[Motility disorders of the esophagus]. / Motilitätsstörungen des Ösophagus.

Motility disorders of the esophagus comprise a heterogeneous spectrum of diseases. Primary malformations of the esophagus are now amenable to improved surgical and gastroenterological therapies; however, they often lead to persistent long-term esophageal dysmotility. Achalasia originates from impaired relaxation of the gastroesophageal sphincter apparatus. Systemic diseases may give rise to secondary disorders of esophageal motility. A number of visceral neuromuscular disorders show an esophageal manifestation but aganglionosis rarely extends into the esophagus. The growing group of myopathies includes metabolic and mitochondrial disorders with increasing levels of genetic characterization and incipient emergence of therapeutic strategies. Esophagitis with an infectious etiology causes severe dysmotility particularly in immunocompromised patients. Immunologically mediated inflammatory processes involving the esophagus are increasingly better understood. Finally, rare tumors and tumor-like lesions may impair esophageal motor function.

[Twenty years diagnostic competence center for Hirschsprung's disease in Basel]. / Zwanzig Jahre diagnostisches Hirschsprung-Kompetenzzentrum in Basel.

BACKGROUND: The experience gained by the Basel Hirschsprung Competence Center over 20 years is presented. MATERIALS AND METHODS: A total of 19,365 rectal mucosal biopsies were investigated in the 20 years between 1987 and 2006. All biopsies of rectal mucosa originated from 6,615 children aged between 1 week and 4 years. Biopsies were collected in teaching hospitals all over Germany and transported on dry ice by Intercity Courier Service. Serial sections of frozen tissue were made using a cryostat. Enzyme histochemical staining was performed. RESULTS: A total of 935 cases of Hirschsprung's disease (14%) were observed (769 cases of classical Hirschsprung's disease, 68 total colon aganglionosis, 98 ultrashort rectum aganglionosis). Total colon aganglionosis was found in 1.0% and the frequency of ultrashort Hirschsprung' disease was 1.4%. The quality of the histological results was confirmed by a second independent investigator. There were neither false positive nor false negative diagnoses. Enzyme histochemical staining results were readable within 2 h. Acetylcholinesterase, which is significantly increased in Hirschsprung's disease, was used for nerve fiber staining. Succinic and lactic dehydrogenases and nitric oxide synthase served as confirmatory proof of aganglionosis (elective nerve cell staining of the submucous plexus). CONCLUSION: Among 100 children with chronic constipation an average of 12 children were diagnosed with Hirschsprung's disease. Of these 2% showed total colon aganglionosis or ultrashort Hirschsprung's disease. Enzyme histochemical diagnosis of Hirschsprung's disease proved 100% reliable and time saving.

[Enzyme histochemical diagnosis of gastrointestinal motility disorders. A laboratory guide]. / Enzymhistochemische Diagnostik gastrointestinaler Motilitätsstörungen. Ein Laborleitfaden.

The enzyme histochemical reactions for acetylcholinesterase, lactic dehydrogenase, succinic dehydrogenase and nitroxide synthase are currently the gold standards for the diagnosis of gastrointestinal motility disorders. The acetylcholinesterase staining reaction shows the cholinergic nerve fibre network of the muscularis mucosae and muscularis propria, and correlates with their acetylcholinesterase activity. Lactic dehydrogenase, succinic dehydrogenase and nitroxide synthase selectively demonstrate the nerve cells of the myenteric and submucous plexus. These enzyme histochemical techniques require fresh, native tissue. Consequently, the transport of biopsies from gastroenterology or surgery to pathology must be well organized and feasible without time loss. Alternatively, biopsies may be mailed on dry ice to more distant pathology institutes. The enzyme histochemical laboratory technique has been optimized and refined over four decades. The optimized reactions are highly reliable and reproducible. In particular, a standardized methodology is a prerequisite for the interinstitutional comparability of results. This laboratory manual provides a detailed methodological description of the most important enzyme histochemical reactions for the diagnosis of gastrointestinal motility disorders.

[Hypoganglionosis as a cause of chronic constipation]. / Hypoganglionose als Ursache chronischer Obstipation.

