Paresis of peristalsis and ileus lead to death in lactating mice
Transcrição
Paresis of peristalsis and ileus lead to death in lactating mice
32 Laboratory Animals (1986) 20, 32-35. Paresis of peristalsis and ileus lead to death in lactating mice* I. KUNSTYR /nstitllt fiir Versuchstierkllnde im Zentralen Tierlabor, Medizinische Hochschu/e Hannover, D-3000 Hannover 6/, Federal Republic of Germany Summary Based on the examination of'45 dead and 5 moribund female mice during a 2-year period, we are able to describe a new disease entity: ileus of the small intestine in lactating mice caused by a paresis of' peristalsis. Diarrhoea was not observed and innammation and infectious agents were not found. Females were affected during the 2nd week of their first lactation. The condition may have a mortality rate as high as 40%. It is assumed that exhaustion (calcium, glucose, etc.) is the cause of this condition. Consequentl}', the development of' a dietary supplement or of'a special diet for lactating mice may prove beneficial in preventing this disease. Endogenic (Clostridia) or exogenic toxic components may also playa role. Keywords: Mice; Gastrointestinal system, gastrointestinal motility; Lactation. During post-mortem examinations of breeding female mice which died spontaneously during lactation, we noticed unusual changes in the digestive tract not described for any known infectious agent. Between October 1982 and October 1984, we examined a total of 50 mice with this syndrome and our results have led us to discover a new disease which we refer to as paresis (partial paralysis) of peristalsis and ileus in lactating mice. Material and methods 50 affected lactating mice were examined. All of them were kept in the Institute as either breeding females or as experimental animals for mutagenicity testing (Fahrig, 1981). Housing and feeding conditions have been previously described (Kunstyf, Matthiesen, Giirtner, Maess & Heimann, 1982). The mice were fed a standardized pelleted diet for breeding mice and rats (Altromin 1310 from Altromin Spezialfutterwerke GmbH, 0-4937 Lage, FRG). Examination included necropsy, photodocumentation and bacteriological observations. "Partly Malm(i Received presented during the 2nd FELASA 18-20 June. 1984. 25 lalll/ary NBS. Accepted symposiulll, 25 AI/gust /985. Bacteriological techniques comprised routine cultivation of aerobes and anaerobes (Kunstyf, 1983) and at a later phase (in about 15 animals) anaerobic cultures were instigated and direct smears (Gram stain) of the intestinal contents were examined to rule out Clostridia. In four cases special techniques for Campy/ohacler sp. were used (Weber, Lembke & Schafer, (982). The animal strain was recorded, as well as the day of lactation, litter size, and the number and age of the young. The organs of 3 mice were examin~d histologically. Results Of 50 affected females, 45 were presented dead for necropsy and 5 were alive, but moribund. Figs 1 to 3 illustrate normal and affected digestive tracts. Clinical signs Enlarged abdomen, apathy, no defaecation, no milk yield (the young are hungry and cold) and spontaneous death were observed. Necropsy The mammary glands had long nipples but no milk. The lungs showed varying degrees of generalized emphysema. The stomach was slightly dilated and filled with a watery fluid. In the small intestine the proximal part showed a distinct distension with thin watery contents which gradually became thicker along the length of the proximal small intestine until it became a hard conical 'plug' leading to impaction and ileus. The distal part of the small intestine was either empty or contained 'faecal' pellets which are totally misplaced in that part of the intestine. fn the caecum the tail contained hard material whereas the body was nearly empty or slightly filled with thin contents. The large intestine was either empty or filled with a few faecal pellets and occasionally with mucous material. 6 females showed atypical findings: 2 cases had a limited distension of the intestine (few centimetres); 2 cases had impaction with a 'plug' but no obvious dilatation; I case had a subnormal filling of the stomach and 1 case had an occlusion of the large, rather than small, intestine. Paresis of peristalsis 33 in lactating mice Fig. I. The digestive tract of a normal healthy mouse. Fig. 2. The digestive tract of a mouse which died as a result of the disease. Note the slightly distended stomach and the distinct distension of the proximal part of the small intestine. In the distal part there is a segment with a hard plug-like content (noted by forceps impressions). The content in the 'tail' of the caecum has a similar (hard) consistency. The distal part of the small intestine and the large intestine are empty. a Fig. 3. Schematic drawings of the digestive tracts in healthy (a) and affected (b) mice respectively. The degree of distension of certain parts can be scen and the compactness of gut contents is indicated by the darkness of the pattern. 