Safety of Anti-TNF Treatment in Liver Transplant Recipients: A Systematic Review and Meta-analysis.

BACKGROUND AND AIM: Little is known about the risk of serious infection when combining anti-tumour necrosis factor [TNF] therapy for refractory inflammatory bowel disease [IBD] with immunosuppression after liver transplantation [LT]. Our aim was to investigate the infection risk in this patient group by systematic review and meta-analysis of the available data. METHODS: A search was conducted for full papers and conference proceedings through September 2015, regarding liver transplant recipients and anti-TNF therapy. All studies were appraised using the adapted Newcastle-Ottawa Scale [NOS]. Two reviewers independently extracted patient data [age, duration of follow-up, number of all infections, number of serious infections, time since transplant]. As an additional control population, primary sclerosing cholangitis [PSC]-IBD patients from the Leiden University Medical Center [LUMC] LT cohort were used. Poisson regression was used to compare serious infections (according to International Conference on Harmonisation [ICH] definition) per patien-year follow-up between the anti-TNF and control groups. RESULTS: In all 465 articles and abstracts were identified, of which eight were included. These contained 53 post-LT patients on anti-TNF therapy and 23 post-LT patients not exposed to anti-TNF therapy. From the LUMC LT-cohort, 41 PSC patients with PSC-IBD not exposed to anti-TNF therapy were included as control population. The infection rate for TNF-exposed patients was 0.168 serious infections per patient year, compared with 0.149 in the control patients (rate ratio 1.12 [95% confidence interval: 0.233-5.404, P = 0.886]. When correcting for time since transplant, the infection rate was 0.194 in the TNF-exposed vs 0.115 in the non-exposed [p = 0.219]. CONCLUSIONS: No significant increase in the rate of serious infection was observed in LT recipients with PSC-IBD during exposure to anti-TNF therapy.

Glucagon-like peptide-1 receptor agonist treatment reduces beta cell mass in normoglycaemic mice.

AIMS/HYPOTHESIS: Incretin-based therapies improve glycaemic control in patients with type 2 diabetes. In animal models of diabetes, glucagon-like peptide-1 receptor agonists (GLP-1RAs) increase beta cell mass. GLP-1RAs are also evaluated in non-diabetic individuals with obesity and cardiovascular disease. However, their effect on beta cell mass in normoglycaemic conditions is not clear. Here, we investigate the effects of the GLP-1RA liraglutide on beta cell mass and function in normoglycaemic mice. METHODS: C57BL/6J mice were treated with the GLP-1RA liraglutide or PBS and fed a control or high-fat diet (HFD) for 1 or 6 weeks. Glucose and insulin tolerance tests were performed after 6 weeks. BrdU was given to label proliferating cells 1 week before the animals were killed. The pancreas was taken for either histology or islet isolation followed by a glucose-induced insulin-secretion test. RESULTS: Treatment with liraglutide for 6 weeks led to increased insulin sensitivity and attenuation of HFD-induced insulin resistance. A reduction in beta cell mass was observed in liraglutide-treated control and HFD-fed mice at 6 weeks, and was associated with a lower beta cell proliferation rate after 1 week of treatment. A similar reduction in alpha cell mass occurred, resulting in an unchanged alpha to beta cell ratio. In contrast, acinar cell proliferation was increased. Finally, islets isolated from liraglutide-treated control mice had enhanced glucose-induced insulin secretion. CONCLUSIONS/INTERPRETATION: Our data show that GLP-1RA treatment in normoglycaemic mice leads to increases in insulin sensitivity and beta cell function that are associated with reduced beta cell mass to maintain normoglycaemia.

Root-surface phosphatase activity in shrublands across a European gradient: effects of warming.

