loss of collagen, but also by a changed solubility of the remaining collagen.

Small bowel transplantation in the rat: The adverse effect of increased pressure during the flushing procedure of the graft

The influence of the pressure during the flushing procedure on the results of the subsequent transplantation was investigated in a model of heterotopic functional small bowel transplantation in the outbred Wistar rat. In this model insufficient small bowel preservation will result in a lethal shock, soon after revascularization. If the size of the small bowel graft was reduced to a 15-cm segment of the proximal jejunum, improper preservation did not lead to lethal shock, but to histological changes of the graft. The influence of high flushing pressure (80 cm), medium flushing pressure (50 cm), low flushing pressure (35 cm), and no flushing procedure at all, was investigated in different groups of rats. Flushing was performed by gravity using chilled Ringers lactate solution (4 degrees C), buffered with NaHCO3 at a pH of 7.4. The results were evaluated histologically as well as clinically. Results indicated flushing of the graft to be superior to a nonflushing procedure. A flushing pressure of 80 cm and even 50 cm proved to be harmful to the jejunal graft. Flushing pressure of 35 cm resulted in successful segmental (jejunal) and subtotal (minus 5- to 7-cm distal ileum) small bowel transplantation. However, survival of a total small bowel graft could not be achieved with the optimal flushing procedure indicating that the functional integrity of a small bowel graft also depends on conditions other than the method of short-term preservation.

Partial ileal bypass inhibits atherosclerosis in WHHL rabbits.

The effectiveness of partial ileal bypass (PIB) as a counter-measure against atherosclerosis was evaluated in WHHL rabbits. The effects of PIB and sham operation, each performed in five animals, on serum lipids, lipoproteins and plaque formation were investigated. PIB resulted in an immediate and sustained decrease of 52% (range 29-67%) in serum cholesterol, while sham operation had no effect. The main reduction was in LDL cholesterol; VLDL-cholesterol was lowered to a lesser extent. PIB also appeared to change the electrophoretic behaviour of total serum, very low density and low density lipoproteins. Plaque formation, measured 30 weeks after operation in various aortic segments and arteries, was significantly reduced after PIB. It is concluded that an induced lowering of serum cholesterol can prevent atherosclerosis in WHHL rabbits. Also, these animals must be considered as a model for the receptor-defective cellular phenotype of homozygous familial hypercholesterolemia, not for the receptor-negative type, which is the only truly genetically homozygous form.

The role of mammography in the detection of bilateral primary breast cancer

The significance of mammography in the detection of contralateral primary breast cancer was evaluated in 55 patients with bilateral breast disease. Fifteen (65%) of 23 patients in the synchronous group and 16 (50%) of 32 patients in the metachronous group had clinically occult carcinoma in the opposite breast. Excluding the 2 malignancies discovered by prophylactic mastectomy, mammography alone was responsible for the detection of 29 (52.7%) nonpalpable, contralateral breast carcinomas. The whole series of 110 malignant breasts comprised 41 nonpalpable carcinomas, of which 12 were noninvasive [ductal carcinoma in situ (7) and lobular carcinoma in situ (5)] and the remaining 29 were invasive carcinomas, either ductal of various types (25) or lobular (4). With regard to the évaluable axillary nodes, 20 (54.1%) of 37 palpable breast cancers and only 3 (11.5%) of 26 nonpalpable breast carcinomas had positive lymph nodes. The multicentricity rate was particularly high in synchronous tumors (70.6%), and in invasive lobular (73.3%) and noninvasive (75%) carcinomas. The favorable 5- and 10-year survival of patients, both in synchronous and metachronous bilateral primary breast cancer, justify that they be treated with aggressive optimism.RésuméLa valeur de la mammographie dans le dépistage du cancer mammaire primitif controlatéral a été étudié chez 55 malades qui ont présenté un cancer bilatéral du sein. Quinze des 23 malades (65%) dans le groupe synchrone et seize des 32 malades (50%) dans le groupe métachrone présentaient un cancer cliniquement occulte dans le sein opposé. Exclusion faite de 2 cas de tumeurs malignes découverts par une mammectomie prophylactique la mammographie à elle seule permit de dépister dans le sein opposé 29 (52.7%) cas de cancers impalpables. La série, au total 110 cas de tumeurs malignes, comprenait 41 cancers impalpables dont 12 étaient non invasifs (7 cancers in situ canaliculaires et 5 cancers in situ lobulaires) et 29 étaient invasifs (25 cancers canaliculaires de type variable et 4 cancers lobulaires). En ce qui concerne les ganglions axillaires ils étaient envahis dans 20 (54.1%) des 37 des cancers palpables et 3 (11.5%) des 26 cancers non palpables. Le taux de foyers multiples était particulièrement élevé dans les tumeurs synchrones (70.6%), dans les cancers lobulaires invasifs (73.3%) et dans les cancers non invasifs (75%). Le taux favorable de survie à 5 ans et à 10 ans des malades atteints de cancers du sein, aussi bien dans le groupe synchrone que dans le groupe métachrone justifie de les traiter avec aggressivité et optimisme.ResumenLa significación de la mamografía en la detección del cáncer mamario primario contralateral fue valorada en 55 pacientes con enfermedad mamaria bilateral. Quince (65%) de 23 pacientes en el grupo con enfermedad síncrona y 16 (50%) de 32 pacientes en el grupo con enfermedad metácrona poseían carcinoma clínicamente oculto en el otro seno. Excluyendo las 2 neoplasias malignas descubiertas en mastectomfa profiláctica, la mamografía de por sí fue responsable de la detección de 29 (52.7%) carcinomas contralaterales no palpables. La totalidad de la serie de 110 neoplasias malignas comprendió 41 carcinomas no palpables, de los cuales 12 fueron no invasivos (7 carcinomas ductales in situ y 5 carcinomas lobulillares in situ) y los 29 restantes fueron carcinomas invasivos, unos ductales de diversos tipos (25) y otros lobulillares (4). En relación con los ganglios axilares valorables, 20 (54.1%) de 37 cánceres palpables y sólo 3 (11.5%) de 26 carcinomas no palpables tenían ganglios linfáticos palpables. La tasa de multicentricidad apareció particularmente alta en los tumores síncronos (70.6%) y en los carcinomas lobulillares invasivos (73.3%) y no invasivos (75%). La supervivencia favorable a 5 y 10 años de los pacientes, tanto en el cáncer primario bilateral síncrono como en el metácrono, justifica que sean tratadas con agresivo optimismo.