Clinical evaluation of different treatment strategies for motor recovery in poststroke rehabilitation during the first 90 days

Background: Motor recovery after stroke is based on neuronal plasticity and the structural reorganization of the brain. Questions are debated about the proper moment to start rehabilitation in the acute period of stroke, the significance of rehabilitation interventions during the so-called “plastic window”, and the advantages of modern and traditional programs. The aims of this study were to evaluate the role of different rehabilitation strategies and their combinations for motor recovery and the impact on functional disability by way of neurological and functional outcomes 3 months after ischemic stroke. Methods: We used three rehabilitation approaches: early rehabilitation from the first day of stroke (Phase I), traditional exercise programs (Phase II), and an author’s new method of biofeedback rehabilitation using motion sensors and augmented reality (AR) rehabilitation (Phase III). Clinical and functional outcomes were measured on the 90th day after stroke. We developed algorithms for quantifying the quality of movements during the execution of tasks in the motor domains of the AR rehabilitation program. Results: Phase I of rehabilitation led to an improvement in functional independence, and the recovery of motor functions of the extremities with an absence of mortality and clinical deterioration. AR rehabilitation led to significant improvement both with respect to clinical and functional scores on scales and to variables reflecting the quality of movements. Patients who were actively treated during Phases II and III achieved the same final level of motor recovery and functional outcomes as that of participants who had only received AR rehabilitation during Phase III. Patients who underwent outpatient observation after Phase I showed a deficit of spontaneous motor recovery on the 90th day after stroke. Conclusions: Early rehabilitation was successful but was not enough; rehabilitation programs should be carried out throughout the entire “sensitive period” of poststroke plasticity. The newly developed AR biofeedback motion training is effective and safe as a separate rehabilitation method in the early recovery period of moderately severe, hemiparalytic, and ischemic stroke. These two rehabilitation approaches must be applied together or after each other, not instead of each other, as shown in clinical practice

Serum BDNF's Role as a Biomarker for Motor Training in the Context of AR-Based Rehabilitation after Ischemic Stroke

BACKGROUND: brain-derived neurotrophic factor (BDNF) may play a role during neurorehabilitation following ischemic stroke. This study aimed to elucidate the possible role of BDNF during early recovery from ischemic stroke assisted by motor training. METHODS: fifty patients were included after acute recovery from ischemic stroke: 21 first received classical rehabilitation followed by 'motor rehabilitation using motion sensors and augmented reality' (AR-rehabilitation), 14 only received AR-rehabilitation, and 15 were only observed. Serum BDNF levels were measured on the first day of stroke, on the 14th day, before AR-based rehabilitation (median, 45th day), and after the AR-based rehabilitation (median, 82nd day). Motor impairment was quantified clinically using the Fugl-Meyer scale (FMA); functional disability and activities of daily living (ADL) were measured using the Modified Rankin Scale (mRS). For comparison, serum BDNF was measured in 50 healthy individuals. RESULTS: BDNF levels were found to significantly increase during the phase with AR-based rehabilitation. The pattern of the sequentially measured BDNF levels was similar in the treated patients. Untreated patients had significantly lower BDNF levels at the endpoint. CONCLUSIONS: the fluctuations of BDNF levels are not consistently related to motor improvement but seem to react to active treatment. Without active rehabilitation treatment, BDNF tends to decrease

Паранеопластическая мозжечковая дегенерация у пациента с антителами anti-Yo и аденокарциномой простаты