Root-surface phosphatase activities were measured in natural and semi-natural shrublands across an European climatic gradient of temperature and rainfall including Wales (WL), Denmark (DK), Netherlands (NL), Hungary (HU), Italy (IT) and Spain (SP). In each site a warming experiment was conducted since 1999 or 2001 by means of passive night-time warming using reflective curtains that covered the vegetation at night. The treatments increased yearly average soil temperatures around 0. 8 degrees C in most of sites. Root-surface phosphatase activity values ranged between 56 mg PNP g(-1) h(-1) in IT and 3.5 mg PNP g(-1) h(-1) in HU. Warming had no effect on root-surface phosphatase activity across the sites and only in Hungary a slight increase was detected. Plants at Mediterranean sites (IT, SP) showed a higher root-surface phosphatase activity than plants at temperate sites (WL, NL, DK). We suggest it might be an adaptation of plant species evolved under Mediterranean climate that allows them a) to compensate in wet period for the decrease in phosphatase activity, and thus P uptake, during drought periods, and/or b) to benefit from soluble organic P flushes following the frequent drying-rewetting episodes experienced by soils in Mediterranean ecosystems.

Polyunsaturated fatty acid supplementation stimulates differentiation of oligodendroglia cells.

Dietary polyunsaturated fatty acids (PUFAs) have been postulated as alternative supportive treatment for multiple sclerosis, since they may promote myelin repair. We set out to study the effect of supplementation with n-3 and n-6 PUFAs on OLN-93 oligodendroglia and rat primary oligodendrocyte differentiation in vitro. It appeared that OLN-93 cells actively incorporate and metabolise the supplemented PUFAs in their cell membrane. The effect of PUFAs on OLN-93 differentiation was further assessed by morphological and Western blot evaluation of markers of oligodendroglia differentiation: 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP), zonula occludens-1 (ZO-1) and myelin-associated glycoprotein (MAG). Supplementation of the OLN-93 cells with n-3 and n-6 PUFAs increased the degree of differentiation determined by morphological analysis. Moreover, CNP protein expression was significantly increased by gamma-linolenic acid (GLA, 18:3n-6) supplementation. In accordance with the OLN-93 results, studies with rat primary oligodendrocytes, a more advanced model of cell differentiation, showed GLA supplementation to promote oligodendrocyte differentiation. Following GLA supplementation, increased numbers of proteolipid protein (PLP)-positive oligodendrocytes and increased myelin sheet formation was observed during differentiation of primary oligodendrocytes. Moreover, increased CNP, and enhanced PLP and myelin basic protein expression were found after GLA administration. These studies provide support for the dietary supplementation of specific PUFAs to support oligodendrocyte differentiation and function.

Antioxidants and polyunsaturated fatty acids in multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). Oligodendrocyte damage and subsequent axonal demyelination is a hallmark of this disease. Different pathomechanisms, for example, immune-mediated inflammation, oxidative stress and excitotoxicity, are involved in the immunopathology of MS. The risk of developing MS is associated with increased dietary intake of saturated fatty acids. Polyunsaturated fatty acid (PUFA) and antioxidant deficiencies along with decreased cellular antioxidant defence mechanisms have been observed in MS patients. Furthermore, antioxidant and PUFA treatment in experimental allergic encephalomyelitis, an animal model of MS, decreased the clinical signs of disease. Low-molecular-weight antioxidants may support cellular antioxidant defences in various ways, including radical scavenging, interfering with gene transcription, protein expression, enzyme activity and by metal chelation. PUFAs may not only exert immunosuppressive actions through their incorporation in immune cells but also may affect cell function within the CNS. Both dietary antioxidants and PUFAs have the potential to diminish disease symptoms by targeting specific pathomechanisms and supporting recovery in MS.

[Thrombosis prevention in orthopaedic surgery: clinical practice in the Netherlands in 2002]. / Tromboseprofylaxe in de orthopedische chirurgie: de klinische praktijk in Nederland anno 2002.

