Architectural and functional alterations of the small intestinal mucosa in classical Whipple's disease.

Classical Whipple's disease (CWD) affects the gastrointestinal tract and rather elicits regulatory than inflammatory immune reactions. Mechanisms of malabsorption, diarrhea, and systemic immune activation are unknown. We here analyzed mucosal architecture, barrier function, and immune activation as potential diarrheal trigger in specimens from 52 CWD patients. Our data demonstrate villus atrophy and crypt hyperplasia associated with epithelial apoptosis and reduced alkaline phosphatase expression in the duodenum of CWD patients. Electrophysiological and flux experiments revealed increased duodenal permeability to small solutes and macromolecules. Duodenal architecture and permeability ameliorated upon antibiotic treatment. Structural correlates for these alterations were concordant changes of membranous claudin-1, claudin-2, claudin-3, and tricellulin expression. Tumor necrosis factor-α and interleukin-13 were identified as probable mediators of epithelial apoptosis, and altered tight junction expression. Increased serum markers of microbial translocation and their decline following treatment corroborated the biological significance of the mucosal barrier defect. Hence, mucosal immune responses in CWD elicit barrier dysfunction. Diarrhea is caused by loss of absorptive capacity and leak flux of ions and water. Downregulation of tricellulin causes increased permeability to macromolecules and subsequent microbial translocation contributes to systemic inflammation. Thus, therapeutic strategies to reconstitute the mucosal barrier and control inflammation could assist symptomatic control of CWD.

TcpC protein from E. coli Nissle improves epithelial barrier function involving PKCζ and ERK1/2 signaling in HT-29/B6 cells.

The probiotic Escherichia coli Nissle 1917 (EcN) is widely used to maintain remission in ulcerative colitis. This is thought to be mediated by various immunomodulatory and barrier-stabilizing effects in the intestine. In this study, the mechanisms of barrier modulation by EcN were studied in the human epithelial HT-29/B6 cell culture model.EcN supernatant increased transepithelial resistance (TER) and reduced permeability to mannitol because of sealing of the paracellular passage pathway as revealed by two-path impedance spectroscopy. This increase in TER was attributed to the TcpC protein of EcN. TcpC induced protein kinase C-ζ (PKCζ) and extracellular-signal-regulated kinase 1/2 (ERK1/2) phosphorylation, which in turn resulted in upregulation of the barrier-forming tight junction protein claudin-14. By specific silencing of protein expression by small interfering RNA (siRNA), the sealing function of claudin-14 was confirmed. In conclusion, the TcpC protein of EcN affects innate immunity by improving intestinal barrier function through upregulation of claudin-14 via PKCζ and ERK1/2 signaling.

[Prophylaxis of CRPS I and recurrent CRPS I]. / Prophylaxe des CRPS I und des CRPS I-Rezidivs.

In the foreground of the avoidance of a CRPS as well as a recurrent CRPS, also pathophysiological considerations and use-possibilities of different drugs stand beside the observance of generally valid principles for treatment. Its consistent transposition cannot certainly prevent the CRPS in each case admittedly, the installment of the appearance or recurrence of a CRPS clearly lowers however.

[History, classification and clinic of the complex regional pain syndrome (CRPS)]. / Geschichte, Stadieneinteilung und Klinik des komplexen regionalen Schmerzsyndroms (CRPS).

Almost 150 years are gone since the first description of the classic symptoms, what is today summarized under the term CRPS. From a big number of different names, it has been agreed in 1986 to this term and has also defined more exactly the corresponding terms to it. In the pathophysiology of this complex of symptoms is today accepted that it is a combination of inflammatory, vegetative and central-nervous processes in different size and weight as a key position. There are hardly new findings in epidemiology and frequency. In opposite to this a number of results are produced by better methods for examination which let appear the connections in a new view and make new therapy options possible.

Prostaglandin I(2) sensory input into the enteric nervous system during distension-induced colonic chloride secretion in rat colon.

