PTI-125 Reduces Biomarkers of Alzheimer's Disease in Patients.

BACKGROUND: The most common dementia worldwide, Alzheimer's disease is often diagnosed via biomarkers in cerebrospinal fluid, including reduced levels of Aß1-42, and increases in total tau and phosphorylated tau-181. Here we describe results of a Phase 2a study of a promising new drug candidate that significantly reversed all measured biomarkers of Alzheimer's disease, neurodegeneration and neuroinflammation. PTI-125 is an oral small molecule drug candidate that binds and reverses an altered conformation of the scaffolding protein filamin A found in Alzheimer's disease brain. Altered filamin A links to the α7-nicotinic acetylcholine receptor to allow Aß42's toxic signaling through this receptor to hyperphosphorylate tau. Altered filamin A also links to toll-like receptor 4 to enable Aß-induced persistent activation of this receptor and inflammatory cytokine release. Restoring the native shape of filamin A prevents or reverses filamin A's linkages to the α7-nicotinic acetylcholine receptor and toll-like receptor 4, thereby blocking Aß42's activation of these receptors. The result is reduced tau hyperphosphorylation and neuroinflammation, with multiple functional improvements demonstrated in transgenic mice and postmortem Alzheimer's disease brain. OBJECTIVES: Safety, pharmacokinetics, and cerebrospinal fluid and plasma biomarkers were assessed following treatment with PTI-125 for 28 days. Target engagement and mechanism of action were assessed in patient lymphocytes by measuring 1) the reversal of filamin A's altered conformation, 2) linkages of filamin A with α7-nicotinic acetylcholine receptor or toll-like receptor 4, and 3) levels of Aß42 bound to α7-nicotinic acetylcholine receptor or CD14, the co-receptor for toll-like receptor 4. DESIGN: This was a first-in-patient, open-label Phase 2a safety, pharmacokinetics and biomarker study. SETTING: Five clinical trial sites in the U.S. under an Investigational New Drug application. PARTICIPANTS: This study included 13 mild-to-moderate Alzheimer's disease patients, age 50-85, Mini Mental State Exam ≥16 and ≤24 with a cerebrospinal fluid total tau/Aß42 ratio ≥0.30. INTERVENTION: PTI-125 oral tablets (100 mg) were administered twice daily for 28 consecutive days. MEASUREMENTS: Safety was assessed by electrocardiograms, clinical laboratory analyses and adverse event monitoring. Plasma levels of PTI-125 were measured in blood samples taken over 12 h after the first and last doses; cerebrospinal fluid levels were measured after the last dose. Commercial enzyme linked immunosorbent assays assessed levels of biomarkers of Alzheimer's disease in cerebrospinal fluid and plasma before and after treatment with PTI-125. The study measured biomarkers of pathology (pT181 tau, total tau and Aß42), neurodegeneration (neurofilament light chain and neurogranin) and neuroinflammation (YKL-40, interleukin-6, interleukin-1ß and tumor necrosis factor α). Plasma levels of phosphorylated and nitrated tau were assessed by immunoprecipitation of tau followed by immunoblotting of three different phospho-epitopes elevated in AD (pT181-tau, pS202-tau and pT231-tau) and nY29-tau. Changes in conformation of filamin A in lymphocytes were measured by isoelectric focusing point. Filamin A linkages to α7-nicotinic acetylcholine receptor and toll-like receptor 4 were assessed by immunoblot detection of α7-nicotinic acetylcholine receptor and toll-like receptor 4 in anti-filamin A immunoprecipitates from lymphocytes. Aß42 complexed with α7-nicotinic acetylcholine receptor or CD14 in lymphocytes was also measured by co-immunoprecipitation. The trial did not measure cognition. RESULTS: Consistent with the drug's mechanism of action and preclinical data, PTI-125 reduced cerebrospinal fluid biomarkers of Alzheimer's disease pathology, neurodegeneration and neuroinflammation from baseline to Day 28. All patients showed a biomarker response to PTI-125. Total tau, neurogranin, and neurofilament light chain decreased by 20%, 32% and 22%, respectively. Phospho-tau (pT181) decreased 34%, evidence that PTI-125 suppresses tau hyperphosphorylation induced by Aß42's signaling through α7-nicotinic acetylcholine receptor. Cerebrospinal fluid biomarkers of neuroinflammation (YKL-40 and inflammatory cytokines) decreased by 5-14%. Biomarker effects were similar in plasma. Aß42 increased slightly - a desirable result because low Aß42 indicates Alzheimer's disease. This increase is consistent with PTI-125's 1,000-fold reduction of Aß42's femtomolar binding affinity to α7-nicotinic acetylcholine receptor. Biomarker reductions were at least p ≤ 0.001 by paired t test. Target engagement was shown in lymphocytes by a shift in filamin A's conformation from aberrant to native: 93% was aberrant on Day 1 vs. 40% on Day 28. As a result, filamin A linkages with α7-nicotinic acetylcholine receptor and toll-like receptor 4, and Aß42 complexes with α7-nicotinic acetylcholine receptor and CD14, were all significantly reduced by PTI-125. PTI-125 was safe and well-tolerated in all patients. Plasma half-life was 4.5 h and approximately 30% drug accumulation was observed on Day 28 vs. Day 1. CONCLUSIONS: PTI-125 significantly reduced biomarkers of Alzheimer's disease pathology, neurodegeneration, and neuroinflammation in both cerebrospinal fluid and plasma. All patients responded to treatment. The magnitude and consistency of reductions in established, objective biomarkers imply that PTI-125 treatment counteracted disease processes and reduced the rate of neurodegeneration. Based on encouraging biomarker data and safety profile, approximately 60 patients with mild-to-moderate AD are currently being enrolled in a Phase 2b randomized, placebo-controlled confirmatory study to assess the safety, tolerability and efficacy of PTI-125.

