Percivall Pott (1713-1788) on the curvature of the spine and the French contribution.

Physicians remember the name of the surgeon Percivall Pott (1713-1788) because of the eponym "Pott's disease", described as "paralysis in the lower limbs, which is often accompanied by curvature of the spine". Pott's writings on surgical subjects are far vaster. For example, he described the fracture-dislocation of the ankle, or Pott's fracture, and determined the cause of scrotum cancer in chimney sweeps. He attributed this disease to contact with tar that contaminated the clothing of workers, often very young children because they were small enough to fit into chimney conduits. His work led to the first law addressing the employment of children. After a brief account of Pott's life, this article presents the description of Pott's paraplegia, for which both Jean-Martin Charcot and Yvonne Sorrel-Dejerine paid him homage. The contribution of some of his predecessors and of French contemporaries is highlighted. Pott was also a pioneer in neurosurgery, describing the non-symptomatic interval between cranial trauma and coma and the indication for trepanation to remove a haematoma.

Is sarcopenia a better predictor of complications than body mass index? Sarcopenia and surgical outcomes in patients with rectal cancer.

AIM: Sarcopenia, or a reduction of lean muscle mass, is associated with poorer outcomes in cancer patients. Few previous studies have examined this potentially correctable risk factor in patients with locally advanced rectal cancer. METHOD: Skeletal muscle mass index was measured retrospectively on initial staging CT scans of patients undergoing chemoradiation followed by radical resection for rectal cancer for the period 2007-2013. Patients were categorized as sarcopenic or nonsarcopenic and differences in terms of demographics, pre-, peri- and postoperative outcomes were examined. RESULTS: Forty-seven patients were included; their mean age was 59.3 (36-82) years and 61.7% were men. We considered that 55.2% of men and 44.4% of women were sarcopenic; the overall prevalence of sarcopenia was 51.1%. Age, preoperative haemoglobin and albumin were significantly related to sarcopenia. Body mass index (BMI) and obesity (BMI > 30 kg/m2 ) were not associated with sarcopenia. Blood transfusions were more frequent in sarcopenic patients (P = 0.001). Although readmissions and length of stay were not increased, overall postoperative complications were significantly higher in sarcopenic patients (P = 0.03). Neither BMI nor obesity was associated with postoperative complications. CONCLUSION: Sarcopenia was present in over 50% of patients with locally advanced rectal cancer at diagnosis. It was associated with a higher incidence of both blood transfusion and postoperative complications. BMI did not correlate with these negative outcomes. Sarcopenia may be a better predictor of surgical outcomes than BMI or obesity.

HMGCR is a genetic modifier for risk, age of onset and MCI conversion to Alzheimer's disease in a three cohorts study.

Several retrospective epidemiological studies report that utilization of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) inhibitors called statins at mid-life can reduce the risk of developing sporadic Alzheimer's disease (AD) by as much as 70%. Conversely, the administration of these inhibitors in clinically diagnosed subjects with AD confers little or no benefits over time. Here, we investigated the association between AD and HMGCR rs3846662, a polymorphism known to be involved in the regulation of HMGCR exon 13 skipping, in a founder population and in two distinct mixed North American populations of converting mild cognitively impaired (MCI) subjects (Alzheimer's disease Cooperative study (ADCS) and Alzheimer's disease Neuroimaging Initiative (ADNI) cohorts). Targeting more specifically women, the G allele negative (G-) AD subjects exhibit delayed age of onset of AD (P=0.017) and significantly reduced risk of AD (OR: 0.521; P=0.0028), matching the effect size reported by the apolipoprotein E type 2 variant. Stratification for APOE4 in a large sample of MCI patients from the ADCS cohort revealed a significant protective effect of G negative carriers on AD conversion 3 years after MCI diagnosis (odds ratio (OR): 0.554; P=0.041). Conversion rate among APOE4 carriers with the HMGCR's G negative allele was markedly reduced (from 76% to 27%) to levels similar to APOE4 non-carriers (27.14%), which strongly indicate protection. Conversion data from the independent ADNI cohort also showed significantly reduced MCI or AD conversion among APOE4 carriers with the protective A allele (P=0.005). In conclusion, HMGCR rs3846662 acts as a potent genetic modifier for AD risk, age of onset and conversion.

