Staged Mucosal Advancement Flap versus Staged Fibrin Sealant in the Treatment of Complex Perianal Fistulas

Background. In this prospective randomised study, the staged mucosal advancement flap is compared with staged fibrin sealant application in the treatment of perianal fistulas. Methods. All patients with high complex cryptoglandular fistulas were randomised to closure of the internal opening by a mucosal advancement flap (MF) or injection with fibrin sealant (FS) after treatment with setons. Recurrence rate and incontinence disorders were explored. Results. The MF group (5 females and 10 males) with a median age of 51 years and a median followup of 52 months. The FS group (4 females and 11 males) with a median age of 45 years and a median followup of 49 months. Three (20%) patients of the MF group had a recurrent fistula compared to 9 (60%) of the FS group (P = 0.03). No new continence disorders developed. Conclusion. Staged FS injection has a much lower success rate compared to MF

Somatostatin analogues for receptor targeted photodynamic therapy

Photodynamic therapy (PDT) is an established treatment modality, used mainly for anticancer therapy that relies on the interaction of photosensitizer, light and oxygen. For the treatment of pathologies in certain anatomical sites, improved targeting of the photosensitizer is necessary to prevent damage to healthy tissue. We report on a novel dual approach of targeted PDT (vascular and cellular targeting) utilizing the expression of neuropeptide somatostatin receptor (sst2) on tumor and neovascular-endothelial cells. We synthesized two conjugates containing the somatostatin analogue [Tyr3]-octreotate and Chlorin e6 (Ce6): Ce6-K3-[Tyr3]-octreotate (1) and Ce6-[Tyr3]-octreotate-K3-[Tyr3]-octreotate (2). Investigation of the uptake and photodynamic activity of conjugates in-vitro in human erythroleukemic K562 cells showed that conjugation of [Tyr3]-octreotate with Ce6 in conjugate 1 enhances uptake (by a factor 2) in cells over-expressing sst2 compared to wild-type cells. Co-treatment with excess free Octreotide abrogated the phototoxicity of conjugate 1 indicative of a specific sst2-mediated effect. In contrast conjugate 2 showed no receptor-mediated effect due to its high hydrophobicity. When compared with un-conjugated Ce6, the PDT activity of conjugate 1 was lower. However, it showed higher photostability which may compensate for its lower phototoxicity. Intra-vital fluorescence pharmacokinetic studies of conjugate 1 in rat skin-fold observation chambers transplanted with sst2+ AR42J acinar pancreas tumors showed significantly different uptake profiles compared to free Ce6. Co-treatment with free Octreotide significantly reduced conjugate uptake in tumor tissue (by a factor 4) as well as in the chamber neo-vasculature. These results show that conjugate 1 might have potential as an in-vivo sst2 targeting photosensitizer conjugate

TNF- α augments intratumoural concentrations of doxorubicin in TNF- α -based isolated limb perfusion in rat sarcoma models and enhances anti-tumour effects

We have shown previously that isolated limb perfusion (ILP) in sarcoma-bearing rats results in high response rates when melphalan is used in combination with tumour necrosis factor alpha (TNF-α). This is in line with observations in patients. Here we show that ILP with doxorubicin in combination with TNF-α has comparable effects in two different rat sarcoma tumour models. The addition of TNF-α exhibits a synergistic anti-tumour effect, resulting in regression of the tumour in 54% and 100% of the cases for the BN175-fibrosarcoma and the ROS-1 osteosarcoma respectively. The combination is shown to be mandatory for optimal tumour response. The effect of high dose TNF-α on the activity of cytotoxic agents in ILP is still unclear. We investigated possible modes by which TNF-α could modulate the activity of doxorubicin. In both tumour models increased accumulation of doxorubicin in tumour tissue was found: 3.1-fold in the BN175 and 1.8-fold in the ROS-1 sarcoma after ILP with doxorubicin combined with TNF-α in comparison with an ILP with doxorubicin alone. This increase in local drug concentration may explain the synergistic anti-tumour responses after ILP with the combination. In vitro TNF-α fails to augment drug uptake in tumour cells or to increase cytotoxicity of the drug. These findings make it unlikely that TNF-α directly modulates the activity of doxorubicin in vivo. As TNF-α by itself has no or only minimal effect on tumour growth, an increase in local concentrations of chemotherapeutic drugs might well be the main mechanism for the synergistic anti-tumour effects. © 2000 Cancer Research Campaig

