Excision of high and mid cervical spinal cord arteriovenous malformations by anterior operation

Symptomatic cervical spinal arteriovenous malformations (AVMs) located on the anterior aspect of the spinal cord are rare and surgical removal of these AVMs presents considerable challenges and risks. Surgical techniques to date have usually been by posterior approach and lateral dissection around the cord or via midline myelotomy, both approaches involving cord manipulation and retraction and in the latter, dissection through the spinal cord. We present two teenage patients with symptomatic anteriorly placed mid to high cervical spinal AVMs and associated aneurysm in which excision of the AVMs and aneurysm was performed by an anterior approach using vertebrectomy/corpectomy. The first case had a small perimedullary glomus-type AVM with an aneurysm on the anterior aspect of the cord at the C3/4 level; excision was performed using a single level vertebrectomy/corpectomy, the patient remaining neurologically intact. The second case had a medium-sized juvenile AVM with an aneurysm, both perimedullary and intramedullary, centred at the C5/6 level; excision was performed using a two-level vertebrectomy/corpectomy with no deterioration in the marked pre-operative tetraparesis, which at long-term follow up had improved and stabilised. Anterior approaches have been recently described for treatment of anteriorly placed cervical arteriovenous fistulas (AVFs) and an intramedullary haemangioblastoma, but not as yet for spinal AVMs. These are the first two reported cases of anteriorly situated cervical AVMs successfully removed surgically by an anterior approach and with good neurological outcomes.

Is a sustaining rod necessary for diverting loop ileostomy?

Objective: Whether or not a protective stoma reduces the rate of anastomotic leakage after distal colorectal anastomosis is still discussed controversially. It does however facilitate clinical management once leakage has occurred. Loop ileostomies seem to be associated with a lower morbidity and a better quality of life compared to loop colostomies. Generally, diverting loop ileostomies are secured at skin level by means of a supporting device in order to prevent retraction of the ileostomy into the abdomen. However, due to the supporting rod, difficulties may occur in applying a stoma bag correctly and leakage of faeces onto the skin may occur even with correct eversion of the afferent limb. Our aim was to compare morbidity and time to self-sufficient stoma-care in patients having a loop ileostomy with rod to those without rod. Methods: A total of 60 patients necessitating loop ileostomy were analyzed. Patients received surgery in of the two involved institutions according to inhouse standard procedures. 30 patients had an ileostomy with rod (VCHK Inselspital) and a further 30 without rod (KSW Winterthur). Morbidity and time to self-sufficiency regarding stoma care was analyzed during the first 90 postoperative days. Morbidity was determined according to a scoring system ranging from 0 to 4 points for any given set of possible complications (bleeding, necrosis, skin irritation, abscess, stenosis, retraction, fistula, prolapse, parastomal hernia, incomplete diversion), where 0 = no complication and 4 = severe complication. Continuous variables were expressed as median (95% Confidence Interval). For comparisons between the groups the Mann-Whitney U test was used, between categorical variables the X2 test was applied. Results: There were no significant differences in length of hospital stay or time to self-sufficient stoma-care between the groups. Although not significant, patients with a rod ileostomy had a tendency towards more stoma-related complications as well as stoma-related reoperations. The number of patients reaching total self-sufficiency regarding stoma care was higher after rodless ileostomy. Conclusion: According to our data, rodless ileostomies seemto fare just as well as those with a supporting rod, with equal morbidity rates and more patients reaching self-sufficient stoma care. Therefore routine application of a rod for diverting loop ileostomy seems unnecessary

Neer Award 2007: Reversion of structural muscle changes caused by chronic rotator cuff tears using continuous musculotendinous traction. An experimental study in sheep

