Efficacy, safety, tolerability and pharmacokinetics of a novel human immune globulin subcutaneous, 20%: a Phase 2/3 study in Europe in patients with primary immunodeficiencies.

A highly concentrated (20%) immunoglobulin (Ig)G preparation for subcutaneous administration (IGSC 20%), would offer a new option for antibody replacement therapy in patients with primary immunodeficiency diseases (PIDD). The efficacy, safety, tolerability and pharmacokinetics of IGSC 20% were evaluated in a prospective trial in Europe in 49 patients with PIDD aged 2-67 years. Over a median of 358 days, patients received 2349 IGSC 20% infusions at monthly doses equivalent to those administered for previous intravenous or subcutaneous IgG treatment. The rate of validated acute bacterial infections (VASBIs) was significantly lower than 1 per year (0·022/patient-year, P < 0·0001); the rate of all infections was 4·38/patient-year. Median trough IgG concentrations were ≥ 8 g/l. There was no serious adverse event (AE) deemed related to IGSC 20% treatment; related non-serious AEs occurred at a rate of 0·101 event/infusion. The incidence of local related AEs was 0·069 event/infusion (0·036 event/infusion, when excluding a 13-year-old patient who reported 79 of 162 total related local AEs). The incidence of related systemic AEs was 0·032 event/infusion. Most related AEs were mild, none were severe. For 64·6% of patients and in 94·8% of IGSC 20% infusions, no local related AE occurred. The median infusion duration was 0·95 (range = 0·3-4·1) h using mainly one to two administration sites [median = 2 sites (range = 1-5)]. Almost all infusions (99·8%) were administered without interruption/stopping or rate reduction. These results demonstrate that IGSC 20% provides an effective and well-tolerated therapy for patients previously on intravenous or subcutaneous treatment, without the need for dose adjustment.

Difficulties in the Diagnosis and Management of Paediatric Posterior Circulation Stroke.

We present two children with posterior circulation stroke (PCS) highlighting the wide spectrum of presentation, the need for complete radiological assessment, and the relatively high recurrence risk.

Spontaneous and field-induced mesomorphism of a silyl-terminated bent-core liquid crystal as determined from second-harmonic generation and resonant X-ray scattering.

The polarity and structure of the phases of a liquid crystal constituted by thiophene-based bent-core molecules is investigated by means of optical second-harmonic generation (SHG), and resonant and conventional X-ray diffraction. The material studied is representative of a wide family of mesogens that contain silyl groups at the ends of the chains. These bulky terminal groups have been reported to give rise to smectic phases showing ferroelectric switching. However, the analysis of the SHG signal before and after application of electric fields has allowed us to establish unambiguously that the reported ferroelectricity is not intrinsic to the material but stabilized by the cell substrates once an electric field has been applied. In addition, the results obtained from resonant X-ray diffraction indicate that virgin samples have antiferroelectric undulated synclinic smectic structures.

Investigation of an association between onset of narcolepsy and vaccination with pandemic influenza vaccine, Ireland April 2009-December 2010.

In 2011, the Irish Medicines Board received reports of onset of narcolepsy following vaccination against influenza A(H1N1)pdm09 with Pandemrix. A national steering committee was convened to examine the association between narcolepsy and pandemic vaccination. We conducted a retrospective population-based cohort study. Narcolepsy cases with onset from 1 April 2009 to 31 December 2010 were identified through active case finding. Narcolepsy history was gathered from medical records. Pandemic vaccination status was obtained from vaccination databases. Two independent experts classified cases using the Brighton case definition. Date of onset was defined as date of first healthcare contact for narcolepsy symptoms. Incidence of narcolepsy in vaccinated and non-vaccinated individuals was compared. Of 32 narcolepsy cases identified, 28 occurred in children/adolescents and for 24 first healthcare contact was between April 2009 and December 2010. Narcolepsy incidence was 5.7 (95% confidence interval (CI): 3.4­8.9) per 100,000 children/adolescents vaccinated with Pandemrix and 0.4 (95% CI: 0.1­1.0) per 100,000 unvaccinated children/adolescents (relative risk: 13.9; absolute attributable risk: 5.3 cases per 100,000 vaccinated children/adolescents). This study confirms the crude association between Pandemrix vaccination and narcolepsy as observed in Finland and Sweden. The vaccine is no longer in use in Ireland. Further studies are needed to explore the immunogenetic mechanism of narcolepsy.

Resonant x-ray diffraction study of an unusually large phase coexistence in smectic liquid-crystal films.

