Effects of ganaxolone on non-seizure outcomes in CDKL5 Deficiency Disorder: Double-blind placebo-controlled randomized trial.

CDKL5 deficiency disorder (CDD) is a rare developmental and epileptic encephalopathy. Ganaxolone, a neuroactive steroid, reduces the frequency of major motor seizures in children with CDD. This analysis explored the effect of ganaxolone on non-seizure outcomes. Children (2-19 years) with genetically confirmed CDD and ≥ 16 major motor seizures per month were enrolled in a double-blind randomized placebo-controlled trial. Ganaxolone or placebo was administered three times daily for 17 weeks. Behaviour was measured with the Anxiety, Depression and Mood Scale (ADAMS), daytime sleepiness with the Child Health Sleep Questionnaire, and quality of life with the Quality of Life Inventory-Disability (QI-Disability) scale. Scores were compared using ANOVA, adjusted for age, sex, number of anti-seizure mediations, baseline 28-day major motor seizure frequency, baseline developmental skills, and behaviour, sleep or quality of life scores. 101 children with CDD (39 clinical sites, 8 countries) were randomized. Median (IQR) age was 6 (3-10) years, 79.2 % were female, and 50 received ganaxolone. After 17 weeks of treatment, Manic/Hyperactive scores (mean difference 1.27, 95%CI -2.38,-0.16) and Compulsive Behaviour scores (mean difference 0.58, 95%CI -1.14,-0.01) were lower (improved) in the ganaxolone group compared with the placebo group. Daytime sleepiness scores were similar between groups. The total change in QOL score for children in the ganaxolone group was 2.6 points (95%CI -1.74,7.02) higher (improved) than in the placebo group but without statistical significance. Along with better seizure control, children who received ganaxolone had improved behavioural scores in select domains compared to placebo.

Adapting a measure of gross motor skills for individuals with CDKL5 deficiency disorder: A psychometric study.

PURPOSE: Validated measures capable of demonstrating meaningful interventional change in the CDKL5 deficiency disorder (CDD) are lacking. The study objective was to modify the Rett Syndrome Gross Motor Scale (RSGMS) and evaluate its psychometric properties for individuals with CDD. METHODS: Item and scoring categories of the RSGMS were modified. Caregivers registered with the International CDKL5 Clinical Research Network uploaded motor videos filmed at home to a protected server and completed a feedback questionnaire (n = 70). Rasch (n = 137), known groups (n = 109), and intra- and inter-rater reliability analyses (n = 50) were conducted. RESULTS: The age of individuals with CDD ranged from 1.5 to 34.1 years. The modified scale, Gross Motor-Complex Disability (GM-CD), comprised 17 items. There were no floor or ceiling effects and inter- and intra-rater reliability were good. Rasch analysis demonstrated that the items encompassed a large range of performance difficulty, although there was some item redundancy and some disordered categories. One item, Prone Head Position, was a poor fit. Caregiver-reported acceptability was positive. Scores differed by age and functional abilities. SUMMARY: GM-CD appears to be a suitable remotely administered measure and psychometrically sound for individuals with CDD. This study provides the foundation to propose the use of GM-CD in CDD clinical trials. Longitudinal evaluation is planned.

A New Wavelet Collocation Algorithm for Solving a Nonlinear Boundary Value Problem of the Human Corneal Shape.

The Hermite wavelet method (HWM) is introduced in this study to solve a nonlinear differential equation determining the human corneal morphology. The changes in curvature of the human cornea in hypotony, normal intraocular pressure, glaucoma, and other conditions are discussed. The Hermite wavelet operational matrices of derivatives are used to generate wavelet solutions based on this technique. The solutions of the nonlinear differential equation are determined for various values of constant parameters that can appear in the diverse physical situations. The proposed wavelet solutions are more accurate than the other approximate analytical solutions listed in the literature. The HWM solutions are compared to homotopy perturbation method, Taylor series, pertur-bation technique and artificial neural network solutions. There is broad consensus. This illustrates that HWM is a useful and appropriate strategy for handling difficulties with nonlinear boundary value problems that emerge in corneal geometry.