HYPOTHESIS: Chronic rotator cuff tears are associated with irreversible architectural muscle changes and a high rate of repair failure. The changes observed in man and their irreversibility with a single stage repair can be reproduced in sheep. It was the purpose of this experiment to test the hypothesis that slow, continuous elongation of a retracted musculotendinous unit allows reversal of the currently irreversible structural muscle changes. MATERIALS AND METHODS: The infraspinatus tendon of 12 sheep was released using a greater tuberosity osteotomy and allowed to retract for 4 months. Then, a new device was mounted on the scapular spine and used to extend the infraspinatus muscuculotendinous unit transcutaneously by 1 mm per day. Thereafter, the tendon was repaired back to the greater tuberosity. We assessed the muscular architecture using magnetic resonance imaging, macroscopic dissection, histology, and electron microscopy. Fatty infiltration (in Hounsfield units 1/4 HU) and muscular cross-sectional area (in % of the control side) were monitored with computed tomography at tendon release, initiation of elongation, repair, and at sacrifice. RESULTS: Sixteen weeks after tendon release, the mean tendon retraction was 29 +/- 6 mm (14% of original length, P = .008). In 8 sheep, elongation was achieved as planned (group I), but in 4, the elongation failed technically (group II). The mean traction time was 24 +/- 6 days with a mean traction distance of 19 +/- 4 mm. At sacrifice, the mean pennation angle in the infraspinatus of group I was not different from the control side (29.8 degrees +/-7.5 degrees vs. 30 degrees +/-6 degrees , P = .575). In group II, the pennation angle had increased from 30 degrees +/-6 degrees to 55 degrees +/-14 degrees (P = .035). There was no fatty infiltration at the time of tendon release. After retraction, there was a significant increase in fatty infiltration of the infraspinatus muscle and a decrease of its cross-sectional area to 57% of the contralateral side (P = .0001). During traction, the degree of fatty infiltration remained unchanged (36 HU to 38 HU, P = .381), and atrophy improved to a muscle square area of 78% of the contralateral side (P = .0001) in group I. In group II, an increase of fatty infiltration was measured from 36 HU to 28 HU; however, this increase was not significant (P = .144). Atrophy did not change in group II (57-55%, P = .946). At sacrifice, the remaining muscle mass was 64% in group I and 46% in group II (P = .019). DISCUSSION: Our preliminary results document, that continuous elongation of a retracted, fatty infiltrated and atrophied musculotendinous unit is technically feasible. CONCLUSION: In the sheep, continuous elongation can lead to restoration of normal muscle architecture, to partial reversal of muscle atrophy, and to arrest of the progression of fatty infiltration. LEVEL OF EVIDENCE: Basic science level 2; Prospective comparative therapeutic study.

Modified temporal approach for a rostro-temporal basal meningioma in a cat

An 11-year-old neutered female domestic shorthair indoor cat was presented to our hospital for treatment of a left-sided rostro-temporal basal meningioma. Focal seizures in the facial muscles had been observed sporadically for 1 year. Two weeks prior to presentation the cat had developed generalised seizures and was treated with symptomatic anticonvulsive treatment. Focal facial seizures, especially on the right side, persisted after medical therapy. From the computed tomography scan, a basal meningioma was suspected by the treating veterinarian. A left-sided suprazygomatical temporobasal approach to the zygomatic arch was chosen because it causes less soft tissue damage. After craniotomy, durotomy and gentle dorsal retraction of the left piriform lobe, the meningioma was removed. Postoperative magnetic resonance imaging confirmed complete excision of the tumour. One day after surgery the cat was alert and a left-sided facial nerve palsy was noticed. Otherwise the neurological examination was normal. Anticonvulsive and eye moistening therapy was continued for 3 months. Six months after surgery the cat was clinically normal without any recurrence of seizures.

Effectiveness of non-conventional methods for accelerated orthodontic tooth movement: a systematic review and meta-analysis.