The hypertriglyceridemic-waist phenotype is associated with the Framingham risk score and subclinical atherosclerosis in Canadian Cree.

BACKGROUND AND AIMS: For primary prevention of cardiovascular disease (CVD), Canadian guidelines recommend that asymptomatic Canadians with abdominal obesity undergo Framingham risk score (FRS) assessment, and that in Indigenous Peoples, indicators of metabolic syndrome also be used to identify at-risk individuals. The hypertriglyceridemic-waist phenotype (HTGW) has been proposed to be a surrogate marker of visceral obesity and a simple proxy measure for metabolic syndrome. The primary aim of this study was to evaluate whether the HTGW and the FRS associated with sub-clinical atherosclerosis. METHODS AND RESULTS: Asymptomatic Cree participants in a cross-sectional study conducted 2005-2009 (n = 446, 18-81 y) were assessed for the HTGW using NCEP-ATP-III gender-specific-cutoffs (waist circumference: for men, ≥102 cm; for women ≥88 cm) and fasting triglycerides ≥1.7 mmol/L. Sub-clinical atherosclerosis was defined by the presence of a high sex-specific common-carotid-intimal-medial-wall-thickness (≥75th percentile). HTGW was present in 26.7% and a 10-y FRS greater than 10% was present in 18.8% of participants. The multivariate adjusted OR (95% CI) for sub-clinical atherosclerosis associated with an FRS greater than 10% was 4.10 (2.20-7.50) while that associated with the HTGW phenotype was 1.74 (95% CI 1.61-1.88) from a model including age, body mass index, alcohol consumption, FRS and the HTGW. CONCLUSIONS: The HTGW phenotype is prevalent in the Cree. Our findings support further study on the utility of combining the HTGW with the FRS in the prediction of cardiovascular disease outcomes and in health screening and intervention programs among indigenous peoples.

A new prognostic clinicopathological classification of pituitary adenomas: a multicentric case-control study of 410 patients with 8 years post-operative follow-up.

Pituitary adenomas are currently classified by histological, immunocytochemical and numerous ultrastructural characteristics lacking unequivocal prognostic correlations. We investigated the prognostic value of a new clinicopathological classification with grades based on invasion and proliferation. This retrospective multicentric case-control study comprised 410 patients who had surgery for a pituitary tumour with long-term follow-up. Using pituitary magnetic resonance imaging for diagnosis of cavernous or sphenoid sinus invasion, immunocytochemistry, markers of the cell cycle (Ki-67, mitoses) and p53, tumours were classified according to size (micro, macro and giant), type (PRL, GH, FSH/LH, ACTH and TSH) and grade (grade 1a: non-invasive, 1b: non-invasive and proliferative, 2a: invasive, 2b: invasive and proliferative, and 3: metastatic). The association between patient status at 8-year follow-up and age, sex, and classification was evaluated by two multivariate analyses assessing disease- or recurrence/progression-free status. At 8 years after surgery, 195 patients were disease-free (controls) and 215 patients were not (cases). In 125 of the cases the tumours had recurred or progressed. Analyses of disease-free and recurrence/progression-free status revealed the significant prognostic value (p < 0.001; p < 0.05) of age, tumour type, and grade across all tumour types and for each tumour type. Invasive and proliferative tumours (grade 2b) had a poor prognosis with an increased probability of tumour persistence or progression of 25- or 12-fold, respectively, as compared to non-invasive tumours (grade 1a). This new, easy to use clinicopathological classification of pituitary endocrine tumours has demonstrated its prognostic worth by strongly predicting the probability of post-operative complete remission or tumour progression and so could help clinicians choose the best post-operative therapy.

Organotypic human lung bud microarrays identify BMP-dependent SARS-CoV-2 infection in lung cells.

Although lung disease is the primary clinical outcome in COVID-19 patients, how SARS-CoV-2 induces lung pathology remains elusive. Here we describe a high-throughput platform to generate self-organizing and commensurate human lung buds derived from hESCs cultured on micropatterned substrates. Lung buds resemble human fetal lungs and display proximodistal patterning of alveolar and airway tissue directed by KGF. These lung buds are susceptible to infection by SARS-CoV-2 and endemic coronaviruses and can be used to track cell type-specific cytopathic effects in hundreds of lung buds in parallel. Transcriptomic comparisons of infected lung buds and postmortem tissue of COVID-19 patients identified an induction of BMP signaling pathway. BMP activity renders lung cells more susceptible to SARS-CoV-2 infection and its pharmacological inhibition impairs infection by this virus. These data highlight the rapid and scalable access to disease-relevant tissue using lung buds that recapitulate key features of human lung morphogenesis and viral infection biology.

