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Biomedical subjects

Udo Rolle

Publications and source records attributed to Udo Rolle.

At least 19 recordsLinked to original sources
PubMed2006

Enteric nervous system and developmental abnormalities in childhood.

ENS consists of a complex network of neurons, organised in several plexuses, which interact by means of numerous neurotransmitters. It is capable of modulating the intestinal motility, exocrine and endocrine secretions, microcirculation and immune and inflammatory responses within the gastrointestinal tract, independent of the central nervous system. Though the embryological development of various plexuses are completed by mid-way of gestation, the maturation of neurons and nerve plexuses appear to continue well after birth. Therefore, any histological or functional abnormalities related to the gastrointestinal function must be investigated with the ongoing maturational processes in mind.

Animals↗
PubMed2006

Postnatal development of the mucosal plexus in the porcine small and large intestine.

Knowledge regarding the foetal and postnatal development of the enteric nervous system is crucial for the understanding of congenital disorders. While lot of information exists regarding the myenteric and submucosal plexuses, the development of the mucosal plexus has not been previously studied. The mucosal innervation seems to play an important role in the local reflex activity of the gut. In this study, we examined the development of enteric mucosal innervation in the pig at various ages of life. Small and large bowel paraffin-embedded specimens were stained with PGP 9.5 and neurofilament protein in three piglets from six age groups (60 and 90 days gestation, newborn, 4 and 12 weeks old, and adult pigs). Small and large bowel demonstrated identical innervation patterns. Myenteric and submucosal plexuses were stained with PGP 9.5 at 60 days gestation. However, the mucosal staining was first noted clearly at the newborn period. By 4 weeks, PGP 9.5 staining was noted in small amounts within the mucosa. Inner proprial and villous fibres were seen ahead in time to the subepithelial fibres. Both inner proprial and villous staining became quiet prominent by 12 weeks of age and remained unchanged into adulthood. However, the subepithelial fibres appear to increase in adulthood. This study demonstrates for the first time that enteric mucosal innervation first appears only at birth. The immaturity of the mucosa generated reflex activity, and secretory functions may have implication in the management of functional intestinal obstruction in the premature infant.

Age Factors↗
PubMed2006

Experimental study evaluating the effect of a barrier method on postoperative intraabdominal adhesions.

The purpose of this animal study was to determine if tissue glue-coated collagen sponge is an effective barrier method to prevent localized adhesions in a modified rabbit sidewall model. Rabbits were divided into two groups and underwent laparotomy with subsequent creation of a cecal wound according to the rabbit sidewall model. Rabbits of group I (treatment group; n = 10) were treated with a TachoComb H patch placed on the defect, whereas group II animals (control group; n = 6) did not receive further treatment. All animals were sacrificed 2 weeks postoperatively and adhesions were evaluated using special adhesion score. A further six rabbits underwent TachoComb H application at the cecum to investigate the histological changes during a course of 12 weeks. The average adhesion scores were significantly (P < 0.05) reduced in the treatment group compared to the controls. Histologically the TachoComb H patch was surrounded by granulation tissue without signs of infection. Tissue glue-coated collagen sponge (TachoComb H) is effective to prevent localized intraabdominal adhesions in the modified rabbit sidewall model.

Abdominal Wall↗
PubMed2006

Developmental changes in submucosal nitrergic neurons in the porcine distal colon.

BACKGROUND/PURPOSE: As our understanding of the enteric nervous system improves, it becomes clear that it is no longer sufficient to simply determine whether enteric ganglion cells are present but also to determine whether correct number and types of ganglion cells are present. Nitric oxide is recognized as a potent mediator of inhibitory nerves responsible for the relaxation of the smooth muscle of the gastrointestinal tract. The aim of this study was to determine the normal nitrergic neuronal density and morphology in the submucosal plexus of the porcine distal bowel from fetal life to adulthood. METHODS: Distal large bowel specimens were obtained from porcine fetuses of gestational age E60 (n = 5), E90 (n = 5), 1-day-old piglets (n = 5), 4-week-old piglets (n = 5), 12-week-old piglets (n = 5), and adult pigs (n = 5). Whole-mount preparations of the submucosal plexus were made and stained with NADPH diaphorase histochemistry. The ganglia density, the number of ganglion cells per ganglia, and nucleus and cytoplasmic area were measured. RESULTS: Ganglia density decreased progressively and markedly with age until the adulthood (P < .001). On the contrary, ganglion cells increased their size over time predominantly because of increase in cytoplasm (P < .001). The number of ganglion cells per ganglia increased significantly during the fetal life. However, there was a significant reduction in the number of ganglion cells per ganglia during the period from birth to 4 weeks, remaining constant thereafter (P < .001). CONCLUSIONS: The quantitative and qualitative morphometric analysis of the colonic submucous plexus shows that significant developmental changes occur during fetal and postnatal life. These findings indicate that the age of the patient is of utmost importance during histopathologic evaluation of enteric nervous system disorders.