Hypoganglionosis comprises 3-5% of gastrointestinal innervation defects which are connected to therapy-resistant chronic constipation in children and adults. Similar to Hirschsprung's disease, hypoganglionosis may be complicated by megacolon formation and must be considered in the differential diagnosis. Three main subtypes may be distinguished: congenital hypoplastic hypoganglionosis occurs predominantly in Hirschsprung's disease proximal to the aganglionic segment and consists of small paucicellular ganglia with increased interganglionic distances. Oligoneuronal dysganglionic hypoganglionosis manifests in childhood. Initially, myenteric ganglia are of normal size and have normal interganglionic spacing and normal neuronal content. However, nerve cells are hypoplastic and ganglia undergo progressive nerve cell loss. This type of hypoganglionosis may progress into atrophic hypoganglionosis, which shows a morphology similar to hypoplastic hypoganglionosis. All subtypes of hypoganglionosis result in decreased acetylcholinesterase activity in the nerve fiber network of the muscularis propria. The pathogenesis of hypoganglionosis is still poorly understood. In Hirschsprung associated hypoganglionosis, mutations in the RET and GDNF-genes have been found. Despite a heterozygote GDNF+/- animal model for hypoganglionosis, no GDNF mutations have so far been demonstrated in human Hirschsprung independent, isolated hypoganglionosis.

[The morphological characteristics of aplastic and atrophic desmosis of the intestine]. / Morphologisches Bild der aplastischen und atrophischen Desmose des Darms.

In addition to the enteric nervous system, the interstitial cells of Cajal and the smooth musculature, the collagenous fibre network of the muscularis propria plays a major role in the coordination of peristalsis. Partial or complete absence of this network in patients with chronic constipation has been described as 'desmosis'. Two major subtypes of desmosis can be distinguished: in the rare congenital (primary) aplastic desmosis of childhood, the collagenous fibre network is not formed. This is characteristic of microcolon megacystis syndrome and is associated with aperistalsis. The more common atrophic (secondary) desmosis of adulthood is typically incomplete and associated with a hypoperistaltic syndrome. Neither the etiology nor the pathogenesis of desmosis are currently understood. Atrophic desmosis may occur after previous inflammatory episodes. Further extensive studies are needed to better understand the pathogenesis, etiology and functional implications of this disease.

[Conventional histological diagnostics in coloproctology]. / Konventionelle histologische Diagnostik in der Koloproktologie.

With the introduction of immunohistochemical methods, histopathological diagnosis based on formalin fixed, paraffin embedded tissue in coloproctology has substantially improved. In recent years, the routine use of immunohistochemistry for S100, cathepsin D and a picrosirius red staining has proven to be sufficient for the diagnosis of hypoganglionosis of the myenteric plexus and desmosis of the muscularis propria. In some cases, an immunohistochemical reaction for CD 117 is also necessary for the evaluation of Cajal cells. In contrast, in ultrashort Hirschsprung's disease, aganglionosis of the anal ring, aganglionosis of the musculus corrugator cutis ani, and internal sphincter, the histochemical acetylcholinesterase reaction is essential and not replaceable by any immunohistochemical method.Immunohistochemistry, classical histological stains and enzyme histochemistry are complementary histopathological techniques. In contrast to immunohistochemistry, enzyme histochemistry requires native cryostat sections for the assessment of enzyme activity. As a consequence, biopsy performance and transport to pathology departments should be particularly well organized.

[Intestinal neuronal dysplasia type B: how do we understand it today?]. / Intestinale neuronale Dysplasie Typ B: Wie verstehen wir sie heute?

Intestinal neuronal dysplasia type B (IND B) is currently considered to be a subtle malformation of the submucosal plexus, leading to an increased proportion of over-sized ganglia and potentially accompanied by a mild, chronic gastrointestinal motility disturbance. The diagnosis of IND B is morphologically based and involves the demonstration of an increased proportion of giant ganglia in the submucous plexus related to the patient's age. Giant ganglia are physiologically frequent in the neonatal period. Therefore, IND B should not be diagnosed prior to 1 year of age. Morphological features of IND B may occur as an isolated finding or may be observed proximal to an aganglionic segment. IND B and constipation may resolve spontaneously up to the age of 4 years. Treatment of IND B is usually conservative, surgical resection is currently deemed necessary only in a minority of patients. The pathogenesis of IND B is still incompletely understood and the etiology unknown. Future research on the basis of standardized diagnostic conditions is expected to result in a better understanding of this disease, and to reveal the cause of aberrant ganglion development.

