[Periodic limb movements in sleep and cerebral small vessel disease progression: a prospective cohort study]. / Periodicheskie dvizheniya konechnostei vo sne i progressirovanie tserebral'noi mikroangiopatii: prospektivnoe kogortnoe issledovanie.

OBJECTIVE: To determine the predictive role of periodic limb movements in sleep (PLMS) in cerebral small vessel disease (cSVD) progression rate. MATERIAL AND METHODS: Fifty patients with cSVD, aged 60-75 y.o., were enrolled. The study protocol included MRI assessment of white matter hyperintensities (WMH), nocturnal actigraphy and cognitive assessment. Depending on the PLMS, the main (PLM index ≥15) and the control (PLM index <15) groups were formed. The second visit was carried out in one year follow-up period, the examination consisted of brain MRI and cognitive assessment under the same protocol. ANCOVA was performed to determine if PLMS influence the degree of MRI- and neuropsychological changes. RESULTS: A significant effect of PLMS on the increase in the volume of WMH was revealed, both in the form of an increase in the index by more than 15 movements per hour (p=0.03), and quantitatively in the form of a connection with the index value (p=0.048). The influence of PLMS on the progression of cognitive dysfunction has not been found, however, it has been shown that the presence of PLMS is associated with lesions in the deep white matter (r=0.42, p<0.0001), and the results of neuropsychological tests are associated with lesions in the periventricular and juxtacortical WMH (p < 0.05 for each test). CONCLUSION: PLMS predict WMH progression in cSVD.

[The acute tetraparesis as a rare presentation of Chiari malformation]. / Ostroe razvitie tetrapareza kak redkoe proyavlenie anomalii Kiari I tipa.

The authors present a case-report of a 25-year-old patient who developed symptoms of transversal injury of the spine. The patient was followed-up for 2 years and had a stable course of Chiari malformation I and syringomyelia. Motor disorders and deep sensory disorders developed without external cause and continued to increase during 2.5 weeks with the further development of pelvic disorders. After the urgent cranial/vertebral decompression with the plastics of the dura mater by a fragment of a wide fascia of the thigh, there was an increase in muscle power (with the complete recovery in hands), regress of deep sensory disorders in hands and pelvic disorders. A literature review on case-reports of acute neurological symptoms in Chiari malformation I and syringomyelia in presented.

[Specific features of cognitive impairments in patients with predialysis chronic kidney disease].

AIM: To study the specific features of cognitive impairments (CI) in patients with predialysis chronic kidney disease (CKD). SUBJECTS AND METHODS: Examinations were made in 51 patients aged 52 +/- 10 years with CKD, including 20 patients with Stages I-II CKD (glomerular filtration rate (GFR) > or = 60 ml/min/1.73 m2; signs of kidney lesion), 20 with Stage III (GFR 60-30 ml/min/1.73 m2), and 11 with Stage IV (GFR 30-15 ml/min/1.73 m2). GFR was estimated using the Modification of Diet in Renal Disease (DMRD) formula. The authors made a questionnaire survey to identify day-to-day activity limitations and depressions and performed neuropsychological tests using the mini-mental state examination (MMSE), a frontal assessment battery (FAB) for frontal lobe dysfunction, a short-term and delayed memory test (Luria's 10 words test), and a regulatory function assessment test (RFAT). Magnetic resonance imaging (MRI) was carried out to clarify the etiology of CI. RESULTS: CI was detected more frequently in the patients with chronic renal failure (CRF) (Stages III-IV CKD) than in those without CRF (Stages I-II CKD) (in 90.3 and 35%, respectively (p < 0.001)). CI was statistically significantly more frequently found using MMSE (p < 0.001), FAB (p = 0.001), and RFAT (p < 0.001). There was a statistically significant rise in the magnitude of CI with the higher stage of CKD, as shown by MMSE, FAB, and RFAT, other than the short-term and delayed memory test. Brain MRI in the patients with CI revealed focal changes in 9 (30%) patients, leukoaraiosis in 7 (23.3%), lateral cerebral ventricular dilatation in 15 (50%), and markedly dilated hemispheric sulci in 3 (10%). CONCLUSION: The higher stage of CKD is associated with the increased incidence and magnitude of CI, as evidenced by MMSE, and with those of anterior brain dysfunctions. The comparisons of clinical and MRI findings suggest that cerebrovascular disorders underlie CI in CKD.

