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Background Context: Mechanical Diagnosis and Treatment (MDT) and epidural steroid injections have the potential to reduce pain and disability in sciatica patients and prevent surgery. However, data on their combined influence in reducing the amount of sciatica surgeries is lacking., Purpose: To assess if a combination therapy (MDT and TESIs), administered while being on the waiting list for lumbar herniated disc surgery, is effective and cost-effective compared to no intervention (i.e., usual care)., Study Design: Multicentre randomized controlled trial with economic evaluation and one-year follow-up., Patient Sample: Seventy-two adult patients on a waiting list for lumbar herniated disc surgery., Outcome Measures: Primary outcome was undergoing lumbar disc surgery during follow-up (yes/no). Secondary outcomes included back and leg pain intensity (NPRS), physical functioning (RMDQ-23), self-perceived recovery (GPE), and health-related quality of life (EQ-5D-5L). Total societal and total healthcare were measured., Methods: Participants were randomly assigned to combination therapy (intervention group, n=34) or no intervention (control group, n=38)., Results: Twenty-nine out of 38 control group patients and 11 out of 34 intervention group patients received surgery. The adjusted odds ratio of receiving surgery in the intervention group compared to the control group was 0.09 (95%CI: 0.02 to 0.35) and the adjusted risk ratio 0.29 (95%CI: 0.08 to 0.69). There were no differences in clinical effects between both groups. Surgical, total societal, and total healthcare costs were on average €1,969, €1,754, and €2,363 lower in the intervention group, respectively. The combination therapy's probability of being cost-effective was moderate (≤0.66) across a range of willingness-to-pay values from €20,000/QALY to €80,000/QALY, from a societal perspective., Conclusion: Patients on the waiting list for lumbar disc surgery and who are open to postpone surgery, may benefit from the combination therapy intervention., Competing Interests: Declaration of competing interest Nil, (Copyright © 2025. Published by Elsevier Inc.)

Background Context: Lumbar microdiscectomy is an effective treatment for short-term pain relief and improvements in disability in patients with lumbar radiculopathy, however, many patients experience residual pain and long-term disability. The 'people like me' approach seeks to enhance personalized prognosis and treatment effectiveness, utilizing historical data from similar patients to forecast individual outcomes., Purpose: The primary objective was to develop and test the 'people-like-me' approach for leg pain intensity and disability at 12-month follow-up after lumbar microdiscectomy and postoperative physical therapy. The secondary objective was to verify the clinical utility of the prediction tool via case vignettes., Study Design/setting: A 12-month prospective cohort study., Patient Sample: Patients (N=618, mean age: 44.7) with lumbar radiculopathy who undergo a lumbar microdiscectomy and postoperative physical therapy., Outcome Measures: Leg pain intensity (Visual Analogue Scale) and disability (Roland-Morris Disability Questionnaire) were measured at 12-months following surgery., Methods: Predictors were selected from data collected in routine practice before and 3-months after lumbar microdiscectomy. Predictive mean matching was used to select matches. Predictions were developed using preoperative data alone or combined with 3-month postoperative data. The prediction performance was evaluated for bias (difference between predicted and actual outcomes), coverage (proportion of actual outcomes within prediction intervals), and precision (accuracy of predictions) using leave-one-out cross-validation., Results: Overall, the 'people-like-me' approach using preoperative data showed accurate coverage and minimal average bias. However, precision based on preoperative data alone was limited. Incorporating 3-month postoperative data alongside preoperative predictors significantly enhanced prognostic precision for both leg pain and disability. Including postoperative data, leg pain prediction accuracy improved by 43% and disability by 23% compared to the sample mean. Adjusted R 2 values improved from 0.04 to 0.21 for leg pain, and from 0.07 to 0.34 for disability, enhancing model precision. The effectiveness of this method was highlighted in two case vignettes, illustrating its application in similar patient scenarios., Conclusion: The 'people-like-me' approach generated an accurate prognosis of 12-months outcomes following lumbar discectomy and physical therapy. Scheduling a 3-month postoperative follow-up to evaluate the course, and refine therapy plans and expectations for patients undergoing lumbar microdiscectomy would be recommended to assist clinicians and patients in more personalized healthcare planning and expectation setting., Competing Interests: Declaration of Competing Interest One or more of the authors declare financial or professional relationships on ICMJE-TSJ disclosure forms., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Rationale: Cervical radiculopathy is initially typically managed conservatively. Surgery is indicated when conservative management fails or with severe/progressive neurological signs. Personalised multimodal physiotherapy could be a promising conservative strategy. However, aggregated evidence on the (cost-)effectiveness of personalised multimodal physiotherapy compared to surgery with/without post-operative physiotherapy is lacking., Aim/objectives: To systematically summarise the literature on the (cost-)effectiveness of personalised multimodal physiotherapy compared to surgery with or without post-operative physiotherapy in patients with cervical radiculopathy., Methods: PubMed, Embase, CINAHL, PsycINFO and Web of Science were searched from inception to 1st of March 2023. Primary outcomes were effectiveness regarding costs, arm pain intensity and disability. Neck pain intensity, perceived recovery, quality of life, neurological symptoms, range-of-motion, return-to-work, medication use, (re)surgeries and adverse events were considered secondary outcomes. Randomised clinical trials comparing personalised multimodal physiotherapy versus surgical approaches with/without post-operative physiotherapy were included. Two independent reviewers performed study selection, data-extraction, and risk of bias assessment using the Cochrane RoB 2 and Consolidated Health Economic Evaluation Reporting Standards statement. Certainty of the evidence was determined using Grading of Recommendations, Assessment, Development and Evaluations., Results: From 2109 records, eight papers from two original trials, with 117 participants in total were included. Low certainty evidence showed there were no significant differences on arm pain intensity and disability, except for the subscale 'heavy work' related disability (12 months) and disability at 5-8 years. Cost-effectiveness was not assessed. There was low certainty evidence that physiotherapy improved significantly less on neck pain intensity, sensory loss and perceived recovery compared to surgery with/without physiotherapy. Low certainty evidence showed there were no significant differences on numbness, range of motion, medication use, and quality of life. No adverse events were reported., Conclusion: Considering the clinical importance of accurate management recommendations and the current low level of certainty, high-quality cost-effectiveness studies are needed., (© 2024 The Author(s). Journal of Evaluation in Clinical Practice published by John Wiley & Sons Ltd.)