[Enzyme histochemistry of classical and ultrashort Hirschsprung's disease]. / Enzymhistochemie des klassischen und des ultrakurzen Morbus Hirschsprung.

Hirschsprung's disease is the most important type of gastrointestinal dysmotility in neonatal pathology. Aberrant craniocaudal migration of neural crest stem cells results in an intestinal aganglionic segment of variable length. In 'classical' Hirschsprung's disease (60-75% of cases), the aganglionic segment spans the rectum and sigma. Ultrashort Hirschsprung's disease (5-10%) is restricted to the most distal 3-4 cm or immediate rectoanal transition only. In the normal enteric nervous system, myenteric ganglia modulate the parasympathetic innervation of the sacral roots S2-S4. The absence of myenteric ganglia in Hirschsprung's disease results in massively increased parasympathetic activity with abundant acetylcholine release and pseudo-obstruction in the aganglionic segment. This can be demonstrated in an enzyme histochemical reaction for acetylcholinesterase on frozen sections, which is sufficient to diagnose the classical disease in rectal mucosal biopsies. In ultrashort Hirschsprung's disease, increased acetylcholinesterase activity is demonstrable only in nerve fibres of the muscularis mucosae and submucosa, but not the lamina propria mucosae. Submucosal and myenteric ganglia are physiologically scarce in the most distal rectum; absence of ganglia in a biopsy of the rectoanal transition must not be (wrongly) interpreted as ultrashort Hirschsprung's disease. Therefore, a diagnosis of ultrashort Hirschsprung's disease can be made exclusively using an enzyme histochemical reaction for acetylcholinesterase.

Updated results on intestinal neuronal dysplasia (IND B).

BACKGROUND: Intestinal neuronal dysplasia (IND B) is still a subject of controversy. The aim of this paper is to review the present state of knowledge on IND B. A summary is given of the technical and diagnostic criteria which have to be considered in order to arrive at a reliable diagnosis. In addition, the available therapeutic interventions are discussed. METHODS: Between 1992 and 2001, 3984 colonic mucosal biopsies from 1328 children were investigated. Nerve cell staining was performed on native tissue sections: 15 microm thick cryostat sections, which, after spreading and drying on a microscopic slide, have a final thickness of 4-5 microm, with dehydrogenase reactions (lactic dehydrogenase, nitroxide synthase, succinic dehydrogenase). The biopsies were taken 8-10 cm above the dentate line (proximal to the ampulla recti, because of the caudo-cranial increase of giant ganglia proximal to the 4 cm biopsy) with a sufficient amount of submucosa. The criteria for IND is 15-20 % submucosal giant ganglia with more than eight nerve cells in 30 sections of a single biopsy (i.e. four to seven giant ganglia). RESULTS: The diagnosis of IND B is quantitative. A diagnosis of IND B was made over the past 10 years in 51 Hirschsprung resections (about 5 per year; 6 % of all Hirschsprung cases), and in 92 children with chronic constipation (about 9 children per year; 2.3 % incidence). Up to their fourth year of life, most children with isolated IND can be treated conservatively. This is due to the delayed maturation of the enteric nervous system which is characteristic of IND B. Only children who showed an additional hypoplastic hypoganglionosis were treated surgically. Children with Hirschsprung's disease (HD) and IND B proximal to the aganglionosis often showed, in those cases with a disseminated IND, postoperative disturbances in intestinal motility. CONCLUSION: The diagnosis of IND B requires that biopsies are taken proximal to the ampulla recti (about 8-10 cm above the dentate line) with a sufficient amount of submucosa. The biopsies must be cut rectangular to the surface of the mucosa. A diagnosis of IND B can be made only if, in the submucosa of 30 serial sections, 15-20 % of all ganglia are giant ganglia with more than eight nerve cells. Ganglioneuromatosis (MEN2B) must be clearly differentiated from IND. The clinical course of IND B depends on the extent of disturbed bowel innervation, the severity of motility failure, and the coexistence of MH. The conservative management of isolated IND is possible in most children. In individual cases, however, a transient enterostomy or a segmental resection is unavoidable.

Diagnosis and therapy of ultrashort Hirschsprung's disease.