AIM: Intestinal pressure differences or experimental distension induce ion secretion via the enteric nervous system, the sensorial origin of which is only poorly understood. This study aimed to investigate sensorial inputs and the role of afferent and interneurones in mechanically activated submucosal secretory reflex circuits. METHODS: Distension-induced rheogenic chloride secretion was measured as increase in short-circuit current 10 min after distension (DeltaI(SC)(10); distension parameters +/- 100 microL, 2 Hz, 20 s) in partially stripped rat distal colon in the Ussing-chamber in vitro. PGE(2) and PGI(2) were measured by radioimmunoassay. RESULTS: DeltaI(SC)(10) was 2.0 +/- 0.2 micromol h(-1) cm(-2) and could be attenuated by lobeline, mecamylamine and dimethylphenylpiperazine, indicating an influence of nicotinergic interneurones. Additionally, a contribution of afferent neurones was indicated from the short-term potentiation of DeltaI(SC)(10) by capsaicin (1 microm). As evidence for its initial event, indomethacin (1 microm) inhibited distension-induced secretion and the release of PGI(2) was directly detected after distension. Furthermore, serotoninergic mediation was confirmed by granisetron (100 microm) which was functionally localized distally to PGI(2) in this reflex circuit, as granisetron inhibited an iloprost-induced I(SC), while indomethacin did not affect serotonin-activated ion secretion. CONCLUSIONS: Distension-induced active electrogenic chloride secretion in rat colon is mediated by a neuronal reflex circuit which includes afferent neurones and nicotinergic interneurones. It is initiated by distension-induced PGI(2) release from subepithelial cells triggering this reflex via serotoninergic 5-HT(3) receptor transmission. Functionally, this mechanism may help to protect against intestinal stasis but could also contribute to luminal fluid loss, e.g. during intestinal obstruction.

Structural and functional changes of the duodenum in human norovirus infection.

BACKGROUND: Norovirus infection is the most frequent cause of infectious diarrhoea in the western world. This study aimed to characterise functionally and histomorphologically the diseased duodenum in human biopsies. METHODS: Norovirus infection was diagnosed by the Kaplan criteria and confirmed by PCR of stool samples. Duodenal biopsies were obtained endoscopically. In miniaturised Ussing chambers, short circuit current, flux measurements and impedance spectroscopy were performed. Histological analysis including apoptosis staining and characterisation of intraepithelial lymphocytes was performed. Tight junction proteins were quantified by immunoblotting. RESULTS: In norovirus infection, epithelial resistance decreased from (mean (SEM)) 24 (2) Omega cm(2) in controls to 10 (1) Omega cm(2). Mannitol flux increased from 113 (24) nmol h(-1) cm(-2) in controls to 242 (29) nmol h(-1) cm(-2). Microdissection revealed a villus surface area reduced by 47% (6.6%). Intraepithelial lymphocytes were increased to 63 (7) per 100 enterocytes, with an increased rate of perforin-positive cytotoxic T cells. Expression of tight junctional proteins occludin, claudin-4 and claudin-5 was reduced. The epithelial apoptotic ratio was doubled in norovirus infection. Furthermore, the basal short circuit current was increased in norovirus infection and could be reduced by bumetanide and 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB). CONCLUSIONS: Norovirus infection leads to epithelial barrier dysfunction paralleled by a reduction of sealing tight junctional proteins and an increase in epithelial apoptosis, which may partly be mediated by increased cytotoxic intraepithelial lymphocytes. Furthermore, active anion secretion is markedly stimulated. Thus, the diarrhoea in norovirus infection is driven by both a leak flux and a secretory component.

Impairment of the intestinal barrier is evident in untreated but absent in suppressively treated HIV-infected patients.

BACKGROUND AND AIMS: Impairment of the gastrointestinal mucosal barrier contributes to progression of HIV infection. The purpose of this study was to investigate the effect of highly active antiretroviral therapy (HAART) on the HIV-induced intestinal barrier defect and to identify underlying mechanisms. METHODS: Epithelial barrier function was characterised by impedance spectroscopy and [(3)H]mannitol fluxes in duodenal biopsies from 11 untreated and 8 suppressively treated HIV-infected patients, and 9 HIV-seronegative controls. The villus/crypt ratio was determined microscopically. Epithelial apoptoses were analysed by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelling (TUNEL) and caspase-3 staining. Tight junction protein expression was quantified by densitometric analysis of immunoblots. Mucosal cytokine production was determined by cytometric bead array. RESULTS: Only in untreated but not in treated HIV-infected patients, epithelial resistance was reduced (13 (1) vs 23 (2) ohm cm(2), p<0.01) and mannitol permeability was increased compared with HIV-negative controls (19 (3) vs 9 (1) nm/s, p<0.05). As structural correlates, epithelial apoptoses and expression of the pore-forming claudin-2 were increased while expression of the sealing claudin-1 was reduced in untreated compared with treated patients and HIV-negative controls. Furthermore, villous atrophy was evident and mucosal production of interleukin 2 (IL2), IL4 and tumour necrosis factor alpha (TNFalpha) was increased in untreated but not in treated HIV-infected patients. Incubation with IL2, IL4, TNFalpha and IL13 reduced the transepithelial resistance of rat jejunal mucosa. CONCLUSIONS: Suppressive HAART abrogates HIV-induced intestinal barrier defect and villous atrophy. The HIV-induced barrier defect is due to altered tight junction protein composition and elevated epithelial apoptoses. Mucosal cytokines are mediators of the HIV-induced mucosal barrier defect and villous atrophy.