Pressure-Induced Amorphization of Diisopropylammonium Perchlorate Studied by Raman Spectroscopy and X-ray Diffraction.

Diisopropylammonium salts have drawn attention in recent years due to their room-temperature ferroelectric properties. Triclinic diisopropylammonium perchlorate (DIPAP) exhibits ferroelectricity at room temperature. We have carried out density functional theory calculations to assign the phonon modes in DIPAP. High-pressure Raman spectra of DIPAP are recorded up to ∼3 GPa. Discontinuity in the NH2 bending and stretching mode frequencies and the appearance of new bands at 0.7 GPa suggest a phase transition by a rearrangement in the hydrogen network. Broadening of lattice modes at 1.3-1.7 GPa indicates a loss of crystalline nature above 1.7 GPa. High-pressure synchrotron X-ray diffraction of DIPAP shows an isostructural phase transition at 0.6 GPa and confirms amorphization at 1.5 GPa that may lead to a loss of ferroelectricity above this pressure. The ambient phase becomes reversible after releasing the pressure. The bulk modulus of DIPAP is determined to be 16.5 GPa.

Absence of the frequently reported PIK3CA, CASP8, and NOTCH1 mutations in South Indian oral cancers.

OBJECTIVES: Somatic mutations of the PIK3CA, CASP8, and NOTCH1 have been frequently detected in various human cancers. Our study aimed to analyze the mutational status of these genes in South Indian oral cancers. SUBJECTS AND METHODS: We performed mutational analysis of the PIK3CA (exons 9 and 20), CASP8 (exon 9), and NOTCH1 (exons 5, 6, 7, 8, and 9) genes in 96, 48, and 44 oral cancer samples, respectively. All the specified exons were PCR (polymerase chain reaction)-amplified and directly sequenced by Sanger sequencing. RESULTS: PIK3CA gene mutations were not found; however, a synonymous single nucleotide polymorphism (SNP) [rs17849079] was observed frequently [35/96 (36.4%)] in oral cancer samples. Further, no mutations were detected in the CASP8 gene, but observed a frequent [32/48 (66.6%)] SNP [rs1045487] in the oral cancer samples. We did not detect any mutation in the NOTCH1 gene (exons 5, 6, 7, 8, and 9) in all the [0/44] analyzed oral cancer samples. CONCLUSIONS: This is the first study that reports the status of the PIK3CA, CASP8, and NOTCH1 mutations in South Indian oral cancer samples. Our study suggests that either mutations in these genes are uncommon in South Indian oral cancer samples or likely other genes in this pathway might be mutated.

Primary lesser sac myxoid liposarcoma: A case report.

INTRODUCTION: Lesser sac pathological entities are uncommon. Most of these are tumors and are generally misdiagnosed as retroperitoneal lesions. CASE REPORT: A 62year old male with past history of treated hypopharyngeal cancer presented with progressive abdominal distension. Physical examination revealed a midline intra abdominal mass in the epigastrium and umbilical region. Radiological investigations were suggestive of a retroperitoneal tumor,an image guided biopsy was reported as atypical lipoma. Surgical exploration confirmed a large multi lobulated tumor arising primarily from the lesser sac, post operative histopathological examination confirmed a myxoid liposarcoma. DISCUSSION: Primary lesser sac tumors are rare, a literature review of primary lesser sac tumors with particular reference to myxoid liposarcoma is presented. CONCLUSION: Primary lesser sac liposarcomas are rare neoplasms. The myxoid variant is unique for its peculiar biological behavior, in its sensitivity to chemotherapy and radiotherapy and for the presence of specific cytogenetic marker.

Uterine Sarcoma: The Indian Scenario.