BACKGROUND: Although ultrashort Hirschsprung's disease (UHD) was enzyme-histochemically characterised about 35 years ago, its existence is still often ignored. The aim of this study is to summarise the clinical diagnostic, incidence, gender ratio, morphological characteristics, and therapy over 15 years. METHODOLOGY: The reliable diagnosis of suspected UHD requires a minimal enema of contrast medium to exclude Hirschsprung's disease (HD). In UHD during pressing or crying no reflux of contrast medium is observed. Final proof of UHD is an enzyme-histochemical biopsy examination of distal rectal mucosa. The biopsies must demonstrate submucosa and be taken from the dentate line and 1 cm, 2 cm, 4 cm and 6 cm above the dentate line. The cryostat sections must be cut 15 microm thick; this thickness is reduced to 4.5 microm by the thawing, spreading and drying of the sections on microscope slides. A reliable diagnosis of UHD needs an enzyme-histochemical acetylcholinesterase reaction of native sections of rectal mucosa. RESULTS: UHD develops with first symptoms of chronic constipation in the second half of the first year of life. The chronic constipation proves to be therapy resistant. In HD constipation occurs in the first weeks of life or after weaning. In contrast to HD, no nerve fibres with increased AChE activity are observed in the lamina propria mucosa. Nets of nerve fibres with increased AChE activity can be found only in the muscularis mucosa and the musculus corrugator cutis ani (MCCA). The therapy of choice has proven to be a partial myectomy of the distal internal sphincter if dilatation of the internal sphincter was ineffective. UHD is either limited to the anal ring, or extends 3 - 4 cm into the distal rectum. Over the past 15 years, UHD had in our series an incidence of 13.4 % of all aganglionoses. The gender ratio of girls to boys was 1 : 2. CONCLUSION: UHD is reliably diagnosed by an AChE reaction in native biopsy sections from the anocutaneous transitional zone and, potentially, from 3 - 4 cm above the pectinate line. As UHD is always accompanied by aganglionosis of the distal internal sphincter, an increase in AChE activity is observed in the nerve fibres of the MCCA. The therapy of choice is a partial myectomy of the distal internal sphincter.

Chronic constipation due to Hirschsprung's disease and desmosis coli in a family.

Five members of a family are described, all of whom suffered from chronic constipation and megacolon. Detailed clinical and histologic evaluation of each member revealed that two individuals have histologic evidence of desmosis coli and three have Hirschsprung's disease, one of whom also has desmosis coli. The latter combination has never been described before, either in a family or in a single patient. Genetic studies of the family did not reveal an increase in the number of shared markers for the RET proto-oncogene, suggesting that this previously undescribed familial association is likely not caused by a mutation in the RET gene, but by other genetic abnormalities.

New pathogenetic aspects of gut dysmotility in aplastic and hypoplastic desmosis of early childhood.

The peristaltic movement of the gut is a function of the alternating contraction and relaxation of circular and longitudinal muscles. This movement is induced by a tendon-like connective-tissue net (TCTN) in the circular and longitudinal muscles, which are both rooted in a connective-tissue plexus layer (CTPL). In children with a therapy-resistant aperistaltic or hypoperistaltic syndrome who had normally-developed enteric innervation, a lack of the TCTN in the muscularis propria was observed. Over the last 2 years, 241 children with chronic constipation were investigated histopathologically; 46 children surgically treated by partial resection of the gut or diagnostically investigated by whole-mount biopsy. Fifteen children had a hypoperistalsis syndrome and 3 had an aperistalsis syndrome. All specimens were native and cut in a cryostat. Enteric innervation was examined by acetylcholinesterase and dehydrogenase reactions. The TCTN in the muscularis propria was stained with picric acid/sirius red. In the children with an aperistalsis syndrome, a complete lack of the TCTN in circular and longitudinal muscles was observed. A CTPL was not developed. The children with a hypoperistalsis syndrome had no CTPL, but had a partly-developed TCTN in the circular and longitudinal muscles, which gradually faded in the direction of the plexus layer. Independent of a well-developed enteric nervous system, a lack of the TCTN in longitudinal and circular muscles and a missing CTPL (aplastic desmosis) abolishes the coordinated peristaltic movement of the gut. An isolated lack of the CTPL in the myenteric plexus (hypoplastic desmosis) results in a hypoperistalsis syndrome. An anomaly of the TCTN in the muscularis propria disturbs gut-muscle mechanics, and is another cause of gut dysmotility.