Background Context: The proportion of patients who undergo lumbar microdiscectomy due to lumbar radiculopathy who are also overweight or obese is high. However, whether high body mass index (BMI) affects clinical outcomes is not well-studied., Purpose: To investigate the difference in the clinical course between normal weight, overweight, and obese patients with radiculopathy who underwent lumbar microdiscectomy followed by physical therapy and to evaluate whether high BMI is associated with poor recovery., Study Design/setting: A prospective cohort study with a 12-month follow-up was conducted in a multidisciplinary clinic., Patient Sample: We included 583 patients (median [IQR] age: 45 [35-52] years; 41% female) with clinical signs and symptoms of lumbar radiculopathy, consistent with magnetic resonance imaging findings, who underwent microdiscectomy followed by postoperative physical therapy., Outcome Measures: Outcomes were leg pain and back pain intensity measured with a visual analogue scale, disability measured with the Roland Morris Disability Questionnaire at 3 and 12-month follow-ups, and complications., Methods: Patients were classified as being normal weight (46.9%), overweight (38.4%), or obese (14.7%). A linear mixed-effects model was used to assess the difference in the clinical course of pain and disability between the three BMI categories. The association between BMI and outcomes was evaluated using univariable and multivariable logistic regression analyses., Results: All three patient groups experienced a significant improvement in leg pain, back pain, and disability over 3 and 12-month follow-up. Patients who were overweight, obese, or normal weight experienced comparable leg pain (p=.14) and disability (p=.06) over the clinical course (p=.14); however, obese patients experienced higher back pain (MD=-6.81 [95%CI: -13.50 to -0.14]; p=.03). The difference in back pain scores was not clinically relevant., Conclusions: In the first year following lumbar microdiscectomy, patients demonstrated clinical improvements and complications that were unrelated to their preoperative BMI., Competing Interests: Declaration of competing interest One or more of the authors declare financial or professional relationships on ICMJE-TSJ disclosure forms., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: The clinical course of lumbar radiculopathy following microdiscectomy and post-operative physiotherapy varies substantially. No prior studies assessed this variability by deriving outcome trajectories. The primary aims of this study were to evaluate the variability in long-term recovery after lumbar microdiscectomy followed by post-operative physiotherapy and to identify outcome trajectories. The secondary aim was to assess whether demographic, clinical characteristics and patient-reported outcome measures routinely collected at baseline could predict poor outcome trajectories., Methods: We conducted a prospective cohort study with a 24-month follow-up. We included 479 patients with clinical signs and symptoms of lumbar radiculopathy confirmed by Magnetic Resonance Imaging findings, who underwent microdiscectomy and post-operative physiotherapy. Outcomes were leg pain and back pain measured with Visual Analogue Scales, and disability measured with the Roland-Morris Disability Questionnaire. Descriptive statistics were performed to present the average and the individual clinical course. A latent class trajectory analysis was conducted to identify leg pain, back pain, and disability outcome trajectories. The best number of clusters was determined using the Bayesian Information Criterion, Akaike's information criteria, entropy, and overall interpretability. Prediction models for poor outcome trajectories were assessed using multivariable logistic regression analyses., Results: Several outcome trajectories were identified. Most patients were assigned to the 'large improvement' trajectory (leg pain: 79.3%; back pain: 70.2%; disability: 59.5% of patients). Smaller proportions of patients were assigned to the 'moderate improvement' trajectory (leg pain: 7.9%; back pain: 10.6%; disability: 20.7% of patients), the 'minimal improvement' trajectory (leg pain: 4.9%, back pain: 6.7%, disability: 16.3% of patients) and the 'relapse' trajectory (leg pain: 7.9%; back pain: 12.5%; disability: 3.5%). Approximately one-third of patients (32.6%) belonged to one or more than one poor outcome trajectory. Patients with previous treatment (prior back surgery, injection therapy, and medication use) and those who had higher baseline pain and disability scores were more likely to belong to the poor outcome trajectories in comparison to the large improvement trajectories in back pain, leg pain and disability, and the moderate improvement trajectory in disability. The explained variance (Nagelkerke R2) of the prediction models ranged from 0.06 to 0.13 and the discriminative ability (Area Under the Curve) from 0.66 to 0.73., Conclusion: The clinical course of lumbar radiculopathy varied following microdiscectomy and post-operative physiotherapy, and several outcome trajectories could be identified. Although most patients were allocated to favorable trajectories, one in three patients was assigned to one or more poor outcome trajectories following microdiscectomy and post-operative physiotherapy for lumbar radiculopathy. Routinely gathered data were unable to predict the poor outcome trajectories accurately. Prior to surgery, clinicians should discuss the high variability and the distinctive subgroups that are present in the clinical course with their patients., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: To determine the diagnostic accuracy of patient interview items and clinical tests to diagnose cervical radiculopathy., Design: A prospective diagnostic accuracy study., Participants: Consecutive patients (N=134) with a suspicion of cervical radiculopathy were included. A medical specialist made the diagnosis of cervical radiculopathy based on the patient's clinical presentation and corresponding Magnetic Resonance Imaging findings. Participants completed a list of patient interview items and the clinical tests were performed by a physiotherapist., Main Outcome Measures: Diagnostic accuracy was determined in terms of sensitivity, specificity, and positive (+LR) and negative likelihood ratios (-LR). Sensitivity and specificity values ≥0.80 were considered high. We considered +LR≥5 and -LR≤0.20 moderate, and +LR≥10 and -LR≤0.10 high., Results: The history items 'arm pain worse than neck pain', 'provocation of symptoms when ironing', 'reduction of symptoms by walking with your hand in your pocket', the Spurling test and the presence of reduced reflexes showed high specificity and are therefore useful to increase the probability of cervical radiculopathy when positive. The presence of 'paraesthesia' and 'paraesthesia and/or numbness' showed high sensitivity, indicating that the absence of these patient interview items decreases the probability of cervical radiculopathy. Although most of these items had potentially relevant likelihood ratios, none showed moderate or high likelihood ratios., Conclusions: Several patient interview items, the Spurling test and reduced reflexes are useful to assist in the diagnosis of cervical radiculopathy. Because there is no gold standard for cervical radiculopathy, caution is required to not over-interpret diagnostic accuracy values., (Copyright © 2020 Chartered Society of Physiotherapy. Published by Elsevier Ltd. All rights reserved.)