Laparoscopic fistula excision and omentoplasty for high rectovaginal fistulas: a prospective study of 40 patients

AIM: The aim of this study is to prospectively evaluate 40 patients with a high rectovaginal fistula treated by a laparoscopic fistula division and closure, followed by an omentoplasty. PATIENTS AND METHODS: Forty patients with a rectovaginal fistula, between the middle third of the rectum and the posterior vaginal fornix, resulting from different causes (IBD, iatrogenic and birth trauma) were treated by a laparoscopic excision of the fistula and insertion of an omentoplasty in the rectovaginal septum. The patients completed the gastrointestinal quality of life index questionnaire (GIQLI) and the Cleveland Clinic incontinence score (CCIS). All tests were performed at regular intervals after treatment. RESULTS: In 38 (95%) patients with a median age of 53 years (range 33-72), the surgical procedure was feasible. In two patients, the fistula was closed without an omentoplasty, and a diverting stoma was performed. The median follow-up was 28 months (range 10-35). Two patients (5%) developed a recurrent fistula. In one patient, the interposed omentum became necrotic and was successfully treated laparoscopically. In another patient, an abscess developed, which needed drainage procedures. The mean CCIS was 9 (range 7-10) before treatment and 10 (range 7-13) after treatment (p = 0.5 Wilcoxon). The median GIQLI score was 85 (range 34-129) before treatment and 120 (range75-142) after treatment (p = 0.0001, Wilcoxon). CONCLUSIONS: Laparoscopic fistula excision combined with omentoplasty is a good treatment modality with a high healing rate for high rectovaginal fistulas and an acceptable complication rate

Expectations, perceptions, and physiotherapy predict prolonged sick leave in subacute low back pain

<p>Abstract</p> <p>Background</p> <p>Brief intervention programs for subacute low back pain (LBP) result in significant reduction of sick leave compared to treatment as usual. Although effective, a substantial proportion of the patients do not return to work. This study investigates predictors of return to work in LBP patients participating in a randomized controlled trial comparing a brief intervention program (BI) with BI and physical exercise.</p> <p>Methods</p> <p>Predictors for not returning to work was examined in 246 patients sick listed 8-12 weeks for low back pain. The patients had participated in a randomized controlled trial, with BI (n = 122) and BI + physical exercise (n = 124). There were no significant differences between the two intervention groups on return to work. The groups were therefore merged in the analyses of predictors. Multiple logistic regression analysis was used to identify predictors for non return to work at 3, 12, and 24 months of follow-up.</p> <p>Results</p> <p>At 3 months of follow-up, the strongest predictors for not returning to work were pain intensity while resting (OR = 5.6; CI = 1.7-19), the perception of constant back strain when working (OR = 4.1; CI = 1.5-12), negative expectations for return to work (OR = 4.2; CI = 1.7-10), and having been to a physiotherapist prior to participation in the trial (OR = 3.3; CI = 1.3-8.3). At 12 months, perceived reduced ability to walk far due to the complaints (OR = 2.6; CI = 1.3-5.4), pain during activities (OR = 2.4; CI = 1.1-5.1), and having been to a physiotherapist prior to participation in the trial (OR = 2.1; CI = 1.1-4.3) were the strongest predictors for non return to work. At 24 months age below 41 years (OR = 2.9; CI = 1.4-6.0) was the only significant predictor for non return to work.</p> <p>Conclusion</p> <p>It appears that return to work is highly dependant on individual and cognitive factors. Patients not returning to work after the interventions were characterized by negative expectations, perceptions about pain and disability, and previous physiotherapy treatment. This is the first study reporting that previous treatment by physiotherapists is a risk factor for long-term sick leave. This has not been reported before and is an interesting finding that deserves more scrutiny.</p

Bioinformatic meta-analysis reveals novel differentially expressed genes and pathways in sarcoidosis