Age Factors↗
PubMed2004

Variant Hirschsprung's disease.

Conditions that clinically resemble HD despite the presence of ganglion cells on suction rectal biopsy results, can be diagnosed by providing an adequate biopsy and employing a variety of histological techniques. Intestinal neuronal dysplasia is a distinct clinical entity that can be clearly proven histologically. Patients with IND not only have abnormalities of submucosal and myenteric plexuses but also defective innervation of the muscle. Internal sphincter achalasia, which is histologically characterized by nitrergic nerve depletion, can be diagnosed on anorectal manometry and successfully treated by internal sphincter myectomy. The outcome of smooth muscle disorders is generally fatal. The need for surgical intervention should be weighed carefully and individualized because most explorations have not been helpful and are probably not necessary.

Biopsy, Needle↗
PubMed2004

Interstitial cells of Cajal in the human normal urinary bladder and in the bladder of patients with megacystis-microcolon intestinal hypoperistalsis syndrome.

OBJECTIVE: To investigate the distribution of c-kit-positive interstitial cells of Cajal (ICCs) in normal bladder and bladders from patients with megacystis-microcolon-intestinal peristalsis syndrome (MMIHS, a rare congenital and generally fatal cause of functional intestinal obstruction in the newborn), the most characteristic feature of which is abdominal distension caused by a distended unobstructed urinary bladder. PATIENTS AND METHODS: Full-thickness bladder specimens were obtained from four infants with MMIHS and four controls, and processed as paraffin-wax and frozen sections. Sections were assessed using single immunohistochemistry with monoclonal and polyclonal anti-c-kit antibodies. Anti-alpha-smooth muscle actin (SMA) antibody was used to investigate the contractile apparatus in smooth muscle cells of the urinary bladder. Specimens were examined using light and confocal scanning microscopy. RESULTS: There were many c-kit positive ICCs in the normal urinary bladder, appearing as small, long, bipolar cells with only two long and several short processes. In contrast, ICCs were absent in the MMIHS bladder. alpha-SMA immunoreactivity was lower in MMIHS urinary bladder than in control sections. CONCLUSION: This study shows for the first time the presence of c-kit-positive ICCs in the normal human urinary bladder. The lack of ICCs in the MMIHS bladder may contribute to the voiding dysfunction in this disease.

Colon↗
PubMed2004

The role of nitric oxide in bladder urothelial injury after bladder outlet obstruction.