Paraneoplastic cerebellar degeneration is the damage to cerebellar Purkinje cells by anti-Yo antibodies synthesized by the immune system in response to the generation of neuronal proteins by malignant prostate adenocarcinoma cells in 25% of cases. Neurological symptoms of cerebellar lesions appear on average 2 years before cancer manifestation in 70% of patients. During the early stages of the disease, when the tumor cannot be visualized nor clinically manifested, a high titer of anti-Yo antibodies in the cerebrospinal fluid of patients. The presence of anti-Yo antibodies prostate cancer with a clinically latent course was present in 90–98% of patients with cerebellar ataxia. Onconeural autoantibodies (IgG) are well detected in serum by immunoblotting and indirect immunofluorescence.The death of Purkinje cells of the granular and molecular layers of the cerebellar cortex, moderate perivascular lymphocytic infiltration, and further proliferation of microglia lead to atrophy. Inflammatory infiltrates may also be present in the brainstem and cortex, although in significantly less number in compar the cerebellum.This difference accounts for the presence of additional neurological symptoms. The results of the brain MR imaging at the initial stages of paraneoplastic cerebellar degeneration are of little informative value, and degenerative changes in the cerebellum are revealed only a few months later with a subsequent increase in neurological deficit. Removal of malignant tumors leads to the regression of neurological symptoms in 80% of cases. This finding confirms the advisability of a targeted oncological search in patients with symptoms of paraneoplastic cerebellar degeneration and positive onconeural antibodies in the serum. Immunomodulatory therapy, including the use of intravenous immunoglobulin, plasmapheresis, and hormone therapy, is also effective in the treatment of neurological disorders. This paper describes a clinical case of paraneoplastic cerebellar degeneration in a 65-year-old male, with the appearance of neurological symptoms 5 months before the diagnosis of prostate adenocarcinoma. The difficulties of differential diagnosis of this neurological disorder and the course of neurological diseases in the background of tumor removal and conducted immunotherapy are discussed.Паранеопластическая мозжечковая дегенерация представляет собой поражение клеток Пуркинье мозжечка антителами anti-Yo, синтезируемыми иммунной системой в ответ на выработку нейрональных белков злокачественными клетками аденокарциномы простаты в 25% случаев.Неврологические симптомы поражения мозжечка опережают манифестацию рака в среднем на два года у 70% пациентов. Уже на ранних стадиях заболевания, когда опухоль еще не визуализируется и клинически себя не проявляет, отмечается высокий титр антител anti-Yo в спинномозговой жидкости больных.У 90–98% больных с мозжечковой атаксией и наличием антител anti-Yo обнаруживают рак простаты с клинически скрытым течением. Онконевральные аутоантитела класса IgG хорошо детектируются в сыворотке крови методами иммуноблоттинга и непрямой иммунофлуоресценции. Гибель клеток Пуркинье зернистого и молекулярного слоев коры мозжечка, умеренная периваскулярная лимфоцитарная инфильтрация, дальнейшая пролиферация микроглии приводят к атрофии. Воспалительные инфильтраты могут также быть в стволе и коре головного мозга, хотя их значительно меньше, чем в мозжечке. Этим объясняется наличие дополнительных неврологических симптомов. Результаты томографии головного мозга на начальных стадиях паранеопластической мозжечковой дегенерации мало информативны и только через несколько месяцев по мере нарастания неврологического дефицита обнаруживаются дегенеративные изменения мозжечка. Удаление злокачественной опухоли приводит к регрессу неврологической симптоматики в 80% случаев. Это свидетельствует о целесообразности проведения направленного онкологического поиска у пациентов с симптомами паранеопластической мозжечковой дегенерации и обнаруженными в крови онконевральными антителами. Иммуномодулирующая терапия, включающая применение внутривенных иммуноглобулинов, плазмафереза, гормонотерапии, также эффективна в лечении неврологических нарушений.В статье описан клинический случай паранеопластической мозжечковой дегенерации у мужчины 65 лет с возникновением неврологических симптомов за 5 мес до диагностики аденокарциномы простаты.Обсуждены трудности дифференциальной диагностики неврологического расстройства и течение неврологического заболевания на фоне удаления опухоли и проводимой иммунотерапии

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Clinical and microbiological evaluation of the efficacy of autoprobiotics in the combination treatment of chronic generalized periodontitis

Combination treatment of patients with inflammatory periodontal diseases may be ineffective due to the variability of periodontal pathogens and the polyetiology of the disease. This disadvantage can be overcome by using highly antagonistic, enzymatic, and immunostimulating drugs, in addition to the main treatment. The objective of this study is to evaluate the efficacy of autoprobiotics clinically and microbiologically in the combination treatment of chronic generalized periodontitis. The presented study involved a survey of 37 patients aged 29 to 64 years with mild chronic generalized periodontitis. The patients were divided into three groups. Group I consisted of patients whose combination treatment included an S. salivarius-based autoprobiotic (subgroup 1 - patients who had their periodontal pockets irrigated with an autoprobiotic, subgroup 2 - patients who used oral baths with autoprobiotic). Group II consisted of patients who used a common S. salivarius-based probiotic in combination treatment (subgroup 1 - patients who had their periodontal pockets irrigated with a probiotic, subgroup 2 - patients who used oral baths with a probiotic). The control group consisted of patients with mild chronic generalized periodontitis, whose combination treatment consisted of professional oral hygiene and correction of individual hygiene. Microbiological examination of the content of periodontal pockets was carried out using PCR screening for periodontal pathogens, such as P. gingivalis, T. denticola, T. forsythia, P. intermedia. Based on the clinical and microbiological results of the study, the efficacy of an autoprobiotic and probiotic based on S. salivarius in the combination treatment of mild chronic generalized periodontitis was demonstrated