OBJECTIVE: Establish the use of thromboprophylaxis in orthopaedic surgery both during and after the hospital admission. DESIGN: Cross-sectional study. METHOD: In April 2002, a letter was sent to all orthopaedic surgeons in the Netherlands announcing that at every hospital with a Department of Orthopaedic Surgery, an orthopaedic surgeon would be approached for a telephone survey. They were phoned in the months April-June 2002. This study included hospitals where major orthopaedic surgery (e.g. the insertion of hip or knee prostheses and hip fracture surgery) took place (n = 124) as well as clinics that only performed day treatments (n = 5). RESULTS: For major orthopaedic operations, 91% of the hospitals used low molecular weight heparin (LMWH) during the admission period: 36% as monotherapy and 55% in combination with coumarin derivates. In 85% of cases the use of LMWH was started preoperatively. Coumarin derivates were used as a monotherapy in 9% of the hospitals. In 37% of the hospitals the use of NSAIDs was continued, particularly in patients with rheumatoid arthritis. In 94% of the hospitals, the use of acetylsalicylic acid was always stopped. In 97% of the hospitals prophylaxis was given after discharge in the form of LMWH (37% of the cases) or coumarin derivates (63% of the cases). The use of thromboprophylaxis with respect to arthroscopies and plaster immobilisation was variable.

Interleukin-2-Deficient mice: effect on cytokines and inflammatory cells in chronic colonic disease.

Mice deficient in interleukin-2 (IL-2-/-) develop inflammatory bowel disease resembling human ulcerative colitis. After death, macroscopic and microscopic scores were used to determine colonic inflammation. Both scores were significantly increased in the colon of IL-2-/- mice as compared to wild types mice. The level of IL-1beta 24-week-old was increased in IL-2-/- mice produced by the colon as compared with IL-2+/+ controls. However, the concentrations of IL-6 and IL-10 were not changed. The spleen weight of IL-2-/- mice was significantly increased compared with IL-2+/+ controls. We used immunochemical techniques in low-temperature paraffin-embedded spleen of IL-2-/- mice to examine pathological changes of CD4+ T cells, CD8' T cells, and CD11b+ cells. The tissue was successfully stained and was well preserved. The percentage CD4+ T cells was not significantly changed, while the percentage CD8+ T cells was significantly decreased in IL-2-/- mice compared with IL-2+/+ controls. On the other hand, the percentage CD11b+ cells was significantly increased in the spleen of IL-2-/- mice compared with IL-2+/- controls. As well as the marked difference in CD8+ and CD11b+ cells in the spleen, the increased level of IL-1beta in colonic tissue might indicate that cytotoxic T cells as well as macrophages are involved in the development and/or perpetuation of the inflammatory reactions in IL-2-/- mice.

The effect of dexamethasone treatment on murine colitis.

BACKGROUND: Corticosteroids are used as anti-inflammatory drugs in the treatment of inflammatory bowel disease. We wanted to know whether dexamethasone (DEX) treatment could prevent dextran sulphate sodium (DSS)-induced colitis in mice. METHODS: Acute colitis was induced after oral administration of 10% DSS for 2 days. Controls received normal tap water. Five days before and during DSS or tap water exposure half the group was treated with 0.06 mg/day DEX, and the other half received saline. After the mice had been killed, macroscopic observation and histologic evaluation were used to determine the degree of colonic inflammation. RESULTS: The macroscopic score was significantly increased in untreated DSS mice (P < 0.001). The induction of colitis was not prevented by DEX pretreatment (5.9 +/- 0.9 versus 4.2 +/- 0.6; NS). In addition, the macroscopic scores of DEX-treated controls were significantly increased (1.8 +/- 0.2 versus 0.7 +/- 0.2; P = 0.007), which suggests that DEX has a stimulating effect on colitis induction. The histology score was significantly increased in untreated DSS mice compared with controls (P = 0.016). Analogous to the macroscopic scoring results, the histology score of DEX-treated controls was significantly increased compared with untreated controls (P = 0.046). CONCLUSIONS: Pretreatment with dexamethasone did not prevent the induction of acute DSS colitis, reflected by both aggravated macroscopic and histologic inflammation scores.

