An anemia of Alzheimer's disease.

Lower hemoglobin is associated with cognitive impairment and Alzheimer's disease (AD). Since brain iron homeostasis is perturbed in AD, we investigated whether this is peripherally reflected in the hematological and related blood chemistry values from the Australian Imaging Biomarker and Lifestyle (AIBL) study (a community-based, cross-sectional cohort comprising 768 healthy controls (HC), 133 participants with mild cognitive impairment (MCI) and 211 participants with AD). We found that individuals with AD had significantly lower hemoglobin, mean cell hemoglobin concentrations, packed cell volume and higher erythrocyte sedimentation rates (adjusted for age, gender, APOE-ɛ4 and site). In AD, plasma iron, transferrin, transferrin saturation and red cell folate levels exhibited a significant distortion of their customary relationship to hemoglobin levels. There was a strong association between anemia and AD (adjusted odds ratio (OR)=2.43, confidence interval (CI) (1.31, 4.54)). Moreover, AD emerged as a strong risk factor for anemia on step-down regression, even when controlling for all other available explanations for anemia (adjusted OR=3.41, 95% CI (1.68, 6.92)). These data indicated that AD is complicated by anemia, which may itself contribute to cognitive decline.

Associations between gonadotropins, testosterone and ß amyloid in men at risk of Alzheimer's disease.

Testosterone and gonadotropins have been associated with cognitive decline in men and the modulation of ß amyloid (Aß) metabolism. The relatively few studies that have investigated whether changes in one or a combination of these hormones influence Aß levels have focused primarily on plasma Aß(1-40) and not on the more pathogenic Aß(1-42). Currently, no study has investigated whether these hormones are associated with an increase in brain amyloid deposition, ante mortem. Through the highly characterised Australian imaging, biomarkers and lifestyle study, we have determined the impact of these hormones on plasma Aß levels and brain amyloid burden (Pittsburgh compound B (PiB) retention). Spearman's rank correlation and linear regression analysis was carried out across the cohort and within subclassifications. Luteinizing hormone (LH) was the only variable shown, in the total cohort, to have a significant impact on plasma Aß(1-40) and Aß(1-42) levels (beta=0.163, P<0.001; beta=0.446, P<0.001). This held in subjective memory complainers (SMC) (Aß(1-40); beta=0.208, P=0.017; Aß(1-42); beta=0.215, P=0.017) but was absent in mild cognitive impairment (MCI) and Alzheimer's disease (AD) groups. In SMC, increased frequency of the APOE-ɛ4 allele (beta=0.536, P<0.001) and increasing serum LH levels (beta=0.421, P=0.004) had a significant impact on PiB retention. Whereas in MCI, PiB retention was associated with increased APOE-ɛ4 allele copy number (beta=0.674, P<0.001) and decreasing calculated free testosterone (beta=-0.303, P=0.043). These findings suggest a potential progressive involvement of LH and testosterone in the early preclinical stages of AD. Furthermore, these hormones should be considered while attempting to predict AD at these earliest stages of the disease.

A blood-based predictor for neocortical Aß burden in Alzheimer's disease: results from the AIBL study.

Dementia is a global epidemic with Alzheimer's disease (AD) being the leading cause. Early identification of patients at risk of developing AD is now becoming an international priority. Neocortical Aß (extracellular ß-amyloid) burden (NAB), as assessed by positron emission tomography (PET), represents one such marker for early identification. These scans are expensive and are not widely available, thus, there is a need for cheaper and more widely accessible alternatives. Addressing this need, a blood biomarker-based signature having efficacy for the prediction of NAB and which can be easily adapted for population screening is described. Blood data (176 analytes measured in plasma) and Pittsburgh Compound B (PiB)-PET measurements from 273 participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study were utilised. Univariate analysis was conducted to assess the difference of plasma measures between high and low NAB groups, and cross-validated machine-learning models were generated for predicting NAB. These models were applied to 817 non-imaged AIBL subjects and 82 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) for validation. Five analytes showed significant difference between subjects with high compared to low NAB. A machine-learning model (based on nine markers) achieved sensitivity and specificity of 80 and 82%, respectively, for predicting NAB. Validation using the ADNI cohort yielded similar results (sensitivity 79% and specificity 76%). These results show that a panel of blood-based biomarkers is able to accurately predict NAB, supporting the hypothesis for a relationship between a blood-based signature and Aß accumulation, therefore, providing a platform for developing a population-based screen.