Inflammation in the tumor-adjacent lung as a predictor of clinical outcome in lung adenocarcinoma.

Approximately 30% of early-stage lung adenocarcinoma patients present with disease progression after successful surgical resection. Despite efforts of mapping the genetic landscape, there has been limited success in discovering predictive biomarkers of disease outcomes. Here we performed a systematic multi-omic assessment of 143 tumors and matched tumor-adjacent, histologically-normal lung tissue with long-term patient follow-up. Through histologic, mutational, and transcriptomic profiling of tumor and adjacent-normal tissue, we identified an inflammatory gene signature in tumor-adjacent tissue as the strongest clinical predictor of disease progression. Single-cell transcriptomic analysis demonstrated the progression-associated inflammatory signature was expressed in both immune and non-immune cells, and cell type-specific profiling in monocytes further improved outcome predictions. Additional analyses of tumor-adjacent transcriptomic data from The Cancer Genome Atlas validated the association of the inflammatory signature with worse outcomes across cancers. Collectively, our study suggests that molecular profiling of tumor-adjacent tissue can identify patients at high risk for disease progression.

Figures and Institutions of the neurological sciences in Paris from 1800 to 1950. Part IV: Psychiatry and psychology.

We present a short historical review on the major institutions and figures who contributed to make Paris a renowned centre of physiology and neurology during the XIXth and the first half of the XXth century. We purposely chose to focus on the period 1800-1950, as 1800 corresponds to the actual beginning of neurosciences, and as 1950 marks their exponential rise. Our presentation is divided into four chapters, matching the main disciplines that have progressed and contributed most to the knowledge we have of the brain sciences: anatomy, physiology, neurology, and psychiatry-psychology. The present article is the fourth of the four parts of this review, which deals with the chapter on psychiatry and psychology. When the French Revolution occurred, only a few institutions were taking care of the mentally ill. In the Paris area, these included Maison Royale de Charenton, Les Petites Maisons, and one of the departments of larger hospitals such as Hôtel-Dieu, the Salpêtrière Hospital and Bicêtre Hospital. One of the founders of psychiatry in Paris at that time and thereafter was Philippe Pinel (1745-1826) who was the first to distinguish insane/alienated patients from misfits, beggars, and other vagabonds. During the first half of the XIXth century, his student Jean-Étienne Esquirol (1772-1840) also played a major role with his treatise on mental diseases and the 1838 law and the creation of asylums in all parts of France. Alienists were in general caregivers and learned by themselves. In contrast, at the academic level, the emerging disciplines psychiatry and neurology were very close to each other in the second half of the XIXth century, the best example being Jules Baillarger (1809-1890). The actual development of psychiatry and psychology and the foundation of psychoanalysis later in the XIXth century and in the first half of the XXth century owed much to several European doctors and scientists, particularly those from British institutions and from German-speaking universities in Central Europe. In France, important advances were once again initiated in Paris by Jean-Martin Charcot (1825-1893) and some of his pupils who renewed the concept of hysteria and the use of hypnosis. Sainte-Anne Hospital was created in 1867. This new institution located in the southern part of Paris became (and is still) one of the most important places in France for the treatment, research and teaching of mental diseases. Thereafter started new disciplines such as clinical psychology and neuropsychology; the scientific basis of psychology and notably the psychopathology hypothesis were established. A major revolutionary step occurred in Paris in the early 1950s with the discovery of neuroleptics and the birth of psychopharmacology. Here we present the biographical sketches of the most important Parisian scientists of these disciplines from that era, Philippe Pinel, Jean-Étienne Esquirol, Théodule Armand Ribot, Pierre Janet, Henri Louis Charles Piéron, Henry Ey, Jean Delay, Henri Laborit and Henri Hécaen.

Figures and institutions of the neurological sciences in Paris from 1800 to 1950. Part III: neurology.

