Diffusion of brain metabolites highlights altered brain microstructure in type C hepatic encephalopathy: a 9.4 T preliminary study.

Introduction: Type C hepatic encephalopathy (HE) is a decompensating event of chronic liver disease leading to severe motor and cognitive impairment. The progression of type C HE is associated with changes in brain metabolite concentrations measured by 1H magnetic resonance spectroscopy (MRS), most noticeably a strong increase in glutamine to detoxify brain ammonia. In addition, alterations of brain cellular architecture have been measured ex vivo by histology in a rat model of type C HE. The aim of this study was to assess the potential of diffusion-weighted MRS (dMRS) for probing these cellular shape alterations in vivo by monitoring the diffusion properties of the major brain metabolites. Methods: The bile duct-ligated (BDL) rat model of type C HE was used. Five animals were scanned before surgery and 6- to 7-week post-BDL surgery, with each animal being used as its own control. 1H-MRS was performed in the hippocampus (SPECIAL, TE = 2.8 ms) and dMRS in a voxel encompassing the entire brain (DW-STEAM, TE = 15 ms, diffusion time = 120 ms, maximum b-value = 25 ms/µm2) on a 9.4 T scanner. The in vivo MRS acquisitions were further validated with histological measures (immunohistochemistry, Golgi-Cox, electron microscopy). Results: The characteristic 1H-MRS pattern of type C HE, i.e., a gradual increase of brain glutamine and a decrease of the main organic osmolytes, was observed in the hippocampus of BDL rats. Overall increased metabolite diffusivities (apparent diffusion coefficient and intra-stick diffusivity-Callaghan's model, significant for glutamine, myo-inositol, and taurine) and decreased kurtosis coefficients were observed in BDL rats compared to control, highlighting the presence of osmotic stress and possibly of astrocytic and neuronal alterations. These results were consistent with the microstructure depicted by histology and represented by a decline in dendritic spines density in neurons, a shortening and decreased number of astrocytic processes, and extracellular edema. Discussion: dMRS enables non-invasive and longitudinal monitoring of the diffusion behavior of brain metabolites, reflecting in the present study the globally altered brain microstructure in BDL rats, as confirmed ex vivo by histology. These findings give new insights into metabolic and microstructural abnormalities associated with high brain glutamine and its consequences in type C HE.

Inhibition of urease-mediated ammonia production by 2-octynohydroxamic acid in hepatic encephalopathy.

Hepatic encephalopathy is a neuropsychiatric complication of liver disease which is partly associated with elevated ammonemia. Urea hydrolysis by urease-producing bacteria in the colon is often mentioned as one of the main routes of ammonia production in the body, yet research on treatments targeting bacterial ureases in hepatic encephalopathy is limited. Herein we report a hydroxamate-based urease inhibitor, 2-octynohydroxamic acid, exhibiting improved in vitro potency compared to hydroxamic acids that were previously investigated for hepatic encephalopathy. 2-octynohydroxamic acid shows low cytotoxic and mutagenic potential within a micromolar concentration range as well as reduces ammonemia in rodent models of liver disease. Furthermore, 2-octynohydroxamic acid treatment decreases cerebellar glutamine, a product of ammonia metabolism, in male bile duct ligated rats. A prototype colonic formulation enables reduced systemic exposure to 2-octynohydroxamic acid in male dogs. Overall, this work suggests that urease inhibitors delivered to the colon by means of colonic formulations represent a prospective approach for the treatment of hepatic encephalopathy.

Lessons on brain edema in HE: from cellular to animal models and clinical studies.

Brain edema is considered as a common feature associated with hepatic encephalopathy (HE). However, its central role as cause or consequence of HE and its implication in the development of the neurological alterations linked to HE are still under debate. It is now well accepted that type A and type C HE are biologically and clinically different, leading to different manifestations of brain edema. As a result, the findings on brain edema/swelling in type C HE are variable and sometimes controversial. In the light of the changing natural history of liver disease, better description of the clinical trajectory of cirrhosis and understanding of molecular mechanisms of HE, and the role of brain edema as a central component in the pathogenesis of HE is revisited in the current review. Furthermore, this review highlights the main techniques to measure brain edema and their advantages/disadvantages together with an in-depth description of the main ex-vivo/in-vivo findings using cell cultures, animal models and humans with HE. These findings are instrumental in elucidating the role of brain edema in HE and also in designing new multimodal studies by performing in-vivo combined with ex-vivo experiments for a better characterization of brain edema longitudinally and of its role in HE, especially in type C HE where water content changes are small.