Paraneoplastic cerebellar degeneration in a patient with anti-Yo antibodies and prostate adenocarcinoma

Paraneoplastic cerebellar degeneration is the damage to cerebellar Purkinje cells by anti-Yo antibodies synthesized by the immune system in response to the generation of neuronal proteins by malignant prostate adenocarcinoma cells in 25% of cases. Neurological symptoms of cerebellar lesions appear on average 2 years before cancer manifestation in 70% of patients. During the early stages of the disease, when the tumor cannot be visualized nor clinically manifested, a high titer of anti-Yo antibodies in the cerebrospinal fluid of patients. The presence of anti-Yo antibodies prostate cancer with a clinically latent course was present in 90–98% of patients with cerebellar ataxia. Onconeural autoantibodies (IgG) are well detected in serum by immunoblotting and indirect immunofluorescence.The death of Purkinje cells of the granular and molecular layers of the cerebellar cortex, moderate perivascular lymphocytic infiltration, and further proliferation of microglia lead to atrophy. Inflammatory infiltrates may also be present in the brainstem and cortex, although in significantly less number in compar the cerebellum.This difference accounts for the presence of additional neurological symptoms. The results of the brain MR imaging at the initial stages of paraneoplastic cerebellar degeneration are of little informative value, and degenerative changes in the cerebellum are revealed only a few months later with a subsequent increase in neurological deficit. Removal of malignant tumors leads to the regression of neurological symptoms in 80% of cases. This finding confirms the advisability of a targeted oncological search in patients with symptoms of paraneoplastic cerebellar degeneration and positive onconeural antibodies in the serum. Immunomodulatory therapy, including the use of intravenous immunoglobulin, plasmapheresis, and hormone therapy, is also effective in the treatment of neurological disorders. This paper describes a clinical case of paraneoplastic cerebellar degeneration in a 65-year-old male, with the appearance of neurological symptoms 5 months before the diagnosis of prostate adenocarcinoma. The difficulties of differential diagnosis of this neurological disorder and the course of neurological diseases in the background of tumor removal and conducted immunotherapy are discussed

Anti-Idiotypic Nanobodies Mimicking an Epitope of the Needle Protein of the Chlamydial Type III Secretion System for Targeted Immune Stimulation

The development of new approaches and drugs for effective control of the chronic and complicated forms of urogenital chlamydia caused by Chlamydia trachomatis, which is suspected to be one of the main causes of infertility in both women and men, is an urgent task. We used the technology of single-domain antibody (nanobody) generation both for the production of targeting anti-chlamydia molecules and for the subsequent acquisition of anti-idiotypic nanobodies (ai-Nbs) mimicking the structure of a given epitope of the pathogen (the epitope of the Chlamydial Type III Secretion System Needle Protein). In a mouse model, we have shown that the obtained ai-Nbs are able to induce a narrowly specific humoral immune response in the host, leading to the generation of intrinsic anti-Chlamydia antibodies, potentially therapeutic, specifically recognizing a given antigenic epitope of Chlamydia. The immune sera derived from mice immunized with ai-Nbs are able to suppress chlamydial infection in vitro. We hypothesize that the proposed method of the creation and use of ai-Nbs, which mimic and present to the host immune system exactly the desired region of the antigen, create a fundamentally new universal approach to generating molecular structures as a part of specific vaccine for the targeted induction of immune response, especially useful in cases where it is difficult to prepare an antigen preserving the desired epitope in its native conformation

LIGHT/TNFSR14 Can Regulate Hepatic Lipase Expression by Hepatocytes Independent of T Cells and Kupffer Cells

