INITIAL LOADING (400 μg TWICE DAILY) VERSUS STATIC (400 μg NOCTE) DOSE BUDESONIDE FOR ASTHMA MANAGEMENT

SUMMARY This double-blind study aimed to determine whether superior asthma control is achieved with budesonide (Pulmicort® Turbohaler®) at a loading dose (LD) (400 μg b.d.) for 6 weeks, followed by step down to 400 μg nocte for 12 weeks, compared with a static dose (SD) (400 μg nocte) for 18 weeks. A total of 682 patients (mean peak expiratory flow rate (PEFR) 413 l/min), who demonstrated ≥15% reversibility in PEFR, were randomised into the study. After 18 weeks, patients experienced improvements in morning PEFR (+45 l/min, both groups), symptom score (LD -0.57, SD -0.49, on a scale of 0-3), sleep disturbance (LD -1.21 nights/week, SD -1.06 nights/week) and to-agonist use (LD -1.36 puffs/day, SD -1.06 puffs/day), within both groups (each p=0.0001). At 18 weeks, 82% (LD) and 84% (SD) of patients benefited from no nocturnal wakening in the previous 7 days. Overall, at 18 weeks, asthma control was not significantly different between the groups. After 6 weeks, improvements in morning PEFR (LD +36 l/min, SD +26 l/min) and β₂-agonist use (LD -1.10 puffs/day, SD -0.94 puffs/day) were greater in the loading dose than in the static dose group (each p<0.05). The greater improvement in morning PEFR in the loading dose group was significant by day 7 (p<0.05). While both regimens are equally effective in achieving asthma control at 18 weeks, early clinical advantage is gained with initial loading dose budesonide (400 μg b.d.).     

NCAM/spectrin complex disassembly results in PSD perforation and postsynaptic endocytic zone formation

Mechanisms inducing perforation of the postsynaptic density (PSD) are poorly understood. We show that neural cell adhesion molecule- deficient (NCAM-/-) hippocampal neurons have an abnormally high percentage of synapses with perforated PSDs. The percentage of synapses with perforated PSDs is also increased in wild-type (NCAM+/+) neurons after the disruption of the NCAM/spectrin complex indicating that the NCAM-assembled spectrin cytoskeleton maintains the structural integrity of PSDs. We demonstrate that PSD perforations contain endocytic zones involved in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) internalization. Induction of long-term potentiation in NCAM+/+ neurons accompanied by insertion of AMPAR into the neuronal cell surface is subsequently followed by formation of perforated synapses and AMPAR endocytosis suggesting that perforation of PSDs is important for membrane homeostasis in activated synapses. In NCAM-/- or NCAM+/+ neurons with dissociated spectrin meshwork, AMPAR endocytosis is enhanced under conditions of basal activity. An abnormally high rate of postsynaptic membrane endocytosis may thus contribute to brain pathologies associated with mutations in NCAM or spectrin.     

Intracortical connectivity of layer VI pyramidal neurons in the somatosensory cortex of normal and barrelless mice

In mice, barrels in layer IV of the somatosensory cortex correspond to the columnar representations of whisker follicles. In barrelless (BRL) mice, barrels are absent, but functionally, a columnar organization persists. Previously we characterized the aberrant geometry of thalamic projection of BRL mice using axonal reconstructions of individual neurons. Here we proceeded with the analysis of the intracortical projections from layer VI pyramidal neurons, to assess their contribution to the columnar organization. From series of tangential sections we reconstructed the axon collaterals of individual layer VI pyramidal neurons in the C2 barrel column that were labelled with biocytin [controls from normal (NOR) strain, 19 cells; BRL strain, nine cells]. Using six morphological parameters in a cluster analysis, we showed that layer VI neurons in NOR mice are distributed into four clusters distinguished by the radial and tangential extent of their intracortical projections. These clusters correlated with the cortical or subcortical projection of the main axon. In BRL mice, neurons were distributed within the same four clusters, but their projections to the granular and supragranular layers were significantly smaller and their tangential projection was less columnar than in NOR mice. However, in both strains the intracortical projections had a preference for the appropriate barrel column (C2), indicating that layer VI pyramidal cells could participate in the functional columnar organization of the barrel cortex. Correlative light and electron microscopy analyses provided morphometric data on the intracortical synaptic boutons and synapses of layer VI pyramidal neurons and revealed that projections to layer IV preferentially target excitatory dendritic spines and shafts.     

