We report our pediatric experience with lacosamide, a new antiepileptic drug, approved by the US Food and Drug Administration as adjunctive therapy in focal epilepsy in patients more than 17 years ...old. We retrospectively reviewed charts for lacosamide use and seizure frequency outcome in patients with focal epilepsy (Wilcoxon signed rank test). Sixteen patients (7 boys) were identified (median dose 275 mg daily, 4.7 mg/kg daily; mean age 14.9 years, range 8-21 years). Patients were receiving a median of 2 antiepileptic drugs (interquartile range IQR 1.7-3) in addition to having undergone previous epilepsy surgery ( n = 3), vagus nerve stimulation ( n = 9), and ketogenic diet ( n = 3). Causes included structural (encephalomalacia and diffuse encephalitis, 1 each; stroke in 2) and genetic abnormalities (Aarskog and Rett syndromes, 1 each) or cause not known ( n = 10). Median seizure frequency at baseline was 57 per month (IQR 7-75), and after a median follow-up of 4 months (range 1-13 months) of receiving lacosamide, it was 12.5 per month (IQR 3-75), ( P < 0.01). Six patients (37.5%; 3 seizure free) were classified as having disease that responded to therapy (≥50% reduction seizure frequency) and 10 as having disease that did not respond to therapy (<50% in 3; increase in 1; unchanged in 6). Adverse events (tics, behavioral disturbance, seizure worsening, and depression with suicidal ideation in 1 patient each) prompted lacosamide discontinuation in 4/16 (25%). This retrospective study of 16 children with drug-resistant focal epilepsy demonstrated good response to adjunctive lacosamide therapy (median seizure reduction of 39.6%; 37.5% with ≥50% seizure reduction) without severe adverse events.
Abstract Purpose To study glycemic control and hypoglycemia development upon initiation of insulin through a self-titration schedule in a 24-week trial, conducted with 4875 insulin-naïve patients ...with poorly controlled type 2 diabetes, predominantly in a primary care setting. Methods Subjects initiated twice-daily biphasic insulin aspart 70/30 with 6 units prebreakfast and 6 units presupper, self-titrating according to self-measured blood glucose values. Subjects were randomized (1:1:1) to telephone counseling provided by a registered dietician: no counseling (NC), 1 counseling session (1C), or 3 sessions (3C). Results Mean baseline HbA1c (9.9% across groups) decreased ∼2.5% to 7.49% ± 1.48, 7.48% ± 1.50, and 7.44% ± 1.46 in the NC, 1C, and 3C groups, respectively. Within these groups, a hemoglobin A1c (HbA1c ) value <7% was achieved by 40.2%, 41.6%, and 41.8% of subjects, respectively. Eight-point blood glucose profiles were substantially improved from baseline for all groups. Hypoglycemia was experienced by 10.2%-11.4% of the subjects in each group. Rates of minor and major hypoglycemia were low but decreased as dietary counseling increased (minor hypoglycemia: 56 vs 50 vs 45 episodes per 100 patient-years; major hypoglycemia, 9 vs 6 vs 4 episodes per 100 patient-years, for the NC vs 1C vs 3C groups, respectively; P <.001, 3C vs NC). Weight increased by 3.13, 3.40, and 2.88 kg for the NC, 1C, and 3C groups, respectively. Conclusion In the primary care setting, self-titration of biphasic insulin aspart 70/30 was effective in achieving recommended HbA1c goals even with minimal dietary counseling.