SPARCQ: A new approach for fat fraction mapping using asymmetries in the phase-cycled balanced SSFP signal profile.

PURPOSE: To develop SPARCQ (Signal Profile Asymmetries for Rapid Compartment Quantification), a novel approach to quantify fat fraction (FF) using asymmetries in the phase-cycled balanced SSFP (bSSFP) profile. METHODS: SPARCQ uses phase-cycling to obtain bSSFP frequency profiles, which display asymmetries in the presence of fat and water at certain TRs. For each voxel, the measured signal profile is decomposed into a weighted sum of simulated profiles via multi-compartment dictionary matching. Each dictionary entry represents a single-compartment bSSFP profile with a specific off-resonance frequency and relaxation time ratio. Using the results of dictionary matching, the fractions of the different off-resonance components are extracted for each voxel, generating quantitative maps of water and FF and banding-artifact-free images for the entire image volume. SPARCQ was validated using simulations, experiments in a water-fat phantom and in knees of healthy volunteers. Experimental results were compared with reference proton density FFs obtained with 1 H-MRS (phantoms) and with multiecho gradient-echo MRI (phantoms and volunteers). SPARCQ repeatability was evaluated in six scan-rescan experiments. RESULTS: Simulations showed that FF quantification is accurate and robust for SNRs greater than 20. Phantom experiments demonstrated good agreement between SPARCQ and gold standard FFs. In volunteers, banding-artifact-free quantitative maps and water-fat-separated images obtained with SPARCQ and ME-GRE demonstrated the expected contrast between fatty and non-fatty tissues. The coefficient of repeatability of SPARCQ FF was 0.0512. CONCLUSION: SPARCQ demonstrates potential for fat quantification using asymmetries in bSSFP profiles and may be a promising alternative to conventional FF quantification techniques.

Abnormal brain oxygen homeostasis in an animal model of liver disease.

Background & Aims: Increased plasma ammonia concentration and consequent disruption of brain energy metabolism could underpin the pathogenesis of hepatic encephalopathy (HE). Brain energy homeostasis relies on effective maintenance of brain oxygenation, and dysregulation impairs neuronal function leading to cognitive impairment. We hypothesised that HE is associated with reduced brain oxygenation and we explored the potential role of ammonia as an underlying pathophysiological factor. Methods: In a rat model of chronic liver disease with minimal HE (mHE; bile duct ligation [BDL]), brain tissue oxygen measurement, and proton magnetic resonance spectroscopy were used to investigate how hyperammonaemia impacts oxygenation and metabolic substrate availability in the central nervous system. Ornithine phenylacetate (OP, OCR-002; Ocera Therapeutics, CA, USA) was used as an experimental treatment to reduce plasma ammonia concentration. Results: In BDL animals, glucose, lactate, and tissue oxygen concentration in the cerebral cortex were significantly lower than those in sham-operated controls. OP treatment corrected the hyperammonaemia and restored brain tissue oxygen. Although BDL animals were hypotensive, cortical tissue oxygen concentration was significantly improved by treatments that increased arterial blood pressure. Cerebrovascular reactivity to exogenously applied CO2 was found to be normal in BDL animals. Conclusions: These data suggest that hyperammonaemia significantly decreases cortical oxygenation, potentially compromising brain energy metabolism. These findings have potential clinical implications for the treatment of patients with mHE. Lay summary: Brain dysfunction is a serious complication of cirrhosis and affects approximately 30% of these patients; however, its treatment continues to be an unmet clinical need. This study shows that oxygen concentration in the brain of an animal model of cirrhosis is markedly reduced. Low arterial blood pressure and increased ammonia (a neurotoxin that accumulates in patients with liver failure) are shown to be the main underlying causes. Experimental correction of these abnormalities restored oxygen concentration in the brain, suggesting potential therapeutic avenues to explore.

Probiotics combined with rifaximin influence the neurometabolic changes in a rat model of type C HE.