OBJECTIVE: To investigate the role of nitric oxide (NO) in the pathogenesis of injury to the bladder mucosa after bladder outlet obstruction (BOO). MATERIALS AND METHODS: The response of bladder mucosa to BOO consists of thickening with fibrous connective tissue; NO is a multipurpose messenger important in blood vessel relaxation, neuronal communication and inflammatory activities of macrophages, and is synthesized by NO synthase (NOS), with three distinct isoforms; inducible (iNOS), endothelial (eNOS) and neuronal (nNOS). Fifteen male guinea pigs had a silk ligature placed around the bladder neck to induce BOO; controls included five sham-operated animals. The animals were killed at 2, 4, 6, 8 and 12 weeks after BOO. NADPH-diaphorase staining was used as a nonspecific method to determine NOS isoform distribution. Single- and double-label immunofluorescence histochemistry for iNOS, eNOS, nNOS and macrophage colony stimulating factor (M-CSF) were used, with laser scanning confocal microscopy to assess the results. The relative amount of iNOS mRNA was evaluated using reverse-transcription-polymerase chain reaction (RT-PCR), and a standard method to determine the degree of apoptosis. RESULTS: Bladder mucosa had a markedly increased intensity of NADPH-diaphorase staining 2 weeks after BOO. iNOS immunoreactivity was markedly greater in the bladder mucosa 2 weeks after BOO than in controls. The immunolocalization of iNOS and M-CSF was identical in bladder mucosa after BOO. RT-PCR showed stronger iNOS mRNA expression in the obstructed bladder mucosa 2 weeks after BOO than in controls. eNOS and nNOS expression was detected only 8 weeks after BOO, with markedly more immunoreactivity 12 weeks after initiating BOO. Increased eNOS and nNOS immunoreactivity strongly correlated with the induction of apoptosis in the bladder mucosa. CONCLUSION: There was overexpression of iNOS by activated macrophages in the early stages of BOO. This overexpression did not induce apoptosis in the iNOS-expressing cells of bladder mucosa in the early stages. After long-term BOO bladder mucosa showed strong eNOS and nNOS immunoreactivity, correlating with apoptosis. Thus we suggest that eNOS and nNOS, by triggering cell death, may be important in eliminating hyperplastic urothelial cells, reflecting the plasticity of the bladder response to obstructive stimuli.

Animals↗
PubMed2003

Abnormal vasculature in intestinal neuronal dysplasia.

Intestinal neuronal dysplasia (IND) is an intestinal motility disorder, which clinically resembles Hirschsprung's disease (HD). Adventitial fibromuscular dysplasia (AFMD) consists of proliferation of smooth muscle cells and collagen fibers in the adventitia of blood vessels. The purpose of this study was to investigate vascular abnormalities in large bowel biopsies from patients with isolated HD, IND associated with HD and isolated IND. Large bowel biopsies from patients presenting with isolated HD ( n=23), IND associated with HD ( n=11), isolated IND ( n=16) and normal bowel as controls ( n=6) were investigated using acetylcholinesterase (AChE) histochemistry, van Gieson staining and alpha-smooth muscle actin (alpha-SMA) immunohistochemistry. Increased AChE activity around submucosal vessels was found in 9/16 (56%) cases with isolated IND, 3/11 (27%) cases of IND associated with HD, 5/23 (21%) isolated HD cases and 0/6 controls. AFMD was found in 10/16 (62%) of the isolated IND cases, 4/11 (362) of the cases with IND associated with HD and 4/23 (17%) cases of HD without IND using van Gieson staining. None of the control specimens revealed AFMD. Increased alpha-SMA immunoreactivity filaments were demonstrated in the submucosal vessel wall in 9/16 (56%) of isolated IND and 2/11(18%) of IND associated with HD cases. Normal alpha-SMA immunoreactivity around submucosal vessels was seen in isolated HD and controls. Abnormal submucosal vasculature is a common histological finding in isolated IND and IND associated with HD and may be a useful additional diagnostic feature in these patients.

Adolescent↗
PubMed2003

Nitrergic hyperinnervation in appendicitis and in appendices histologically classified as normal.

CONTEXT: The pathogenesis of appendicitis remains poorly understood. Despite new diagnostic techniques, appendices removed from patients with suspected appendicitis often appear histologically normal on conventional examination. There is increasing evidence of involvement of the enteric nervous system in immune regulation and in inflammatory responses in the gastrointestinal system. OBJECTIVE: To investigate the nitrergic innervation of (a) acutely inflamed appendices, (b) appendices classified as histologically normal from patients with a clinical diagnosis of appendicitis, and (c) normal control appendix specimens, using the whole-mount preparation technique. PATIENTS AND DESIGN: Full-thickness specimens were collected from 28 acutely inflamed appendices (age range, 3.2-13.4 years), 31 histologically normal appendices removed from patients (age range, 5.7-13.6 years) with suspected appendicitis, and 23 histologically normal appendices from patients (age range, newborn to 12.1 years) undergoing elective abdominal surgery (controls). Whole-mount preparation using nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase histochemistry and neuronal nitric oxide synthase immunohistochemistry were performed. The density of myenteric plexus was measured with a computerized analysis system. RESULTS: The density of myenteric plexus in normal appendix specimens was similar to that of large bowel from the newborn period up to 3 years of age; this density decreased significantly thereafter. The myenteric plexus of normal appendix specimens from patients older than 4 years demonstrated smaller ganglia connected by thin nerve bundles, compared to larger ganglia and nerve bundles in large bowel. Significant neuronal hypertrophy was found in 55% of acutely inflamed and 41% of histologically classified normal appendix specimens. The myenteric plexus of these appendix specimens had even thicker nerve bundles connecting an increased number of ganglion cells. CONCLUSIONS: Differences in the architecture of the myenteric plexus in patients older than 3 years suggest an altered function and motility of appendix in the early years of life. The significant increase in neuronal components of the myenteric plexus in a high proportion of acutely inflamed and histologically normal appendix specimens is unlikely to have developed during a single acute inflammatory episode. This suggests an underlying chronic abnormality as a secondary response to chronic luminal obstruction or repeated inflammatory episodes in the histologically normal appendix.