34 Kunstyf Histology In 2 cases there was no inflammation in any part of the digestive tract, and with the exception of lung emphysema, no changes in heart, liver, spleen and kidneys. In 1 case there was oedema of the submucosa of the ileum and some necrosis of Peyer's patches. Bacteriology The organs were sterile and no pathogenic were detected in the intestine. microbes Strain distribution The distribution of the syndrome amongst the various strains reflected the number kept in the Institute rather than any strain specificity. (C57BU 6J (20); DBA (10); C57BUKS (9); AKR (3); T-strain (2); Dwarf (2); C57BU"1 (I); not known (3)). Information on parity, litter size and day of death after parturition is given in Table 1. Table l. Incidence of disease in relation to time after parturition, parity and fecundity Mean (range) ± SD No. of animals evaluated Time of death (days) 13·73 ± 4-44 after parturition (8-25) 37 Number of litters \·72 ± )·4 (1-6) 32 Number born 6·96 ± [·95 (5-11) 29 Discussion The syndrome described here seems not to be strain-specific and is characterized by a paralysis of peristalsis, mainly in the proximal small intestine. Impairment of gut motility appears to be the primary cause and occlusion of the intestine (ileus) is the most likely consequence. The slightly enlarged stomach with a watery content may be the result of enhanced water intake. Previous failure to recognize this syndrome by researchers is probably due to its misinterpretation as a post-mortem change. In his lecture, Niissel (1980) was the first to describe a high mortality in lactating mice and he considered it was due to Clostridium perfringens enterotoxemia. He was most probably confronted with the same syndrome described here together with a high bacterial load of C/. perfril/gens, and the toxins of this ubiquitous micro-organism may have aggravated the symptoms. However, in contrast to his observation of diarrhoea in the affected females and/or their young, we made no such observations. The syndrome does not seem to be identical with either the 'obturation ileus' or the 'paralytical ileus' described by Giittner & Karasek (1979). However, it may be a combination of both, i.e. a mechanical occlu.sion by a plug-like impaction of the intestine (obturation ileus) together with a partial paralysis (paralytical ileus), the latter seeming to be a precondition for the former. Organ changes in the liver, spleen and lymph nodes accompanying both forms of paresis (Giittner & Karasek, 1979) were not found in the present study. A recent published handbook on the pathology of laboratory animals (McClure, Chapman, Hooper, Smith & Fletcher, 1978) does not mention any similar condition. Although in some strains of mice (Niissel, 1980) and in some experiments with mutagenicity testing (Fahrig, 1983), the number of affected females reached 30-40%, the syndrome seems to be sporadic having no obvious epidemiology. In cases of high mortality other complicating factors were most probably involved and in agreement with Niissel (1980), the syndrome has never been observed in males. It is noticeable that an overwhelming proportion of females were affected during their first lactation (Table I) and this finding coincides with those of Niissel (1980) and Rapp, Kluge & Burow (1984). In a study using 47 000 breeding mice the latter researchers observed a significantly higher mortality during the first lactation - partly associated with Citrobacter induced colitis (Deerberg, 1984). At this stage the primiparous mouse is lactating after parturition, often simultaneously pregnant for a second time, and yet not fully grown. We attribute the disease to the failure to adapt to this physiological overload, in other words the disorder is due to 'exhaustion'. Similar health complications are well known in high-producing female farm animals. Our hypothesis is additionally supported by the lack of any inflammation or recovering any infectious agent. Exhaustion of the animals may well be linked to calcium and its role in muscle contraction (Goldenberg & Meurer, 1983; Grover & Daniel, 1985). Thus, an imbalance or severe exhaustion of calcium reserves or other electrolytes, as well as glucose and/or vitamin E, may reduce muscle tone. Subsequent paralysis of peristalsis will ultimately result