A HIF-LIMD1 negative feedback mechanism mitigates the pro-tumorigenic effects of hypoxia

The adaptive cellular response to low oxygen tensions is mediated by the hypoxia inducible factors (HIFs), a family of heterodimeric transcription factors composed of HIF-α and β subunits. Prolonged HIF expression is a key contributor to cellular transformation, tumourigenesis and metastasis. As such, HIF degradation under hypoxic conditions is an essential homeostatic and tumour suppressive mechanism. LIMD1 complexes with PHD2 and VHL in physiological oxygen levels (normoxia) to facilitate proteasomal degradation of the HIF-α subunit. Here, we identify LIMD1 as a HIF-1 target gene, which mediates a previously uncharacterised, negative regulatory feedback mechanism for hypoxic HIF-α degradation by modulating PHD2-LIMD1- VHL complex formation. Hypoxic induction of LIMD1 expression results in increased HIF-α protein degradation, inhibiting HIF-1 target-gene expression, tumour growth and vascularisation. Furthermore, we report that copy number variation at the LIMD1 locus occurs in 47.1% of lung adenocarcinoma patients, correlates with enhanced expression of a HIF target gene signature and is a negative prognostic indicator. Taken together, our data open a new field of research into the aetiology, diagnosis and prognosis of LIMD1-negative lung cancers

Pathogenesis of adolescent idiopathic scoliosis in girls - a double neuro-osseous theory involving disharmony between two nervous systems, somatic and autonomic expressed in the spine and trunk: possible dependency on sympathetic nervous system and hormones with implications for medical therapy

Anthropometric data from three groups of adolescent girls - preoperative adolescent idiopathic scoliosis (AIS), screened for scoliosis and normals were analysed by comparing skeletal data between higher and lower body mass index subsets. Unexpected findings for each of skeletal maturation, asymmetries and overgrowth are not explained by prevailing theories of AIS pathogenesis. A speculative pathogenetic theory for girls is formulated after surveying evidence including: (1) the thoracospinal concept for right thoracic AIS in girls; (2) the new neuroskeletal biology relating the sympathetic nervous system to bone formation/resorption and bone growth; (3) white adipose tissue storing triglycerides and the adiposity hormone leptin which functions as satiety hormone and sentinel of energy balance to the hypothalamus for long-term adiposity; and (4) central leptin resistance in obesity and possibly in healthy females. The new theory states that AIS in girls results from developmental disharmony expressed in spine and trunk between autonomic and somatic nervous systems. The autonomic component of this double neuro-osseous theory for AIS pathogenesis in girls involves selectively increased sensitivity of the hypothalamus to circulating leptin (genetically-determined up-regulation possibly involving inhibitory or sensitizing intracellular molecules, such as SOC3, PTP-1B and SH2B1 respectively), with asymmetry as an adverse response (hormesis); this asymmetry is routed bilaterally via the sympathetic nervous system to the growing axial skeleton where it may initiate the scoliosis deformity (leptin-hypothalamic-sympathetic nervous system concept = LHS concept). In some younger preoperative AIS girls, the hypothalamic up-regulation to circulating leptin also involves the somatotropic (growth hormone/IGF) axis which exaggerates the sympathetically-induced asymmetric skeletal effects and contributes to curve progression, a concept with therapeutic implications. In the somatic nervous system, dysfunction of a postural mechanism involving the CNS body schema fails to control, or may induce, the spinal deformity of AIS in girls (escalator concept). Biomechanical factors affecting ribs and/or vertebrae and spinal cord during growth may localize AIS to the thoracic spine and contribute to sagittal spinal shape alterations. The developmental disharmony in spine and trunk is compounded by any osteopenia, biomechanical spinal growth modulation, disc degeneration and platelet calmodulin dysfunction. Methods for testing the theory are outlined. Implications are discussed for neuroendocrine dysfunctions, osteopontin, sympathoactivation, medical therapy, Rett and Prader-Willi syndromes, infantile idiopathic scoliosis, and human evolution. AIS pathogenesis in girls is predicated on two putative normal mechanisms involved in trunk growth, each acquired in evolution and unique to humans

Schober Test and Its Modifications Revisited—What Are We Actually Measuring? Computerized Tomography-Based Analysis

Objective: Examine Schober test’s (ST), Modified ST (MST), and Modified–Modified ST (MMST) surface markers’ accuracy in spanning lumbar L1-S1 motion segments and repeatability related to actual patient anatomy as measured on sagittal CT scans. Methods: The study included 25 patients of varying heights, weights, and gender without prior spinal surgery or deformity. Researchers assessed patients’ CT scans for ST, MST, and MMST skin levels of the measured cephalic and caudal endpoints. Results: The original ST failed to include at least one lumbar motion segment in all patients, omitting the L1-L2 motion segment in 17 patients and the L2-L3 in another eight. The additional cephalic length of the MST did not improve the inclusion of the actual L1-S1 components. The MMST measured 19 ‘patients’ entire L1-S1 motion segments, reaching a 76% accuracy rate. WMST, measuring 16 cm (instead of MMST’s 15 cm), improved the measurement significantly, measuring the L1-S1 motion segments in all cases (with 100% accuracy). Conclusion: ST and its modifications fail to span the L1-S1 motion segments and are thus prone to underestimating lumbar spine motion. This study shows that the WMST is much more accurate than previous modifications and is a better tool for evaluating lumbar spine motion