Morphometric assessment of Hirschsprung's disease: associated hypoganglionosis of the colonic myenteric plexus.

At present, there are no generally acceptable criteria for the evaluation of hypoganglionosis of the myenteric plexus. The aim of this morphometrical investigation was to examine the most important quantitative characteristics of hypoganglionosis. Colon specimens from 35 children with Hirschsprung's disease were assessed morphometrically. Twenty specimens with Hirschsprung's disease and proximal hypoganglionosis of the myenteric plexus were compared with 15 specimens with Hirschsprung's disease and normal innervation in the proximal myenteric plexus. All native surgical specimens were caudocranial coiled and sectioned in a cryostat. Nerve cells and ganglia were selectively stained with an enzyme-histochemical lactic dehydrogenase reaction. Morphometric measurements were done with an optic-electronic image analysis system. Hirschsprung's disease-associated hypoganglionosis of the myenteric plexus is characterized by a significant decrease in ganglion cross-sectional area (-56.2%) and in plexus area per mm colon (-53.5%). Together with these data, an increase in ganglion distance (+20%) was also determined, and the number of nerve cells per mm colon was decreased by -25.5%. The decrease in ganglion area and in the number of nerve cells per mm colon in the myenteric plexus proved to be the most characteristic parameters of a hypoganglionosis.

[Idiopathic megacolon. New findings on histopathology and musculo-mechanical causes]. / Das idiopathische Megacolon. Neue Erkenntnisse zur Histopathologie und den muskelmechanischen Ursachen.

Nineteen native surgical specimens of an idiopathic megacolon were histopathologically investigated and a lack of the tendon-like collagen III movement net of circular and longitudinal muscles observed, including a lack of the connective tissue layer of myenteric plexus. This disease of the muscularis propria could be considered as a desmolysis, a hypoplastic or an aplastic desmosis. With reference to the normal muscle mechanics of the gut, it is shown that the pathogenetic principle of the idiopathic megacolon consists in absence of the tendon-like connective tissue net in the muscularis propria which results in a lack of peristalsis of the gut, despite of a regular enteric innervation. This finding demonstrates that an idiopathic megacolon can be histopathologically verified in whole-mount biopsies and referred for curative surgical treatment.

Histopathologic observations of anorectal abnormalities in anal atresia.

Over the years from 1992 to 1997, 41 anorectal malformations (ARM) with histopathologic alterations were investigated to determine which morphologic abnormalities of the distal rectum accompany ARMs. Three other cases showed normal neuromuscular morphology; 9 further cases could not be evaluated owing to scanty biopsies. All resected specimens were caudocranially coiled and cryostat cut at -20 degrees C into serial sections, which were stained with a lactic dehydrogenase, succinic dehydrogenase, nitroxide synthase, and acetylcholinesterase reaction as well as hemalum and sirius red. Ten low, 15 intermediate, and 10 high forms of anal atresia (AA) were studied. In addition, six cloacal abnormalities were investigated. In 7 cases (17%) (5 intermediate, 2 low AAs), the characteristics of Hirschsprung's disease were observed. Oligoneuronal hypoganglionosis of the myenteric plexus proximal to the anal floor was diagnosed in 7 AAs (12%). In 10 children with high-type AA and resection of 1-5 cm distal rectum and in all cloacal anomalies (n = 6) defects of the muscularis propria were seen in the rectal-atresia sac. These defects were characterized by hypoplasia of the circular-muscle layer and/or the internal anal sphincter (IAS). Intestinal neuronal dysplasia of the submucous plexus was most frequently observed (12%) in high-type AA. A correlation between innervation anomalies or anomalies of the muscularis propria and the type of fistula could not be seen. In conclusion, all cases with high-type AA and cloacal anomalies were characterized by anomalies of the muscularis propria and/or IAS but this was not the case in intermediate and low-type AAs. Anomalies of the enteric nervous system were diagnosed in 60% of AAs.

Mitochondrial genome lesions in the pathogenesis of sporadic Alzheimer's disease.