Type C hepatic encephalopathy (HE) is a neuropsychiatric disease caused by chronic liver disease. Management of type C HE remains an important challenge because treatment options are limited. Both the antibiotic rifaximin and probiotics have been reported to reduce the symptoms of HE, but longitudinal studies assessing their effects on brain metabolism are lacking and the molecular mechanisms underpinning their effects are not fully understood. Therefore, we evaluated in detail the effects of these different treatments on the neurometabolic changes associated with type C HE using a multimodal approach including ultra-high field in vivo 1H MRS. We analyzed longitudinally the effect of rifaximin alone or in combination with the probiotic Vivomixx on the brain metabolic profile in the hippocampus and cerebellum of bile duct ligated (BDL) rats, an established model of type C HE. Overall, while rifaximin alone appeared to induce no significant effect on the neurometabolic profile of BDL rats, its association with the probiotic resulted in more attenuated neurometabolic alterations in BDL rats followed longitudinally (i.e. a smaller increase in Gln and milder decrease in Glu and Cr levels). Given that both rifaximin and some probiotics are used in the treatment of HE, the implications of these findings may be clinically relevant.

Chromophore of an Enhanced Green Fluorescent Protein Can Play a Photoprotective Role Due to Photobleaching.

Under stress conditions, elevated levels of cellular reactive oxygen species (ROS) may impair crucial cellular structures. To counteract the resulting oxidative damage, living cells are equipped with several defense mechanisms, including photoprotective functions of specific proteins. Here, we discuss the plausible ROS scavenging mechanisms by the enhanced green fluorescent protein, EGFP. To check if this protein could fulfill a photoprotective function, we employed electron spin resonance (ESR) in combination with spin-trapping. Two organic photosensitizers, rose bengal and methylene blue, as well as an inorganic photocatalyst, nano-TiO2, were used to photogenerate ROS. Spin-traps, TMP-OH and DMPO, and a nitroxide radical, TEMPOL, served as molecular targets for ROS. Our results show that EGFP quenches various forms of ROS, including superoxide radicals and singlet oxygen. Compared to the three proteins PNP, papain, and BSA, EGFP revealed high ROS quenching ability, which suggests its photoprotective role in living systems. Damage to the EGFP chromophore was also observed under strong photo-oxidative conditions. This study contributes to the discussion on the protective function of fluorescent proteins homologous to the green fluorescent protein (GFP). It also draws attention to the possible interactions of GFP-like proteins with ROS in systems where such proteins are used as biological markers.

Synchronous nonmonotonic changes in functional connectivity and white matter integrity in a rat model of sporadic Alzheimer's disease.

Brain glucose hypometabolism has been singled out as an important contributor and possibly main trigger to Alzheimer's disease (AD). Intracerebroventricular injections of streptozotocin (icv-STZ) cause brain glucose hypometabolism without systemic diabetes. Here, a first-time longitudinal study of brain glucose metabolism, functional connectivity and white matter microstructure was performed in icv-STZ rats using PET and MRI. Histological markers of pathology were tested at an advanced stage of disease. STZ rats exhibited altered functional connectivity and intra-axonal damage and demyelination in brain regions typical of AD, in a temporal pattern of acute injury, transient recovery/compensation and chronic degeneration. In the context of sustained glucose hypometabolism, these nonmonotonic trends - also reported in behavioral studies of this animal model as well as in human AD - suggest a compensatory mechanism, possibly recruiting ketone bodies, that allows a partial and temporary repair of brain structure and function. The early acute phase could thus become a valuable therapeutic window to strengthen the recovery phase and prevent or delay chronic degeneration, to be considered both in preclinical and clinical studies of AD. In conclusion, this work reveals the consequences of brain insulin resistance on structure and function, highlights signature nonmonotonic trajectories in their evolution and proposes potent MRI-derived biomarkers translatable to human AD and diabetic populations.

Residual hip dysplasia in children: osseous and cartilaginous acetabular angles to guide further treatment-a pilot study.

