Long-Term Follow-up Study after Lentiviral Hematopoietic Stem/Progenitor Cell Gene Therapy for Wiskott - Aldrich Syndrome

Wiskott Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency associated with thrombocytopenia, eczema, infectious, autoimmune complications, and lymphomas. Patients lacking an HLA-matched donor may benefit from an alternative therapeutic approach based on the infusion of autologous gene corrected CD34+ cells. We previously reported a non-randomised, open-label, phase 1/2 clinical study applying a lentiviral vector based gene therapy (GT) protocol in 7 paediatric patients with severe WAS (score ≥ 3/5) (S. Hacein-Bey Abina et al, JAMA 2015). One patient died 7 months after GT because of pre-existing severe opportunistic infections, as reported. Two additional patients have been treated since that initial report, with a follow-up of at least 4 years. We here present a comprehensive long-term study on 8 patients with a follow-up from 4 to 9 years (median 7.6). The safety and efficacy of the approach is thoroughly investigated, with a particular focus on the correction of thrombocytopenia and auto-immunity. A stable engraftment of genetically and functionally corrected lymphoid and myeloid cells was reached in all patients, with no serious treatment-associated adverse events or concerning clonal expansion. Corrected lymphoid cells displayed a selective advantage over time with increasing vector copy number (VCN) level. In turn, this led to (i) sustained expression of WAS protein (WASp) in the patients' cells and (ii) clinical resolution of severe eczema and susceptibility to recurrent infections. In line with these results, T-cell function was restored after GT, as shown by the recovery of immune synapse assembly and the normalization of naïve T cell numbers. The T-cell compartment was also reconstituted in the patient treated at the age of 30 years, suggesting that GT for WAS is a treatment option in adult patients. In parallel with the robustness of T-cell reconstitution a normalized B-cell compartment was observed after GT, as shown in particular by increasing levels of WASp + switched memory B cells over time and the age-matched levels of KRECs. Five patients out of 8 were able to discontinue Ig replacement therapy while achieving normal post-vaccination antibody titers. Autoimmune disorders and bleeding episodes were significantly less frequent, despite only partial correction of the platelet compartment. After GT, a few autoimmune manifestations were observed: the persistence of lower extremity vasculitis (P2, very severe prior to GT), the new occurrence of nephrotic syndrome (P9), and the presence of anti-platelet antibodies (P2, P4, P7). The levels of circulating autoantibodies detected before GT (including ANA and vasculitis-related autoantibodies) normalized after treatment. Following GT, platelets were found to express sub-normal levels of WASp and to only partially augment their size. Platelet function studies indicated a partial correction of the platelet compartment achieved by GT, which may be sufficient to prevent occurrence of the hemorrhagic symptoms typical of WAS. Our results suggest that lentiviral GT provides sustained clinical benefits for patients with WAS. Overall clinical remission was observed in our patients despite very severe disease scores before GT. More efficacious and more reliable transduction protocols and conditioning regimen are likely to further improve outcomes, particularly with regard to platelet recovery, where the advantages of intrinsic correction are less apparent. Disclosures Booth: Orchard Therapeutics: Consultancy, Honoraria; SOBI: Consultancy, Honoraria; Takeda: Honoraria; GSK: Honoraria; Rocket Pharmaceuticals, Inc.: Consultancy. Thrasher: Orchard Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Generation bio: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; 4Bio Capital: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rocket Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Cavazzana: Smart Immune: Other: co-founder.

Updating Social Theory: Redefinition of Modernization

The article considered a critical appraisal of the modernization theory in its mono-paradigm frames and offers a heterodox conceptual meaning of modernization. Obviously, the varieties of methodological ap- proaches to that important theoretical topic would have to be much more comprehensive than con- temporary interpretations of linear pattern mainstream theories propose. Rethinking the conceptual foun- dations of the existing interpretation of the very concept is the model of adaptive modernization. Protect- ing its own matrix core, the system carries out partial correction of specific parameters, in which there is a lag, to increase their own vitality. Constructive changes are intra-systemic and occur within the existing order, without destroying its foundations, main institutional structures, and preserve the generic socio- cultural genotype Modernization, as reception of foreign cultural innovations (technical and technological) with their appropriate adaptation to the endogenous conditions, is an adequate adaptive response of a so- cial system to external risks or exogenous origin impact.