LIGHT/TNFSF14 is a costimulatory molecule expressed on activated T cells for activation and maintenance of T cell homeostasis. LIGHT over expressed in T cells also down regulates hepatic lipase levels in mice through lymphotoxin beta receptor (LTβR) signaling. It is unclear whether LIGHT regulates hepatic lipase directly by interacting with LTβR expressing cells in the liver or indirectly by activation of T cells, and whether Kupffer cells, a major cell populations in the liver that expresses the LTβR, are required. Here we report that LIGHT expression via an adenoviral vector (Ad-LIGHT) is sufficient to down regulate hepatic lipase expression in mice. Depletion of Kupffer cells using clodronate liposomes had no effect on LIGHT-mediated down regulation of hepatic lipase. LIGHT-mediated regulation of hepatic lipase is also independent of LIGHT expression by T cells or activation of T cells. This is demonstrated by the decreased hepatic lipase expression in the liver of Ad-LIGHT infected recombination activating gene deficient mice that lack mature T cells and by the Ad-LIGHT infection of primary hepatocytes. Hepatic lipase expression was not responsive to LIGHT when mice lacking LTβR globally or only on hepatocytes were infected with Ad-LIGHT. Therefore, our data argues that interaction of LIGHT with LTβR on hepatocytes, but not Kupffer cells, is sufficient to down regulate hepatic lipase expression and that this effect can be independent of LIGHT’s costimulatory function.</p

LIGHT/TNFSR14 can regulate hepatic lipase expression by hepatocytes independent of T cells and Kupffer cells.

LIGHT/TNFSF14 is a costimulatory molecule expressed on activated T cells for activation and maintenance of T cell homeostasis. LIGHT over expressed in T cells also down regulates hepatic lipase levels in mice through lymphotoxin beta receptor (LTβR) signaling. It is unclear whether LIGHT regulates hepatic lipase directly by interacting with LTβR expressing cells in the liver or indirectly by activation of T cells, and whether Kupffer cells, a major cell populations in the liver that expresses the LTβR, are required. Here we report that LIGHT expression via an adenoviral vector (Ad-LIGHT) is sufficient to down regulate hepatic lipase expression in mice. Depletion of Kupffer cells using clodronate liposomes had no effect on LIGHT-mediated down regulation of hepatic lipase. LIGHT-mediated regulation of hepatic lipase is also independent of LIGHT expression by T cells or activation of T cells. This is demonstrated by the decreased hepatic lipase expression in the liver of Ad-LIGHT infected recombination activating gene deficient mice that lack mature T cells and by the Ad-LIGHT infection of primary hepatocytes. Hepatic lipase expression was not responsive to LIGHT when mice lacking LTβR globally or only on hepatocytes were infected with Ad-LIGHT. Therefore, our data argues that interaction of LIGHT with LTβR on hepatocytes, but not Kupffer cells, is sufficient to down regulate hepatic lipase expression and that this effect can be independent of LIGHT's costimulatory function

Chlamydial Type III Secretion System Needle Protein Induces Protective Immunity against Chlamydia muridarum Intravaginal Infection

Chlamydia trachomatis imposes serious health problems and causes infertility. Because of asymptomatic onset, it often escapes antibiotic treatment. Therefore, vaccines offer a better option for the prevention of unwanted inflammatory sequelae. The existence of serologically distinct serovars of C. trachomatis suggests that a vaccine will need to provide protection against multiple serovars. Chlamydia spp. use a highly conserved type III secretion system (T3SS) composed of structural and effector proteins which is an essential virulence factor. In this study, we expressed the T3SS needle protein of Chlamydia muridarum, TC_0037, an ortholog of C. trachomatis CdsF, in a replication-defective adenoviral vector (AdTC_0037) and evaluated its protective efficacy in an intravaginal Chlamydia muridarum model. For better immune responses, we employed a heterologous prime-boost immunization protocol in which mice were intranasally primed with AdTC_0037 and subcutaneously boosted with recombinant TC_0037 and Toll-like receptor 4 agonist monophosphoryl lipid A mixed in a squalene nanoscale emulsion. We found that immunization with TC_0037 antigen induced specific humoral and T cell responses, decreased Chlamydia loads in the genital tract, and abrogated pathology of upper genital organs. Together, our results suggest that TC_0037, a highly conserved chlamydial T3SS protein, is a good candidate for inclusion in a Chlamydia vaccine