Background: Mobile eHealth apps are important tools in personal health care management. The Patient Journey app was developed to inform patients with musculoskeletal disorders during their perioperative period. The app contains timely information, video exercises, and functional tasks. Although the Patient Journey app and other health apps are widely used, little research is available on how patients appreciate these apps., Objective: The primary aim of this study was to evaluate the user-friendliness of the Patient Journey app in terms of its usability and the attitudes of users toward the app. The secondary aim was to evaluate positive and negative user experiences., Methods: A web-based questionnaire was sent to 2114 patients scheduled for surgery for a musculoskeletal disorder. Primary outcomes were usability (measured with the System Usability Scale) and user attitudes regarding the Patient Journey app (assessed with the second part of the eHealth Impact Questionnaire). The secondary outcomes were evaluated with multiple choice questions and open-ended questions, which were analyzed via inductive thematic content analyses., Results: Of the 940 patients who responded, 526 used the Patient Journey app. The usability of the app was high (System Usability Scale: median 85.0, IQR 72.5-92.5), and users had a positive attitude toward the Information and Presentation provided via the app (eHealth Impact Questionnaire: median 78.0, IQR 68.8-84.4). The app did not adequately improve the users' confidence in discussing health with others (eHealth Impact Questionnaire: median 63.9, IQR 50.0-75.0) or motivation to manage health (eHealth Impact Questionnaire: median 61.1, IQR 55.6-72.2). Three core themes emerged regarding positive and negative user experiences: (1) content and information, (2) expectations and experiences, and (3) technical performance. Users experienced timely information and instructions positively and found that the app prepared and guided them optimally through the perioperative period. Negative user experiences were overly optimistic information, scarcely presented information about pain (medication), lack of reference data, insufficient information regarding clinical course deviations and complications, and lack of interaction with clinicians., Conclusions: The Patient Journey app is a usable, informative, and presentable tool to inform patients with musculoskeletal disorders during their perioperative period. The qualitative analyses identified aspects that can further improve the user experiences of the app., (©Stijn J Willems, Michel W Coppieters, Yvette Pronk, Miranda J F Diks, Klaas W A P van der Heijden, Servan Rooker, Gwendolyne G M Scholten-Peeters. Originally published in JMIR Human Factors (http://humanfactors.jmir.org), 08.02.2021.)

Study Design: Prospective cohort study., Objective: To develop and internally validate prognostic models based on commonly collected preoperative data for good and poor outcomes of lumbar microdiscectomy followed by physiotherapy., Summary of Background Data: Lumbar microdiscectomy followed by physiotherapy is a common intervention for lumbar radiculopathy. Postoperatively, a considerable percentage of people continues to experience pain and disability. Prognostic models for recovery are scarce., Methods: We included 298 patients with lumbar radiculopathy who underwent microdiscectomy followed by physiotherapy. Primary outcomes were recovery and secondary outcomes were pain and disability at 12 months follow-up. Potential prognostic factors were selected from sociodemographic and biomedical data commonly captured preoperatively. The association between baseline characteristics and outcomes was evaluated using multivariable logistic regression analyses., Results: At 12 months follow-up, 75.8% of the participants met the criterion for recovery. Variables in the model for good recovery included: younger age, leg pain greater than back pain, high level of disability, and a disc herniation at another level than L3-L4. The model for poor recovery included: lower educational level, prior back surgery, and disc herniation at L3-L4. Following internal validation, the explained variance (Nagelkerke R) and area under the curve for both models were poor (≤0.02 and ≤0.60, respectively). The discriminative ability of the models for disability and pain were also poor., Conclusion: The outcome of microdiscectomy followed by postoperative physiotherapy cannot be predicted accurately by commonly captured preoperative sociodemographic and biomedical factors. The potential value of other biomedical, personal, and external factors should be further investigated., Level of Evidence: 3.