PURPOSE: In case of residual hip dysplasia (RHD) in children, pelvic radiographs are sometimes insufficient to precisely evaluate the entire coverage of the femoral head, when trying to decide on the need for further reconstructive procedures. METHODS: This study retrospectively compares the bony and the cartilaginous acetabular angle of Hilgenreiner (HTE) of 60 paediatric hips on pelvic MRI separated in two groups. Group 1 included 31 hips with RHD defined by a bony HTE > 20°. Group 2 included 27 hips with a HTE < 20°. They were compared by introducing a new ratio calculated from the square of cartilaginous HTE above the bony HTE on frontal MRI. The normal upper limit for this acetabular angle ratio was extrapolated from the published normal values of cartilaginous HTE and bony HTE in children. RESULTS: The acetabular angle ratio was statistically significantly increased in the hips with RHD with a mean value of 7.1 ± 4.7 compared to the hips in the control group presenting a mean value of 2.1 ± 1.9 (p < 0.00001). CONCLUSIONS: This newly introduced ratio seems to be a helpful tool to orientate the further treatment in children presenting borderline RHD.

Early Perfusion Computed Tomography Scan for Prediction of Vasospasm and Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage.

OBJECTIVE: We investigated the ability of early alteration of cerebral perfusion-computed tomography (PCT) parameters to predict the risk of vasospasm, delayed cerebral ischemia (DCI), and clinical outcome in patients with aneurysmal subarachnoid hemorrhage (aSAH). METHODS: A retrospective cohort study of 38 aSAH patients investigated with PCT within 48 hours after hemorrhage. Cerebral blood flow (CBF), cerebral blood volume, and mean transit time (MTT) values were recorded. Mean values were compared with clinical data. Vasospasm and DCI were determined by imaging and clinical criteria. Neurologic outcome was assessed by the modified Rankin Scale at discharge and 1-year follow-up visit. RESULTS: More than a third (39.5%) of patients developed DCI, of whom 86.7% presented moderate-severe vasospasm. There was a significant correlation between perfusion parameters in the early phase and occurrence of DCI and vasospasm. The occurrence of DCI and vasospasm correlated significantly with lower mean early PCT values. DCI was correlated with lower mean early CBF values (P = 0.049) and vasospasm with lower mean CBF (P = 0.01) and MTT (P < 0.00001) values. MTT values of 5.5s were shown to have 94% specificity and 100% sensitivity for predicting the risk of developing vasospasm. The severity of the SAH according to the Barrow Neurological Institute scale correlated significantly with the risk of developing DCI and vasospasm, both significantly associated with unfavorable neurologic outcome (modified Rankin Scale score 3-6) (P = 0.0002 and P = 0.02, respectively). CONCLUSIONS: Early alterations in PCT parameters and high Barrow Neurological Institute grade may identify a subgroup of patients at high risk of developing DCI and vasospasm after aSAH, thus prompting more robust preventative measures and treatment in this subgroup.

Longitudinal neurometabolic changes in the hippocampus of a rat model of chronic hepatic encephalopathy.

BACKGROUND & AIMS: The sequence of events in hepatic encephalopathy (HE) remains unclear. Using the advantages of in vivo 1H-MRS (9.4T) we aimed to analyse the time-course of disease in an established model of type C HE by analysing the longitudinal changes in a large number of brain metabolites together with biochemical, histological and behavioural assessment. We hypothesized that neurometabolic changes are detectable very early, and that these early changes will offer insight into the primary events underpinning HE. METHODS: Wistar rats underwent bile-duct ligation (BDL) and were studied before BDL and at post-operative weeks 2, 4, 6 and 8 (n = 26). In vivo short echo-time 1H-MRS (9.4T) of the hippocampus was performed in a longitudinal manner, as were biochemical (plasma), histological and behavioural tests. RESULTS: Plasma ammonium increased early after BDL and remained high during the study. Brain glutamine increased (+47%) as early as 2-4 weeks post-BDL while creatine (-8%) and ascorbate (-12%) decreased. Brain glutamine and ascorbate correlated closely with rising plasma ammonium, while brain creatine correlated with brain glutamine. The increases in brain glutamine and plasma ammonium were correlated, while plasma ammonium correlated negatively with distance moved. Changes in astrocyte morphology were observed at 4 weeks. These early changes were further accentuated at 6-8 weeks post-BDL, concurrently with the known decreases in brain organic osmolytes. CONCLUSION: Using a multimodal, in vivo and longitudinal approach we have shown that neurometabolic changes are already noticeable 2 weeks after BDL. These early changes are suggestive of osmotic/oxidative stress and are likely the premise of some later changes. Early decreases in cerebral creatine and ascorbate are novel findings offering new avenues to explore neuroprotective strategies for HE treatment. LAY SUMMARY: The sequence of events in chronic hepatic encephalopathy (HE) remains unclear, therefore using the advantages of in vivo proton magnetic resonance spectroscopy at 9.4T we aimed to test the hypothesis that neurometabolic changes are detectable very early in an established model of type C HE, offering insight into the primary events underpinning HE, before advanced liver disease confounds the findings. These early, previously unreported neurometabolic changes occurred as early as 2 to 4 weeks after bile-duct ligation, namely an increase in plasma ammonium and brain glutamine, a decrease in brain creatine and ascorbate together with behavioural and astrocyte morphology changes, and continued to progress throughout the 8-week course of the disease.

