Immunomodulation profile of the biosimilar trastuzumab MYL-1401O in a bioequivalence phase I study.

The initial Phase-I single centre, single dose, randomized, double-blind, cross-over study was planned to assess the pharmacokinetic and pharmacodynamic bioequivalence of the trastuzumab biosimilar (MYL-1401O) compared to the reference Herceptin®. Their respective immunomodulation profile presented in this paper involved healthy males receiving a single infusion of both monoclonals, separated by a washout period. Sixty parameters were assessed in total, including serum cytokines, peripheral mononuclear cell (PBMC) subsets, cell activation and response to recall antigens and mitogen, pre- and post- infusion, as well as a cytokine release assay (CRA) at baseline. Trastuzumab infusion induced a transient and weak peak of serum IL-6 at 6 h, and a modulation of mononuclear cell subset profile and activation level, notably CD16 + cells. Except for CD8 + T cells, there were no significant differences between Herceptin® and MYL-1401O. In CRA, PBMC stimulated with MYL-1401O or Herceptin® similarly secreted IL-6, TNF-α, IL-1ß, GM-CSF, IFN-γ, and IL-10, but no or low level of IL-2. Interestingly, some observed adverse events correlated with IL-2 and IFN-γ in CRA. MYL-1401O exhibited a very similar immunomodulation profile to Herceptin®, strongly supporting its bioequivalence. This approach may thus be included in a proof-of-concept study. CRA may be used as a predictive assay for the evaluation of clinical monoclonals.

Phase II trial of modified FOLFOX6 and erlotinib in patients with metastatic or advanced adenocarcinoma of the oesophagus and gastro-oesophageal junction.

BACKGROUND: There is increased recognition that cancers of the upper GI tract comprise distinct epidemiological and molecular entities. Erlotinib has shown activity in patients with adenocarcinoma of the oesophagus/gastro-oesophageal junction (GEJ), but not in distal gastric cancer. mFOLFOX6 is one of several active regimens used to treat adenocarcinoma of the Eso/GEJ. This study evaluates the efficacy and safety of mFOLFOX6 and erlotinib in patients with metastatic or advanced Eso/GEJ cancers. METHODS: Patients with previously untreated advanced or metastatic Eso/GEJ adenocarcinoma are treated with oxaliplatin 85 mg m(-2), 5-FU 400 mg m(-2), LV 400 mg m(-2) on day 1, 5-FU 2400 mg m(-2) over 48 h and erlotinib 150 mg PO daily. Treatment was repeated every 14 days. The primary objective was response rate (RR), secondary objectives include toxicity, progression-free survival (PFS), overall survival (OS) and to correlate clinical outcome with expression patterns and molecular alterations in the epidermal growth factor receptor-dependent pathways. RESULTS: A total of 33 patients were treated and evaluable: there were two complete responses, 15 partial responses for an objective RR of 51.5% (95% CI, 34.5-68.6%). Median PFS was 5.5 months (95% CI, 3.1-7.5 months) and median OS was 11.0 months (95% CI, 8.0-17.4 months). The most common grade 3-4 toxicities were: diarrhoea (24%), nausea/vomiting (11%), skin rash (8%) and peripheral neuropathy (8%). The frequency of alterations was KRAS mutations (8%), EGFR mutations (0%) and HER2 amplification (19%). CONCLUSION: In patients with Eso/GEJ adenocarcinoma, mFOLFOX6 and erlotinib is active, has an acceptable toxicity profile and FOLFOX ± erlotinib could be considered for further development.

Autophagy as a common pathway in amyotrophic lateral sclerosis.

Age-dependent neurodegenerative diseases are associated with a decline in protein quality control systems including autophagy. Amyotrophic lateral sclerosis (ALS) is a motor neuron degenerative disease of complex etiology with increasing connections to other neurodegenerative conditions such as frontotemporal dementia. Among the diverse genetic causes for ALS, a striking feature is the common connection to autophagy and its associated pathways. There is a recurring theme of protein misfolding as in other neurodegenerative diseases, but importantly there is a distinct common thread among ALS genes that connects them to the cascade of autophagy. However, the roles of autophagy in ALS remain enigmatic and it is still unclear whether activation or inhibition of autophagy would be a reliable avenue to ameliorate the disease. The main evidence that links autophagy to different genetic forms of ALS is discussed.

[Problem Of Diabetic Foot Amputations]. / ProbléMatique Des Amputations Du Pied Diabétique.