Collateral Sensitivity to ß-Lactam Drugs in Drug-Resistant Tuberculosis Is Driven by the Transcriptional Wiring of BlaI Operon Genes.

The evolution of resistance to one antimicrobial can result in enhanced sensitivity to another, known as "collateral sensitivity." This underexplored phenomenon opens new therapeutic possibilities for patients infected with pathogens unresponsive to classical treatments. Intrinsic resistance to ß-lactams in Mycobacterium tuberculosis (the causative agent of tuberculosis) has traditionally curtailed the use of these low-cost and easy-to-administer drugs for tuberculosis treatment. Recently, ß-lactam sensitivity has been reported in strains resistant to classical tuberculosis therapy, resurging the interest in ß-lactams for tuberculosis. However, a lack of understanding of the molecular underpinnings of this sensitivity has delayed exploration in the clinic. We performed gene expression and network analyses and in silico knockout simulations of genes associated with ß-lactam sensitivity and genes associated with resistance to classical tuberculosis drugs to investigate regulatory interactions and identify key gene mediators. We found activation of the key inhibitor of ß-lactam resistance, blaI, following classical drug treatment as well as transcriptional links between genes associated with ß-lactam sensitivity and those associated with resistance to classical treatment, suggesting that regulatory links might explain collateral sensitivity to ß-lactams. Our results support M. tuberculosis ß-lactam sensitivity as a collateral consequence of the evolution of resistance to classical tuberculosis drugs, mediated through changes to transcriptional regulation. These findings support continued exploration of ß-lactams for the treatment of patients infected with tuberculosis strains resistant to classical therapies. IMPORTANCE Tuberculosis remains a significant cause of global mortality, with strains resistant to classical drug treatment considered a major health concern by the World Health Organization. Challenging treatment regimens and difficulty accessing drugs in low-income communities have led to a high prevalence of strains resistant to multiple drugs, making the development of alternative therapies a priority. Although Mycobacterium tuberculosis is naturally resistant to ß-lactam drugs, previous studies have shown sensitivity in strains resistant to classical drug treatment, but we currently lack understanding of the molecular underpinnings behind this phenomenon. We found that genes involved in ß-lactam susceptibility are activated after classical drug treatment resulting from tight regulatory links with genes involved in drug resistance. Our study supports the hypothesis that ß-lactam susceptibility observed in drug-resistant strains results from the underlying regulatory network of M. tuberculosis, supporting further exploration of the use of ß-lactams for tuberculosis treatment.

Length-dependent degeneration of fibers in Portuguese amyloid polyneuropathy: a clinicopathologic study.

We investigated two patients with Portuguese amyloid polyneuropathy to learn more about the role played by amyloid in this condition. In sural nerves, axonal loss predominated in unmyelinated axons. Different abnormalities of single fibers near amyloid deposits included distortion of the myelin sheath, segmental demyelination, and wallerian degeneration. Electronmicroscopic studies showed degenerative changes of endoneurial cells in contact with fibrils of amyloid. Therefore, amyloid plays an important role in the length-dependent degeneration of fibers of this condition. Why unmyelinated fibers are so heavily affected remains unclear.

[Unilateral involvement of IX, X, Xi and XII in cervical zoster. Cranial nerve contribution to vascular pathology]. / Atteinte unilaterale des IX, X, XI et XII au cours d'un zona cervical. Contribution à la pathologie vasculaire des nerfs crâniens.

The authors report a case of a cervical zoster (C2 - C4) with unilateral involvement of the IXth, Xth, XIth and XIIth cranial nerves. Angiography failed to opacify the ascending pharyngeal artery on the same side, presumably because of a thrombosis secondary to the zoster infection. As the ascending pharyngeal artery is known to supply the last four cranial nerves, this study should be seen as a further example of the varied cranial nerve involvement which may arise on a vascular basis.

[Diffuse bone metastases revealing pleural mesothelioma. Case report]. / Métastases osseuses diffuses révélatrices d'un mésothéliome pleural. Rapport d'un cas.

A 76 year old man, presenting with symptoms of general malaise alone, had a marrow biopsy which showed and undifferentiated carcinoma. A subsequent autopsy revealed a multi-nodular pleural mesothelioma, which was not seen radiologically, presumably because of the small size of the nodule. There were bilateral adrenal metastases and diffuse bony metastases involving the marrow. An occupational contact with asbestos was retrospectively confirmed. It is rare that a pleural mesothelioma does not exhibit thoracic signs and very uncommon that bony metastases should give the diagnosis in such a tumour.