We present a short historical review of the major figures, their administrative functions and their works that contributed to make Paris a renowned centre of physiology and neurology during the xixth and the first half of the xxth century. We purposely chose to focus on the period 1800-1950, as 1800 corresponds to the actual beginning of neurosciences, and 1950 marks their exponential rise. Our presentation is divided into four chapters, matching the main disciplines which have progressed and contributed the most to the knowledge we have of the brain sciences: anatomy, physiology, neurology, and psychiatry-psychology. The present article is the third of four parts of this review, and deals with neurology. A special credit should be given to Jean-Martin Charcot who founded the Salpêtrière School of neurology and became one of the world's most important neurologists of the xixth century. We provide below the biographical sketches of Armand Trousseau, Guillaume Benjamin Amand Duchenne, Jean-Martin Charcot, Alfred Vulpian, Désiré-Magloire Bourneville, Paul Richer, Henri Parinaud, Albert Pitres, Jules Joseph Dejerine, Mrs. Augusta Dejerine-Klumpke, Édouard Brissaud, Pierre Marie, Georges Édouard Brutus Gilles de la Tourette, Joseph Babinski, André Thomas, Georges Marinesco, Achille Alexandre Souques, Georges Guillain and Charles Foix.

Figures and institutions of the neurological sciences in Paris from 1800 to 1950. Introduction and Part I: Neuroanatomy.

We present a short historical review on the major institutions and figures that contributed to make Paris a renowned centre of physiology and neurology during the xixth and the first half of the xxth centuries. We purposely chose to focus on the period 1800-1950, as 1800 corresponds to the development of brain science and 1950 marks the true beginning of neuroscience. Our presentation is divided into four chapters, matching the main disciplines which have progressed and contributed the most to the knowledge we have of the brain sciences: anatomy, physiology, neurology, and psychiatry-psychology. The present article is the first of four parts of this review, which includes an introduction followed by the chapter on neuroanatomy and on anatomo-pathology, which includes biographical sketches of Félix Vicq d'Azyr, François-Xavier Bichat, Franz Joseph Gall, Jean Cruveilhier, Jules Bernard Luys, Paul Broca, Louis Ranvier, André-Victor Cornil, Albert Gombault, Jean Nageotte and René Couteaux.

Figures and institutions of the neurological sciences in Paris from 1800 to 1950. Part II: Neurophysiology.

We present a short historical review of the major figures and institutions that contributed to make Paris a renowned centre of physiology and neurology during the xixth and the first half of the xxth century. We purposely chose to focus on the period 1800-1950, as 1800 corresponds to the actual beginning of experimental physiology of the nervous system - what is here referred to as "neuroscience"-and 1950 marks its exponential rise. Our presentation is divided into four chapters, matching the main disciplines which have progressed and contributed the most to the knowledge we have of the brain sciences: anatomy, physiology, neurology, and psychiatry-psychology. The present article is the second of four parts of this review which includes the chapter on neurophysiology with selected biographical sketches of François Magendie, Marie Jean-Pierre Flourens, Claude Bernard, Charles-Édouard Brown-Séquard, Étienne-Jules Marey, Alfred Fessard and Denise Albe-Fessard.

Influence of glioma tumour microenvironment on the transport of ANG1005 via low-density lipoprotein receptor-related protein 1.

BACKGROUND: ANG1005 consists of three molecules of paclitaxel conjugated via ester bonds to the 19-amino-acid peptide Angiopep-2. The new chemical agent has been shown to cross the blood-brain barrier (BBB) by receptor-mediated transcytosis via low-density lipoprotein receptor-related protein 1 (LRP1). The experiments here examined the role of LRP1 in the subsequent endocytosis of drug into cancer cells. METHODS: Localisation of ANG1005 and Angiopep-2 was examined by immunohistochemistry and in-vivo near-infrared fluorescence imaging in mice carrying orthotopic glioma tumours. Transport of ANG1005 and Angiopep-2 was examined in U87 glioblastoma cell lines. RESULTS: Systemically administered ANG1005 and Cy5.5Angiopep-2 localised to orthotopic glioma tumours in mice. The glioma transplants correlated with high expression levels of LRP1. Decreasing LRP1 activity, by RNA silencing or LRP1 competitors, decreased uptake of ANG1005 and Angiopep-2 into U87 glioblastoma cells. Conversely, LRP1 expression and endocytosis rates for ANG1005 and Angiopep-2 increased in U87 cells under conditions that mimicked the microenvironment near aggressive tumours, that is, hypoxic and acidic conditions. CONCLUSION: ANG1005 might be a particularly effective chemotherapeutic agent for the wide array of known LRP1-expressing brain and non-brain cancers, in particular those with an aggressive phenotype.