Uterine sarcomas are rare, highly malignant tumours comprising < 1 % of all gynaecologic malignancies. To evaluate clinical presentation, histolopathologic pattern and outcome of uterine sarcomas presenting to a tertiary referral centre over an 8 year period (2004-2012). All histologically proven uterine sarcomas were retrospectively analysed. Clinical presentation, histology, treatment and outcome were analysed. Mean age was 42 years. Predominant histopathology was endometrial stromal sarcoma (n = 13); 9 were low grade, carcinosarcoma (n = 8) and leiomyosarcoma (n = 2). Fourteen patients had Stage I disease, 3 Stage II, 4 Stage III and 2 were Stage IV at presentation. Patients with disease confined to uterus received no adjuvant treatment (61 %). Of these, 11 were endometrial stromal sarcoma (7 were low grade) and 3 were carcinosarcomas. Four patients received adjuvant EBRT following hysterectomy (17 %). Two patients who presented with metastases received palliative chemotherapy. Mean follow-up period was 46 months (0-86 months). Eleven patients (47 %) developed disease recurrence. Seven (30 %) had local recurrence, while 4 (17 %) developed pulmonary metastases. A total of eight patients died and all deaths were within 1 year of recurrence. The only prognostic factor that correlated with survival was the stage of disease at diagnosis.

An efficient wavelet-based approximation method to gene propagation model arising in population biology.

In this paper, we have applied an efficient wavelet-based approximation method for solving the Fisher's type and the fractional Fisher's type equations arising in biological sciences. To the best of our knowledge, until now there is no rigorous wavelet solution has been addressed for the Fisher's and fractional Fisher's equations. The highest derivative in the differential equation is expanded into Legendre series; this approximation is integrated while the boundary conditions are applied using integration constants. With the help of Legendre wavelets operational matrices, the Fisher's equation and the fractional Fisher's equation are converted into a system of algebraic equations. Block-pulse functions are used to investigate the Legendre wavelets coefficient vectors of nonlinear terms. The convergence of the proposed methods is proved. Finally, we have given some numerical examples to demonstrate the validity and applicability of the method.

Alleviation of oxidative and nitrosative stress following curative resection in patient with oral cavity cancer.

BACKGROUND: Oxidative stress by reactive oxygen species (ROS) and nitrosative stress by reactive nitrogen species (RNS) are proven initiators and promoters in carcinogenesis. Elevated ROS/RNS with lowered antioxidants occur in patients with squamous cell carcinoma of oral cavity. Ours is the first study to evaluate the effect of curative resection on both oxidative and nitrosative stress in such patients. METHODS: This study was conducted on 24 cancer patients and with age- and sex-matched healthy controls. Lipid peroxidation products, nitric oxide (NO) products and ceruloplasmin (CPL) in plasma were measured before and after surgery. Similarly enzymatic antioxidants in erythrocytes and non-enzymatic antioxidants in plasma were measured. RESULTS: Statistically significant elevation of lipid peroxidation, NO products and CPL and depletion of antioxidants were found in cancer patients compared with controls. After curative surgical resection there was a statistically significant fall in oxidants and CPL coupled with a rise in antioxidants. CONCLUSIONS: Our results suggest that oxidative/nitrosative stress could play a significant role in oral cavity cancer (OCC) and that curative resection is effective in alleviating this oxidative/nitrosative burden. Significant mitigation of oxidative/nitrosative stress could indicate the completeness of resection since tumor forms the major source of oxidants.

Effective attraction between like-charged colloids in a two-dimensional plasma.

The existence of attractions between like-charged colloids immersed in ionic solution has been discovered in recent experiments. This phenomenon contradicts the predictions of Derjaguin-Landau-Verwey-Overbeek and indicates a failure of mean-field theory. We study a toy model based on a two-dimensional one-component plasma, which is exactly soluble at one particular coupling constant. We show that colloidal interaction results from a competition between ion-ion repulsion and longer ranged ion-void attraction.

Neuromuscular ventilatory insufficiency: effect of home mechanical ventilator use v oxygen therapy on pneumonia and hospitalization rates.