BACKGROUND: The recent, magnificent results of molecular biology concerning beta-amyloid (betaA) metabolism in early onset Alzheimer's disease (AD) have generated a series of new findings and, in turn, a new etiological concept. Attention on the early events in the pathogenesis of AD has been shifted from the chromosomal abnormalities in the nucleus of nerve cells onto genetic changes in the mitochondrial genome. This offers a new pathogenetic approach which also opens new pharmacological challenges particularly for the episodic forms of AD. OBJECTIVE: Alterations occurring at the mitochondrial genome result in major consequences of oxidative phosphorylation and, if a specific threshold is exceeded, they may constitute important causative events in the apoptosis of selected nerve cells. The fact that the main source of mitochondrial metabolism is its glucose turnover allows monitoring brain changes in glucose metabolism by 18F-2 deoxyglucose positron emission tomography. In the demented brain, a low glucose turnover causes a cholinergic deficit by decreasing the synthetic rate of acetyl coenzyme A (AcCoA). AcCoA represents the key substrate for the acetylation of choline to acetylcholine by choline acetyltransferase. The consistent energy need for AcCoA synthesis appears obvious when considering that 1 molecule of glucose generates just 2 molecules of AcCoA, but 38 molecules of ATP. In the brain, AcCoA is exclusively synthesized in the glycolitic pathway. Generation of betaA is increased if the synthetic rate of ATP drops below a critical threshold: under these conditions, the betaA precursor protein (betaAPP) is inserted only in part into synaptic membranes which have the highest betaAPP turnover. In conditions of short ATP supply, betaAPP is not split at the beta region by an ATP-activated protease and this results in a substantial increase in uncleaved betaA molecules. CONCLUSION: Peroxidative alterations in mitochondrial DNA are of importance in degenerative diseases of postmitotic tissues, particularly in degenerative diseases. This offers a new pharmacological approach for the treatment of AD. Neurotrophic factors and estrogen seem to be the first pharmacological leads.

A correlative morphometric and clinical investigation of hypoganglionosis of the colon in children.

Hypoganglionosis of the myenteric plexus of the colon is not clearly defined and seldom investigated. Colon segments from 15 children with an extended oligoeuronal hypoganglionosis up to the proximal resection end were morphometrically studied and compared to normally innervated colon segments. The study was performed with resected specimens from 7 children with isolated hypoganglionoses, 8 children with a Hirschsprung-associated hypoganglionosis, and 12 colon segments with normal innervation. The resected colon specimens were caudo-cranial coiled. The native tissue was frozen at -80 degrees C on a cryostat carrier and cut at -20 degrees C in 15 microns-thick sections (equivalent to 4-5-micron-thick paraffin sections). The air-dried sections underwent an enzyme-histochemical procedure for an acetylcholinesterase reaction to stain the parasympathetically innervated myenteric plexus. For histological identification and morphometric measurements, ganglia and nerve cells were selectively stained using a lactic dehydrogenase reaction. The morphometric measurements were performed with an optic-electronic image analysis system that determined ganglion size, ganglion distances, nerve cell number per ganglion, and ganglion number per mm colon. The results showed that hypoganglionosis of the myenteric plexus is characterised by a 42% decrease in plexus area and a 55% decrease of the nerve cell number per mm length of colon. The number and area of myenteric ganglia showed a decrease of 59% and a doubling of the ganglion distances. The histopathological diagnosis of a hypoganglionosis of the colon was not necessarily an indication of a chronic constipation, but rather an indication of a disposition for constipation. A chronic constipation is often caused by a long hypoganglionic segment proximal to a resected short Hirschsprung segment.

Desmosis of the colon: a working hypothesis of primary chronic constipation.