Adolescent↗
PubMed2003

The intramural innervation of the rabbit upper urinary tract.

The role of the autonomic innervation of the upper urinary tract for pyeloureteral motility is not completely understood. It is still debatable if the autonomic nervous system might play a modulating role on the ureteral peristalsis. The aim of this study was to investigate the distribution and regional variation of the intramural innervation using whole-mount preparations of the rabbit upper urinary tract. Whole-mount preparation was performed at upper urinary tracts of healthy rabbits. Immunohistochemistry was employed using Neurofilament (NF), Tyrosine Hydroxylase (TH), Choline Acetyltransferase (ChAT) and Substance P (SP) antibodies. NADPH-diaphorase and Acetylcholinesterase (AChE) histochemistry was carried out at the specimens. The stains were evaluated using brightfield, fluorescence and laser confocal microscopy. NF-, TH-, ChAT- and SP-immunoreactive (-IR) nerves formed distinct neuronal plexuses at the submucosal and muscle layers. Perivascular TH-, ChAT- and SP-IR fibres were demonstrated. AChE positive nerves were revealed in all layers, but only moderate NADPH-diaphorase positive innervation was found. Renal pelvis, upper and lower ureter showed enriched intrinsic innervation. Ganglia were found at the ureteropelvic border and the distal ureter. Whole-mount preparation technique revealed detailed informations about morphology and regional variation of the intramural innervation of the rabbit upper urinary tract.

Acetylcholinesterase↗
PubMed2002

The role of nitric oxide in reflux nephropathy.

Reflux nephropathy (RN) is recognized as a major cause of end-stage renal failure in children and young adults. Inhibition of nitric oxide (NO) exacerbates and enhanced production ameliorates tubulointerstitial fibrosis (TIF) in experimental obstructive uropathy. NO is synthesised by NO synthase (NOS), three distinct isoforms of which have been identified: inducible (iNOS), endothelial (eNOS), and neuronal (nNOS). It has been reported that iNOS induces immunologic injury to glomerular cells and enhances accumulation of extracellular matrix in the glomerulus and tubulointerstitial space. Furthermore, it has been suggested that nNOS and eNOS have beneficial effects in ameliorating TIF. We investigated the expression of different isoforms of NOS in severe refluxing kidneys in order to further understand the pathogenesis of RN in kidney specimens from nine children with severe RN obtained at nephrectomy. Control material included normal kidney specimens from three adult patients undergoing partial nephrectomy for small kidney tumours. Histochemistry for NO was performed using nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase. Single-label immunofluorescence histochemistry was carried out using polyclonal antibodies to nNOS, iNOS, eNOS, and transforming growth factor (TGF)-beta 1 employing laser-scanning confocal microscopy. The TUNEL method was used to assess tubular apoptosis. Strong NADPH staining was observed in the proximal tubules of RN kidneys compared to controls, where there was weak staining. Control kidneys demonstrated weak immunoreactivity for iNOS in the proximal tubules and a lack of immunoreactivity for nNOS and eNOS. RN kidneys demonstrated strong immunoreactivity for nNOS in the tubulointerstitial space, for eNOS in the glomerulus, and for iNOS in the glomerulus and proximal tubules. Strong immunoreactivity for TGF beta 1 was seen in the glomerulus and proximal tubules identical to iNOS. Increased immunoreactivity for iNOS and TGF-beta 1 strongly correlated with the severity of apoptosis in RN. Our data demonstrate that NO derived from nNOS, iNOS, and eNOS is strongly expressed in RN. The selective shunting of NO via iNOS may induce renal fibrosis in RN. The upregulation of nNOS and eNOS in RN appears to be a compensatory mechanism of ameliorating TIF.