INTRODUCTION: The diabetic foot wound is a real public health problem, 10% of the reasons for hospitalization. The risk of amputation is 10 to 30 times higher in diabetics than the general population. OBJECTIVE: To study the problem of amputations of the diabetic foot. METHOD: This was a descriptive and cross-sectional study that took place in the Department of Medicine and Endocrinology of the Mali Hospital from July 1st, 2016 to June 30th, 2017. RESULTS: Twenty-five (25) diabetic patients were enrolled in our study. The sex ratio was 0.66. At admission, 100% of our patients had arterial disease, 96% neuropathy, and mixed foot in 80%. Poor glycemic control in 64% of patients; osteitis in 52% of cases; 92% of the patients had a 100% amputation risk according to the University of Texas classification. Nearly half or 46% of patients had amputations in the leg. We recorded 1 death case that is 4%. CONCLUSION: The problem of amputation of diabetic feet is a function of the poor equilibrium and progressive neurological and vascular complications of diabetes.

INTRODUCTION: La plaie du pied diabétique constitue un réel problème de santé publique, 10% des motifs d'hospitalisation. Le risque d'amputation est de 10 à 30 fois plus élevé chez les diabétiques que la population générale. OBJECTIF: Etudier la problématique des amputations du pied diabétique. MÉTHODE: II s'agissait d'une étude descriptive et transversale qui s'est déroulée dans le service de médecine et d'endocrinologie de l'hôpital du Mali du 1er Juillet 2016 au 30 Juin 2017. RÉSULTATS: Vingt-cinq (25) patients diabétiques ont été recrutés dans notre étude. Le sex ratio était de 0,66. A l'admission, 100% de nos patients avaient une artériopathie, 96% une neuropathie, et un pied mixte dans 80%. Un mauvais équilibre glycémique chez 64% des patients ; l'ostéite dans 52% des cas; 92% des patients avaient un risque d'amputation à 100% selon la classification de l'université du Texas. Près de la moitié soit 46% des patients ont été amputé au niveau de la jambe. Nous avons enregistré 1 cas de décès soit 4%. CONCLUSION: La problématique de l'amputation des pieds diabétiques est fonction du mauvais équilibre et des complications évolutives neurologiques et vasculaires du diabète.

[Appendiceal Duplication In A Patient Operated For Chilled Appendix Breastplate At Gao Regional Hospital]. / Duplication Appendiculaire Chez Une Patiente Operee Pour Plastron Appendiculaire Refroidi A L'Hopital Regional De Gao, A Propos D'Un Cas.

Appendiceal duplication is the very rare malformation. It was first described by Picoli in 1892. It is a condition that is most often seen in the first years of life, sometimes some forms may remain asymptomatic and only occur in adulthood. We report the case of appendiceal duplication in a patient operated for chilled appendix breastplate at Gao Regional Hospital. CONCLUSION: appendiceal duplication is a rare abnormal abnormality of intraoperative discovery in general. Each surgeon must think about it during an appendectomy.

La duplication appendiculaire est une malformation très rare. Elle a été décrite pour la première fois par Picoli en 1892. C'est une affection qui se manifeste le plus souvent dans les premières années de vie, parfois certaines formes peuvent rester asymptomatiques et ne s'expriment qu'à l'âge adulte. Nous rapportons le cas de duplication appendiculaire chez une patiente opérée pour plastron appendiculaire refroidi à l'hôpital régional de Gao. CONCLUSION: la duplication appendiculaire est une anomalie malformative rare de découverte per opératoire en général. Chaque chirurgien doit y penser au cours d'une appendicectomie.

Age-related mutations and chronic myelomonocytic leukemia.

Chronic myelomonocytic leukemia (CMML) is a hematologic malignancy nearly confined to the elderly. Previous studies to determine incidence and prognostic significance of somatic mutations in CMML have relied on candidate gene sequencing, although an unbiased mutational search has not been conducted. As many of the genes commonly mutated in CMML were recently associated with age-related clonal hematopoiesis (ARCH) and aged hematopoiesis is characterized by a myelomonocytic differentiation bias, we hypothesized that CMML and aged hematopoiesis may be closely related. We initially established the somatic mutation landscape of CMML by whole exome sequencing followed by gene-targeted validation. Genes mutated in ⩾10% of patients were SRSF2, TET2, ASXL1, RUNX1, SETBP1, KRAS, EZH2, CBL and NRAS, as well as the novel CMML genes FAT4, ARIH1, DNAH2 and CSMD1. Most CMML patients (71%) had mutations in ⩾2 ARCH genes and 52% had ⩾7 mutations overall. Higher mutation burden was associated with shorter survival. Age-adjusted population incidence and reported ARCH mutation rates are consistent with a model in which clinical CMML ensues when a sufficient number of stochastically acquired age-related mutations has accumulated, suggesting that CMML represents the leukemic conversion of the myelomonocytic-lineage-biased aged hematopoietic system.