IntroductionSarcoidosis is a multi-system inflammatory disease of unknown origin with heterogeneous clinical manifestations varying from a single organ non-caseating granuloma site to chronic systemic inflammation and fibrosis. Gene expression studies have suggested several genes and pathways implicated in the pathogenesis of sarcoidosis, however, due to differences in study design and variable statistical approaches, results were frequently not reproducible or concordant. Therefore, meta-analysis of sarcoidosis gene-expression datasets is of great importance to robustly establish differentially expressed genes and signalling pathways.MethodsWe performed meta-analysis on 22 published gene-expression studies on sarcoidosis. Datasets were analysed systematically using same statistical cut-offs. Differentially expressed genes were identified by pooling of p-values using Edgington’s method and analysed for pathways using Ingenuity Pathway Analysis software.ResultsA consistent and significant signature of novel and well-known genes was identified, those collectively implicated both type I and type II interferon mediated signalling pathways in sarcoidosis. In silico functional analysis showed consistent downregulation of eukaryotic initiation factor 2 signalling, whereas cytokines like interferons and transcription factor STAT1 were upregulated. Furthermore, we analysed affected tissues to detect differentially expressed genes likely to be involved in granuloma biology. This revealed that matrix metallopeptidase 12 was exclusively upregulated in affected tissues, suggesting a crucial role in disease pathogenesis.DiscussionOur analysis provides a concise gene signature in sarcoidosis and expands our knowledge about the pathogenesis. Our results are of importance to improve current diagnostic approaches and monitoring strategies as well as in the development of targeted therapeutics

Versatile Coordination of Cyclopentadienyl-Arene Ligands and Its Role in Titanium-Catalyzed Ethylene Trimerization

Cationic titanium(IV) complexes with ansa-(η5-cyclopentadienyl,η6-arene) ligands were synthesized and characterized by X-ray crystallography. The strength of the metal-arene interaction in these systems was studied by variable-temperature NMR spectroscopy. Complexes with a C1 bridge between the cyclopentadienyl and arene moieties feature hemilabile coordination behavior of the ligand and consequently are active ethylene trimerization catalysts. Reaction of the titanium(IV) dimethyl cations with CO results in conversion to the analogous cationic titanium(II) dicarbonyl species. Metal-to-ligand backdonation in these formally low-valent complexes gives rise to a strongly bonded, partially reduced arene moiety. In contrast to the η6-arene coordination mode observed for titanium, the more electron-rich vanadium(V) cations [cyclopentadienyl-arene]V(NiPr2)(NC6H4-4-Me)+ feature η1-arene binding, as determined by a crystallographic study. The three different metal-arene coordination modes that we experimentally observed model intermediates in the cycle for titanium-catalyzed ethylene trimerization. The nature of the metal-arene interaction in these systems was studied by DFT calculations.

Patient-Reported Outcomes and Function after Surgical Repair of the Ulnar Collateral Ligament of the Thumb

Purpose: The purpose of this study was to report prospectively collected patient-reported outcomes of patients who underwent open thumb ulnar collateral ligament (UCL) repair and to find risk factors associated with poor patient-reported outcomes. Methods: Patients undergoing open surgical repair for a complete thumb UCL rupture were included between December 2011 and February 2021. Michigan Hand Outcomes Questionnaire (MHQ) total scores at baseline were compared to MHQ total scores at three and 12 months after surgery. Associations between the 12-month MHQ total score and several variables (i.e., sex, injury to surgery time, K-wire immobilization) were analyzed. Results: Seventy-six patients were included. From baseline to three and 12 months after surgery, patients improved significantly with a mean MHQ total score of 65 (standard deviation [SD] 15) to 78 (SD 14) and 87 (SD 12), respectively. We did not find any differences in outcomes between patients who underwent surgery in the acute (&lt;3 weeks) setting compared to a delayed setting (&lt;6 months). Conclusions: We found that patient-reported outcomes improve significantly at three and 12 months after open surgical repair of the thumb UCL compared to baseline. We did not find an association between injury to surgery time and lower MHQ total scores. This suggests that acute repair for full-thickness UCL tears might not always be necessary. Type of study/level of evidence: Therapeutic II.</p