Restitution of single-cell defects in the mouse colon epithelium differs from that of cultured cells.

Integrity of colon epithelium is of crucial importance and, as small defects occur constantly, rapid repair (restitution) is essential. To investigate the mechanism of restitution, single-cell lesions were induced in mouse colonic surface epithelia by iontophoretic injection of Ca2+. Closure of the resulting defects was monitored using confocal laser scanning microscopy (CLSM), and functional sealing by electrophysiological techniques. Restitution was evaluated as the time constant tau of the exponential decrease in conductance of an induced leak and amounted to 0.28 min under control conditions. After 4 min, the leak was completely sealed. Repair was thus considerably faster than in previously investigated HT-29/B6 cells (tau=5.73 min). As in cultured cells, cytochalasin D delayed restitution in native colon epithelia (tau=0.69 min), indicating the involvement of actin in the healing process; however, no accumulation of actin surrounding the lesion was detected. Long-term incubation of epithelia with IFN-gamma alone or in combination with TNF-alpha increased tau to 0.49 and 0.59 min, respectively. In contrast to cultured cells, TNF-alpha alone did not affect restitution. A brief (<10 min) exposure to the sterile filtered supernatant of hemolytic E. coli O4 cultures did not affect the morphology of the epithelium, but delayed restitution. In CLSM studies, defects were still clearly visible 4 min after the onset of lesion induction. The supernatant of a nonhemolytic E. coli O4 mutant did not exhibit this effect. In conclusion, single-cell defects in native colon cause functional leaks that seal faster than in cell cultures. Proinflammatory cytokines and pathogenic bacteria delay restitution. This suggests a key role of very small lesions at the onset of pathogenic processes in the intestine.

[Fibular nerve compression due to an unusual cause. A case report]. / Kompression des Nervus peroneus communis mit ungewöhnlicher Ursache. Ein Fallbericht.

There are many factors causing a compression of the fibular nerve accompanied by a loss of function. We describe an unknown cause: a chronic low-grade infection after implantation of a knee endoprosthesis. Perforation of the capsule of the knee joint followed by discharge of polyethylene particles originating from the endoprosthesis. A granuloma developed which resulted in a compression of the peroneal nerve with sensomotor disabilities. Preoperatively we were not able to define the dignity of the tumour. Neurolysis was performed followed by excision of the tumour. The infection was treated by long term antibiotics without removal of the endoprosthesis. Histological examination revealed the definitive diagnosis.

Enhanced 11beta-hydroxysteroid dehydrogenase type 1 activity in stress adaptation in the guinea pig.

The 11beta-hydroxysteroid dehydrogenases (11beta-HSDs) convert cortisol to its inactive metabolite cortisone and vice versa. 11beta-HSD type 1 (11beta-HSD-1) functions as a reductase in vivo, regulating intracellular cortisol levels and its access to the glucocorticoid receptor. In contrast, 11beta-HSD-2 only mediates oxidation of natural glucocorticoids, and protects the mineralocorticoid receptor from high cortisol concentrations. We investigated the in vivo and in vitro effects of ACTH on the recently characterized 11beta-HSDs in guinea pig liver and kidney. Tissue slices of untreated guinea pigs were incubated with (3)H-labelled cortisol or cortisone and ACTH(1-24) (10(-10) and 10(-9) mol/l). The 11beta-HSD activities in liver and kidney slices were not influenced by in vitro incubation with ACTH(1-24). In addition, guinea pigs were treated with ACTH(1-24) or saline injections s.c. for 3 days. Liver and kidney tissue slices of these animals were incubated with (3)H-labelled cortisol or cortisone. In vivo ACTH treatment significantly increased reductase and decreased oxidase activity in liver and kidney. Furthermore, 11beta-HSD-1 activity assessed by measurement of the urinary ratio of (tetrahydrocortisol (THF)+5alphaTHF)/(tetrahydrocortisone) was significantly increased after ACTH treatment compared with the control group. Plasma levels of cortisol, cortisone, progesterone, 17-hydroxyprogesterone and androstenedione increased significantly following in vivo ACTH treatment. The enhanced reductase activity of the hepatic and renal 11beta-HSD-1 is apparently caused by cortisol or other ACTH-dependent steroids rather than by ACTH itself. This may be an important fine regulation of the glucocorticoid tonus for stress adaptation in every organ, e.g. enhanced gluconeogenesis in liver.