A fully replication-competent adenovirus vector with enhanced oncolytic properties.

We have studied the oncolytic efficacy of two adenovirus vectors named KD3 and INGN 007, which differ from each other only in that whereas KD3 has two small deletions in its e1a gene that restrict its replication to rapidly cycling cells, INGN 007 has wild-type e1a gene. Both vectors overexpress the adenovirus death protein (ADP). Both KD3 and INGN 007 effectively suppressed the growth of subcutaneous human A549 and Hep3B tumors in nude mice upon intratumoral injection, and contained the growth of subcutaneous LNCaP tumors after intravenous injection, making some tumors shrink or disappear. However, in a more demanding model, intravenous injections of neither KD3 nor wild-type Ad5 were effective against subcutaneous A549 tumors, whereas INGN 007 increased the mean survival time by 35%. INGN 007 was also effective in suppressing tumor growth in a challenging A549 orthotopic lung cancer model. INGN 007 was superior to dl1520 (ONYX-015) in repressing subcutaneous A549 tumors. Our results suggest that vectors such as INGN 007 might provide better antitumor efficacy in the clinic as well.

INGN 007, an oncolytic adenovirus vector, replicates in Syrian hamsters but not mice: comparison of biodistribution studies.

Preclinical biodistribution studies with INGN 007, an oncolytic adenovirus (Ad) vector, supporting an early stage clinical trial were conducted in Syrian hamsters, which are permissive for Ad replication, and mice, which are a standard model for assessing toxicity and biodistribution of replication-defective (RD) Ad vectors. Vector dissemination and pharmacokinetics following intravenous administration were examined by real-time PCR in nine tissues and blood at five time points spanning 1 year. Select organs were also examined for the presence of infectious vector/virus. INGN 007 (VRX-007), wild-type Ad5 and AdCMVpA (an RD vector) were compared in the hamster model, whereas only INGN 007 was examined in mice. DNA of all vectors was widely disseminated early after injection, but decayed rapidly in most organs. In the hamster model, DNA of INGN 007 and Ad5 was more abundant than that of the RD vector AdCMVpA at early times after injection, but similar levels were seen later. An increased level of INGN 007 and Ad5 DNA but not AdCMVpA DNA in certain organs early after injection, and the presence of infectious INGN 007 and Ad5 in lung and liver samples at early times after injection, strongly suggests that replication of INGN 007 and Ad5 occurred in several Syrian hamster organs. There was no evidence of INGN 007 replication in mice. In addition to providing important information about INGN 007, the results underscore the utility of the Syrian hamster as a permissive immunocompetent model for Ad5 pathogenesis and oncolytic Ad vectors.

An acute toxicology study with INGN 007, an oncolytic adenovirus vector, in mice and permissive Syrian hamsters; comparisons with wild-type Ad5 and a replication-defective adenovirus vector.

Oncolytic (replication-competent) adenoviruses as anticancer agents provide new, promising tools to fight cancer. In support of a Phase I clinical trial, here we report safety data with INGN 007 (VRX-007), an oncolytic adenovirus with increased anti-tumor efficacy due to overexpression of the adenovirus-encoded ADP protein. Wild-type adenovirus type 5 (Ad5) and a replication-defective version of Ad5 were also studied as controls. A parallel study investigating the biodistribution of these viruses is described elsewhere in this issue. The toxicology experiments were conducted in two species, the Syrian hamster, which is permissive for INGN 007 and Ad5 replication and the poorly permissive mouse. The studies demonstrated that the safety profile of INGN 007 is similar to Ad5. Both viruses caused transient liver damage upon intravenous injection that resolved by 28 days post-infection. The No-Observable-Adverse-Effect-Level (NOAEL) for INGN 007 in hamsters was 3 x 10(10) viral particles per kg. In hamsters, the replication-defective vector caused less toxicity, indicating that replication of Ad vectors in the host is an important factor in pathogenesis. With mice, INGN 007 and Ad5 caused toxicity comparable to the replication-defective adenovirus vector. Partially based on these results, the FDA granted permission to enter into a Phase I clinical trial with INGN 007.

Anticancer activity of oncolytic adenovirus vector armed with IFN-alpha and ADP is enhanced by pharmacologically controlled expression of TRAIL.