A comprehensive model of care for rehabilitation of children with acquired brain injuries.

BACKGROUND: Acquired brain injury (ABI) is a leading cause of death and lifelong acquired disability in children and remains a significant public health issue. Deficits may only become fully apparent when developmental demands increase and once cognitive processes are expected to be fully developed. It is therefore necessary to provide organized long-term follow-up for children post ABI. Despite these recommendations, it has been shown that only a small proportion of children received specialized rehabilitation and adequate follow-up after ABI. AIMS: The aims are: (i) to describe a comprehensive model of care devoted to children with acquired brain injuries; and (ii) to provide descriptive data analysing the characteristics of children followed up, the type/amount of services provided and general outcomes. PROGRAMME DESCRIPTION: The programme features an in- and outpatient rehabilitation facility, where multidisciplinary rehabilitation and specialized schooling are provided. The ultimate goal of the programme is to promote each child's successful reintegration in school and in the community. Adequate preparation of discharge is essential, long-term follow-up is organized, and an outreach programme has been developed to deal with the complex delayed psychosocial issues. RESULTS: Overall outcome, as measured by the Glasgow Outcome Scale, improved dramatically between admission (3.3; SD = 0.45) and discharge (2.15; SD = 0.74). Most of the children were discharged home with an adequate personalized plan for ongoing rehabilitation and school adaptations. Analysis of the outreach programme underlines the more challenging issues arising in late adolescence-early adulthood. CONCLUSION: Given the specificities of childhood ABI, long-term specific care must be organized and co-ordinated, regardless of injury severity.

Dislocations in spinel and garnet high-pressure polymorphs of olivine and pyroxene: implications for mantle rheology.

The meteorite Tenham was observed by transmission electron microscopy and ringwoodite and majorite, the high-pressure polymorphs of olivine and pyroxene, were identified. Ringwoodite contains antiphase boundaries and straight dislocations that are probably dissociated. Mantle flow of spinel might proceed by pure climb, and whole-mantle convection may be possible if the grain size is small enough.

Metabolic response to a ketogenic breakfast in the healthy elderly.

OBJECTIVE: To determine whether the metabolism of glucose or ketones differs in the healthy elderly compared to young or middle-aged adults during mild, short-term ketosis induced by a ketogenic breakfast. DESIGN AND PARTICIPANTS: Healthy subjects in three age groups (23 +/- 1, 50 +/- 1 and 76 +/- 2 y old) were given a ketogenic meal and plasma beta -hydroxybutyrate, glucose, insulin, triacylglycerols, total cholesterol, non-esterified fatty acids and breath acetone were measured over the subsequent 6 h. Each subject completed the protocol twice in order to determine the oxidation of a tracer dose of both carbon-13 (13C) glucose and 13C-beta-hydroxybutyrate. The tracers were given separately in random order. Apolipoprotein E genotype was also determined in all subjects. RESULTS: Plasma glucose decreased and beta-hydroxybutyrate, acetone and insulin increased similarly over 6 h in all three groups after the ketogenic meal. There was no significant change in cholesterol, triacylglycerols or non-esterified fatty acids over the 6 h. 13C-glucose and 13C-beta-hydroxybutyrate oxidation peaked at 2-3 h postdose for all age groups. Cumulative 13C-glucose oxidation over 24 h was significantly higher in the elderly but only versus the middle-aged group. There was no difference in cumulative 13C-beta-hydroxybutyrate oxidation between the three groups. Apolipoprotein E (epsilon 4) was associated with elevated fasting cholesterol but was unrelated to the other plasma metabolites. CONCLUSION: Elderly people in relatively good health have a similar capacity to produce ketones and to oxidize 13C-beta-hydroxybutyrate as middle-aged or young adults, but oxidize 13C-glucose a little more rapidly than healthy middle-aged adults.