The recent discovery of the new smectic-C(d6)(*) (SmC(d6)(*)) phase [S. Wang et al., Phys. Rev. Lett. 104, 027801 (2010)] also revealed the existence of a noisy region in the temperature window between the SmC(d6)(*) phase and the smectic-C(d4)(*) (SmC(d4)(*)) phase. Characterized by multiple resonant peaks spanning a wide region in Q(Z), the corresponding structure of this temperature window has been a mystery. In this Letter, through a careful resonant x-ray diffraction study and simulations of the diffraction spectra, we show that this region is in fact an unusually large coexistence region of the SmC(d6)(*) phase and the SmC(d4)(*) phase. The structure of the noisy region is found to be a heterogeneous mixture of local SmC(d6)(*) and SmC(d4)(*) orders on the sub-µm scale.

Surface and bulk uniaxial to biaxial smectic-A transition in a bent core liquid crystal.

A null transmission ellipsometer was employed to study the uniaxial to biaxial smectic-A phase transition of a bent core liquid crystal material. Free-standing films of thicknesses ranging from 5 molecular layers to more than 300 were prepared and studied. Critical exponents for both the surface and interior biaxiality were obtained. The results were discussed in the general framework of phase transition in lower dimensions.

Recovery of a reversed phase sequence in one ternary liquid-crystal-mixture system.

The nOHFBBB1M7 (n=10) compound, 10OHF, shows a reversed SmC{FI2}-SmC phase sequence, unique among all known antiferroelectric liquid crystals. This reversed phase sequence is stabilized when 10OHF is doped with 9OTBBB1M7(C9) or 11OTBBB1M7(C11). In contrast, doping of the homologous members ( n=9 , 11, or 12) eliminates the SmC{FI2} phase. One 10OHF/11OHF mixture without the SmC{FI2} phase was selected for further studies. By adding C9 into this particular mixture, the reversed phase sequence is revived. To our surprise, even though 11OHF destabilizes the SmC_{FI2} phase in binary mixtures with 10OHF, it significantly increases the SmC_{FI2} temperature range in the 10OHF/11OHF/C9 ternary mixtures.

Nonplanar tilts in very thin smectic films of one liquid-crystal compound.

Surface effects cause tilted molecular arrangements in smectic layers near the surface of a free-standing liquid-crystal film in which the bulk of the film is in the smectic- A phase. One recent work has shown that the tilt directions in adjacent surface layers may be nonplanar. In this paper we study films with thicknesses of two to six smectic layers. Surface effects dominate in these very thin films. We show that the molecular tilts are nonplanar even in these very thin films.

Sensory-motor polyneuropathy occurring in variant maple syrup urine disease.

Maple syrup urine disease (MSUD; OMIM 248600) results from an inherited deficiency of the branched-chain ketoacid dehydrogenase (BCKD) complex. Approximately 20% of patients with BCKD deficiency are non-classic variants of MSUD with differing clinical severity. Outcomes for this cohort are generally favourable; episodes of metabolic decompensation do not appear to correlate with adverse events if acute management is promptly provided. A case of predominantly axonal sensory-motor neuropathy following metabolic decompensation which persisted for a number of months is presented in an adolescent girl with variant (intermediate type) MSUD. EMG and nerve conduction studies suggested a pre-existent asymptomatic chronic neuropathy, exacerbated by the acute decompensation. Peak leucine concentration at decompensation was 1083 µmol/L. The patient had laboratory signs of secondary mitochondrial respiratory chain dysfunction at presentation. She had been on a moderate dose of thiamine prior to decompensation; thiamine and pyridoxine blood concentrations were normal. This, to our knowledge, is the first report of a neuropathy presenting in a patient with a decompensation of variant MSUD. We propose that this presentation resembles the intermittent neuropathy observed in pyruvate dehydrogenase deficiency and may reflect secondary inhibition of pyruvate dehydrogenase activity by MSUD metabolites.

Effects of doping on an unusual smectic- C*alpha-smectic-C*FI2-smectic-C* phase sequence.

The compound 10OHF has a partially inverted phase sequence, unique among the series of nOHF homologous compounds and all other known liquid crystals, with the smectic-C*FI2 (SmC*FI2) phase occurring at higher temperature than the smectic-C* (SmC*) phase. We present ellipsometric data to identify the phase sequences of 9OHF, 10OHF, 11OHF, and 12OHF. Binary mixtures of 10OHF with C11, a compound with the typical phase sequence among the smectic phases, show that the unusual phase sequence of 10OHF stabilizes upon mixing and that SmC*FI2 predominates over SmC* throughout the entire mixing phase diagram. In thin films of some mixtures, surface interactions induce a reentrant SmC*FI2-SmC*-SmC*FI2 transition in the rest of the film.

Smectic-C*alpha phase with two coexistent helical pitch values and a first-order smectic-C*alpha to smectic-C* transition.