OBJECTIVES To assess the available evidence on the effectiveness of accelerated orthodontic tooth movement through surgical and non-surgical approaches in orthodontic patients. METHODS Randomized controlled trials and controlled clinical trials were identified through electronic and hand searches (last update: March 2014). Orthognathic surgery, distraction osteogenesis, and pharmacological approaches were excluded. Risk of bias was assessed using the Cochrane risk of bias tool. RESULTS Eighteen trials involving 354 participants were included for qualitative and quantitative synthesis. Eight trials reported on low-intensity laser, one on photobiomodulation, one on pulsed electromagnetic fields, seven on corticotomy, and one on interseptal bone reduction. Two studies on corticotomy and two on low-intensity laser, which had low or unclear risk of bias, were mathematically combined using the random effects model. Higher canine retraction rate was evident with corticotomy during the first month of therapy (WMD=0.73; 95% CI: 0.28, 1.19, p<0.01) and with low-intensity laser (WMD=0.42mm/month; 95% CI: 0.26, 0.57, p<0.001) in a period longer than 3 months. The quality of evidence supporting the interventions is moderate for laser therapy and low for corticotomy intervention. CONCLUSIONS There is some evidence that low laser therapy and corticotomy are effective, whereas the evidence is weak for interseptal bone reduction and very weak for photobiomodulation and pulsed electromagnetic fields. Overall, the results should be interpreted with caution given the small number, quality, and heterogeneity of the included studies. Further research is required in this field with additional attention to application protocols, adverse effects, and cost-benefit analysis. CLINICAL SIGNIFICANCE From the qualitative and quantitative synthesis of the studies, it could be concluded that there is some evidence that low laser therapy and corticotomy are associated with accelerated orthodontic tooth movement, while further investigation is required before routine application.

Evaluation of colon cancer histomorphology: a comparison between formalin and PAXgene tissue fixation by an international ring trial.

The aim of our study was to evaluate the quality of histo- and cytomorphological features of PAXgene-fixed specimens and their suitability for histomorphological classification in comparison to standard formalin fixation. Fifteen colon cancer tissues were collected, divided into two mirrored samples and either formalin fixed (FFPE) or PAXgene fixed (PFPE) before paraffin embedding. HE- and PAS-stained sections were scanned and evaluated in a blinded, randomised ring trial by 20 pathologists from Europe and the USA using virtual microscopy. The pathologists evaluated histological grading, histological subtype, presence of adenoma, presence of lymphovascular invasion, quality of histomorphology and quality of nuclear features. Statistical analysis revealed that the reproducibility with regard to grading between both fixation methods was rather satisfactory (weighted kappa statistic (k w) = 0.73 (95 % confidence interval (CI), 0.41-0.94)), with a higher agreement between the reference evaluation and the PFPE samples (k w = 0.86 (95 % CI, 0.67-1.00)). Independent from preservation method, inter-observer reproducibility was not completely satisfactory (k w = 0.60). Histomorphological quality parameters were scored equal or better for PFPE than for FFPE samples. For example, overall quality and nuclear features, especially the detection of mitosis, were judged significantly better for PFPE cases. By contrast, significant retraction artefacts were observed more frequently in PFPE samples. In conclusion, our findings suggest that the PAXgene Tissue System leads to excellent preservation of histomorphology and nuclear features of colon cancer tissue and allows routine morphological diagnosis.

Preclinical studies identify non-apoptotic low-level caspase-3 as therapeutic target in pemphigus vulgaris

The majority of pemphigus vulgaris (PV) patients suffer from a live-threatening loss of intercellular adhesion between keratinocytes (acantholysis). The disease is caused by auto-antibodies that bind to desmosomal cadherins desmoglein (Dsg) 3 or Dsg3 and Dsg1 in mucous membranes and skin. A currently unresolved controversy in PV is whether apoptosis is involved in the pathogenic process. The objective of this study was to perform preclinical studies to investigate apoptotic pathway activation in PV pathogenesis with the goal to assess its potential for clinical therapy. For this purpose, we investigated mouse and human skin keratinocyte cultures treated with PV antibodies (the experimental Dsg3 monospecific antibody AK23 or PV patients IgG), PV mouse models (passive transfer of AK23 or PVIgG into adult and neonatal mice) as well as PV patients' biopsies (n=6). A combination of TUNEL assay, analyses of membrane integrity, early apoptotic markers such as cleaved poly-ADP-ribose polymerase (PARP) and the collapse of actin cytoskeleton failed to provide evidence for apoptosis in PV pathogenesis. However, the in vitro and in vivo PV models, allowing to monitor progression of lesion formation, revealed an early, transient and low-level caspase-3 activation. Pharmacological inhibition confirmed the functional implication of caspase-3 in major events in PV such as shedding of Dsg3, keratin retraction, proliferation including c-Myc induction, p38MAPK activation and acantholysis. Together, these data identify low-level caspase-3 activation downstream of disrupted Dsg3 trans- or cis-adhesion as a major event in PV pathogenesis that is non-synonymous with apoptosis and represents, unlike apoptotic components, a promising target for clinical therapy. At a broader level, these results posit that an impairment of adhesive functions in concert with low-level, non-lethal caspase-3 activation can evoke profound cellular changes which may be of relevance for other diseases including cancer.