Metabolomics reveals tepotinib-related mitochondrial dysfunction in MET-activating mutations-driven models.

Genetic aberrations in the hepatocyte growth factor receptor tyrosine kinase MET induce oncogenic addiction in various types of human cancers, advocating MET as a viable anticancer target. Here, we report that MET signaling plays an important role in conferring a unique metabolic phenotype to cellular models expressing MET-activating mutated variants that are either sensitive or resistant toward MET small molecule inhibitors. MET phosphorylation downregulated by the specific MET inhibitor tepotinib resulted in markedly decreased viability and increased apoptosis in tepotinib-sensitive cells. Moreover, prior to the induction of MET inhibition-dependent cell death, tepotinib also led to an altered metabolic signature, characterized by a prominent reduction of metabolite ions related to amino sugar metabolism, gluconeogenesis, glycine and serine metabolism, and of numerous TCA cycle-related metabolites such as succinate, malate, and citrate. Functionally, a decrease in oxygen consumption rate, a reduced citrate synthase activity, a drop in membrane potential, and an associated misbalanced mitochondrial function were observed exclusively in MET inhibitor-sensitive cells. These data imply that interference with metabolic state can be considered an early indicator of efficient MET inhibition and particular changes reported here could be explored in the future as markers of efficacy of anti-MET therapies.

Thyrotropin-secreting pituitary adenomas: a systematic review and meta-analysis of postoperative outcomes and management.

PURPOSE: TSH-secreting pituitary adenomas are rare pituitary tumors. An efficient treatment is essential to limit the mortality and morbidity in untreated patients. The aim of this study is to summarize the evidence about the postoperative outcomes and management of this rare pathology. METHODS: A systematic search and meta-analysis of surgical series was performed. RESULTS: Our analysis included 23 articles (536 patients). No sex difference was observed and mean age at diagnosis was 45 years. Hyperthyroidism was reportedly clinical in 67% and biochemical in 90% of patients. Co-secretion of other pituitary hormones was present in 42% of cases. Macroadenomas were found in 79% of patients, showing in 44% and 30% of cases respectively extrasellar extension and cavernous sinus invasion. The pooled rate of postoperative biochemical remission was 69.7% and a gross total resection (GTR) was observed in 54% of patients. The extent of resection was significantly increased in microadenomas (p < 0.001) and cavernous sinus invasion was predictive of lower GTR rate (p < 0.001). A biochemical remission was achieved in 66% of patients after adjuvant radiation therapy and in 76% after adjuvant medical treatment. The combination of both allowed remission in 67% of cases. At final follow-up the overall biochemical remission rate was significantly improved (85.8%) when compared to the postoperative biochemical remission (p < 0.001). CONCLUSION: When compared to the early postoperative period, at last follow-up biochemical remission was significantly greater (p < 0.001). GTR was achieved in half of patients; the size of tumor and cavernous sinus invasion determined the extent of resection.

Do intra-operative neurophysiological changes predict functional outcome following decompressive surgery for lumbar spinal stenosis? A prospective study.