Purpose: To describe the clinical course and develop prognostic models for poor recovery in patients with cervical radiculopathy who are managed conservatively., Methods: Sixty-one consecutive adults with cervical radiculopathy who were referred for conservative management were included in a prospective cohort study, with 6- and 12-month follow-up assessments. Exclusion criteria were the presence of known serious pathology or spinal surgery in the past. Outcome measures were perceived recovery, neck pain intensity and disability level. Multiple imputation analyses were performed for missing values. Prognostic models were developed using multivariable logistic regression analyses, with bootstrapping techniques for internal validation., Results: About 55% of participants reported to be recovered at 6 and 12 months. All multivariable models contained 2 baseline predictors. Longer symptoms duration increased the risk of poor perceived recovery, whereas the presence of paresthesia decreased this risk. A higher neck pain intensity and a longer duration of symptoms increased the risk of poor relief of neck pain. A higher disability score increased the risk of poor relief of disability, and larger active range of rotation toward the affected side decreased this risk. Following bootstrapping, the explained variance of the models varied between 0.22 and 0.30, and the median area under the curve varied between 0.75 and 0.79., Conclusions: The clinical course of cervical radiculopathy appears to be long, with most of the reduction in symptoms occurring within the first 6 months. All prognostic models showed an adequate predictive performance with modest diagnostic accuracy and explained variance. These slides can be retrieved under Electronic Supplementary Material.

Background: It is important to identify neuropathic pain early to guide treatment decisions and prevent chronicity. There is lack of evidence whether the Dutch painDETECT questionnaire and Douleure Neuropathique en 4 questions (DN4) can adequately assess neuropathic pain., Methods: Patients suspected of cervical or lumbar radiculopathy were eligible for inclusion. The Dutch painDETECT and DN4 were considered as the index tests and were compared to the reference test consisting of the consensus expert diagnosis by using the grading system for neuropathic pain. The index tests and neuropathic pain diagnosis were blindly performed. Diagnostic accuracy was determined by calculating sensitivity, specificity, predictive values and likely hood ratios. Test-retest reliability for the index tests was assessed using Intraclass Correlation Coefficients (ICC)., Results: A total of 180 patients were included, of which 110 for the reliability analysis. Fifty-nine patients (33%) had neuropathic pain according to the reference test. Both the painDETECT and DN4 had moderate sensitivity of respectively 75% (95% CI: 61.6-85.0) and 76% (95% CI: 63.4-86.4) and poor specificity of respectively 51% (95% CI: 42.0-60.4) and 42% (95% CI: 33.2-51.5). Combining negative test results for both screening tools increased the sensitivity up to 83% (95% CI: 71.0-91.6). The ICC for the painDETECT was 0.91 (95% CI: 0.86-0.94) and for the DN4 0.86 (95% CI: 0.80-0.91)., Conclusions: The use of the Dutch painDETECT and the DN4 in patients with suspected radiculopathy should not be recommended yet. A combination of both screening tools seems most suitable to rule out neuropathic pain in patients suspected of radiculopathy., Level of Evidence: Diagnosis, Level 1B., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Melanoma, the most aggressive skin cancer type, is responsible for 75% of skin cancer related deaths worldwide. Given that New Zealand (NZ) has the world's highest melanoma incidence, we sought to determine the frequency of mutations in NZ melanomas in recurrently mutated genes. NZ melanomas were from localities distributed between North (35°S-42°S) and South Islands (41°S-47°S). A total of 529 melanomas were analyzed for BRAF exon 15 mutations by Sanger sequencing, and also by Sequenom MelaCarta MassARRAY. While, a relatively low incidence of BRAFV600E mutations (23.4%) was observed overall in NZ melanomas, the incidence of NRAS mutations in South Island melanomas was high compared to North Island melanomas (38.3% vs. 21.9%, P=0.0005), and to The Cancer Genome Atlas database (TCGA) (38.3% vs. 22%, P=0.0004). In contrast, the incidence of EPHB6G404S mutations was 0% in South Island melanomas, and was 7.8% in North Island (P=0.0002). Overall, these data suggest that melanomas from geographically different regions in NZ have markedly different mutation frequencies, in particular in the NRAS and EPHB6 genes, when compared to TCGA or other populations. These data have implications for the causation and treatment of malignant melanoma in NZ., Competing Interests: The authors declare no conflicts of interest.

Wnt proteins are lipid-modified, short-range signals that control stem cell self-renewal and tissue regeneration. We identified a population of Wnt responsive cells in the pulp cavity, characterized their function, and then created a pulp injury. The repair response was evaluated over time using molecular, cellular, and quantitative assays. We tested how healing was impacted by wound environments in which Wnt signaling was amplified. We found that a Wnt-amplified environment was associated with superior pulp healing. Although cell death was still rampant, the number of cells undergoing apoptosis was significantly reduced. This resulted in significantly better survival of injured pulp cells, and resulted in the formation of more tertiary dentin. We engineered a liposome-reconstituted form of WNT3A then tested whether this biomimetic compound could activate cells in the injured tooth pulp and stimulate dentin regeneration. Pulp cells responded to the elevated Wnt stimulus by differentiating into secretory odontoblasts. Thus, transiently amplifying the body's natural Wnt response resulted in improved pulp vitality. These data have direct clinical implications for treating dental caries, the most prevalent disease affecting mankind., (© 2015 American Society for Bone and Mineral Research.)