Protected stent retriever thrombectomy prevents iatrogenic emboli in new vascular territories

INTRODUCTION Diagnostic tools to show emboli reliably and protection techniques against embolization when employing stent retrievers are necessary to improve endovascular stroke therapy. The aim of the present study was to investigate iatrogenic emboli using susceptibility-weighted imaging (SWI) in an open series of patients who had been treated with stent retriever thrombectomy using emboli protection techniques. METHODS Patients with anterior circulation stroke examined with MRI before and after stent retriever thrombectomy were assessed for iatrogenic embolic events. Thrombectomy was performed in flow arrest and under aspiration using a balloon-mounted guiding catheter, a distal access catheter, or both. RESULTS In 13 of 57 patients (22.8 %) post-interventional SWI sequences detected 16 microemboli. Three of them were associated with small ischemic lesions on diffusion-weighted imaging (DWI). None of the microemboli were located in a new vascular territory, none showed clinical signs, and all 13 patients have been rated as Thrombolysis in Cerebral Infarction (TICI) 2b (n = 3) or 3 (n = 10). Retrospective reevaluation of the digital subtraction angiography (DSA) detected discrete flow stagnation nearby the iatrogenic microemboli in four patients with a positive persistent collateral sign in one. CONCLUSION Our study demonstrates two things: First, SWI seems to be more sensitive to detect emboli than DWI and DSA and, second, proximal or distal protected stent retriever thrombectomy seems to prevent iatrogenic embolization into new vascular territories during retraction of the thrombus, but not downstream during mobilization of the thrombus. Both techniques should be investigated and refined further.

Influence of two types of self-retaining retractors on multifidus muscle blood flow during dorsolateral thoracolumbar hemilaminectomy in dogs

OBJECTIVES To assess the influence of the use of Gelpi and Grevel retractors on multifidus muscle blood flow during hemilaminectomy, using a dorsolateral approach, for acute disc extrusion in dogs as measured by laser speckle contrast imaging (LSCI). METHODS Blood flow in the multifidus muscles was measured intra-operatively using LSCI prior to insertion of the retractors, immediately after hemilaminectomy and removal of the retractors, and after 10 minutes of lavage of the surgical site. Plasma creatine kinase levels were measured preoperatively and 12-24 hours postoperatively. RESULTS Muscular blood flow was significantly decreased following retraction and remained lower than initial values 10 minutes after lavage in all dogs. The decrease in blood flow was significantly greater with Gelpi retractors (n = 8) than with Grevel retractors (n = 10). No significant relation was found between the duration of retraction and postoperative changes in creatine kinase levels or blood flow. CLINICAL SIGNIFICANCE Findings in this study demonstrate a drop in blood flow within the multifidus muscles using the dorsolateral approach regardless of retractor type used. Gelpi retractors seem to have greater influence on muscular blood flow than Grevel retractors. Further studies are warranted to confirm this second finding.

Computer vision profiling of neurite outgrowth dynamics reveals spatiotemporal modularity of Rho GTPase signaling

Rho guanosine triphosphatases (GTPases) control the cytoskeletal dynamics that power neurite outgrowth. This process consists of dynamic neurite initiation, elongation, retraction, and branching cycles that are likely to be regulated by specific spatiotemporal signaling networks, which cannot be resolved with static, steady-state assays. We present NeuriteTracker, a computer-vision approach to automatically segment and track neuronal morphodynamics in time-lapse datasets. Feature extraction then quantifies dynamic neurite outgrowth phenotypes. We identify a set of stereotypic neurite outgrowth morphodynamic behaviors in a cultured neuronal cell system. Systematic RNA interference perturbation of a Rho GTPase interactome consisting of 219 proteins reveals a limited set of morphodynamic phenotypes. As proof of concept, we show that loss of function of two distinct RhoA-specific GTPase-activating proteins (GAPs) leads to opposite neurite outgrowth phenotypes. Imaging of RhoA activation dynamics indicates that both GAPs regulate different spatiotemporal Rho GTPase pools, with distinct functions. Our results provide a starting point to dissect spatiotemporal Rho GTPase signaling networks that regulate neurite outgrowth.