A prospective study of the role of bladder scanning and post-void residual volume measurement in improving diagnostic accuracy of cauda equina syndrome

Aims: Diagnosis of cauda equina syndrome (CES) remains difficult; clinical assessment has low accuracy in reliably predicting MRI compression of the cauda equina (CE). This prospective study tests the usefulness of ultrasound bladder scans as an adjunct for diagnosing CES.Methods: A total of 260 patients with suspected CES were referred to a tertiary spinal unit over a 16-month period. All were assessed by Board-eligible spinal surgeons and had transabdominal ultrasound bladder scans for pre- and post-voiding residual (PVR) volume measurements before lumbosacral MRI.Results: The study confirms the low predictive value of \u27red flag\u27 symptoms and signs. Of note \u27bilateral sciatica\u27 had a sensitivity of 32.4%, and a positive predictive value (PPV) of only 17.2%, and negative predictive value (NPV) 88.3%. Use of a PVR volume of ≥ 200 ml was a demonstrably more accurate test for predicting cauda equina compression on subsequent MRI (p \u3c 0.001). The PVR sensitivity was 94.1%, specificity 66.8%, PPV 29.9% and NPV 98.7%. The PVR allowed risk-stratification with 13% patients deemed \u27low-risk\u27 of CES. They had non-urgent MRI scans. None of the latter scans showed any cauda equina compression (p \u3c 0.006) or individuals developed subsequent CES in the intervening period. There were considerable cost-savings associated with the above strategy.Conclusion: This is the largest reported prospective evaluation of suspected CES. Use of the PVR volume ≥ 200 ml was considerably more accurate in predicting CES. It is a useful adjunct to conventional clinical assessment and allows risk-stratification in managing suspected CES. If adopted widely it is less likely incomplete CES would be missed. Cite this article: Bone Joint J 2020;102-B(6):677-682

Bladder Scans and Postvoid Residual Volume Measurement Improve Diagnostic Accuracy of Cauda Equina Syndrome

Study Design. A prospective, observational cohort study. Objective. The aim of this study was to determine the role of pre and postvoid bladder scan in predicting cauda equina syndrome (CES). The thesis was that bladder scanning [specifically postvoid residual (PVR) volume] would have higher diagnostic accuracy than physical examination alone. Summary of Background Data. CES is an ill-defined condition with a spectrum of presenting symptoms. There is neither a combination of clinical symptoms and/or signs that reliably predicts cauda equina compression nor single defining clinical criterion that has 100% predictive value to confirm or exclude CES. Methods. Patients with suspected CES admitted over a 6-month period at a single institution were prospectively assessed by physical examination (including digital rectal examination and pin prick perianal sensation) and bladder ultrasound scanning (recording pre- and PVR volume). These results were compared with the subsequent magnetic resonance imaging (MRI) scans and those patients who had emergent surgery for CES. Results. Ninety-two patients were included in the study (52 women) with a mean age of 44.9 years. An MRI scan demonstrating causing compression of the cauda equina was present in only 18% (17/92). The sensitivity of anal tone to predict CES was 52.9%. Peri-anal numbness (either unilateral or bilateral) had sensitivity of 82.3% and negative predictive value of 92%. For nonoperated group (without CES), mean PVR was 199 mL (95% confidence interval +/- 59 mL). On the basis of receiver operating curves, the optimal bladder volume cut-off for predicting CES was >= 200 mL for PVR volume. A PVR of 200 mL, then the probability of having CES is 43% (P < 0.000003). A PVR Conclusion. Bladder scanning was a useful adjunct in the diagnosis of CES. It had a better negative predictive value than physical examination

Total Disc Replacement Versus Anterior-Posterior Interbody Fusion in the Lumbar Spine and Lumbosacral Junction: A Cost Analysis

Study Design: Prospective observational cohort study.Objectives: To analyze clinical and economic results in patients with degenerative disc disease in the lumbar area for patients who received combined anterior and posterior fusion or total disc replacement (TDR).Methods: The study included 75 patients, 38 in the fusion group and 37 in the TDR group, who received either anterior/posterior fusion or TDR for lumbar disc disease from January 2005 to December 2008 with a minimum follow-up of 24 months. We collected data with regard to clinical parameters, demographics, visual analogue scale scores, Oswestry Disability Index scores, SF-36 and SF-6D data, surgery time, amount of blood loss, transfusion of blood products, number of levels, duration of hospital stay, and complications. For cost analysis, general infrastructure, theatre costs, as well as implant costs were examined, leading to primary hospital costs. Furthermore, average revision costs were examined, based on the actual data. Statistical analysis was performed using t tests for normal contribution and Mann-Whitney test for skew distributed values. The significance level was set to.05.Results: There was a higher surgery time, more blood loss, and longer hospital stay for the fusion group, compared with the TDR group. In addition, the hospital costs for the primary procedure and revision were 35% higher in the fusion group. The clinical data in terms of SF-36 and SF-6D showed no difference between these 2 groups.Conclusions: TDR is a good alternative to anterior and posterior lumbar fusion in terms of short follow-up analysis for clinical data and cost analysis. General advice cannot be given due to missing data for long-term costs in terms of surgical treatment of adjacent level or further fusion techniques

Long-term outcome after surgical treatment of Scheuermann\u27s Kyphosis (SK).