in impaction and death. It was possible to bleed and examine the serum of 2 female mice with this syndrome. In addition to a high sodium level, reduced levels of calcium and glucose were found. It was not clear, however, if these changes could be related to the syndrome or to terminal (agonal) exhaustion. It is, likewise, unclear why the intestine is the single target organ. Shirley (1984) reported the increased nutritional Paresis of peristalsis 35 in lactating mice requirements of lactating rats compared with pregnant rats and such requirements may well hold for mice too. Non-breeding and breeding mice are usually fed 2 different kinds of standard diet. The development of a third supplemented or enriched diet for lactating breeding mice might possibly prevent the syndrome described. Interestingly, we have observed similar changes in 3 non-lactating females which had been given a carcinogenic compound, a polycyclic carbohydrate 2-acetylaminofluorene (Fahrig, 1984), which directly impairs peristalsis. This finding suggests that a pathologic condition similar to the syndrome described can be induced by toxic substances. Acknowledgements I am indebted to Mrs Dr Susanne to Dr H. Ernst for the histological Naumann and examinations. References Dcerberg, F. (1984). Personal communication. Fahrig, R. (1981). Mutagenitiitsforschung - ein Weg zur Krebserkennung. Die Geschichte der Mutationsforschung bis zum Spot-Test. Umschall in Wissenschaji lind Technik 81. 529-533. Fahrig, R. (1983). Personal communication. Fahrig, R. (1984). Personal communication. Goldenberg. M. M. & Meurer, R. D. (1983). The effect of calcium antagonists on contractions of the sensitized and normal guinea pig ileum. Prm'wglandins 26, 615-622. Grover. A. K. & Daniel. E. E. (eds) (1985). Calcillm and Contractilitv. Smooth Mliscle. Clifton: Humana Press. Giittner. J. '& Karasek, E. (1979). Einfrihrung in die Versllchstierkunde, vol. 3. Versuehstierkrankheiten. Jena: VEB G. Fischer. KunstYr. I. (1983). Schwerpunkte der bakteriologisehen Ubcrwachung von Versuchstierbestiinden. In Schwer- {JlInkte der Infektionsiibenvachung bestiinden (ed. K. Bonath). pp. in 23-39. VersllchstierBerlin & Hamburg: Parey. Kunstyi" I., Matthiesen, Th .. Giirtner, K., Maess, J. & Heimann, W. (1982). Post-mating non-infectious hydrometra in BALB/c:Bom mice. Laboratory Animals 16, 51-55. Parese der Peristaltik McClure, H. M., Chapman, W. L.. Hooper, B. E .. Smith. F. G. & Fletcher, O. J. (1978). The digestive systcm. In Pathology of Laboratory Animals, vol. 1 (cds. K. Bcnirschke, F. M. Garner & 1'. C. Jones), pp. 17()-317. New York. Heidelberg, Berlin: Springer. Niissel, M. (1980). C1ostridien-Enterotoxiimie bei weiblichen Zuehtmiiusen. Lecture during the 13th Scientific Meeting of GV-SOLAS, Lausanne 2R-30 May 1980. Abstract. Rapp, K. G., Kluge, R. & Burow. K. (1984). Zusammenhiinge zwischen bioehemisehen Polymorphismen und quantitativen Merkmalen bei Han:NMRI Miiusen. Hannover Colloqllillm of Laboratory Animal Science - a lecture, Hannover 17 April 1984. Shirley, B. (1984). The food intake of rats during pregnancy and lactation. Laboratory Animal Science 34. 169-172. Weber. A., Lembke. C. & Schiifer, R. (1982). Untersuchungen zum Vorkammen von Campylobacter jejlllli bei Kaninchen, Meersehweinchen, Ratten und Miiusen in der Versuehtierhaltung. Berliner lind Miinchener Tieriirztliche Wochenschrift 95, 488-489. und Ileus mit tOdlichem Ausgang bei laktierenden Miiusen I. KUNSTYR Zusammenfassung Auf der Grundlage von Beobachtungen an 45 spontan gestorbenen und 5 kranken Miiuseweibehen. die wiihrend zwei Jahren unterslicht wurden, wird cine neue nosologisehe Einheit beschrieben: die Parese der Peristaltik und Ileus bei laktierenden Miiusen. Das pathologisehe Leitsymptom war dabei die Parese der Peristaltik mit sekundiirelll Ileus, lokalisiert iiberwiegend im Diinndarm. Durchfall wurde nicht registriert, die Entziindungskomponente fehlte, es wurden keine infektii:isen Erreger isoliert. Betroffen waren Miiusemiitter von versehiedenen Stiilllmen. Illeistens naeh dem ersten Wurf. iiberwiegend am Ende der zweiten Laktationswoche. Diese sporadisch auftretende Erkrankung kann bis zu 40% Mortalitiit verursaehen. Es wird postuliert. das Ersehi:ipfung - von Calcium-Reserven, Glukose, usw. - die Ursache dieses nicht-infektii:isen pathologischen Zustandcs ist. Endogene (C1ostridien) oder exogene toxisehe Komponenten kilnnen vermutlich diesen Zustand versehlechtern, bzw. seiber herbeifiihren. Um diesem pathologischcn Zustand vorzubeugen wird die Entwicklung eines diiitctisehen Zusatzes oder einer speziellen Diiit fiir laktierende Miiusc diskutiert und el1lpfohlen.