INTRODUCTION: Over the last few years, resected specimens of colon from children and young adults have been systematically studied with regard to the vegetative innervation of the colon and its net of stabilizing connective tissue in the muscularis propria. From the basic investigations of Goerttler, it is known that this connective tissue net has important functions in the coordinated movement of longitudinal and circular muscles. The present study reports on cases of chronic constipation, which showed in most cases histopathologically a normal number of nerve cells and ganglia in the myenteric plexus, but abnormalities in the connective tissue net (desmosis). SUBJECTS AND METHODS: Over 6 years, 236 cases (12 +/- 8 years of age), which were treated surgically for an aganglionosis, hypoganglionosis, hypoperistalsis syndrome and megacolon development, were histopathologically investigated. All surgical specimens were native, caudo-cranially coiled, and were cut 15 microns (equiv. to 4-5 microns paraffin sections) by a cryostat. The vegetative nervous system of the gut was stained with acetylcholinesterase and dehydrogenase reactions. The tissue was also fixed in formalin, embedded in paraffin, and 4 microns sections were stained with hematoxylineosin and picric acid/sirius red. Collagen III; S 100 and PGP 9.5 immunohistochemical reactions were performed. RESULTS: 14 surgical specimens (6%) showed total or focal lack of the connective tissue net in the vicinity of the myenteric plexus. Between the connective tissue net of circular and longitudinal muscles, a continuous connection was missing. These cases were mainly characterized by a hypoperistalsis syndrome or a megacolon without any anomaly of the vegetative innervation. 222 cases (94%) were treated for Hirschsprung's disease or hypoganglionosis without any anomaly of the connective tissue of the muscularis propria. CONCLUSION: The missing continuity of the connective tissue net in the muscularis propria seems to abolish coordinated alternative movement of circular and longitudinal muscles. Therefore, the lack of coordinated propulsive activity of the colon results in a therapy-resistant chronic constipation, with a hypoperistalsis syndrome.

Pathogenesis of decreased glucose turnover and oxidative phosphorylation in ischemic and trauma-induced dementia of the Alzheimer type.

The pathogenetic mechanisms causing a dementing brain disease after temporary ischemia, heat shock, or brain trauma are surveyed. These lesions increase beta amyloid precursor protein (beta APP) synthesis. This process is potentiated by an ischemic glutamate release that opens cellular Ca2+ channels, inhibiting glucose turnover and ATP production, which is, under these conditions, accompanied by the generation of beta amyloid (beta A), even in young persons. Beta amyloid starts a vicious circle by inactivating the glycolytic key enzyme, phosphofructokinase, which, with age, exhausts the functional reserve capacity of the brain. This demonstrates that beta A is an epiphenomenon of a dementing brain disease, triggered by the disturbance of glucose turnover and oxidative phosphorylation. Clinical studies have shown that a dementing brain disease can be clearly objectified and monitored by 18F-2-deoxyglucose PET studies. This paper looks briefly at pharmacologic approaches to this disease using models of temporary ischemia, the testing of 14C-deoxyglucose turnover, or examination with 31P magnetic resonance spectroscopy techniques. In conclusion, the key process of all dementing brain diseases of the Alzheimer type is a decreased glucose turnover and subsequently decreased oxidative phosphorylation, linked directly to a secondary amyloid formation and nerve cell atrophy.

Morphometric determination of the methodological criteria for the diagnosis of intestinal neuronal dysplasia (IND B).

Intestinal neuronal dysplasia of the submucous plexus (IND B) is an indicator of a developmental abnormality of vegetative gut innervation. It is the mildest form of an inborn error of intestinal innervation. The diagnosis of IND B does not result in a functional conclusion or clinical recommendation but is often accompanied by oligoneuronal hypoganglionosis of the myenteric plexus or an aganglionosis of the rectum. The aim of this study was to demonstrate by morphometric means a way in which the diagnosis of IND B could be made much more reliable. In 20 control subjects, 40 IND B cases and 10 hypoganglionoses with IND B, it was shown that a specific nerve cell staining (e.g. Lactic dehydrogenase, Succinic dehydrogenase, Diaphorase reaction or an immunohistochemical nerve cell staining) was necessary for diagnosis. Cross sections of giant ganglions and cross sections with large nerve cell numbers (> 7 nerve cell profiles) were the most reliable diagnostic criteria. The morphometric examinations were performed with an optic electronic image analysis system. Biopsy serial sections of the rectum-mucosa that contained submucosa demonstrated that 30-40% of the sections contained no submucous ganglion. Sixty to 70% of the sections showed ganglia of the submucous plexus. In 100 biopsy sections in subjects with IND B, 20 +/- 5% contained giant ganglions cross sections. In the patients with hypoganglionosis of the submucous plexus, 55 +/- 4% sections had no ganglion and 18 +/- 3% had giant ganglion cross sections. The data demonstrate that for a reliable diagnosis of IND B, at least 30 sections are necessary, stained with a dehydrogenase reaction that contain a minimum of 4 giant ganglion cross sections. These data demonstrate that IND B is not a qualitative diagnosis as Hirschsprung's disease but rather a quantitative diagnosis.