Purpose: Müller glia respond to retinal injury by a reactive gliosis, but only rarely do mammalian glial cells re-enter the cell cycle and generate new neurons. In the nonmammalian retina, however, Müller glia act as stem/progenitor cells. Here, we tested the function of Wnt signaling in the postinjury retina, focusing on its ability to influence mammalian Müller cell dedifferentiation, proliferation, and neurogenesis., Methods: A 532 nm frequency doubled neodymium-doped yttrium aluminum garnet (ND:YAG) laser was used to create light burns on the retina of Axin2(LacZ/+) Wnt reporter mice. At various time points after injury, retinas were analyzed for evidence of Wnt signaling as well as glial cell response, proliferation, and apoptosis. Laser injuries also were created in Axin2(LacZ/LacZ) mice, and the effect of potentiated Wnt signaling on retinal repair was assessed., Results: A subpopulation of mammalian Müller cells are Wnt responsive and, when Wnt signaling is increased, these cells showed enhanced proliferation in response to injury. In an environment of heightened Wnt signaling, caused by the loss of the Wnt negative regulator Axin2, Müller cells proliferated after injury and adopted the expression patterns of retinal progenitor cells (RPCs). The Wnt-responsive Müller cells also exhibited long-term survival and, in some cases, expressed the rod photoreceptor marker, rhodopsin., Conclusions: The Wnt pathway is activated by retinal injury, and prolonging the endogenous Wnt signal causes a subset of Müller cells to proliferate and dedifferentiate into RPCs. These data raised the possibility that transient amplification of Wnt signaling after retinal damage may unlock the latent regenerative capacity long speculated to reside in mammalian neural tissues.

Restriction endonuclease analysis (REA), developed 25 years ago for genotyping Mycobacterium bovis strains, is an important tool for bovine tuberculosis control in New Zealand. While REA gives excellent discrimination, it is technically difficult to perform compared to PCR-based typing systems which are faster and simpler to operate. Genotyping of M. bovis by the use of variable number tandem repeat loci (VNTR) and spoligotyping, either alone or together, has now become the preferred approach for typing M. bovis. Here, we evaluated the widest range of VNTR loci yet investigated for M. bovis, including two VNTR loci not previously studied, one of which (4155) had particular utility for characterizing New Zealand isolates. VNTR typing provided substantial geographical resolution of 26 of the most commonly found REA types and this was improved by the addition of two PCR assays based on parts of the direct repeat (DR) locus. Overall, 68 REA types of M. bovis common in New Zealand were discriminated into 33 VNTR/DR groups by using a minimum of nine VNTR and two DR assays. These 11 VNTR/DR assays concorded for three isolates each of 45 of the REA types but showed some variation with at least one of the VNTR/DR assays for the remaining 23 REA types. Major differences were found in allelic variation of some VNTRs between isolates from New Zealand and other countries, emphasizing the importance of adapting M. bovis typing systems to suit individual countries., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant disorder predisposing humans to cutaneous and uterine leiomyomas; in 20% of affected families, type 2 papillary renal cell cancers (PRCCII) also occur with aggressive course and poor prognosis. HLRCC results from heterozygous germline mutations in the tumour suppressor fumarate hydratase (FH) gene., Methods: As part of the French National Cancer Institute (INCa) 'Inherited predispositions to kidney cancer' network, sequence analysis and a functional study of FH were preformed in 56 families with clinically proven or suspected HLRCC and in 23 patients with isolated PRCCII (5 familial and 18 sporadic)., Results: The study identified 32 different germline FH mutations (15 missense, 6 frameshifts, 4 nonsense, 1 deletion/insertion, 5 splice site, and 1 complete deletion) in 40/56 (71.4%) families with proven or suspected HLRCC and in 4/23 (17.4%) probands with PRCCII alone, including 2 sporadic cases. 21 of these were novel and all were demonstrated as deleterious by significant reduction of FH enzymatic activity. In addition, 5 asymptomatic parents in 3 families were confirmed as carrying disease-causing mutations., Conclusions: This study identified and characterised 21 novel FH mutations and demonstrated that PRCCII can be the only one manifestation of HLRCC. Due to the incomplete penetrance of HLRCC, the authors propose to extend the FH mutation analysis to every patient with PRCCII occurring before 40 years of age or when renal tumour harbours characteristic histologic features, in order to discover previously ignored HLRCC affected families.

There is uncertainty whether the 2009 seasonal influenza vaccination influences the risk of infection with the 2009 pandemic influenza A(H1N1) virus. This issue was investigated in 548 healthcare workers from Capital and Coast District Health Board, Wellington, New Zealand, presenting with influenza-like illness during the influenza pandemic between June and August 2009. All workers completed an assessment sheet and had a nasopharyngeal swab tested by real-time RT-PCR. The risk of pandemic influenza A(H1N1) infection associated with the 2009 seasonal inactivated trivalent influenza vaccine was determined by logistic regression, with adjustment for potential confounding variables. In 96 workers pandemic influenza A(H1N1) RNA was detected and 452 tested negative. The multivariate analysis did not show any effect of vaccination on PCR-confirmed influenza A(H1N1)2009 infection (odds ratio 1.2, 95% confidence interval 0.7–1.9, p=0.48). We conclude that 2009 seasonal influenza vaccination had no protective effect against influenza A(H1N1)2009 infection amongst healthcare workers. To protect against further waves of the current pandemic influenza or future pandemics in which the influenza virus is antigenically distinct from contemporary seasonal influenza viruses, it would be necessary to vaccinate with a specific pandemic influenza vaccine, or a seasonal influenza vaccine that includes the pandemic influenza serotype.