LABOUR CONDITIONS AND POSSIBILITY OF APPLICATION OF ETHYLMETHYLHYDROXYPYRIDINE SUCCINATE IN WORKERS EXPOSED TO FIBROGENIC SILICATE DUST

Labour conditions of workers contacting with fibrogenic silicate dust in isolators’ production were studied. Additional examination included determination of the degree of endothelial disfunction, apoptosis and systemic inflammation. Besides the effect of Ethylmethylhydroxypyridine succinate on these parameters and the lipid profile was evaluated. Atherogenic changes of the lipid profile, moderate endothelial disfunction (level of circulating endotheliocytes is 6,04±1,97*104/l), slight tension of apoptosis (TNF-α 8,11±6,67 pg/ml) and activation of systemic inflammation (C-RP 8,1±4,5 mg/l) were found. Application of Ethylmethylhydroxypyridine succinate led to the partial correction of dyslipidemia and endothelial disfunction without the significant effect on other researching laboratory parameters; significant improvement of respiratory function was noted.

Definitions and Paradigms of European Security

Modern political activity develops on the basis of disclosure and partial correction of previously developed algorithms and approaches, which significantly increases the practical significance of the historical and political science methodology, with the help of which it is possible to identify the content, directions of evolution, the prospects for changing traditional models and phenomena. The article attempts to study the essence of the security phenomenon in the context of currently emerging paradigms. The working hypothesis was the assumption that the transformational processes of the 1970’s, which subsequently experienced a «security swing», their elements, system hierarchy and logic of representation continue to persist in the current Western model, since multi-factor and successful transformations slow down change. As a result of the study, disparities in the substantive definition of security goals, contradictions between political goals and processes were revealed, a working hypothesis was confirmed, and problems that require further study, including through the expansion of the empirical base, were outlined. The article is written mainly on the materials of the three «White Papers» of the Bundeswehr. It is controversial in nature, but already at this stage of the study has a practical value, reflected in four recommendation-prognostic conclusions.

Semigroup quasivarieties: Two lattices and a reopened problem

We determine all quasivarieties of aperiodic semigroups that are contained in some residually finite variety. This endeavor was initially motivated by a problem in natural dualities, but our work here also serves as a partial correction to an error found in a result of Sapir from the 1980s.

The Effect of Prolonged Pre-Operative Halo Gravity Traction for Severe Spinal Deformities on the Cervical Spine Radiographs

Study Design: Retrospective review of consecutive series. Objective: The study sought to assess the effect of prolonged pre-operative halo gravity traction (HGT) on the c-spine radiographs Methods: Data of 37 pediatric and adult patients who underwent ≥ 12wks pre-op HGT prior to definitive spine surgery from 2013-2015 at a single site in West Africa was reviewed. Radiographic assessment of the c-spine including ADI, SVA and C2-C7 Lordosis were done at pre HGT and at 4 weekly intervals. Paired T-Test was performed to evaluate changes in these parameters during HGT. Results: 37pts, 18/19 (F/M). Average age 18.2yrs. Diagnoses: 22 idiopathic, 6 congenital, 3 Post TB, 2 NM and 4 NF. Average duration of HGT: 125 days. Baseline coronal Cobb:130 deg, corrected 30% in HGT; baseline sagittal Cobb:146 deg, corrected 32% post HGT. Baseline ADI (3.17 ± 0.63 mm) did not change at 4wks ( P > 0.05) but reduced at 8wks (2.80 ± 0.56 mm) and 12wks (2.67 ± 0.51 mm) post HGT ( P < 0.05). Baseline HGT SVA (20.7 ± 14.98 mm) significantly improved at 4wks (11.55 ± 10.26 mm), 8wks (7.54 ± 6.78 mm) and 12wks (8.88 ± 4.5 mm) ( P < 0.05). Baseline C2-C7 lordosis (43 ± 20.1 deg) reduced at 4wks (26 ± 16.37 deg), 8wks (17.8 ± 14.77 deg) and 12wks (16.7 ± 11.33 deg) post HGT ( P < 0.05). There was no incidence of atlanto-axial instability on flexion extension radiographs at any interval. Conclusion: Prolonged HGT, while providing partial correction of severe spine deformities, also appeared to have no adverse effect on atlanto-axial stability or cervical alignment. Therefore, HGT can be safely applied for several weeks in the preoperative management of severe spine deformities in pediatric/adult patients.