The purpose of this study was to determine rates of pneumonia and hospitalization for patients receiving oxygen therapy, patients having indwelling tracheostomy tubes, and those using tracheostomy or noninvasive methods of home mechanical ventilation. Six hundred eighty-four users of assisted ventilation for 13,751 patient-years or 19.8 years per patient were surveyed by mail and twice by telephone over a span of four years. Pneumonia and hospitalization rates were significantly higher for ventilator users with chronic obstructive pulmonary disease or with neuromuscular ventilatory insufficiency and gastrostomy tubes than for ventilator users with neuromuscular ventilatory insufficiency without gastrostomy tubes. Of the latter group, more than 90% of the pneumonias and hospitalizations were triggered by otherwise benign intercurrent upper respiratory tract infections. Oxygen therapy was associated with a significantly (P < 0.001) higher rate of pneumonias and hospitalizations than that seen for untreated patients after initial episodes of respiratory distress or during the use of either tracheostomy intermittent positive pressure ventilation or noninvasive ventilatory assistance methods. The lowest pneumonia and hospitalization rates (P < 0.001) were by full-time, noninvasive intermittent positive pressure ventilation users. We conclude that oxygen therapy is not an effective substitute for assisted ventilation for patients with primarily ventilatory insufficiency. Noninvasive ventilatory aids can be used effectively for up to full-time ventilatory support for patients with neuromuscular conditions whose bulbar muscle function is adequate to avert the need for gastrostomy tube placement.

Fibronectin enhances in vitro lipopolysaccharide priming of polymorphonuclear leukocytes.

We investigated the role of humoral factors in lipopolysaccharide (LPS) priming of polymorphonuclear leukocytes (PMN) using cells isolated from adults and from neonates. Plasma from newborn infants had decreased priming activity of adult plasma when mixed with LPS in studies measuring oxidative radical production of PMN after stimulation with a formyl bacterial oligopeptide (fMLP). This marked difference was not caused by LPS binding protein (LBP) because the LBP concentration in newborn and adult plasma were similar (138.4 +/- 12.9 U for adults, and 126.9 +/- 12.1 U for neonates, P = .53). Therefore, we attempted to identify other plasma factors that may contribute to LPS priming of PMN. We identified an LPS priming factor for PMN that is present in plasma, heat stable (56 degrees C for 30 minutes), enhanced by heparin, and concentrated in cold precipitates of plasma. Because these properties resemble those of plasma fibronectin, we assessed the role of fibronectin in LPS priming of PMN. Although fibronectin in phosphate-buffered saline (PBS) had little effect on LPS priming of PMN, fibronectin in combination with other plasma factors appeared to play a role in LPS priming of PMN because (1) removing fibronectin from adult plasma dramatically decreased LPS priming activity from plasma (P < .005), (2) addition of fibronectin to fibronectin-depleted plasma restored its LPS plasma priming activity (P < .05), and (3) neutralizing fibronectin with antibody decreased the LPS priming activity of plasma (60.3 +/- 1.3 v 30.2 +/- 2.2, P < .01). Thus, plasma fibronectin plays a role in LPS priming of PMN in the presence of other factors in plasma.

Avian integrin alpha v subunit associates with multiple beta subunits and shows tissue-specific variation in its association.

Integrins are heterodimeric cell surface receptors involved in cell adhesion to extracellular matrix proteins and in cell-cell interactions. RGD peptide-specific integrin subunit alpha v and its associated beta subunits were isolated by GRGDSPK-Sepharose affinity chromatography. Using Western blot and immunoprecipitation techniques, the nature of this integrin complexity in the avian system was studied in comparison with that of the human system. As found in human cell systems, in chicken embryo fibroblasts the integrin alpha v subunit is associated with both the 90-kDa beta 3 and the 110-kDa beta 1-like subunits with high specific binding to RGD peptides. Furthermore, immunoprecipitation studies revealed the presence of an unidentified 120-kDa subunit and an 85-kDa beta 5 subunit associated with the alpha v subunit in these cells. No qualitative differences were observed in the beta subunit profile associated with alpha v, as a function of the proliferating nonconfluent or nonproliferating confluent states of the embryonic fibroblast cultures. In adult chicken gizzard, a 110-kDa beta 1-like subunit and a 90-kDa subunit that does not cross-react with anti-H-beta 3 and anti-H-beta 5 are associated with the alpha v subunit. The structure of the novel 120-kDa subunit found in the embryonic fibroblasts and the 90-kDa subunit found in adult chicken gizzard and the ligand specificities of these novel combinations of alpha v are not known at present, but these integrins are RGD specific. It is hypothesized that embryonic fibroblasts, being the primordial proliferating cells, display a wider spectrum of alpha v-associated beta subunits, whose expression may progressively be restricted or highly reduced in favor of one or more beta subunits in subsequent progenies as differentiation progresses.