Abstract Background The Initiation of Insulin to reach A1C Target (INITIATEplus) trial studied the effect of self-titrating biphasic insulin aspart 70/30 (BiAsp 30) twice daily during 24 weeks in ...insulin-naïve patients with type 2 diabetes who were poorly controlled by oral medication, and originally randomized according to frequency of dietary counseling interventions. Objective The purpose of this study was to compare the efficacy and tolerability of biphasic insulin aspart 70/30 (BIAsp 30, NovoLog Mix 70/30) in INITIATEplus patients ≤65 versus >65 years old, irrespective of dietary counseling frequency, and to test the hypothesis that self-titrating BIAsp 30 in patients >65 years old could be well-tolerated and effective in this age group. Methods An exploratory post hoc subanalysis, using standard statistical methods, was performed on patients stratified according to age. Data collected from 3492 patients in the intent-to-treat population who were ≤65 years old and 716 patients who were >65 years old compared glycosylated hemoglobin (HbA1c ) and plasma glucose changes from baseline. Hypoglycemia rates and adverse event (AE) incidence were compared for the tolerability population of 4007 patients ≤65 years old and 805 patients >65 years old. Results Baseline-adjusted HbA1c changes for patients ≤65 versus >65 years old were –2.38% versus –2.73% ( P < 0.0001), with final HbA1c achieving 7.55% and 7.06%, respectively. Thirty-nine percent of patients ≤65 years old achieved HbA1c ≤7% compared with 51% of patients >65 years old. Baseline-adjusted fasting plasma glucose decreases were greater for the >65 year old population (85.2 vs 91.2 mg/dL; P = 0.004; ≤65 vs >65 years old, respectively). Minor hypoglycemia was reported in 9.7% and 7.7% of patients ≤65 versus >65 years old, respectively (0.52 vs 0.41 episodes per patient per year ppy; P = 0.01). Major hypoglycemia occurred in 1.5% and 3.1% of patients (0.05 vs 0.14 episodes ppy, ≤65 vs >65 years old, respectively; P < 0.0001). Nocturnal major hypoglycemia was reported for 0.4% and 0.6% of patients ( P = 0.0028), whereas nocturnal minor hypoglycemia was reported for 3.8% and 2.6% ( P = 0.007) of patients ≤65 and >65 years old, respectively. AEs were reported for 24% and 28% of patients ≤65 and >65 years old, respectively, serious AEs were reported for 4% and 9% of patients, respectively, and AE-related withdrawals were reported for 1.3% and 2% of patients, respectively. Conclusions Self-titrated biphasic insulin aspart 70/30 was found to be well-tolerated and effective in type 2 diabetes patients >65 years old, as well as in patients ≤65 years old. HbA1c and fasting plasma glucose decreases were significantly ( P < 0.05) higher for patients >65 years old versus patients ≤65 years old. Tolerability was indicated by major and minor hypoglycemia rates at or below <0.5 episodes ppy in both age groups. Overall rates of AE and serious AEs were higher among patients > 65 years; withdrawals related to AEs were 2% compared with 1.3% in the younger age group. ClinicalTrials.gov identifier: NCT 00101751.
Background Activated phosphoinositide 3-kinase δ syndrome (APDS) is a recently described combined immunodeficiency resulting from gain-of-function mutations in PIK3CD , the gene encoding the ...catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ). Objective We sought to review the clinical, immunologic, histopathologic, and radiologic features of APDS in a large genetically defined international cohort. Methods We applied a clinical questionnaire and performed review of medical notes, radiology, histopathology, and laboratory investigations of 53 patients with APDS. Results Recurrent sinopulmonary infections (98%) and nonneoplastic lymphoproliferation (75%) were common, often from childhood. Other significant complications included herpesvirus infections (49%), autoinflammatory disease (34%), and lymphoma (13%). Unexpectedly, neurodevelopmental delay occurred in 19% of the cohort, suggesting a role for PI3Kδ in the central nervous system; consistent with this, PI3Kδ is broadly expressed in the developing murine central nervous system. Thoracic imaging revealed high rates of mosaic attenuation (90%) and bronchiectasis (60%). Increased IgM levels (78%), IgG deficiency (43%), and CD4 lymphopenia (84%) were significant immunologic features. No immunologic marker reliably predicted clinical severity, which ranged from asymptomatic to death in early childhood. The majority of patients received immunoglobulin replacement and antibiotic prophylaxis, and 5 patients underwent hematopoietic stem cell transplantation. Five patients died from complications of APDS. Conclusion APDS is a combined immunodeficiency with multiple clinical manifestations, many with incomplete penetrance and others with variable expressivity. The severity of complications in some patients supports consideration of hematopoietic stem cell transplantation for severe childhood disease. Clinical trials of selective PI3Kδ inhibitors offer new prospects for APDS treatment.