An Adaptive Algorithm for Calculating the Dynamics of a Hydromechanical Servo Actuator with Throttle Control

The technical, economic, and performance indicators of hydromechanical servo actuators with throttle control (HMSA/T) can be radically improved by structurally correcting the actuator initial configuration followed by parametrically optimizing the found solution. The conventional solution boils down to an analysis of partial correction problems. However, this adds difficulty to comparison of the results and entails a significant scope of refinement and adjustment works. The article presents a unified algorithm for settling matters concerned with structural and parametric correction of an HMSA/T as applied to the most efficient ways of changing the actuator initial structure: damping the hydraulic amplifier sliding valve and introducing additional feedbacks for the output section motion speed and derivative of pressure difference in the hydraulic amplifier outlet hydraulic lines. An integrated HMSA/T model is constructed on the basis of standard structural correction schemes and partial mathematical models of actuators, and the scheme of an algorithm for combined structural and parametric correction of the actuator is presented. It is shown that the algorithm can be implemented using limited computation resources with a quickly running application software.

Disorders of carbohydrate metabolism in critical conditions

Background. Carbohydrate metabolism disorders (CMD) include ketoacidosis and ketoacidotic hyperglycemic coma, non-diabetic ketoacidosis, hyperosmolar coma, hypoglycemic syndrome and hypoglycemic coma, lactic acid coma. The main factors in the development of CMD are newly diagnosed diabetes mellitus (DM) or inadequate therapy of previously diagnosed DM, infectious processes, acute diseases (myocardial infarction, strokes, pancreatitis, renal failure, severe burns, thyrotoxicosis), use of certain drugs (calcium channel blockers, osmotic and thiazide diuretics, propranolol, chemotherapeutic drugs), alcohol or cocaine abuse. Objective. To describe the course and management of patients with CMD. Materials and methods. Review of the available literature on this issue. Results and discussion. CMD in critical conditions leads to the development of hyperglycemia, hyperketonemia, metabolic acidosis, dehydration, hyperosmolarity, electrolyte imbalance, arising against the background of the underlying disease, being masked by it and worsening the patient’s condition. When diagnosing ketoacidosis, one should focus primarily on the clinical condition of the patient, because the test for ketonuria does not reflect the actual level of ketone bodies in the urine. CMD therapy should include rehydration (infusion therapy – IT), insulin therapy, partial correction of severe metabolic acidosis, use of antiketogenic drugs, compensation of electrolyte disorders and elimination of the CMD causes. Isotonic NaCl solution or Ringer solution must be used for IT. Elderly patients and patients with heart failure should be treated with caution, with a possible dose reduction of 50 %. In case of hyperglycemia, insulin therapy (intravenous bolus 0.15 IU/kg, then infusion 0.1 IU/kg/h) is prescribed to ensure a reduction in glucose concentration by 2-3 mmol/L per hour. To correct metabolic acidosis, hydrocarbonate solutions are prescribed under the control of acid-base status (ABS). If it is not possible to determine ABS, in the presence of clinical signs of ketoacidosis, it is possible to prescribe Soda-Bufer (“Yuria-Pharm”) up to 300 ml. Xylitol (Xylate, “Yuria-Pharm”) is the main antiketogenic solution. It reduces the amount of free fatty acids, which oxidize to acetyl-CoA, acts as an insulin-independent energy source, increases the intensity of glycolysis and glycogen production, stimulates insulin secretion. If the patient has a fasting blood glucose level >13.9 mmol/L, nausea, vomiting, dizziness, drowsiness, dry skin and dry mouth, Kussmaul’s breathing, frequent urination, or a patient with diabetes is scheduled for surgery, it is advisable to prescribe xylitol-containing solution. Xylate should be prescribed for various CMD (hyperglycemia, dehydration, hypokalemia, ketoacidosis). Another area of CMD treatment is the normalization of potassium levels, which should be started in the conditions of normokalemia, because CMD are characterized by an initial increase and subsequent decrease in potassium content. The latter should be maintained at 4-5 mmol/h with tight monitoring every 2 hours firstly and then every 4 hours. Conclusions. 1. Many patients in the intensive care unit develop CMD. 2. CMD in critical conditions involve the development of hyperglycemia, hyperketonemia, metabolic acidosis, dehydration, hyperosmolarity, and electrolyte imbalance. 3. CMD therapy should include rehydration, insulin therapy, partial correction of severe metabolic acidosis, use of antiketogenic drugs, compensation of electrolyte disorders and elimination of the CMD causes. 4. Isotonic NaCl solution, Ringer solution, insulin therapy, hydrocarbonate solutions, xylitol, potassium preparations are used in CMD therapy.