Humoral and cellular immune responses in different rat strains on oral exposure to ovalbumin.

No adequate enteral sensitization models are available to study food allergy and allergenicity of food proteins. Using a previously described oral sensitization protocol to sensitize Brown Norway rats (BN) to food proteins, the influence of genetically-based strain-specific characteristics of the immune system on the outcome of oral sensitization studies was investigated. BN, Hooded Lister (HL), Piebald Virol Glaxo (PVG) and Wistar rats were daily administered 1 mg of ovalbumin (OVA) by gavage dosing for 42 days without the use of an adjuvants. The highest OVA-specific IgG responses were detected in the BN rats followed by Wistar, HL and PVG rats. OVA-specific IgE responses were only detectable in the BN rats. The cellular immune response was examined by determination of delayed-type hypersensitivity (DTH) reactions in the animals. The response was most pronounced in the HL and Wistar rats. PVG and BN rats showed comparable DTH responses but the responses were significantly weaker than those observed in HL and Wistar rats. It was concluded that the genetic make-up of different rat strains influences the outcome of oral sensitization studies. In addition, using the described oral sensitization protocol, the BN rat seems to be the most suitable strain for inducing oral sensitization.

In vitro inhibition of thyroid hormone sulfation by hydroxylated metabolites of halogenated aromatic hydrocarbons.

Earlier studies in our laboratory showed that hydroxylated metabolites of polychlorinated biphenyls (PCBs), dibenzo-p-dioxins (PCDDs), and dibenzofurans (PCDFs) competitively inhibit thyroxine (T4) binding to transthyretin (TTR) and type I deiodinase (D1) activity. In this study, we investigated the possible inhibitory effects of hydroxylated metabolites of polyhalogenated aromatic hydrocarbons (PHAHs) on iodothyronine sulfotransferase activity. Rat liver cytosol was used as a source of sulfotransferase enzyme in an in vitro assay with 125I-labeled 3,3'-diiodothyronine (T2) as a model substrate. Increasing amounts of hydroxylated PCBs, PCDDs, or PCDFs or extracts from incubation mixtures of PHAHs and induced liver microsomes were added as potential inhibitors of T2 sulfotransferase activity. Hydroxylated metabolites of PCBs, PCDDs, and PCDFs were found to be potent inhibitors of T2 sulfotransferase activity in vitro with IC50 values in the low micromolar range (0.2-3.8 microM). The most potent inhibitor of T2 sulfotransferase activity in our experiments was the PCB metabolite 3-hydroxy-2,3',4, 4',5-pentachlorobiphenyl with an IC50 value of 0.2 microM. A hydroxyl group in the para or meta position appeared to be an important structural requirement for T2 sulfotransferase inhibition by PCB metabolites. Ortho hydroxy PCBs were much less potent, and none of the parent PHAHs was capable of inhibiting T2 sulfotransferase activity. In addition, the formation of T2 sulfotransferase-inhibiting metabolites of individual brominated diphenyl ethers and nitrofen as well as from some commercial PHAH mixtures (e.g., Bromkal, Clophen A50, and Aroclor 1254) was also demonstrated. These results indicate that hydroxylated PHAHs are potent inhibitors of thyroid hormone sulfation. Since thyroid hormone sulfation may play an important role in regulating free hormone levels in the fetus, and PCB metabolites are known to accumulate in fetal tissues after maternal exposure to PCBs, these observations may have implications for fetal thyroid hormone homeostasis and development.

Improved results in treatment of femoral shaft fractures with the unreamed femoral nail? A multicenter experience.