BACKGROUND: To analyse the relation between immediate intraoperative neurophysiological changes during decompression and clinical outcome in a series of patients with lumbar spinal stenosis (LSS) undergoing surgery. METHODS: Twenty-four patients with neurogenic intermittent claudication (NIC) due to LSS undergoing decompressive surgery were prospectively studied. Intra operative trans-cranial motor evoked potentials (tcMEPs) were recorded before and immediately after surgical decompression. Lower limb normalised tcMEP improvement was used as primary neurophysiological outcome. Clinical outcome was assessed using the Zurich Claudication Questionnaire (ZCQ) self-assessment score, before surgery (baseline) and at an average of 8 and 29 months post-operatively. RESULTS: We found a moderate positive correlation between tcMEP changes and ZCQ at early follow-up (R=0.36). At late follow-up no correlation was found between intra-operative tcMEP and ZCQ changes. Dichotomizing the data showed a statistically significant relationship between tcMEP improvement and better functional outcome at early follow-up (P=0.013) but not at later follow-up (P=1). CONCLUSIONS: Our findings suggest that intra-operative neurophysiological improvement during decompressive surgery may predict a better clinical outcome at early follow-up although this is not applicable to late follow-up possibly due to the observed erosion of functional improvement with time.

Pedicle Screw Insertion Accuracy Using O-Arm, Robotic Guidance, or Freehand Technique: A Comparative Study.

STUDY DESIGN: A retrospective radiological study. OBJECTIVE: The aim of this study was to evaluate the accuracy of pedicle screw insertion using O-Arm navigation, robotic assistance, or a freehand fluoroscopic technique. SUMMARY OF BACKGROUND DATA: Pedicle screw insertion using either "O-Arm" navigation or robotic devices is gaining popularity. Although several studies are available evaluating each of those techniques separately, no direct comparison has been attempted. METHODS: Eighty-four patients undergoing implantation of 569 lumbar and thoracic screws were divided into three groups. Eleven patients (64 screws) had screws inserted using robotic assistance, 25 patients (191 screws) using the O-arm, while 48 patients (314 screws) had screws inserted using lateral fluoroscopy in a freehand technique. A single experienced spine surgeon assisted by a spinal fellow performed all procedures. Screw placement accuracy was assessed by two independent observers on postoperative computed tomography (CTs) according to the A to D Rampersaud criteria. RESULTS: No statistically significant difference was noted between the three groups. About 70.4% of screws in the freehand group, 69.6% in the O arm group, and 78.8% in the robotic group were placed completely within the pedicle margins (grade A) (P > 0.05). About 6.4% of screws were considered misplaced (grades C&D) in the freehand group, 4.2% in the O-arm group, and 4.7% in the robotic group (P > 0.05). The spinal fellow inserted screws with the same accuracy as the senior surgeon (P > 0.05). CONCLUSION: The advent of new technologies does not appear to alter accuracy of screw placement in our setting. Under supervision, spinal fellows might perform equally well to experienced surgeons using new tools. The lack of difference in accuracy does not imply that the above-mentioned techniques have no added advantages. Other issues, such as surgeon/patient radiation, fiddle factor, teaching suitability, etc., outside the scope of our present study, need further assessment. LEVEL OF EVIDENCE: 3.

Influence of anatomical variations on lumbar foraminal stenosis pathogenesis.

INTRODUCTION: Symptomatic foraminal stenosis has been observed in patients with degenerative disc disease, scoliosis, asymmetrical disc degeneration and spondylolisthesis. Nevertheless not all patients with the above pathologies will develop symptomatic foraminal stenosis. We hypothesised that symptomatic patients have anatomical predisposition to foraminal stenosis, namely a larger pedicle height (PH) to vertebral body height (VH) ratio, leaving less room below the pedicle for the exiting nerve root compared to asymptomatic patients. PATIENT SAMPLE: 66 Patients were divided in two groups. The surgical group consisted of 37 patients (average age of 61 years) who presented with severe radicular symptoms resisting to conservative measures and requiring decompression and transforaminal lumbar interbody fusion (TLIF). The control group consisted of 29 patients (average age of 51 years) presenting with low back pain (LBP) but with no radicular symptoms and who were treated conservatively. METHODS: We measured VH at the level of the posterior wall as well as PH on parasagittal images (CT or MRI) on all lumbar levels (L1 to L5). Statistical analysis was performed using Student's t test. RESULTS: No difference in PH was found between the two groups for L1 to L4 levels. By contrast, there was a highly statistically significant difference in VH between the two groups from L1 to L4 level. In the surgical group, the VH was smaller (p < 0.001). CONCLUSIONS: Symptomatic patients with foraminal stenosis have smaller VH leading to lesser space beneath the pedicle and putting the exiting nerve root at risk in cases of spondylolisthesis or disc degeneration.