Previous results from Kundu using dielectric relaxation have suggested a reentrant antiferroelectric-ferroelectric-antiferroelectric transition in the compound LN36. Our comprehensive studies of this compound using differential optical reflectivity, nonadiabatic scanning calorimetry, null transmission ellipsometry, and resonant x-ray diffraction show that in fact LN36 exhibits the usual phase sequence for chiral smectic liquid crystals: SmA*-SmC*alpha-SmC*-SmC*FI1-SmC*A . Moreover, the SmC*alpha-SmC* transition is a first-order transition, characterized by a discontinuous change in the helical pitch. At temperatures just above the SmC*alpha-SmC* transition, two different values for the helical pitch are simultaneously observed for the first time.

Optical studies on the surface-induced tilted layers in freestanding films of two no-layer-shrinkage liquid crystal compounds.

Null transmission ellipsometry has been employed to study the molecular arrangements in freestanding films of two no-layer-shrinkage liquid crystal homologous compounds above the bulk smectic A-smectic C* (Sm C*) transition temperature. An unusual nonplanar-parallel or nonplanar-antiparallel-parallel transition has been observed in both compounds under a proper electric field. With the addition of one CH2 group, while the SmC* phase is more stable thermally, the magnitude of the critical field needed to induce a parallel-antiparallel transition decreases dramatically.

Smectic-Calpha*-smectic-C* phase transition and critical point in binary mixtures.

We have investigated the smectic-Calpha*-smectic-C* (SmCalpha*-SmC*) transition in a series of binary mixtures with resonant x-ray diffraction, differential optical reflectivity, and heat capacity measurements. Results show that the phases are separated by a first-order transition that ends at a critical point. We report the observation of such a critical point. We have proposed the appropriate order parameter and obtained values of two critical exponents associated with this transition. The values of the critical exponents suggest that long-range interactions are present in the SmCalpha*-SmC* critical region.

Investigations of nanoscale helical pitch in smectic-C*alpha and smectic-C* phases of a chiral smectic liquid crystal using differential optical reflectivity measurements.

Differential optical reflectivity (DOR) was used to study the temperature dependence of the short helical pitch in freestanding films of a liquid crystal compound. The experimentally measured DOR signal was fitted using Berreman's 4 x 4 matrix method to get the pitch value in the smectic-C*alpha (sMC*alpha) phase. The results show continuous evolution of the pitch between the smectic-C*alpha and sMC*alpha phases. In sMC*alpha, the pitch decreases as temperature increases and is found to level off at 16+/-1 smectic layers at the sMC*alpha to smectic-A* transition.

Surface-induced multiple reentrant transitions.

We have studied tilted surface layers in the bulk SmA temperature window of one liquid crystal using null transmission ellipsometry. Five distinct nonplanar surface structures were observed. We present analyses of the tilt and azimuthal profiles of the structures and examine the transitions between the structures. The transitions are identified as a double reentrant synclinic-anticlinic-synclinic-anticlinic transition. Meanwhile, the transitions also display reentrant ferroelectric-antiferroelectric-ferroelectric behavior.

Pentagastrin selectively modulates levels of mRNAs encoding apical H/K adenosine triphosphatase and basolateral Na-K-Cl cotransporter in rat gastric fundic mucosa.

BACKGROUND: Gastrin regulates gastric acid secretion and gastric mucosal cell proliferation. We hypothesized that pentagastrin administration would affect mRNA levels of two membrane proteins that are important during stimulated states of HCl secretion, the basolateral Na-K-Cl cotransporter (BSC) and the apical H/K adenosine triphosphatase (H/K). METHODS: Two groups of Fischer rats received intraperitoneal injections of pentagastrin (2.5 or 25 micrograms/kg) every 8 hours for three doses. A third group served as controls. An additional group received pentagastrin plus the gastrin receptor antagonist (GRA) L740,093. Fundic mucosae were subjected to semiquantitative Northern analysis of mRNAs encoding H/K and BSC. The mRNA for Na/K adenosine triphosphatase (Na/K), a transport protein not involved directly in acid secretion, also was evaluated. RESULTS: Administration of pentagastrin caused dose-dependent increases in levels of mRNAs encoding H/K and BSC but had no significant effect on levels of Na/K mRNA. Administration of GRA prevented the pentagastrin-induced changes in mRNA levels for these transporters. CONCLUSIONS: Pentagastrin administration selectively up-regulates levels of mRNA encoding membrane proteins involved in acid secretion. The up-regulation of the mRNAs encoding BSC during pentagastrin stimulation indicates that regulation of basolateral Cl- movement may be as important as the regulation of apical H+ movement under stimulated states.

Vitamin E and the hypercoagulability of neonatal blood.