[Spontaneous hemarthrosis in adolescents and adults, excluding hemophilia]. / Hémarthroses spontanées de l'adolescent et de l'adulte, en dehors de l'hémophilie.

The various etiologies of spontaneous hemarthrosis in adolescents and adults are reviewed: they include systemic diseases and local or regional disorders of the bones or joints. Among systemic diseases, the two main causes are coagulation disorders and hemoglobinopathies. Coagulation disorders may be either acquired (leukemia, thrombopenia, and hypoprothrombinemia induced by anticoagulant drugs with hemarthrosis being one of the major complications) or inherited (hemophilia which is not considered here, von Willebrand disease, and congenital thrombopathies). Hemoglobinopathies, particularly sickle-cell disease, are responsible for hemarthrosis in a few patients. Among local or regional disorders of the bones or joints, tumors such as hemangioma or synovial sarcoma are uncommon causes. Hemarthrosis is the main feature of pigmented villonodular synovitis. Hemarthrosis may occur in degenerative and metabolic diseases: while it is extremely rare in arthritis, it is frequently encountered in articular chondrocalcinosis which is the first diagnosis to consider when hemarthrosis occurs in an elderly patient. The search for an etiology, which is often difficult, should include a review of prior illnesses, a study of coagulation, and local clinical, radiological and biological investigations, with a study of the synovial fluid; in some instances, arthroscopy, synovial biopsy and even surgical exploration are required. Management includes rest, analgesics, antiinflammatory drugs and, above all, arthrocentesis which is essential for the prevention of articular damage and functional sequellae. Specific therapy is dependent on the etiology. In recurrent hemarthrosis, isotopic synoviorthesis may ensure lasting resolution of the effusion.

[Sarcoidosis and hyperthyroidism (author's transl)]. / Sarcoidose et hyperthyroidie.

The authors report the case of a 31-year-old man with thyrotoxicosis which occurred four months after the discontinuation of long-term corticosteroid therapy for sarcoidosis. Clinical and biological features of thyrotoxicosis were reversible when corticosteroid therapy was reinstated. A review of 27 cases from the literature provides the opportunity to recall the characteristic features of hyperthyroidism associated with sarcoidosis: female prevalence, usual presence of sarcoidosis at onset, secondary occurrence of hyperthyroidism, necessity for simultaneous treatment of both diseases, since corticosteroid therapy alone is infrequently sufficient.

[Inflammatory arthritis and osteoarthritis in palmoplantar pustulosis. Case report and review of the literature]. / Arthrites et ostéoarthrites inflammatoires au cours de pustulose palmo-plantaire.

The case of a 46-year-old woman, who had pustulosis palmaris three years ago, and who has been experiencing inflammatory arthritis of the manubriosternal joint for two years with intermittent exacerbations, is reported. The negative bacteriologic investigations and the failure of antibiotic therapy have established that the condition is aseptic. Among patients with a history of palmo-plantar pustulosis, approximately 10% have aseptic inflammatory arthritis or osteitis, most commonly in the anterior chest wall. Other sites are the sacroiliac joints and the spine, where radiological features mimic ankylosing spondylitis, and peripheral joints. Laboratory anomalies are not specific, and HLA B27 antigen is not associated with this syndrome. The course of the arthritis, with exacerbations and remissions, is generally benign. The relationship of this syndrome to psoriatic arthritis is unclear. Non-steroidal antirheumatic drugs are the most effective agents.

The urban cowboy syndrome.

We describe the cases of 20 patients who received injuries while falling from mechanical bulls. Injuries were received in three ways: 1) from striking the ground; 2) from striking the bull or getting caught on the bull; and 3) from the concussion caused by bucking. The severity of injury ranged from minor sprains to thumb fractures and lumbar vertebral fractures. The patients presented with three things in common: 1) they had (with one exception) no previous bull-riding experience; 2) they had consumed alcohol; and 3) they had suffered an orthopedic injury. We have chosen to call this manifestation the Urban Cowboy Syndrome.

[T lymphocytes functions in mercuric chloride-induced membranous glomerulonephritis in man. Evidence for a defect of presentation of the histocompatibility class II molecules at the cell surface (author's transl)]. / Fonctions lymphocytaires T au cours d'une glomérulonéphrite extramembraneuse induite par une intoxication chronique au mercure.