GATE: a simulation toolkit for PET and SPECT.

Monte Carlo simulation is an essential tool in emission tomography that can assist in the design of new medical imaging devices, the optimization of acquisition protocols and the development or assessment of image reconstruction algorithms and correction techniques. GATE, the Geant4 Application for Tomographic Emission, encapsulates the Geant4 libraries to achieve a modular, versatile, scripted simulation toolkit adapted to the field of nuclear medicine. In particular, GATE allows the description of time-dependent phenomena such as source or detector movement, and source decay kinetics. This feature makes it possible to simulate time curves under realistic acquisition conditions and to test dynamic reconstruction algorithms. This paper gives a detailed description of the design and development of GATE by the OpenGATE collaboration, whose continuing objective is to improve, document and validate GATE by simulating commercially available imaging systems for PET and SPECT. Large effort is also invested in the ability and the flexibility to model novel detection systems or systems still under design. A public release of GATE licensed under the GNU Lesser General Public License can be downloaded at http:/www-lphe.epfl.ch/GATE/. Two benchmarks developed for PET and SPECT to test the installation of GATE and to serve as a tutorial for the users are presented. Extensive validation of the GATE simulation platform has been started, comparing simulations and measurements on commercially available acquisition systems. References to those results are listed. The future prospects towards the gridification of GATE and its extension to other domains such as dosimetry are also discussed.

[Osteoarticular brucellosis and signs of autoimmunity]. / Brucellose ostéoarticulaire et signes d'auto-immunité.

UNLABELLED: We report two cases of osteoarticular brucellosis in childhood, which illustrate the diagnostic difficulties in non-endemic areas. CASE REPORT: A 12-year-old boy was admitted for a unilateral sacroiliitis for which the brucellosis origin was established by serological and blood cultures (without fever). Autoimmunity was detected and disappeared following the treatment of the affection. A six-year-old girl was admitted for a monoarthritis of the left ankle (with fever) for which the brucellosis origin was also established by serology and blood cultures. COMMENTS: The above cases underline the importance of knowing the atypical varieties of brucellosis. The brucellosis serologies need to take part in the etiological workup of an infectious osteoarthritis when a classic infectious cause cannot be proved. Blood cultures on a specific medium are essential to carry out, even in the case of apyrexia. Finally, the possibility of autoimmunity signs for the brucellosis has to be known to avoid orientating the diagnosis towards an autoimmune systemic disease.

[Self-healing Hashimoto-Pritzker histiocytosis]. / Histocytose auto-involutive de Hashimoto-Pritzker.

UNLABELLED: Congenital 'self-healing' Langerhans' cell histiocytosis of Hashimoto-Pritzker is a rare disease occurring mainly in the neonatal period. CASE REPORT: We report on the case of a newborn with widespread eruption since birth, consisting of nodules, papulonodules, sometimes with ulcerations and scabs, concerning all the body, with a predilection for the cephalic area and the scalp, without general abnormalities. The clinical examination, histopathological data, immunohistochemistry, and the benign evolution in nine-, 18- and 24-month periods without particular treatment define the diagnosis of congenital self-healing Langerhans' cell histiocytosis of Hashimoto-Pritzker. CONCLUSION: The position of this disease among the Langherans' cell histiocytoses is probably situated at the benign pole. This is a benign self-healing disease restricted to the skin and the prognosis is good (self-involution). It is important to eliminate a malignant form of other Langerhans' cell histiocytosis such as Letterer-Siwe disease by a checkup searching for a visceral disease. The good prognosis should not lead to forget the possibility of error or forms of relapses; it is therefore imperative to have a rigorous, regular and especially long-term follow-up.