Recent investigations have shown that cycloaddition reactions, widely used in organic chemistry to form ring compounds, can also be applied to link organic molecules to the (001) surfaces of ...crystalline silicon, germanium, and diamond. While these surfaces are comprised of SiSi, GeGe, and CC structural units that resemble the CC bonds of organic alkenes, the rates and mechanisms of the surface reactions show some distinct differences from those of their organic counterparts This article reviews recent studies of 2 + 2, 4 + 2 Diels−Alder, and other cycloaddition reactions of organic molecules with semiconductor surfaces and summarizes the current understanding of the reaction pathways.
Local regulation of alpha 1-antitrypsin ( alpha 1-AT) may have importance in maintenance of the protease-antiprotease balance in the microenvironment of inflammatory cells. We therefore studied ...whether lipopolysaccharide (LPS), interleukin-1 beta (IL-1 beta ), and tumor necrosis factor- alpha (TNF alpha ) affect the pericellular concentration of alpha 1-AT in human peripheral blood mononuclear cells (PBMC). PBMC taken from normal healthy volunteers were treated with LPS, IL-1 beta , and TNF alpha , and the concentration of human alpha 1-AT in conditioned supernatants was measured. When compared with unstimulated control supernatants (147 plus or minus 19 ng/ml), LPS (439 plus or minus 66 ng/ml; p less than or equal to 0.001), IL-1 beta (263 plus or minus 37 ng/ml; p less than or equal to 0.01), and TNF alpha (316 plus or minus 59 ng/ml; p less than or equal to 0.05) induced a 2- to 3-fold increase of alpha 1-AT. Up-regulation of alpha 1-AT protein correlated with an increase in alpha 1-AT mRNA, suggesting a simultaneous increase in alpha 1-AT synthesis. Despite the increase in alpha 1-AT concentration, functional antiprotease activity could not be detected. Furthermore, protease activity was present in all samples, with the amount of activity being inversely related to the amount of alpha 1-AT measured in supernatants. These findings suggest that local inflammatory conditions up-regulate alpha 1-AT production by monocytes which complex with a protease derived from the PBMC population.
Ultrathin Organic Layers on Silicon Surfaces Hamers, Robert J.; Hovis, Jennifer S.; Coulter, Sarah K. ...
Japanese Journal of Applied Physics,
07/2000, Letnik:
39, Številka:
7S
Journal Article
Recenzirano
Ultrathin organic layers of organic molecules can be produced on the Silicon(001) surface using surface analogs of well-known cycloaddition reactions from organic chemistry. Molecules containing one ...or more unsaturated C=C can readily bond to the surface at room temperature. Since these reactions form two bonds between the molecule and the surface, the attached molecules are also oriented. More complex molecules containing conjugated pi-electron systems such as styrene can also be bonded to the surface with high selectivity for specific bonds. This manuscript reviews recent progress in forming ultrathin organic layers on silicon, and the current understand of the relevant reaction mechanisms.
Metachromatic leucodystrophy (MLD) is a lysosomal storage disease resulting from a deficiency of arylsulphatase A. We have identified a child with infantile onset MLD who is homozygous for an A212V ...mutation, a mutation previously reported but not further characterised. We have introduced this mutation into an arylsulphatase A expression vector by site directed mutagenesis. Transient expression of this mutant plasmid in COS cells yields very low levels of arylsulphatase A activity consistent with the patient's phenotype. The arylsulphatase A pseudodeficiency also segregates in this family causing difficulty in interpreting enzyme levels in the absence of DNA data. Two other patients from the same province, also carrying the A212V allele, have juvenile and adult onset MLD and are heterozygous for P426L ("A" allele) and I179S alleles respectively, known late onset alleles.
PDF