Membranous glomerulonephritis (MGN) is one of the well documented manifestations of autoimmunity during chronic mercuric chloride (HgCl2) intoxication. We have carried out immunological investigation of the T cell functions in a patient presenting an HgC12-induced MGN. Circulating auto-antibodies and immune complexes were absent from the serum. Lymphocyte transformation with HgCl2 over a wide range of doses (10(-3) to 10(-8) M) was negative. E rosettes, mitogen reactivity, allogeneic reactivity evidenced by a one way mixed lymphocyte culture gave slightly diminished results. These findings contrasted with a severe impairment of the stimulative ability of lymphocytes. This defect might be related to the inability of D, DR products to be exposed at the cell surface and impeding the allogeneic recognition by foreign lymphocytes. This lymphocyte defect in the course of an HgC12 MGN in man would be correlated with lymphocyte abnormalities found in experimental HgC12-treated rats. The results of this study would favour the hypothesis of a direct role of HgC12 on lymphocyte rather than a direct action on glomerular basement membrane.

[Nail pigmentation during therapy with cyclophosphamide and doxorubicin]. / Pigmentation unguéale au cours de traitements par cyclophosphamide et doxorubicine.

Two patients under cytotoxic therapy developed pigmentation of their fingernails. The first, under doxorubicin and cyclophosphamide for lymphoma, had horizontal streaks, while the second, under cyclophosphamide for periarteritis nodosa, exhibited diffuse pigmentation. Nail pigmentation, which occurs after an interval of some weeks or months, varies from diffuse to horizontal or longitudinal streaks. Reversal of nail pigmentation some months after withdrawal of the drug is usual. Skin or mucous membrane pigmentation may coexist. The mechanism of pigmentation remains obscure. These changes are observed more frequently in black than in white patients. In some instances, they have been recorded in several members of the same family.

[Esophageal fistulas in mediastinal tuberculous adenopathies in adults]. / Les fistules oesophagiennes des adénopathies médiastinales tuberculeuses de l'adulte.

An adenopathy perforated into the esophagus in a thirty-two-year old woman from black Africa with mediastinal and abdominal tuberculous adenopathies. The fistula was disclosed upon endoscopic examination in the absence of esophageal symptoms. The characteristics of such fistulas are recalled: location in the middle third of the esophagus, inconspicuousness of symptoms, scarcity of complications among which digestive hemorrhage is the most significant, usually favorable course under medical management alone. The latency of fistulas between tuberculous adenopathies and the esophagus warrants routine fiberoptic endoscopy in patients with mediastinal tuberculous adenopathies.

The peripheral neuropathy of necrotizing arteritis: a clinicopathological study.

We have reviewed the clinical and morphological data from 100 patients with necrotizing arteritis in muscle and/or in nerve samples taken by biopsy. The neuropathy occurred in the context of a multisystem disorder (Group 1) or in apparent isolation (Group 2). The average age of patients was 59 in Group 1 and 61 in Group 2. Females were more commonly affected than males, especially in the first group. Necrotizing arteritis complicated the course of rheumatoid arthritis in 25 patients. In 3 patients necrotizing arteritis was associated with infection with the human immunodeficiency virus, the agent of AIDS. Tests for hepatitis B surface antigen were positive in 19 patients. Mononeuritis was present in 13, mononeuritis multiplex in 62, and distal symmetrical sensory or sensorimotor neuropathy in 19 patients. In both groups of patients, the muscle biopsy was more frequently diagnostic for arteritis than was the nerve biopsy (80% versus 55%). The average incidence of isolated fibers undergoing axonal degeneration was 64.8%; that of demyelinated/remyelinated fibers was 1.9%. We conclude that the combination of nerve and muscle sampling increases the chance of visualizing characteristic arterial lesions in vasculitic neuropathy.

[Yellow-nail syndrome. Review of the literature apropos of 2 cases associated with cancer]. / Syndrome des ongles jaunes. Revue de la littérature à propos de deux cas associés à un cancer.

Two cases of "yellow-nail syndrome" are reported: in the first, nail changes began eight months after the diagnosis of a breast cancer; in the second, yellow dystrophic nails were associated with hypertrophic osteoarthropathy due to pleuro-pulmonary metastatic lesions. Clinical features are described: characteristic nail changes, lymphoedema, pleural effusions, and, often bronchopulmonary infections and sinusitis. Various combinations are seen, and the time between the development of the different manifestations may vary from several months to many years. Among associated diseases, immunological changes and malignancy are emphasized. The pathogenesis remains obscure. Accurate part taken by lymphoedema, immunological changes, is unknown, and the relationships between "yellow-nail syndrome" and malignancy are still uncertain.