Portal vein thrombosis after splenectomy for hereditary stomatocytosis in childhood.

UNLABELLED: Portal vein thrombosis is a rare but potentially lethal complication in children requiring splenectomy. We report on a 15-year-old boy with a dehydrated hereditary stomatocytosis, who underwent splenectomy and presented a postoperative partial portal vein thrombosis. With prompt heparin therapy, neither propagation of the thrombus nor further cavernous transformation in the following occurred 6 years. CONCLUSION: Recent data suggest that hereditary stomatocytosis carries a high risk of thrombotic complications, especially after splenectomy. This procedure, the benefit of which is limited in this condition, should therefore be strongly avoided.

[Micro-morphology of the ovipositor in Hymenoptera and evolution from phytophagous Symphyta to parasitoid Apocrita]. / Micromorphologie de l'ovipositeur des hyménoptères et évolution des symphytes phytophages aux apocrites parasitoïdes.

The ovipositor of 1 Symphyta and 12 primitive parasitoid Apocrita belonging of the family of Ichneumonidae has been studied with the scanning electron microscope (SEM) and for 2 species, semi-thin sections were used. The study shows the presence of closed trachea in the 3 pairs of valvulae and a secretory system in the 2 pairs of valvulae interlocked into a piercing stylus. We discuss the role of trachea and a secretory system leading to excretory pores on the lancets of valvulae which occupy very precisely the site of sensory chemoreceptors known in more advanced species lacking this secretory system. The micromorphological data support the phylogeny within Hymenoptera, from Symphyta to primitive parasitoid Apocrita.

Readthrough transcription occurs at the rho dependent signal F1 TIV in suppressor cells.

Suppressor cells infected with bacteriophage f1 yield phage encoded gene IV transcripts longer than those present in the supo host and identical to those found in a rho- host. However, such longer transcripts do not appear in the suppressor-infected cell when, by changing the translation frame of gene IV, the ribosome is not allowed to proceed to the end of the gene IV message and thus to reach the rho dependent transcription terminator f1 TIV. This suggests that ribosome movement beyond the natural gene IV stop codon disturbs the activity of that termination signal. In contrast to the rho- behaviour, the suppressor does not accumulate high levels of gene IV messages indicating that the accumulation occurring in the rho- mutant may not be a primary effect of the readthrough per se.

[Necrotizing enteritis during the therapeutic induction phase in leukemia. Value of surgical treatment]. / Entérite nécrosante à la phase d'induction thérapeutique d'une leucémie. Intérêt du traitement chirurgical.

A case of typhlitis in a 3,5 year old girl, during induction therapy for acute lymphoblastic leukemia is reported. This typhlitis, or necrotizing enterocolitis involving the coecum and right colon resulted in stercoral peritonitis during the neutropenic phase. After surgery, the patient had a favorable outcome with complete recovery. Knowledge about this uncommon but severe complication of hemopathies leads to follow clinical, microbiologic and radiologic rules of prophylaxis and screening. Typhlitis requires early treatment by supportive care and surgical cure if necessary.

[Myocardial infarction, an unrecognized complication of Behçet's disease?]. / L'infarctus du myocarde, complication méconnue de la maladie de Behçet?

It the vascular complications of Behcet's disease, especially thrombophlebitis, are well known, coronary involvement in seldom described (less than ten cases in the literature). The two cases reported here, of patients under 45, having presented both a myocardial infarction confirmed by coronary arteriography, lead to bring up first the problem of the causal relationship between disease and necrosis (inflammatory syndrome, thrombogenic tendency, vasospastic aspect), to reach a preventive attitude with, firstly, and extended use of anticoagulants in patients severely affected, in evolutive outbreaks, and then with the easier indication of anti-spastic treatments, mostly calcium blockers.

First experimentation of the Spartacus telethesis in a clinical environment.

A prototype 'telethesis', a telemanipulator for high level tetraplegic and similarly disabled persons, has been developed in the French Spartacus project. The system has a modular control structure, both in the choice of transducers and in the microprocessor programmes assuring the ergonomic link with the individual user. A special training procedure has been developed and tested both in the laboratory and in the hospital. Six tetraplegic patients have used the system in the laboratory and seven in hospital. The experience of 6 months of experimentation in the occupational therapy department with the seven patients is reported. The telethesis has been well accepted by four of them, two of whom have used it for prolonged periods of time. One case has not been adapted with great success prior to his departure, and in two others the use of the system has been rejected, largely for psychological reasons.