Adolescent↗
PubMed2002

Acute renal damage in infants after first urinary tract infection.

Urinary tract infection (UTI) is one of the most common causes of unexplained fever in neonates. The aim of this study was to determine the incidence of urinary tract anomalies and acute renal damage in neonates who presented with first urinary tract infection in the first 8 weeks of life. We reviewed the records of 95 infants, who were hospitalised with UTI during a 6-year period (1994-1999). Patients with antenatally diagnosed hydronephrosis and incomplete radiological investigations were excluded from the study. Of the remaining 57 patients, 42 were boys and 15 girls. The mean age at diagnosis was 32 days (range 5-60 days). All patients underwent renal ultrasonography (US), voiding cystourethrogram (VCUG) and (99m)Tc-dimercaptosuccinic acid (DMSA) scan. Urinary tract abnormalities were detected in 20 (35%) patients. Vesicoureteral reflux (VUR) was found in 19 (33%) neonates, 7 girls and 12 boys. Acute cortical defects on DMSA scan were present in 19 kidneys of patients with VUR and in 25 of those without reflux. Only one-third of neonates after first symptomatic UTI had VUR. We recommend that US, VCUG, and DMSA scan should be routinely performed after the first UTI in infants younger than 8 weeks.

Acute Disease↗
PubMed2002

Demonstration of nitrergic and cholinergic innervation in whole-mount preparations of rabbit, pig, and human upper urinary tract.

To investigate the distribution of nitrergic and cholinergic innervation in rabbit, pig, and human upper urinary tract, (UUT) whole-mount preparations and frozen sections were stained with nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase and acetylcholinesterase (AChE) histochemistry. NADPH-diaphorase and AChE staining demonstrated two neuronal plexuses in the submucous and muscular layer of the UUT in all three species. The presence of nitrergic and cholinergic neuronal networks in the normal UUT suggests that autonomic innervation may play an important role in the transmission of ureteral peristalsis.

Adult↗
PubMed2002

Megacystis-microcolon-intestinal hypoperistalsis syndrome: evidence of intestinal myopathy.

We investigated small- and large-bowel specimens of three newborn infants presenting with the clinical and radiological symptoms of megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS). Conventional histological staining revealed marked thinning of the longitudinal muscle layer. Electron-microscopic investigations showed typical "central core" vacuolic degeneration of smooth-muscle-cells combined with proliferation of col lagen fibres. The expression of alpha-smooth-muscle actin was absent or markedly reduced in the circular and longitudinal muscle layers and muscularis mucosae compared to the normal controls. These findings suggest that the intestinal obstruction in MMIHS is due to an abnormality of the smooth-muscle cells.

Abnormalities, Multiple↗
PubMed2002

Nitric oxide, enhanced by macrophage-colony stimulating factor, mediates renal damage in reflux nephropathy.

BACKGROUND: Reflux nephropathy (RN) is a major cause of end-stage renal failure in children and young adults. Nitric oxide (NO) is an important mediator of tissue injury and inflammation. NO production is enhanced by hematopoietic growth factor including macrophage colony stimulating factor (M-CSF). M-CSF plays a pivotal role in the development of nephritis via macrophage activation. The aim of this study was to investigate the expression of inducible NO synthase (iNOS) and M-CSF in the refluxing kidney, in order to further understand the pathogenesis of RN. METHODS: The kidney specimens from 6 patients with severe RN and 6 controls were examined by NADPH-diaphorase histochemistry and immunohistochemistry using ABC method with anti-M-CSF antibody. Double staining using NADPH-diaphorase histochemistry/M-CSF immunohistochemistry and M-CSF/iNOS fluorescence immunohistochemistry also was performed. In situ hybridization was performed using digoxigenin labeled M-CSF specific probe. RT-PCR was performed to evaluate the relative amount of iNOS mRNA expression. Apoptosis was determined using the in situ end-labeling technique. RESULTS: The most striking difference between tissues from RN patients and controls was the marked increase in NADPH-d activity, iNOS immunoreactivity and mRNA and M-CSF immunoreactivity and mRNA expression in the kidneys of RN patients, particularly in the distal tubules, collecting system. Apoptotic cells were markedly increased in RN compared to controls. CONCLUSIONS: Our findings suggest that the increase in M-CSF-stimulated local production of nitric oxide may be a major mediator in the development of reflux nephropathy.