Percutaneous screw fixation or cast immobilization for nondisplaced scaphoid fractures.

BACKGROUND: Nondisplaced scaphoid fractures treated with prolonged cast immobilization may result in temporary joint stiffness and muscle weakness in addition to a delay in return to sports or work. Fixation of scaphoid fractures with a percutaneous cannulated screw has resulted in a shorter time to union and to return to work or sports. The purpose of this prospective, randomized study was to compare cast immobilization with percutaneous cannulated screw fixation of nondisplaced scaphoid fractures with respect to time to radiographic union and to return to work. METHODS: Twenty-five full-time military personnel with an acute nondisplaced fracture of the scaphoid waist consented to be randomized to either cast immobilization or fixation with a percutaneous cannulated Acutrak screw (Acumed, Beaverton, Oregon) for the purpose of this study. Time to fracture union, wrist motion, grip strength, and return to work as well as overall patient satisfaction at the time of a two-year follow-up were evaluated. RESULTS: Eleven patients were randomized to percutaneous cannulated screw fixation, and fourteen were randomized to cast immobilization. The average time to fracture union in the screw fixation group was seven weeks compared with twelve weeks in the cast immobilization group (p = 0.0003). The average time until the patients returned to work was eight weeks compared with fifteen weeks in the cast immobilization group (p = 0.0001). There was no significant difference in the range of motion of the wrist or in grip strength at the two-year follow-up evaluation. Overall patient satisfaction was high in both groups. CONCLUSIONS: Percutaneous cannulated screw fixation of nondisplaced scaphoid fractures resulted in faster radiographic union and return to military duty compared with cast immobilization. The specific indications for and the risks and benefits of percutaneous screw fixation of such fractures must be determined in larger randomized, prospective studies.

Sensitivity of the erythrocyte membrane bilayer to subhemolytic mechanical trauma as detected by fluorescence anisotropy.

Exposure of human erythrocytes to subhemolytic shear stress is known to cause lipid loss and ion fluxes across the red cell membrane and to result in decreased filterability of suspensions of these cells. Damage to the lipid bilayer of traumatized erythrocytes has been examined by fluorescence anisotropy using the probe 1,6-diphenylhexatriene. Because literature methods for the introduction of the probe damaged the cells, a gentler method was developed using liposomes. Significant disruption of the lipid bilayer following subhemolytic trauma was detected by a decreased anisotropy of the membrane-bound fluorescent probe after stress.

T incision for exposure of the distal radius and wrist.

A retrospective review of 66 T-shaped incisions for exposure of the dorsal distal radius and wrist was performed. The incision provided excellent exposure in all cases and no additional incisions were required. Cosmesis was considered acceptable by all patients. Complications occurred in 6% and were more likely in patients undergoing fixation of acute distal radius fractures using Kirschner wires which protruded through the skin flaps.

Humeral shaft nonunions treated with fibular allograft and compression plating.

The present study is a retrospective review of the treatment of 12 humeral shaft nonunions by using an intramedullary allograft with compression plating. The average age of the patients was 61 years (range, 36-82 years). Eight cases involved the proximal shaft, 3 cases were at the mid-diaphyseal level, and 1 case was at the distal one third. Follow-up averaged 30 months (range, 12-96 months). Ten patients (83%) went on to uneventful healing at an average of 3 months after surgery. Two failures involving patients with multiple medical conditions occurred secondary to reinjury. Two cases of postoperative radial nerve neuropraxia involved the posterior approach to the humerus. Each resolved with no long-term residual morbidity. One patient developed postoperative adhesive capsulitis of the shoulder that resolved with nonoperative treatment. We feel that a fibular allograft, along with compression plating, can give satisfactory results for humeral shaft nonunions. This technique can be especially helpful in proximal humeral nonunions and in nonunions involving osteoporotic bone. Patients with multiple medical problems at risk for refalls should be protected until complete healing has occurred.