OBJECTIVES: The first studies of intramedullary nailing with the Arbeidsgemeinschaft fur Osteosynthesefragen (AO) unreamed femoral nail in selected clinics showed favorable results. Daily practice, however, is that femoral fractures are treated in a variety of clinics by a mixture of surgeons. To evaluate whether similar results could be obtained in general practice, a prospective multicenter trial was undertaken, involving a variety of university and general hospitals in one country. METHODS: Between August of 1994 and June of 1996, 122 patients with 129 traumatic femoral shaft fractures treated with the unreamed femoral nail in eight hospitals were included in this study. Patients who had a reoperation with an unreamed femoral nail or patients with a pathologic fracture of the femur were excluded from this part of the study. Of these patients, 58 patients had multiple injuries, and 33 of the fractures had open soft-tissue injury. RESULTS: Postoperative infection occurred in four patients; the nail broke in one patient. In total, nine patients (6.6 %) sustained general complications, five of which developed adult respiratory distress syndrome (3.6%). Non-union occurred in seven patients (5.1%) and delayed union occurred in four cases (2.9%) with a reintervention rate of 6.6%. CONCLUSION: In this study, a decrease in the number of patients who develop adult respiratory distress syndrome through the use of a thin unreamed nail could not be demonstrated. The promising early callus formation and good consolidation mentioned in previous studies could not be confirmed. We find that the technical and clinical results in this study of unreamed femoral nailing in a mixture of clinics and by a variety of surgeons are comparable to the results of reamed nailing in the literature and are not as favorable as in the previous reports.

Intestinal permeability and contractility in murine colitis.

We developed an in vitro organ bath method to measure permeability and contractility simultaneously in murine intestinal segments. To investigate whether permeability and contractility are correlated and influenced by mucosal damage owing to inflammation, BALB/c mice were exposed to a 10% dextran sulphate sodium (DSS) solution for 8 days to induce colitis. The effect of pharmacologically induced smooth muscle relaxation and contraction on permeability was tested in vitro. Regional permeability differences were observed in both control and 10% DSS-treated mice. Distal colon segments were less permeable to 3H-mannitol and 14C-PEG 400 molecules compared with proximal colon and ileum. Intestinal permeability in control vs. 10% DSS mice was not altered, although histologic inflammation score and IFN-gamma pro-inflammatory cytokine levels were significantly increased in proximal and distal colon. IL-1beta levels were enhanced in these proximal and distal segments, but not significantly different from controls. Any effect of pharmacologically induced contractility on intestinal permeability could not be observed. In conclusion, intestinal permeability and contractility are not correlated in this model of experimentally induced colitis in mice. Although simultaneous measurement in a physiological set-up is possible, this method has to be further validated.

Somatostatin does not attenuate intestinal injury in dextran sodium sulphate-induced subacute colitis.

FRom several in vitro and in vivo studies involvement of somatostatin (SMS) in intestinal inflammation emerge. Acute colitis induced in rats is attenuated by the long-acting SMS analogue octreotide. We studied the potential beneficial effect of SMS on non-acute experimental colitis. BALB/c mice received either saline, SMS-14 (36 or 120 microg daily) or octreotide (3 microg daily) subcutaneously delivered by implant osmotic pumps. A non-acute colitis was induced by administration of dextran sodium sulphate (DSS) 10% in drinking water during 7 days. DSS evoked a mild, superficial pancolitis, most characterized by mucosal ulceration and submucosal influx of neutrophils. Neither SMS-14 nor octreotide reduced mucosal inflammatory score or macroscopical disease activity, although reduction of intestinal levels of interleukin-1beta (IL-1beta), IL-6 and IL-10 during DSS was augmented both by SMS and octreotide. A slight increase of neutrophil influx was seen during SMS administration in animals not exposed to DSS. In conclusion, SMS or its long-acting analogue did not reduce intestinal inflammation in non-acute DSS-induced colitis. According to the cytokine profile observed, SMS-14 and octreotide further diminished the reduction of intestinal macrophage and Th2 lymphocyte activity.

Condylar plate fixation of subtrochanteric femoral fractures.