A growth factor-induced, spatially organizing cytoskeletal module enables rapid and persistent fibroblast migration

Directional migration requires robust front/back polarity. We find that fibroblasts treated with platelet-derived growth factor (PDGF) and prepolarized by plating on a fibronectin line substrate exhibit persistent migration for hours. This does not occur in the absence of PDGF or on uniformly coated fibronectin substrates. Persistent migration arises from establishment of two functional modules at cell front and back. At the front, formation of a zone containing podosome-like structures (PLS) dynamically correlates with low RhoA and myosin activity and absence of a contractile lamella. At the back, myosin contractility specifically controls tail retraction with minimal crosstalk to the front module. The PLS zone is maintained in a dynamic steady state that preserves size and position relative to the cell front, allowing for long-term coordination of front and back modules. We propose that front/back uncoupling achieved by the PLS zone is crucial for persistent migration in the absence of directional cues.

Spatio-temporal Rho GTPase signaling - where are we now?

Rho-family GTPases are molecular switches that transmit extracellular cues to intracellular signaling pathways. Their regulation is likely to be highly regulated in space and in time, but most of what is known about Rho-family GTPase signaling has been derived from techniques that do not resolve these dimensions. New imaging technologies now allow the visualization of Rho GTPase signaling with high spatio-temporal resolution. This has led to insights that significantly extend classic models and call for a novel conceptual framework. These approaches clearly show three things. First, Rho GTPase signaling dynamics occur on micrometer length scales and subminute timescales. Second, multiple subcellular pools of one given Rho GTPase can operate simultaneously in time and space to regulate a wide variety of morphogenetic events (e.g. leading-edge membrane protrusion, tail retraction, membrane ruffling). These different Rho GTPase subcellular pools might be described as 'spatio-temporal signaling modules' and might involve the specific interaction of one GTPase with different guanine nucleotide exchange factors (GEFs), GTPase-activating proteins (GAPs) and effectors. Third, complex spatio-temporal signaling programs that involve precise crosstalk between multiple Rho GTPase signaling modules regulate specific morphogenetic events. The next challenge is to decipher the molecular circuitry underlying this complex spatio-temporal modularity to produce integrated models of Rho GTPase signaling.

Activities of fenbendazole in comparison with albendazole against Echinococcus multilocularis metacestodes in vitro and in a murine infection model.

The current chemotherapeutic treatment of alveolar echinococcosis (AE) in humans is based on albendazole and/or mebendazole. However, the costs of treatment, life-long consumption of drugs, parasitostatic rather than parasiticidal activity of chemotherapy, and high recurrence rates after treatment interruption warrant more efficient treatment options. Experimental treatment of mice infected with Echinococcus multilocularis metacestodes with fenbendazole revealed similar efficacy to albendazole. Inspection of parasite tissue from infected and benzimidazole-treated mice by transmission electron microscopy (TEM) demonstrated drug-induced alterations within the germinal layer of the parasites, and most notably an almost complete absence of microtriches. On the other hand, upon in vitro exposure of metacestodes to benzimidazoles, no phosphoglucose isomerase activity could be detected in medium supernatants during treatment with any of these drugs, indicating that in vitro treatment did not severely affect the viability of metacestode tissue. Corresponding TEM analysis also revealed a dramatic shortening/retraction of microtriches as a hallmark of benzimidazole action, and as a consequence separation of the acellular laminated layer from the cellular germinal layer. Since TEM did not reveal any microtubule-based structures within Echinococcus microtriches, this effect cannot be explained by the previously described mechanism of action of benzimidazoles targeting β-tubulin, thus benzimidazoles must interact with additional targets that have not been yet identified. In addition, these results indicate the potential usefulness of fenbendazole for the chemotherapy of AE.