Adolescent↗
PubMed2002

Upregulation of angiotensin II receptors in reflux nephropathy.

BACKGROUND/PURPOSE: Reflux nephropathy (RN) is the cause of end-stage renal failure in 3% to 25% of children and in 10% to 15% of adults. Angiotensin II (Ang II) is a biologically active peptide of the renin-angiotensin system (RAS), which has a profound role not only in the urinary tract-development, but also in the response of the urinary tract to injury. The actions of Ang II are mediated through 2 receptors, angiotensin type 1 receptor (AT(1)R) and angiotensin type 2 receptor (AT(2)R). The aim of this study was to examine the expression of AT(1)R and AT(2)R in severe reflux nephropathy. METHODS: The kidney specimens from 8 patients (age range, 6 months to 14 years) with severe reflux nephropathy secondary to primary high-grade vesicoureteral reflux (VUR) were obtained at the time of nephrectomy. Control material included normal kidney specimens obtained from 3 adult patients during partial nephrectomy for an incidentaloma. Soluble enzyme immunohistochemistry was carried out using polyclonal antibodies to AT(1)R and AT(2)R. Reverse transcriptase polymerase chain reaction (RT-PCR) was performed to evaluate the relative amount of AT(1)R and AT(2)R mRNA. RESULTS: In the refluxing kidney there was strong AT(1)R immunoreactivity in the glomerulus and proximal tubules and moderate to weak immunoreactivity in the distal tubules. There was strong AT(2)R immunoreactivity in the distal tubules with absent or weak staining in the glomerulus and proximal tubules. In the control kidneys, homogeneous weak AT(1)R immunoreactivity was shown in the proximal and AT(2)R in the distal tubules, respectively. RT-PCR showed strong AT(1)R and AT(2)R expression in the refluxing kidneys compared with controls. CONCLUSIONS: Upregulation of angiotensin II receptors in reflux nephropathy suggests that Ang II is involved in the pathogenesis of the renal parenchymal damage in patients with RN. Pharmacologic blockade of angiotensin II receptors may be helpful in preventing renal fibrosis associated with reflux nephropathy.

Adolescent↗
PubMed2002

Abnormalities of C-Kit-positive cellular network in isolated hypoganglionosis.

BACKGROUND/PURPOSE: C-Kit-positive interstitial cells of Cajal (ICCs) have a key role in the normal motility function and development of the bowel. They are pacemaker cells, which facilitate active propagation of electrical events and neurotransmission in the bowel wall. ICCs are present in the bowel as myenteric ICCs (ICC(my)S) and muscular ICCs (ICC(mus)S). The aim of this study was to examine the distribution of c-Kit-positive ICCs and their relationship to the autonomic intrinsic innervation in bowel specimens from patients with isolated hypoganglionosis. METHODS: Full-thickness large bowel specimens were obtained from 6 patients with hypoganglionosis and from 4 patients during bladder augmentation (controls). Frozen sections and whole-mount preparations were stained using c-Kit immunohistochemistry, nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase, and acetylcholinesterase (AChE) histochemistry and evaluated using normal brightfield and confocal laser scanning microscopy. RESULTS: NADPH-diaphorase and AChE histochemistry findings showed characteristic histologic features of hypoganglionosis, eg, sparse and small myenteric ganglia and low or absent AChE activity in the lamina propria. Myenteric plexus in the normal bowel was surrounded by a dense network of c-Kit-positive ICC(my)S, whereas in hypoganglionosis sparse isolated ICC(my)S were found. C-Kit-positive ICC(mus)S were reduced markedly in the longitudinal and circular muscle layer and at the innermost part of the circular muscle in hypoganglionosis. CONCLUSION: Deficient expression of c-Kit-positive myenteric and muscular ICCs in the hypoganglionic colon may contribute to the motility dysfunction in the affected bowel.

Acetylcholinesterase↗