We present a developmental perspective on the concept of phylotypic and phenotypic stages of craniofacial development. Within orders of avians and mammals, a phylotypic period exists when the morphology of the facial prominences is minimally divergent. We postulate that species-specific facial variations arise as a result of subtle shifts in the timing and the duration of molecular pathway activity (e.g., heterochrony), and present evidence demonstrating a critical role for Wnt and FGF signaling in this process. The same molecular pathways that shape the vertebrate face are also implicated in craniofacial deformities, indicating that comparisons between and among animal species may represent a novel method for the identification of human craniofacial disease genes., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Community transmission of influenza A pandemic (H1N1) 2009 was followed by high rates of hospital admissions in the Wellington region of New Zealand, particularly among Maori and Pacific Islanders. These findings may help health authorities anticipate the effects of pandemic (H1N1) 2009 in other communities.

Liposomes offer a method of delivering small molecules, nucleic acids, and proteins to sites within the body. Typically, bioactive materials are encapsulated within the liposomal aqueous core and liposomal phase transition is elicited by pH or temperature changes. We developed a new class of liposomes for the in vivo delivery of lipid-modified proteins. First, we show that the inclusion of a chromophore into the liposomal or vesosomal membrane renders these lipid vesicles extremely sensitive to very small (muJ) changes in energy. Next, we demonstrate that the lipid-modified Wnt protein is not encapsulated within a liposome but rather is tethered to the exoliposomal surface in an active configuration. When applied to intact skin, chromophore-modified liposomes do not penetrate past the corneal layer of the epidermis, but remain localized to the site of application. Injury to the epidermis allows rapid penetration of liposomes into the dermis, which suggests that mild forms of dermabrasion will greatly enhance transdermal delivery of liposome-packaged molecules. Finally, we demonstrate that topical application of Wnt3a liposomes rapidly stimulates proliferation of cells in the corneal layer, resulting in a thicker, more fibrillous epidermis.

Background: Mortality from colorectal cancer is mainly due to metastatic liver disease. Improved understanding of the molecular events underlying metastasis is crucial for the development of new methods for early detection and treatment of colorectal cancer. Loss of chromosome 8p is frequently seen in colorectal cancer and implicated in later stage disease and metastasis, although a single metastasis suppressor gene has yet to be identified. We therefore examined 8p for genes involved in colorectal cancer progression., Methods: Loss of heterozygosity analyses were used to map genetic loss in colorectal liver metastases. Candidate genes in the region of loss were investigated in clinical samples from 44 patients, including 6 with matched colon normal, colon tumour and liver metastasis. We investigated gene disruption at the level of DNA, mRNA and protein using a combination of mutation, semi-quantitative real-time PCR, western blotting and immunohistochemical analyses., Results: We mapped a 2 Mb region of 8p21-22 with loss of heterozygosity in 73% of samples; 8/11 liver metastasis samples had loss which was not present in the corresponding matched primary colon tumour. 13 candidate genes were identified for further analysis. Both up and down-regulation of 8p21-22 gene expression was associated with metastasis. ADAMDEC1 mRNA and protein expression decreased during both tumourigenesis and tumour progression. Increased STC1 and LOXL2 mRNA expression occurred during tumourigenesis. Liver metastases with low DcR1/TNFRSF10C mRNA expression were more likely to present with extrahepatic metastases (p = 0.005). A novel germline truncating mutation of DR5/TNFRSF10B was identified, and DR4/TNFRSF10A SNP rs4872077 was associated with the development of liver metastases (p = 0.02)., Conclusion: Our data confirm that genes on 8p21-22 are dysregulated during colorectal cancer progression. Interestingly, however, instead of harbouring a single candidate colorectal metastasis suppressor 8p21-22 appears to be a hot-spot for tumour progression, encoding at least 13 genes with a putative role in carcinoma development. Thus, we propose that this region of 8p comprises a metastatic susceptibility locus involved in tumour progression whose disruption increases metastatic potential.

A 3 year follow-up study was performed in a patient with foreign accent syndrome (FAS) as the sole cognitive manifestation of a left fronto-parietal stroke. The hypothesis of involvement of the right cerebellum in this motor speech planning disorder was investigated by means of functional neuroimaging (SPECT) and neurobehavioral assessments. Based on the close parallelism between the evolution of FAS symptoms and the perfusional changes in the right cerebellum, it is argued that FAS may result from a disruption of a close functional interplay between the supra- and infratentorial speech centers involved in motor speech planning.

We report a case of a 51-year-old man presenting with rapidly progressive unilateral tinnitus, hearing loss and imbalance. Neuroimaging revealed bilateral VIIIth cranial nerve masses and multiple cerebral and spinal cord lesions that were interpreted as being acoustic schwannomas and multiple meningeomas. An initial tentative diagnosis of neurofibromatosis type 2 (NF2) was made. Both clinical and radiological evolution were atypical for NF2 and the initial diagnosis of NF2 was questioned. Additional technical investigations demonstrated a pulmonary adenocarcinoma. Postmortem examination confirmed that this patient had multiple central nervous system metastases of a primary pulmonary adenocarcinoma, presenting clinically and neuroradiologically as a probable neurofibromatosis type 2. Clinicians should be aware of the rare possibility of central nervous system metastases mimicking NF2.