Monoclonal antibodies against Epstein-Barr virus transformed B lymphocytes from a CLL patient.

Immunization of BALB/c mice with EBV-CLL-1 cells, derived from Epstein-Barr virus transformed B lymphocytes from a chronic lymphocytic leukemia (CLL) patient, yielded 2 monoclonal antibodies (IgG1 Kappa and IgG2a Kappa) against a membrane antigen on a subset of normal B lymphocytes and non-Hodgkin's lymphomas. Immunofluorescence revealed strong reactivity of the antibodies with EBV-CLL-1 cells and with most lymphocytes in tonsil follicles, in the intestinal wall, around splenic arterioles and near Hassall's corpuscles in the neonatal thymus as well as with a small proportion of lymphocytes in some large reactive lymph node follicles, weak reactivity with 1/5 of peripheral blood B lymphocytes (PBL), and no reactivity with platelets, granulocytes and non-lymphoid tissues. PBL from 3 CLL patients showed weak staining of only larger cells. Intense fluorescence was observed in several non-Hodgkin's lymphomas of various histological types and in Burkitt's lymphoma lines but not in the 3 T lymphoblastoid and 12 nonlymphoid tumor lines examined. The antibodies precipitated Mr 22,000 and 33,000 bands from surface labeled RAJI or EBV-CLL-1 cells and cross-competed in a binding inhibition assay. The antibodies had approximately 6 million binding sites per EBV-CLL-1 or RAJI cell but were not cytotoxic. This high antigen-density and limited expression in normal cells may permit their use for immunocytological diagnosis and targeting cytotoxic agents and radionuclides against appropriate lymphoma cells.

Manipulation of macrophage migration inhibition/stimulation responses by adjuvants and interleukins.

C57 B1/6 mice were immunized with bovine serum albumin (BSA) and Freund's complete and incomplete adjuvants in various concentrations. Spleen cells from these animals were subsequently stimulated with concanavalin A (Con A), purified protein derivative or BSA, and lymphokine responses were measured in one-stage migration assays. Con A consistently produced macrophage migration inhibition factor (MIF) responses in nonimmunized animals and those immunized with complete adjuvant. This was switched to migration stimulation factor (MStF) responses by prior immunization with incomplete adjuvant. Immunization with complete adjuvant and with BSA alone was followed by MIF responses to antigenic stimulation whereas incomplete adjuvant promoted MStF responses. The MStF responses to both mitogenic and antigenic stimulation were inhibited by the addition of affinity purified interleukin-1 to the spleen cells. Interleukin-1 also inhibited MStF responses and potentiated MIF responses to Con A stimulation by human mononuclear cells whereas interleukin-2 did not influence these responses.

The cellular basis for differential lymphokine responses to mitogen stimulation.

Human mononuclear cells from some individuals produce macrophage migration inhibition factor (MIF) when stimulated with Con A while those of others produce migration stimulation factor (MStF). T cells were responsible for these different responses but T4 cells produced MIF and T8 cells produced MStF regardless of the global response which was not explained by the individual T4:T8 ratios. Admixing the T-cell subpopulations in vitro revealed that MIF responses switched to MStF responses between T4:T8 ratios of 75:25 and 50:50 with MStF responders switching at higher ratios than MIF responders. Pulse exposure to supernatants from Con A-stimulated T4-enriched cells significantly reduced migration indices resulting from stimulation of fresh cells, promoting MIF responses regardless of the responder status of the supernatant donor. In contrast, supernatants from T8-enriched cells, when obtained from MStF responders, significantly increased migration indices while there was no effect when the supernatants were obtained from MIF responders. These results suggest that soluble factors from T8 cells are primarily responsible for determining whether an individual mounts a MIF or MStF response to Con A stimulation.