Plantar impact causing midfoot fractures result in higher forces in Chopart's joint than in the ankle joint.

PURPOSE: Force effect (impact, extent of foot compartment deformation) and result (fracture pattern) for midfoot fractures in car occupants is known. An analysis of the processes in the foot was intended to improve car safety. MATERIALS AND METHODS: Eleven fresh, unfrozen, unpreserved intact human cadavers (age: 36.8 (16-61) years, gender: male, race: Caucasian) were studied 24-72 h after death. In 3 cadavers (5 feet) the experimental design was established: entire cadaver fixed on a special tray in supine position, pendulum with bar impactor hitting the foot plantar to Lisfranc's joint. A custom-made pressure sensor was inserted in the ankle (A), talonavicular (TN) and calcaneocuboid (CC) joints (resolution: 1 cm2, sampling rate: 500/s). RESULTS: Sixteen feet were measured: midfoot fractures were induced in 11 feet. The maximum pressure amounted to 1.22-2.55 MPa (2.04+/-0.412) at 0.005 0.195 s (0.067+/-0.059) after impact. The maximum pressure occurred in 8 (50%) cases in the ankle, in 7 (44%) of the TN and 1 (6%) of the CC joints. A comparison of the first 200 pressure samples after impact of all sensor fields resulted in higher forces in Chopart's joint than in the ankle (t-test: p < 0.001). These force differences were higher in cases with midfoot fractures (mixed model analysis of variance: p = 0.003). CONCLUSION: Due to considerable forces in Chopart's joint we recommend a modification of the actual crash test dummy lower extremity model with an additional load cell that detects forces in the longitudinal direction of the foot axis.

Recovery after carpal tunnel syndrome operation: the influence of the opposite hand, if operated on in the same session.

In a clinical, retrospectively randomised study, we compared the results of the operation for a carpal tunnel syndrome when one side only or both sides were simultaneously assessed in one session. Of the 125 patients examined, 47.2% had both hands operated on in one session, 52.8% had only one hand operated on in one session or both hands in two sessions. We found the bilateral simultaneous operation to be associated with better results concerning earlier return to work, earlier relief of symptoms and better patient satisfaction than the operation on one side only. These are explained by the necessity of using both hands for daily activities and thus a guaranteed functional follow-up treatment after the bilateral operation. In conclusion, we propose operating on both hands simultaneously whenever possible, even if the opposite hand presents with only a slight CTS, which would otherwise not be considered for operation yet.

Wrist arthroscopy without distraction. A technique to visualise instability of the wrist after a ligamentous tear.

We describe a technique for arthroscopy of the wrist which is carried out without traction and with the arm lying horizontally on the operating table. The wrist is not immobilised, which makes it possible to assess the extent of instability after a ligamentous tear. In a prospective study of 30 patients we compared this technique with conventional wrist arthroscopy, performing the new method first followed by conventional arthroscopy. The advantages are that the horizontal position of the arm allows the surgeon to proceed directly from arthroscopic diagnosis to treatment, and that no change of position is required for fluoroscopy. In terms of diagnostic sensitivity, we found our technique matched that of conventional arthroscopy. We had no difficulty in carrying out minor surgical procedures such as debridement and suturing.

[Malignant course of pigmented villonodular synovitis of the flexor tendon sheath of the small finger--case report and review of the literature]. / Maligner Verlauf einer pigmentierten villonodulären Synovialitis der Beugesehnenscheide des Kleinfingers--Fallbericht und Literaturübersicht.

The case of a 55-year-old patient is described, presenting the clinical sign of a chronic infection of the tendon sheath. Upon incision a mass of brown synovial tumor was found. The X-ray showed a circumscript bone erosion. MRI demonstrated tumor involvement of all flexor tendons up to the forearm. Under radiation the tumor initially was diminished. Half a year later, pulmonary metastases were found. The destruction of the whole skeleton of the hand led to a forearm amputation. Later, a metastasis was found in the tongue. The patient died with the clinical signs of pulmonary insufficiency. Autopsy showed diffuse pulmonary metastases. This case is discussed together with other rare cases of malignant pigmented villonodular synovialitis arising from joints and tendon sheaths.