Inflammatory processes have been implicated in the pathogenesis of traumatic brain damage. We analyzed the spatiotemporal expression pattern of the proinflammatory key molecules: interleukin-1beta, interleukin-6, tumor necrosis factor-alpha, and inducible nitric oxide synthase in a rat closed head injury (CHI) paradigm. 51 rats were used for RT-PCR analysis after CHI, and 18 for immunocytochemistry. We found an early upregulation of IL-1beta, IL-6, and TNF-alpha mRNA between 1h and 7h after injury; the expression of iNOS mRNA only revealed a significant increase at 4h. After 24h, the expression decreased towards baseline levels, and remained low until 7d after injury. Immunocytochemically, IL-1beta induction was localized to ramified microglia in areas surrounding the primary impact place as well as deeper brain structures. Our study shows rapid induction of inflammatory gene expression that exceeds by far the primary impact site and might therefore contribute to tissue damage at remote sites.

It is unknown whether barbiturates suppress cerebral oxygen metabolism after cerebral trauma as they do in normal individuals. We evaluated the influence of pentobarbital on cerebral oxygen handling of normal rats and rats subjected to non-hemorrhagic closed head injury (CHI). Oxygen delivery was assessed by measuring cerebral perfusion and oxygen extraction, enabling the calculation of cerebral metabolic rate of oxygen (CMRO2). Mitochondrial function was assessed by studying changes in the oxidized cytochrome oxidase concentration. CHI caused changes in both systemic and cerebral hemodynamics. Cerebral blood flow was reduced to 66% of its control value, but the cerebral metabolic rate of oxygen remained unchanged. Pentobarbital administration induced a significant lowering of the cerebral oxygen consumption in normal rats associated with a secondary decrease in cerebral perfusion. In rats subjected to CHI, pentobarbital was unable to lower the cerebral metabolic demand and did not cause a further decrease in perfusion. Pentobarbital was unable to significantly modulate mitochondrial function in traumatized rats, whereas it exerted this effect in all control animals. We therefore conclude that, in rats subjected to CHI, pentobarbital is unable to perform its beneficial effects on the cerebral metabolism.

The present study validates a method for continuous measurement of intracranial pressure (ICP) in freely moving rats after experimental induction of impact-acceleration injury. Rats subjected to either mild or moderate trauma were individually placed in a Bas-Ratturn system, equipped with a sensor that synchronously turns the cage in response to the locomotor activity of the animal. In this way correct probe positioning is permanently assured and damage due to coiling is avoided. The evolution of ICP and mean arterial blood pressure (MABP) in injured rats was compared with that of a non-traumatized sham group. Since the animals regained consciousness after surgery, interference of anaesthesia on these sensitive parameters should be minimised. The results showed that immediately after induction of neurotrauma, ICP was significantly higher in traumatized rats (sham: 7.7 +/- 0.5 mmHg; mild trauma: 10.4 +/- 0.7 mmHg; moderate trauma: 14.9 +/- 2.4 mmHg; P<0.05). Regression analysis showed a stable ICP up to 3 h post-insult for all three conditions. From 4 h onwards till the end of the experiment at 10 h post-insult, a significant increase in ICP was seen for sham-operated and mildly traumatized rats (16.1 +/- 3.4 and 30.5 +/- 6.9 mmHg, respectively; P<0.05), but not for moderately traumatized rats (47.3 +/- 11.9 mmHg). The method allows observation of ICP for a critical period up to 3 h. As such the method can be regarded as clinically relevant to study early pathological aspects of intracranial hypertension and to define a therapeutic window for pharmacological intervention after traumatic brain injury (TBI).

Unilateral intracarotid injection of contrast agents may considerably destabilize the blood-brain barrier in rats. This leads to vasogenic edema in the ipsilateral hemisphere. Mortality and extravasation increased significantly when administration of these ultrasound contrast agents was followed by mild traumatic brain injury. Direct administration to the cerebral circulation is, therefore, indicative for edema-related pathology and may amplify the consequences of experimental neurotrauma.

In this study, we evaluated the accuracy of intracranial pressure (ICP) measurement in rats by insertion of a miniature ICP probe in the parenchyma of the cerebellum. A comparison was made between the ICP values measured simultaneously in the parenchyma of the cerebral cortex and the cerebellum. In order to obtain a wide range of ICP, animals were subjected to a severe closed head injury (CHI), a moderate CHI or to a sham operation. ICP values ranged from 0.8 to 43.9 mmHg. After 15 min stabilisation the first measurement was taken and followed by a second measurement 25 min after onset to allow comparison of ICP changes at the two implantation sites. Linear regression analysis showed a highly significant correlation at 15 min: Y = 0.919X + 0.655 (R(2) = 0.977), and at 25 min: Y = 0.931X + 0.698 (R(2) = 0.976). The differences in ICP measurement between cerebellar and cerebral site were not significantly different from zero at both time points. Altman-Bland plots showed that the difference in ICP readings between the two locations could differ maximally by 5.3 mmHg. The largest differences were detected when high ICP values were recorded. We conclude that in rats the ICP measurement in the cerebellum is comparable to the ICP measurement in the cerebral cortex. The cerebellar ICP can be used as a valuable alternative during experimental procedures.