[Upper gastrointestinal endoscopy during Kaposi's sarcoma to the Point G Hospital, Bamako (Mali): case study 20]. / Endoscopie Digestive Haute Au Cours De La Maladie De Kaposi Au CHU Du Point G, Bamako(Mali) : Etude De 20 Cas.

INTRODUCTION: Since the advent of HIV, Kaposi's sarcoma has become one of the most common opportunistic infections and the first cancer in patients with HIV. This cancerous disease occurs most often on the skin but also the viscera. Digestive localization was often observed during the search for other locations before the cutaneous form. No studies in Mali has focused on the upper gastrointestinal location. OBJECTIVES: To describe the epidemiological and clinical aspects of Kaposi's sarcoma in the upper gastrointestinal endoscopy. METHODS: This was a retrospective descriptive study from June 2005 to February 2009 in the center of endoscopy of the Point G Hospital including all patients seen in upper gastrointestinal endoscopy during the study period. RESULTS: 20 cases were reported from a total of 5068 endoscopy performed during this period a frequency of 0.39% hospital. These 20 cases were identified in all 31 patients with cutaneous localization of Kaposi's sarcoma is a frequency of 64.5%. The sex ratio was equal to 0.81. The average age was 36.8 years ± 8.92 years. The stomach and esophagus were found most locations. All patients were HIV positive. The CD4 count below 200 cells/mm3 was observed in 95% of patients.

[Undesirable effects of medicine in the Internal Medicine Service of the University Hospital Center du Point G]. / Les Effets Indesirables des Medicaments dans le Service de Medecine Interne CHU du Point G.

The aim of this study was to determine the frequency of adverse reactions to drugs, the WHO grade, describe the clinical features and identify the drug responsible. This was a descriptive cross-sectional study which took place from February 2005 to January 2006 in the Internal Medicine Department at the hospital point G. Were included in this study, all patients hospitalized during the study period, which presented adverse drug reactions (ADRs) that the relation of cause and effect was certain or likely. Thus, 47 ADRs were identified in 39 patients of 426 admitted during the same period a frequency of 9.2%. The average age of our patients was 48.5 ± 16.5 years. The sex-ratio was 1.6 for women. Eighty-two percent of our patients had an ADR and 18% more than one. The WHO grade 1 was the most met or 36.2%, followed by grades 4 and 2 respectively 27.7% and 25.5%. Antidiabetics were responsible for adverse reactions in 46.8% and 21.3% in TB. Adverse events were neurological in 53.2% and type of manifestations of hypoglycemia 46.8% (22/47 cases), polyneuritis 6.4% (3 / 47 cases) and 29.8% in digestive cases dominated by vomiting 12.8% (6 / 47 cases), the epigastria pain 6.4% (3 / 47 cases). The outcome was favorable in 87.2% of cases, however, 3 cases of death among those over 60 years all grade 4 WHO. ADRs deserve special attention to this high death rate (6.4% 3/47 cases) where the interest to search systematically for all patients under medical treatment with a good clinical examination and questioning some thoroughly.

Increased prevalence of activated CD70+CD4+ T cells in the periphery of patients with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is characterized by loss of immune tolerance. A hallmark of SLE is the presence of autoantibodies resulting from B cell hyperactivity. Previous studies have shown that the presence of abnormal B cell subsets in the periphery, such as CD27highCD20- B cells, correlate with disease activity. We examined the relationship between the expression of CD70, the ligand for CD27 expressed by activated T cells, and indicators of disease activity. A significant increase in median CD70+CD4+ T cell frequencies and memory CD45RA-CD4+ T cell frequencies was observed in SLE samples as compared to healthy controls. The frequencies of CD70+CD4+ T cells correlated with disease duration but not age, treatment, or disease activity. Although a majority of CD70+CD4+ T cells appeared to be effector memory cells, mitogen-stimulated CD70+CD4+ T cells were capable of secreting a full repertoire of effector cytokines. Despite the presence of activated CD4+ T cells, no increase in immunosenescent CD4+ T cells, as defined by the loss of CD28 and/or the acquisition of CD57 was observed in samples from SLE patients. These studies indicate that increased CD70 expression might serve as a useful marker of abnormal T cell activity in SLE.

Determination of total organic carbon in water by thermal combustion-ion chromatography.