Uterine intussusception in immediate postpartum in bitches

Uterine intussusception is a rare condition in bitches. This study aimed to report an unusual case of prolapsed uterine intussusception in a female dog. A 2-year-old American Bully bitch was received with labor history of large fetus requiring manual traction. The animal presented mucosal prolapse through the vulva, unproductive contractions and abdominal discomfort. After partial correction of mucosal prolapse, the dog was referred to ovary-hysterectomy surgery to correct prolapsed mucosa. During the surgical procedure, surgeons observed that the uterine horns were invaginated into the uterine body, rotated, and the tissue was slightly devitalized and congested. As previously described, this condition occurred during the immediate postpartum period. Thus, we suggest that this period can be a facilitator for the establishment of uterine intussusception.

APPLICATION OF QUERCETIN FOR CORRECTION OF THE IMPAIRMENT OF THE FUNCTIONAL STATE OF THE ENDOTHELIUS OF VESSELS (CLINICAL AND EXPERIMENTAL STUDY)

Objective. in the experiment, to investigate the effect of Quercetin on the NO-dependent reactions of isolated vessels involving endothelium and perivascular adipose tissue (PVAT) after a single X-ray irradiation of rats at a sublethal dose. In a clinical study, to investigate the effect of long-term use of Quercetin on the functional state of the microvascular endothelium in the elderly patients with metabolic syndrome (MS). Material and methods. Experimental studies were performed on vascular fragments obtained from adult male rats (7–8 months) of the control group, in animals exposed to a single R-irradiation at a dose of 7 Gy and animals irradiated in the same dose, which received Quercetin orally for 14 days three times a week based on 10 mg/kg body weight. Fragments of the thoracic aorta (TA) and mesenteric artery (MA) were cleaned of perivascular adipose tissue (PVAT-) or left uncleaned (PVAT+), and then were cut into rings (up to 2 mm). The amplitude of the contraction of the rings TA and MA under the influence of phenylephrine (PE, 3 x 10-6 M), the amplitude of the contraction of the rings TA and MA in the presence of a competitive blocker of NO-synthase methyl ester of N-nitro-L-arginine (L-NAME, 10-5 M), the amplitude of relaxation of the rings TA and MA in the presence of N-acetylcysteine (NAC, 10-4 M) were measured. The clinical study examined 110 patients with MS criteria in accordance with ATP III (2001). Patients in the main group for 3 months received Quercetin from the same manufacturer, 80 mg three times a day, patients in the control group received placebo. Results. Single R-irradiation disrupts the regulation of the contractile function of TA and MA, which is evidenced by changes in the contractile reactions of isolated fragments of these vessels as a response to the action of vasoactive compounds. Course use of Quercetin in irradiated rats leads to the normalization of contractile and dilatory vascular responses due to partial correction of NO metabolism in the endothelium and PVAT. For the majority of patients (69 %) who received Quercetin, a post-occlusive hyperemia test showed a statistically significant increase of maximal volumetric velocity of the skin blood flow rate and duration of the recovery period to the baseline, which indicates about improvement of vasomotor vascular endothelial function. Conclusions. Course use of Quercetin improves the functional state of the microvascular endothelium among the elderly people with MS, normalizes contractile and dilatory vascular responses in irradiated rats due to partial correction of NO metabolism in the endothelium and PVAT. Key words: X-ray irradiation, Quercetin, isolated vessels, endothelium, perivascular adipose tissue, metabolic syndrome, functional state of endothelium.