We have previously described oncolytic adenovirus (Ad) vectors KD3 and KD3-interferon (IFN) that were rendered cancer-specific by mutations in the E1A region of Ad; these mutations abolish binding of E1A proteins to p300/CBP and pRB. The antitumor activity of the vectors was enhanced by overexpression of the Adenovirus Death Protein (ADP, E3-11.6K) and by replication-linked expression of IFN-alpha. We hypothesized that the anticancer efficacy of the KD3-IFN vector could be further improved by expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). E1-deleted Ad vectors were constructed carrying reporter genes for enhanced green fluorescent protein or secreted placental alkaline phosphatase (SEAP) and a therapeutic gene for TRAIL under control of the TetON system. Expression of the genes was increased in the presence of a helper virus and the inducer doxycycline such that up to 231-fold activation of expression for the TetON-SEAP vector was obtained. Coinfection with TetON-TRAIL augmented oncolytic activity of KD3 and KD3-IFN in vitro. Induction of TRAIL expression did not reduce the yield of progeny virus. Combination of TetON-TRAIL and KD3-IFN produced superior antitumor activity in vivo as compared with either vector alone demonstrating the efficacy of a four-pronged cancer gene therapy approach, which includes Ad oncolysis, ADP overexpression, IFN-alpha-mediated immunotherapy, and pharmacologically controlled TRAIL activity.

Recombinant avian adenovirus CELO expressing the human interleukin-2: characterization in vitro, in ovo and in vivo.

In our study, a recombinant adenovirus based on the avian adenovirus CELO genome, has been constructed that contains the human interleukin-2 gene. We have shown the production of biologically active recombinant interleukin-2 in vitro (LMH and 293 cells) and in ovo (chicken embryos) infected with recombinant virus CELO-IL2. An increase in the median survival time of C57BL/6 mice carrying B16 melanoma tumors has been demonstrated after multiple intra-tumors injections of the recombinant adenovirus CELO-IL2.

[Eukaryotic vectors of Celo avian adenovirus genome, carrying GFP and human IL-2 genes]. / Eukarioticheskie vektory na osnove genoma adenovirusa ptits Celo, nesushchie geny GFP i IL-2 cheloveka.

Recombinant CELO avian adenoviruses carrying green fluorescent protein (GFP) and and human interleukin-2 (IL-2) genes were obtained by homologous recombination in cell culture. The resultant recombinant CELO viruses are reproduced in chick embryos in the renal tubular and chorionic allantoic membrane cells. The ability of CELO vectors to transduce human and animal cells was studied in vitro (in cell cultures) and in vivo (in laboratory animals). GFP gene delivery and expression in recombinant CELO virus in tumors in C57BL/6 mice were for the first time demonstrated for B16 melanoma. Human IL-2 gene expression and protein accumulation in allantoic fluid of chick embryos infected with CELO-IL-2 vector were detected for the first time.

[Delivery of secreted placental alkaline phosphatase (SEAP) gene in vitro and in vivo as a component of recombinant avian adenovirus (CELO)]. / Dostavka in vitro i in vivo gena sekretiruemoi platsentarnoi shchelochnoi fosfatazy (SEAP) v sostave rekombinantnogo adenovirusa ptits (CELO).

Recombinant adenoviruses capable of expressing the gene of secreted placentary alkaline phosphatase (SEAP) under control of CMV-promoter was obtained on the basis of CELO avian adenovirus and human adenovirus-5 (Ad5) genomes. The efficiency of the CELO vector was determined in experiments with transduction of human (293, A549, and H1299), mouse (B16), and avian (LMH) cell cultures. It was shown in C57BL/6 mice in vivo that SEAP gene is expressed under conditions of intravenous, intranasal, and intratumoral application of recombinant adenovirus CELO-SEAP. The duration of expression of the alkaline phosphatase CELO = SEAP gene in immunocompetent mouse body was 21 days. The level of SEAP gene expression was measured in the allantois fluid of chicken embryo infected with recombinant adenovirus CELO-SEAP.

[Use of computer test systems in the study of age-specific features of higher brain dysfunctions]. / Ispol'zovanie testovykh komp'iuternykh sistem pri izuchenii vosrastnykh osobennostei narushenii vysshikh mozgovykh funktsii.

The paper covers the results of the study whose aim was to determine the quantitative and structural features of neurological and neuropsychological disorders in elderly patients with normotensive hydrocephalus and dyscirculatory encephalopathy from neuropsychological findings and by means of computer test systems.