Sindrome de Cushing cinquenta anos depois. (157 refs.). / Cushing syndrome, 50 years latter

Neste quinquagesimo aniversario do trabalho classico de Harvey Cushing - "The Basophil Adenomas of the Pituitary Body and their Clinical Manifestations(pituitary basophilism)", Bull. Johns Hopk. Hosp. 50:137-95, 1932 -, os autores revisam os principais aspectos desta entidade, assim como das sindromes de Cushing adrenal e ectopica. Particular destaque e conferido a etiopatogenia da sindrome de Cushing hipotalamo-hipofisaria (SCHH) com discussao das hipoteses etiologicas disponiveis. A introducao do novo conceito de displasia nodular primaria (DNP) individualiza melhor e torna mais homogeneo o grupo das hiperplasias macro e micronodulares. As repercussoes do hipercortisolismo endogeno sobre o metabolismo dos carboidritos, lipidos e proteinas e sobre as funcoes organicas sao comentadas, assim como o valor relativo das dosagens hormonais, testes e demais exames laboratoriais, para o diagnostico diferencial das sindromes de Cushing. Finalmente, os autores confrontam os muitos tratamentos, quimioterapicos, radioterapicos e cirurgicos disponiveis para a SCHH e analisam a eficacia, indicacoes, vantagens e inconvenientes de cada um

[Variation in high density lipoprotein cholesterol during treatment of thyroid gland diseases]. / Variations des taux plasmatiques de cholestérol porté par les lipoprotéines de haute densité au cours du traitement des dysthryoïdies.

Serum cholesterol concentration is usually increased in primary hypothyroidism and decreased in hyperthyroidism. The role of hypercholesterolemia in hypothyroidism as a causal factor for coronary atherosclerosis has been extensively discussed. Epidemiologic studies have stablished that there is a very strong negative correlation between plasma HDL cholesterol levels and coronary atherosclerosis. Plasma concentration of HDL cholesterol was determined in 36 controls after separation of HDL from other lipoproteins by ultracentrifugation (uc), by precipitation by heparin-manganese chloride (hmc) and by phosphotungstate magnesium chloride (pmc). The recovery of HDL after both precipitations was almost 100% as shown by HDL immunoassay (kit Behring). There was a very strong correlation between cholesterol HDL values obtained by uc and hmc (r = 0.91) and by uc and pmc (r = 0.90). Normal values were 1.22 +/- 0.27 mmol/1 (mean +/- SD) in males and 1.57 +/- 0.31 mmol/L in females. We have measured HDL cholesterol by both precipitation technics in 17 hypothyroid patients before and under treatment for at least 2 months. Plasma total cholesterol levels were 7.01 +/- 2.61 mmol/1 before and 4.94 +/- 0.85 mmol/1 after treatment (p < 0.001); in contrast plasma HDL cholesterol did not change (1.29 +/- 0.33 vs 1.28 +/- 0.38 mmol/1). In 11 hyperthyroid patients plasma total cholesterol was 4.14 +/- 1.03 before and 5.74 +/- 0.88 mmol/l after recovery (p < 0.001). The mean plasma HDL cholesterol did not change (1.43 +/- 0.23 vs 1.59 +/- 0.42 mmol/1). However, 5 out of 11 patients had an increase of more than 10% of the plasma HDL cholesterol levels.

[Enzymatic characteristics of the catalytic subunit of the protein kinase complex of human lymphocytes]. / Caractéristiques enzymatiques de la sous-unité catalytique dans le complexe de la protéine-kinase du lymphocyte humain

In earlier reports we have shown the existence in human lymphocytes homogenate, of a cyclic-AMP dependent protein-kinase activity. We demonstrate by affinity chromatography that two subunits display respectively cyclic-AMP binding and phosphorylating properties. Divalent cations such as Ca++, Mg++ or Mn++ are required for enzymatic activity. ATP which is an obligatory cosubstrate acts as an inhibitor when its concentration is higher than 10(-6)M.

[Identification of cAMP dependant protein kinases in human lymphocytes]. / Identification dans le lymphocyte humain, de protéine-kinases modulées par l'AMP-3',5'-phosphodiester

Chromatographic purification by "DEAE" cellulose resolves the cAMP binding proteins in human lymphocytes into three parts. In presence of Mg++ each one possesses cAMP dependent protein-kinase activity, one of them showing allosteric characteristics.