Dynamics of gene expression for a hippocampal glycoprotein elevated in Alzheimer's disease and in response to experimental lesions in rat.

A hippocampal poly(A) RNA, pADHC-9, was cloned by differential screening of a human hippocampal cDNA library. By RNA blot analysis, pADHC-9 was elevated 2-fold in Alzheimer's disease hippocampus. In situ analyses identified pADHC-9 expression in pyramidal and non-pyramidal cells of the hippocampus and entorhinal cortex. Nucleotide sequence analysis identified pADHC-9 as a potential human homolog of rat sulfated glycoprotein 2 (SGP-2). SGP-2 expression increased in rat hippocampus following experimental lesions that mimic intrinsic neuronal loss and/or deafferentation. The function of pADHC-9 in brain has not been defined, but in serum, a similar protein inhibits complement-dependent cytolysis. Increased expression of pADHC-9 in Alzheimer's disease hippocampus may be a compensatory response mounted to retard a complement-driven neurodegenerative cascade.

Antitumour activity of ANG1005, a conjugate between paclitaxel and the new brain delivery vector Angiopep-2.

BACKGROUND AND PURPOSE: Paclitaxel is highly efficacious in the treatment of breast, head and neck, non-small cell lung cancers and ovarian carcinoma. For malignant gliomas, paclitaxel is prevented from reaching its target by the presence of the efflux pump P-glycoprotein (P-gp) at the blood-brain barrier. We investigated the utilization of a new drug delivery system to increase brain delivery of paclitaxel. EXPERIMENTAL APPROACH: Paclitaxel molecules were conjugated to a brain peptide vector, Angiopep-2, to provide a paclitaxel-Angiopep-2 conjugate named ANG1005. We determined the brain uptake capacity, intracellular effects and antitumour properties of ANG1005 in vitro against human tumour cell lines and in vivo in human xenografts. We then determined ANG1005 activity on brain tumours with intracerebral human tumour models in nude mice. KEY RESULTS: We show by in situ brain perfusion that ANG1005 enters the brain to a greater extent than paclitaxel and bypasses the P-gp. ANG1005 has an antineoplastic potency similar to that of paclitaxel against human cancer cell lines. We also demonstrate that ANG1005 caused a more potent inhibition of human tumour xenografts than paclitaxel. Finally, ANG1005 administration led to a significant increase in the survival of mice with intracerebral implantation of U87 MG glioblastoma cells or NCI-H460 lung carcinoma cells. CONCLUSIONS AND IMPLICATIONS: These results demonstrate the antitumour potential of a new drug, ANG1005, and establish that conjugation of anticancer agents with the Angiopep-2 peptide vector could increase their efficacy in the treatment of brain cancer.

Babinski, histologist and anatomo-pathologist.

Joseph Babinski (1857-1932), a French neurologist of Polish origin, médecin des hôpitaux de Paris, is well known for the discovery of the Sign (the toes phenomenon) which bears his name. Beyond the Sign, his semiological work in the field of neurology is also important (particularly cutaneous and osteo-tendinous reflexes, cerebellar and vestibular semiology, hysteria and pithiatism) as well as his role in the birth of the French neurosurgery. On the contrary, the implication of Babinski in pathological anatomy and histology is usually unrecognized. However, in the beginning of his career, Babinski worked as an Interne in the clinical departments of Victor Cornil (1837-1908), professor of pathological anatomy and president of the Société d'Anatomie de Paris, Alfred Vulpian (1826-1887), past professor of pathological anatomy and then professor of experimental physiology, and in the laboratory of Louis Ranvier (1835-1922), professor of general anatomy at the Collège de France. Babinski beacame préparateur at the chair of pathological anatomy, member then treasurer of the Société Anatomique, member of the Société de Biologie. He reported on several clinico-pathological observations of general pathology (liver cirrhosis, cancer of the kidney, cancer of a buttock, squamous epithelioma, tuberculosis, multiple cysts of the liver and the kidneys, bowel occlusion), of neuropathology (embolic brain softenings, hydatic cysts of the brain, multiple sclerosis, spinal cord combined sclerosis, tabetic arthropathies, adiposo-genital syndrome due to a pituitary tumor) and of human neuro-muscular histology (neuro-muscular spindles, muscular histology after nerve sectioning, diphtheria paralysis, peripheral neuritis).