This study examines whether vitamin E deficiency has any role in the hypercoagulability of neonatal blood. Blood was collected from mothers and their full-term placental cords. Vitamin E was measured by high-pressure liquid chromatography and whole blood clotting time was measured by recalcification. Cord plasma had significantly lower vitamin E (P < 0.0001) compared with maternal plasma. Whole blood clotting time of cord blood was significantly (P < 0.002) shorter compared with the clotting time of maternal blood. There was a significant correlation between plasma vitamin E and whole blood clotting time (r = 0.54, P < 0.04) of cord blood. The addition of standard vitamin E to cord blood in vitro resulted in prolongation of whole blood clotting time. This suggests that a deficiency of plasma vitamin E can shorten whole blood clotting time in newborns, which may have a role in the disseminated intravascular coagulation frequently experienced by newborn infants.

Nighttime bracing with the Providence brace in adolescent girls with idiopathic scoliosis.

STUDY DESIGN: A prospective study was conducted of 102 consecutive female patients with adolescent idiopathic scoliosis. Those patients with Risser 0, 1, and 2 met the criteria for inclusion and were treated only with the Providence brace. OBJECTIVES: To report the authors' experience with a hypercorrective nighttime brace and to evaluate the results with respect to risk factors for progression. Second, the study compares results with expectations from the natural history as reported by others. SUMMARY OF BACKGROUND DATA: Compliance with full-time brace treatment for adolescent idiopathic scoliosis has been a problem. Since the introduction of the Milwaukee brace, alternatives such as low-profile braces, reduced wearing schedules, and nighttime only bracing have been tried. However, many factors influence the success or failure besides compliance. These include in-brace correction, brace design, and the orthotist's skills. This is the first report of the results of treatment with a new nighttime brace that is made with CAD/CAM technology that can achieve higher initial in-brace corrections than other reported methods. METHODS: Results were analyzed with respect to curve size, curve pattern, maturity, and level of the primary curve apex. Both compliant and noncompliant patients were included in the analysis. A univariate analysis was done on those factors thought to influence success with bracing using the Pearson chi2 test. RESULTS: The average initial in-brace correction with a supine radiograph was 96% for major curves and 98% for minor curves. Seventy-five patients (74%) did not progress >5 degrees and 27 patients (26%) progressed > or =6 degrees or went on to surgery. Twenty-nine percent of Risser 0 or 1 patients progressed and 17% of patients Risser 2 progressed. The risk of progression anticipated by natural history data, which included all curve patterns, was 68% for Risser 0 and 1 and 23% for Risser 2. Risser 3 and 4 patients were excluded from the study. Seventy-six percent of patients with curve apexes between T8 and L1 had successful outcomes using the Providence brace. This is compared with a 74% success rate in the prospective Scoliosis Research Society study of patients wearing a thoraco lumbar sacral orthosis for 16 hours per day with curve apexes between T8 and L1. With the Providence brace, 63% of thoracic curves and 65% of double curves were successful. Ninety-four percent of lumbar curves and 93% of thoracolumbar curves were successful. CONCLUSION: Excellent initial in-brace correction of adolescent idiopathic scoliosis was observed with this computer-designed and manufactured recumbent brace. Patients with high apex curves cephalad to T8 (n = 31) had a success rate of 61% compared with a success rate of 79% (n = 71) if the apex was at or below T9. Compared with previous natural history and the prospective study data, the Providence brace is effective in preventing progression of adolescent idiopathic scoliosis for curves <35 degrees. It was effective for larger curves with a low apex. The authors' experience with patients with curves >35 degrees (n = 8) is too small to validate its effectiveness for larger curves with a higher apex.

Effects of various sera on growth kinetics and collagen synthesis by keloid and normal dermal fibroblasts.

Fibroblasts derived from normal dermis and keloids were cultured in nutrient medium supplemented with fetal bovine serum, serum from keloid patients, and serum from age-, sex-, and race-matched nonkeloid formers. Cell numbers were determined at various times during the growth period, and collagen synthesis was analyzed on day 7. In lag phase, keloid-derived fibroblasts were significantly reduced in all sera compared with normal dermal fibroblasts. However, beyond day 2, the growth kinetics of both cell types were similar in keloid and control human sera. Furthermore, collagen synthesis relative to total protein synthesis (percent) was similar in keloid and control human sera. Although systemic factors have been implicated in the pathogenesis of keloids and other fibrotic diseases such as scleroderma and pulmonary fibrosis, this study demonstrates that serum from keloid patients does not contain a factor(s) that significantly modifies the in vitro growth kinetics or collagen synthesis of keloid-derived or normal dermal fibroblasts.

Collagen production and types in fibrous capsules around breast implants.

This study demonstrates that increased collagen production but not an altered ratio of type III:I collagen is associated with breast capsular contracture. From these findings and previous data, therefore, it appears that capsular contracture is associated with increased foreign-body response biochemically as well as histologically. Further studies are required to directly assess the reasons for contraction around some implants and not others; however, it appears that control of capsular contracture may be achieved by controlling biochemical as well as cellular events associated with contraction. Such studies remain to be done.