We describe our experiences in 40 consecutive patients with subtrochanteric fractures treated with an AO 95 degrees condylar blade plate. Three patients died early due to multiple injuries. One patient developed a delayed union which ultimately resulted in repeated plate fractures due to fatigue. All other fractures heated despite deep postoperative wound infection in three cases. Based on our favourable results, we consider the condylar blade plate fixation of subtrochanteric fractures to be an excellent method, especially if an image intensifier and/or fracture table are not available.

[Reasonably good results of Hansson's pins in elderly patients with a medial femoral neck fracture]. / Redelijk goede resultaten van Hansson-pennen bij bejaarde patiënten met een mediale collumfractuur.

OBJECTIVE: To establish the result of treatment of medial femoral neck fractures in patients aged 70 years and older using Hansson pins introduced percutaneously. DESIGN: Descriptive. SETTING: Department of Surgery, University Hospital Utrecht, the Netherlands. METHOD: Ninety-two patients aged 70 years and older with a medial femoral neck fracture were treated in the period 1986-1994 with osteosynthesis using Hansson pins. The case histories and X-rays of these patients were analysed. All fractures were classified according to Garden and Pauwels, with Singh classification of bone quality. The result of the operation was evaluated with the aid of postoperative X-rays. RESULTS: The patients' mean age was 80 years. There were 16 non-dislocated Garden grades I or II and 71 dislocated Garden III and IV fractures. Four patients died within 30 days after the operation. At the time of the follow-up (after an average of 4.5 years), 45 patients had died. Thirty-three patients in all developed a fracture-related complication; 27 of them underwent reoperations during which 19 (21%) were fitted with a head-neck prosthesis or a total hip prosthesis. All reoperations which included implantation of a prosthesis were performed in dislocated Garden grades III and IV fractures. In fractures of this type in which postoperative repositioning proved inadequate, more reoperations were performed than in the Garden grades III and IV fractures with correct posture. CONCLUSION: Treatment of a medial femoral neck fracture in elderly patients by means of internal fixation with percutaneously introduced Hansson pins gives results similar to those of other types of internal fixation. This is a good operation for Garden grades I and II fractures, whereas in Garden grades III and IV fractures in which repositioning is impossible, internal fixation should be refrained from and a head-neck prosthesis should be implanted in one session.

[Moderate results of the treatment of femoral shaft fractures in children using intramedullary fixation]. / Matig resultaat van de behandeling van femurschachtfracturen bij kinderen door intramedullaire fixatie.

OBJECTIVE: To evaluate the results of treatment of femoral shaft fractures in children with intramedullary nailing. DESIGN: Retrospective. SETTING: Department of Surgery, University Hospital Utrecht, Department of Paediatric Surgery, Wilhelmina Children's Hospital, Utrecht. METHOD: Between 1982 and 1993, 27 femoral shaft fractures in 27 patients under the age of 16 were treated by intramedullary nailing. The charts and radiographs of these patients were reviewed and 24 patients were seen for follow-up examination (mean 7.5 years). Leg length was measured radiographically and anteversion of the affected and normal femora was determined by a standard computed tomography (CT) study. RESULTS: The average hospital stay was 34 days. There were no postoperative complications. At follow-up 10 patients had a leg length discrepancy < 1 cm and a rotational deformity < 10 degrees. Three patients had a shortening of the injured leg > 1 cm (max. 1.7 cm), in 6 patients the injured leg was more than 1 cm longer (max. 3.5 cm). The difference in rotation between fracture side and unaffected side was > 10 degrees in 9 patients. In 6 patients this was due to increased exorotation (max. 22 degrees) and in 3 patients to increased endorotation (max. 27 degrees). Iatrogenic injury of the epiphyseal line was not seen. CONCLUSION: Regarding leg length differences and rotational deformities intramedullary nailing was not superior to the known results of conservative treatment. The indication for operation should be carefully considered and during an operation there should be perfect control of reduction.