Secular changes of spinal canal dimensions in Western Switzerland: a narrowing epidemic?

STUDY DESIGN: Computed tomography-based anatomical study. OBJECTIVE: To study the secular changes in lumbar spinal canal dimensions. SUMMARY OF BACKGROUND DATA: Development of symptomatic lumbar spinal stenosis, among other factors, is related to the dimensions of the bony canal. The canal reaches its adult size early on in life. Several factors, including protein intake, may influence its final dimensions. As with increases in human stature from improvements of socioeconomic conditions, we hypothesized that adult bony canal size has also grown larger in recent generations. METHODS: This study analyzes computed tomographic reconstructions from 184 subjects performed for either trauma (n = 81) or abdominal pathologies (n = 103) and born either between 1940 and 1949 (n = 88) or 1970 and 1979 (n = 96). The cross-sectional area of the bony canal was digitally measured at the level of the pedicle (i.e., at a level not influenced by degenerative changes) for each lumbar vertebra. Intra- and interobserver reliability was assessed. RESULTS: Intra- and interobserver measurement reliability were excellent (interclass correlation coefficient = 0.87) and good (interclass correlation coefficient = 0.61), respectively. Contrary to our hypothesis, the 1940-1949 generation patient group exhibited larger lumbar canals at all levels as compared with the 1970-1979 group. Statistically this difference was highly significant (P < 0.001) and particularly pronounced in the trauma subgroup. CONCLUSION: Given that human stature evolution has stabilized and adult height is established during the first 2 years of long bone growth, it is possible that antenatal factors are responsible for this surprising finding. Maternal smoking and age may be possible explanations. This finding may have significant implications. An increasing number of patients may emerge with lumbar spinal stenosis as degenerative changes develop, putting a strain on health resources. Further studies in different population groups and countries will be important to further confirm this trend. LEVEL OF EVIDENCE: 3.

Photocatalytic and phototoxic properties of TiO2-based nanofilaments: ESR and AFM assays.

There is uncertainty in understanding of the relationship between physico-chemical parameters of nanosized titanium dioxide (nano-TiO(2)) and its toxicity when brought into contact with living cells. This study provides a multidisciplinary experimental insight into the toxicity and phototoxicity of the custom-made TiO(2)-based nanowires (TiO(2)-NWs). We employed electron spin resonance (ESR) to detect reactive oxygen species (ROS) generated in aqueous suspensions of TiO(2)-NWs and combined these results with atomic force microscopy (AFM) to trace the onset of toxic effects towards human melanoma cells. The cells were treated with low concentrations (∼2.5 µg/ml) of TiO(2)-NWs and Degussa P25. High-resolution AFM surface topography and cell elasticity measurements revealed toxic effects both in cells incubated with TiO(2)-NWs in the dark and exposed to the photo-oxidative stress under UVA radiation. In contrast to ROS generation efficacy in the absence of cells in vitro, no direct correlation was found between the physical parameters of nano-TiO(2) and cell toxicity.

Atom-transfer radical addition reactions catalyzed by RuCp* complexes: a mechanistic study.

Kinetic and spectroscopic analyses were performed to gain information about the mechanism of atom-transfer radical reactions catalyzed by the complexes [RuCl2Cp*(PPh3)] and [RuClCp*(PPh3)2] (Cp*=pentamethylcyclopentadienyl), in the presence and in the absence of the reducing agent magnesium. The reactions of styrene with ethyl trichloroacetate, ethyl dichloroacetate, or dichloroacetonitrile were used as test reactions. The results show that for substrates with high intrinsic reactivity, such as ethyl trichloroacetate, the oxidation state of the catalyst in the resting state is +3, and that the reaction is zero-order with respect to the halogenated compound. Furthermore, the kinetic data suggest that the metal catalyst is not directly involved in the rate-limiting step of the reaction.