A sensitive method for determining total organic carbon at microgram per liter levels in industrial, environmental, and drinking waters by thermal combustion ion chromatography was developed using tube furnace and readily accessable HPLC equipment. To achieve complete oxidation, persulfate (0.25%) was added to oxidize nonvolatile organic compounds in solution and cupric oxide heated at 900 °C to convert volatile organic compounds to CO(2), which was scrubbed in a 20 mL solution of 50 mM KOH with 10 drops of butanol added. The carbonate anion obtained was determined by nonsuppressed ion chromatography using 0.6 mM potassium hydrogen phthalate (KHP) as the eluent. Both surfactants and volatile and nonvolatile organic compounds commonly found in environmental waters give highly repeatable recoveries close to 100%. The detection limit (S/N = 2) and linear range for a 1 L water sample are 2 µg of C L(-)(1) and 10-2500 µg of C L(-)(1), respectively, and they can be adjusted using samples ranging from 100 mL to 2 L. Good repeatablity (RSD less than 10%) and close to 100% recoveries were obtained for KHP added to real samples such as deionized, mineral, tap, and river water and seawater. Compared with the ASTM D2579 method, the method developed is 3 orders of magnitude more sensitive, more accurate, and reliable in determining samples with low total organic carbon values and more flexible in adjusting the linear range and sensitivity using variable sample sizes.

Radial artery pseudoaneurysm complication from use of AO/ASIF volar distal radius plate: a case report.

A case of pseudoaneurysm of the radial artery after fixation of a distal radius using the AO/ASIF volar distal radius plate system is presented. This unusual complication resulted from inadequate fracture stabilization and plate preparation. Technical tips on plate shortening and preparation of the cut ends are emphasized.

Volar A1 pulley approach for fixation of avulsion fractures of the base of the proximal phalanx.

Avulsion fractures of the base of the proximal phalanx associated with collateral ligament instability, excluding the thumb, are relatively rare. While the indications for surgical intervention vary, dorsal approaches have been advocated despite the volar location of the fracture fragment and orientation of the collateral ligaments. Ten patients with 11 avulsion fractures at the base of the proximal phalanx associated with collateral ligament instability were treated with open reduction and internal fixation using a volar A1 pulley approach. Anatomic restoration of the articular surface and collateral ligament stability were obtained in all patients. All fractures healed between 5 and 9 weeks (average, 6 weeks). After an average 19.4-month follow-up period all patients had full range of motion of the metacarpophalangeal joint, collateral ligament stability, and grip strength of at least 90% of the uninjured hand. No perioperative complications occurred. The average DASH score at last follow-up examination was 1.8 (range, 0-6). All patients were satisfied with the outcome of surgery. The volar A1 pulley approach is a direct and effective approach for reduction and fixation of avulsion fractures of the base of the proximal phalanx associated with collateral ligament instability.

Rapid evolution in response to high-temperature selection.

Temperature is an important environmental factor affecting all organisms, and there is ample evidence from comparative physiology that species and even conspecific populations can adapt genetically to different temperature regimes. But the effect of these adaptations on fitness and the rapidity of their evolution is unknown, as is the extent to which they depend on pre-existing genetic variation rather than new mutations. We have begun a study of the evolutionary adaptation of Escherichia coli to different temperature regimes, taking advantage of the large population sizes and short generation times in experiments on this bacterial species. We report significant improvement in temperature-specific fitness of lines maintained at 42 degrees C for 200 generations (about one month). These changes in fitness are due to selection on de novo mutations and show that some biological systems can evolve rapidly in response to changes in environmental factors such as temperature.

Adsorption Isotherm of Sodium Octylbenzenesulfonate on Iron Oxide Particles in Aqueous Solutions.

The adsorption isotherm of sodium octylbenzene sulfonate has been determined at two pH values on dispersed maghemite particles in water. The isotherms present an adsorption maximum in the region of the surfactant critical micelle concentration. Additional adsorption experiments at the alumina/water interface as well as at the air/water interface in the presence of ferric ions suggest that the adsorption maximum in the case of the iron oxide particles is due to the presence of very small concentrations of ferric ions in the aqueous solution. These ions form surface active complexes with sodium octylbenzenesulfonate. These complexes are adsolubilized in the surfactant layers on the particles below the critical micelle concentration. They are desorbed from the surface and transferred into free micelles above the critical micelle concentration. These two phenomena are shown to be responsible for the adsorption maximum observed. The presence of ferric ions induces a surface tension minimum of the anionic surfactant at the air/water interface. This effect is discussed in relation to the adsorption maximum at the solid/water interface. Copyright 1998 Academic Press.