[An alternative for defect coverage of the dorsal side of the finger with a pedicled flap]. / Alternative zur Defektdeckung der Fingerdorsalseite mit einem gestielten Lappen.

We present a flap to cover defects of the dorsum of the digits with donor site at the midhand. It may be used by leek of the donor sites of established alternatives i.e. cross-finger flap or an island flap. The flap can size up to 8 x 2 cm, its pedicle is formed by the Vasa perforantia distales of the webspace 2-4. It is inset into the primary defect by rotation of 180 degrees and reaches easily defects beyond the PIP joints.

Increased surface expression of CD18 and CD11b in leukocytes after tourniquet ischemia during elective hand surgery.

The surface expression of beta2-integrins was investigated in leukocytes from patients undergoing ischemia induced by tourniquet application for elective hand surgery. Blood samples were obtained before initiation, at the end of ischemia, and after 15 minutes of reperfusion from ischemic and contralateral arms of five patients. Comparable expression of CD18, CD11a, CD11b, and CD11c could be detected by immunofluorescence in leukocytes from samples drawn from either arm before tourniquet application. In contrast, a significant increase in the expression of CD18 was detectable in monocytes, granulocytes, and lymphocytes from the ischemic arm compared with that in the nonischemic contralateral control, at the end of the ischemia time (80 +/- 16 minutes). A significantly increased expression of CD11b, but not CD11a or CD11c, determinants was also observed in granulocytes and monocytes. Concomitantly, a significant reduction in the percentages of granulocytes in samples from ischemic areas was detectable. After 15 minutes of reperfusion, differences in the expression of these adhesion molecules were no longer significant. The expression of the genes encoding interleukins IL-1alpha, IL-1beta, and IL-6 and tumor necrosis factor alpha (TNFalpha) proinflammatory cytokines was also studied by reverse polymerase chain reaction (rPCR) in peripheral blood mononuclear cells (PBMCs) obtained from the same samples in three patients. IL-1beta or IL-6 gene expression was never observed. Expression of IL-1alpha and TNFalpha genes, as detected in two patients, was not related with induction of ischemia. However, in these patients expression of one or both these genes was observed in samples derived from the ischemic but not the control arm after 15 minutes of reperfusion. These data document that overexpression of adhesion molecules and sequestration of leukocytes take place following short ischemia times, as routinely applied clinically for minor surgical procedures.

[Wrist impaction syndrome after distal radial or forearm fractures treated by ulnar osteotomy. Surgical techniques and results in 26 cases]. / Syndrome d'hyperpression interne du poignet après fracture de l'extrémité distale du radius ou des os de l'avant-bras traité par ostéotomie de raccourcissement de l'ulna. Technique chirurgicale et résultats de vingt-six cas.

Twenty-six of 27 patients in whom an ulnar shortening osteotomy had been performed to treat ulnar impaction following distal radius (20 patients) or forearm (6 patients) fractures were evaluated at an average follow-up of 21 months. All but 3 patients were satisfied with the end-result and according to a modified Gartland-Werley score there were 1 excellent, 10 good, 10 fair and 5 poor results. This is distinctly inferior to other reports of mainly non-traumatic indications. Degenerative changes at the distal radioulnar joint were associated with fair and poor results and careful radiological examination of this joint is mandatory before ulnar shortening is performed in posttraumatic ulnar impaction syndrome. Bony union of the osteotomy was achieved at 12 to 16 weeks postoperatively except for 2 cases and there was no difference between transverse (13 cases) and oblique osteotomies (13 cases). We therefore prefer the technically easier transverse osteotomy and recommend the use of 3.5 dynamic compression plates for stabilisation which resulted in a low complication rate in our series and enables early active wrist mobilisation.

[AO external mini-fixateur for the hand bones. Surgical technique and initial experiences]. / AO-Mini-Fixateur externe für das Handskelett. Operationstechnik und erste Erfahrungen.

Fractures of the hand and fingers showing comminution or associated soft-tissue lesions are best treated with external fixation. In contrast to other systems, the new AO mini-external fixator enables less bulky unilateral fixation facilitating early mobilisation and the special design of the double clamps allows preliminary intraoperative stabilisation with only one wire in each fragment. Modular fixation makes free placement of the wires possible with accommodation of bone and soft tissue lesions. Twenty patients with hand injuries showed uneventful soft tissue healing and there were no cases of non-union in 19 metacarpal and phalangeal fractures.