STUDY DESIGN: A retrospective observational cohort study with a minimum follow-up of 10 years of patients who underwent surgery for Scheurmann Kyphosis (SK). OBJECTIVE: Evaluate the long-term clinical and radiological outcome of patients with SK who either underwent combined anterior-posterior surgery or posterior instrumented fusion alone. There is paucity of literature for long-term outcome studies on SK. The current trend is towards only posterior (PSF) surgical correction for SK. The combined strategy of anterior release, fusion and posterior spinal fusion (AF/PSF) for kyphosis correction has become historic relic. Long-term outcome studies comparing the two procedures are lacking in literature. METHODS: 51 patients (30 M: 21F) who underwent surgery for SK at a single centre were reviewed. Nineteen had posterior instrumentation alone (PSF) (Group 1) and 32 underwent combined anterior release, fusion with posterior instrumentation (AF/PSF) (Group 2). The clinical data included age at surgery, gender, flexibility of spine, instrumented spinal levels, use of cages and morcellised rib grafts (in cases where anterior release was done), posterior osteotomies and instrumentation, complications and indications for revision surgery. Preoperative flexibility was determined by hyperextension radiographs. The radiological indices were evaluated in the pre-operative, 2-year post-operative and final follow-up [Thoracic Kyphosis (TK), Lumbar lordosis (LL), Voustinas index (VI), Sacral inclination (SI) and Sagittal vertical axis (SVA)]. The loss of correction and incidence of JK (Junctional Kyphosis) and its relation to fusion levels were assessed. Complications and difference in outcome between the two groups were analyzed. RESULTS: The mean age at surgery for 51 patients was 20.6 years who were followed up for a minimum of 10 years (mean: 14 years; range 10-16 years). The mean age was 18.5 ± 2.2 years and 21.9 ± 4.8 years in groups 1 and 2, respectively. The mean pre- and 2-year post-operative ODIs were 32.6 ± 12.8 and 8.4 ± 5.4, respectively, in group 1 (p \u3c 0.0001) and 30.7 ± 11.7 and 6.4 ± 5.7, respectively, in group 2 (p \u3c 0.0001). The final SRS-22 scores in group 1 and 2 were 4.1 ± 0.4 and 4.0 ± 0.35, respectively (p = 0.88). The preoperative flexibility index was 49.2 ± 4.2 and 43 ± 5.6 in groups 1 and 2, respectively (p \u3c 0.0001). The mean TKs were 81.4° ± 3.8° and 86.1° ± 6.0° for groups 1 and 2, respectively, which corrected to 45.1° ± 2.6° and 47.3° ± 4.8°, respectively, at final follow-up (p \u3c 0.0001). The mean pre-operative LL angle was 60.0° ± 5.0° and 62.4° ± 7.6° in groups 1 and 2, respectively, which at final follow-up was 45.1° ± 4.4° and 48.1° ± 4.8°, respectively (p \u3c 0.0001). The mean pre-operative and final follow-up Voustinas index (VI) in group 1 were 22.9 ± 2.9 and 11.2 ± 1.2, respectively, and in group 2 was 25.9 ± 3.5 and 14.0 ± 2.3, respectively. The mean pre-operative and final follow-up SI angle were 43.6° ± 3.3° and 31.2° ± 2.5° in group 1, respectively, and 44.3° ± 3.5° and 32.1° ± 3.5° in group 2, respectively (p \u3c 0.0001). The pre-operative and final follow-up SVA in group 1 were - 3.3 ± 1.0 cms and - 1.3 ± 0.5 cms, respectively, and in group 2 was - 4.0 ± 1.3cms and - 1.9 ± 1.1cms, respectively (p \u3c 0.0001). Though the magnitude of curve correction in the groups 1 and 2 was significant 36° vs 39° (p = 0.05), there was no significant difference in correction between the two groups. Proximal JK was seen in seven and distal JK in five patients were observed in the whole cohort. CONCLUSION: The long-term clinical outcomes for both PSF and AF/PSF are comparable with reproducible results. No difference was noted in loss of correction and outcome scores between the two groups. The correction of thoracic kyphosis (TK) had a good correlation with ODI. AF/PSF had much higher complications than PSF group. The objective of correcting the sagittal profile and balancing the whole spinal segment on the pelvis can be achieved through single posterior approach with fewer complications