Purpose: A retrospective study was undertaken to determine the contemporary treatment and outcome of patients with lung cancer and positive lymph nodes proven at mediastinoscopy., Material and Methods: From 1994 to 1999 a cervical mediastinoscopy was performed in 361 patients. Metastatic lymph nodes from a bronchogenic carcinoma were present in 81 patients; 71 were men. Mean age was 61.7 years. Squamous cell carcinoma and adenocarcinoma were present in 26 patients each (32.1%), large cell carcinoma in 19 patients (23.4%), small cell carcinoma in six patients (7.4%) and other histologies in four patients (5%). Stage IIIA was found in 51 patients (69.9%), IIIB in 17 (23.3%) and IV in 5 (6.8%). Of eight patients no precise stage could be determined (9.9%). These patients were retrospectively reviewed. Survival time was analyzed according to the Kaplan-Meier method. A multivariate Cox analysis was performed to determine significant factors in relation to survival., Results: Forty-four patients (54.3%) were treated by induction chemotherapy, of which 15 were operated on, 11 patients (13.6%) had chemotherapy only, 11 (13.6%) radiotherapy only, 3 (3.7%) combined chemo- and radiotherapy, 1 patient (1.2%) had an operation only, and 11 (13.6%) received palliative treatment. Follow-up was complete; 16 patients (19.8%) are alive and 65 (80.2%) died, mostly of local recurrence and metastases. Median survival time (MST) for all 81 patients was 12 months [95% confidence interval (CI) 10-14 months.]. MST for the 15 patients treated by induction chemotherapy + surgery was 27 months [95% CI 18-36 months] and for the 15 patients treated by induction chemotherapy + radiotherapy 15 months [95% CI 12-18 months]. The difference between these two subgroups was significant (p = 0.03). For the 11 patients who had palliative treatment MST was 6 months [95% CI 4-8 months]. The other subgroups had a MST of 10 months or less. In a multivariate Cox analysis only specific treatment (p = 0.0002) and stage (p = 0.02) were found to be significant., Conclusions: Outcome of patients with lung cancer and positive mediastinoscopy remains poor. In this retrospective study best results were obtained by induction chemotherapy + surgery. An effort should be made to include as many of these patients as possible in neoadjuvant trials.

Background: The potential role of the local renin-angiotensin system to differentially affect radial artery and internal thoracic artery graft performance has not been examined., Methods: Contractile responses to angiotensin I and II in the radial artery and the internal thoracic artery were examined in vitro. The expression function, and localization of angiotensin receptors, angiotensin converting enzyme, and chymase were studied in radial artery and internal thoracic artery segments., Results: Angiotensin I and II contractions were significantly greater (p < 0.05) in the radial artery compared to the internal thoracic artery. In both arteries, angiotensin II responses were mediated via the AT1 receptor. Messenger RNA transcripts for angiotensin-converting enzyme and chymase were detected in both arteries. Angiotensin-converting enzyme was localized to luminal and vaso vasorum endothelial cells and smooth muscle cells in both vessels, while chymase was colocalized with mast cells in adventitial and medial layers. An angiotensin converting enzyme or a chymase inhibitor singularly had no effect on angiotensin I contractions, however, when combined, a marked inhibition of the angiotensin I response was observed in both vessels., Conclusions: Our results illustrate the complexities which exist within the local renin angiotensin system and suggest that clinical trials which may modulate the system are warranted.

An acetylcholinesterase (AChE) gene, Ace.x, showing 93% identity of deduced amino acid sequence to Anopheles stephensi Ace has been cloned from a Culex pipiens strain homozygous for insensitive AChE (iAChE) mediated insecticide resistance. DNA sequence of genomic DNA clones identified exons 2-5. RFLP of six clones indicated four possible alleles. Linkage analysis located Ace.x to chromosome I, less than 0.8 centimorgans from the sex locus, whereas the locus conferring resistance was 2.0 centimorgans from plum-eye on chromosome II. Ace.1 coding for AChE1, which is associated with resistance, is therefore autosomal. We propose that Ace.x is the recently postulated Ace.2 coding for the biochemically distinct AChE2, which is not associated with resistance.

In Culex pipiens mosquitoes, resistance to organophosphorous insecticides often results from increased detoxification by two types of esterases, A and B, which are closely linked. Overproduction of all esterase B so far investigated (B1, B2, B4, B5 and B6) is from gene amplification. An esterase A gene (esterase A2) has recently been cloned from mosquitoes with the overproduced esterases A2 and B2, and amplification of this gene has also been reported. We describe the cDNA sequences of three additional esterase genes from insecticide-resistant strains of Culex pipiens originating from France and California which show at least 93 per cent homology with the esterase A2 gene sequence. Restriction enzyme mapping shows that the esterase A gene lies within 2.2 kb of the esterase B gene. In mosquitoes with overproduced esterases A2 and B2, the amplification level of esterase A is equal to that of esterase B suggesting that the genes are coamplified. Furthermore, we show that in one strain with an overproduced A esterase (A1), gene amplification cannot account for the increased protein level. This indicates that overproduction of esterases A can be achieved through two different mechanisms: gene amplification and a regulatory mechanism--the nature of which remains to be identified.

In the mosquito Culex pipiens, over-production of esterases is a common insecticide resistance mechanism. Different alleles at the esterase A and B loci are known to occur in natural populations, as shown by enzyme electrophoresis and RFLP studies on the esterase B locus. Here we analyse the variability of the esterase A locus at the nucleotide level in mosquitoes possessing or lacking over-produced esterase A. A surprisingly high level of nucleotide polymorphism is found in coding and noncoding regions, and the extent of polymorphism detected is higher than that previously described for the most polymorphic loci in Drosophila. We also show that eight strains from different localities (Africa, America, Asia) that possess the over-produced esterase A2 share the same nucleotide sequence at the esterase A locus, strongly supporting the evolutionary scenario of a unique event of amplification of this gene followed by dispersal through migration rather than the occurrence of multiple independent mutational events of the gene.