Patterns of papillary thyroid carcinoma cells analyzed in fine-needle aspiration smears may reveal changes in tumor cell behavior

Fine-needle aspiration (FNA) cytology is widely used to examine thyroid lesions. However, its diagnostic accuracy is limited by the narrow choice of cytopathologic markers indicative of invasive/metastatic powers of a tumor. The aim of this study was to identify features that may serve as such indicators. We have examined FNA smears of 50 histologically proven papillary thyroid carcinoma (PTC) cases applying computer-assisted morphometry to assess patterns formed by PTC cells. Cytokeratine (CK) 8 immunocytochemistry was used to verify the epithelial origin of cells under study. All analyzed smears contained blood, histiocyte-like cells and CK8-positive follicular cells occurring both as single cells and in monolayer cell sheets. In 60% of cases we revealed cell sheets displaying two distinct cell patterns. The first one (pattern R) consisted of moderately pleomorphic, rather regularly arranged cells having an amphophilic cytoplasm. The second one (pattern I) was formed by highly pleomorphic cells with a basophilic cytoplasm. Patterns R and I were clearly different in cell size and shape as well as in nuclear size and shape. These patterns were never observed within the same cell sheet indicating that they may be formed by different subclones of tumor cells. Thus, it can be concluded that PTC frequently displays two definitely different cell patterns. We think that these patterns have a potential to serve as indicators for early events of an invasive/metastatic process. It remains to be seen whether the simultaneous occurrence of these patterns is a PTC-specific feature.     

Excitatory synaptic activity is associated with a rapid structural plasticity of inhibitory synapses on hippocampal CA1 pyramidal cells

Synaptic activity, such as long-term potentiation (LTP), has been shown to induce morphological plasticity of excitatory synapses on dendritic spines through the spine head and postsynaptic density (PSD) enlargement and reorganization. Much less, however, is known about activity-induced morphological modifications of inhibitory synapses. Using an in vitro model of rat organotypic hippocampal slice cultures and electron microscopy, we studied activity-related morphological changes of somatic inhibitory inputs triggered by a brief oxygen-glucose deprivation (OGD) episode, a condition associated with a synaptic enhancement referred to as anoxic LTP and a structural remodeling of excitatory synapses. Three-dimensional reconstruction of inhibitory axo-somatic synapses at different times before and after brief OGD revealed important morphological changes. The PSD area significantly and markedly increased at synapses with large and complex PSDs, but not at synapses with simple, macular PSDs. Activity-related changes of PSD size and presynaptic bouton volume developed in a strongly correlated manner. Analyses of single and serial sections further showed that the density of inhibitory synaptic contacts on the cell soma did not change within 1 h after OGD. In contrast, the proportion of the cell surface covered with inhibitory PSDs, as well as the complexity of these PSDs significantly increased, with less macular PSDs and more complex, segmented shapes. Together, these data reveal a rapid activity-related restructuring of somatic inhibitory synapses characterized by an enlargement and increased complexity of inhibitory PSDs, providing a new mechanism for a quick adjustment of the excitatory-inhibitory balance.This article is part of a Special Issue entitled ‘Synaptic Plasticity & Interneurons’.     

The costs of traumatic brain injury due to motorcycle accidents in Hanoi, Vietnam

Background

Road traffic accidents are the leading cause of fatal and non-fatal injuries in Vietnam. The purpose of this study is to estimate the costs, in the first year post-injury, of non-fatal traumatic brain injury (TBI) in motorcycle users not wearing helmets in Hanoi, Vietnam. The costs are calculated from the perspective of the injured patients and their families, and include quantification of direct, indirect and intangible costs, using years lost due to disability as a proxy.

Methods

The study was a retrospective cross-sectional study. Data on treatment and rehabilitation costs, employment and support were obtained from patients and their families using a structured questionnaire and The European Quality of Life instrument (EQ6D).

Results

Thirty-five patients and their families were interviewed. On average, patients with severe, moderate and minor TBI incurred direct costs at USD 2,365, USD 1,390 and USD 849, with time lost for normal activities averaging 54 weeks, 26 weeks and 17 weeks and years lived with disability (YLD) of 0.46, 0.25 and 0.15 year, respectively.

Conclusion

All three component costs of TBI were high; the direct cost accounted for the largest proportion, with costs rising with the severity of TBI. The results suggest that the burden of TBI can be catastrophic for families because of high direct costs, significant time off work for patients and caregivers, and impact on health-related quality of life. Further research is warranted to explore the actual social and economic benefits of mandatory helmet use.     

Heterozygosity for the mutated X-chromosome-linked L1 cell adhesion molecule gene leads to increased numbers of neurons and enhanced metabolism in the forebrain of female carrier mice

Mutations in the X-chromosomal L1CAM gene lead to severe neurological deficits. In this study, we analyzed brains of female mice heterozygous for L1 (L1+/?) to gain insights into the brain structure of human females carrying one mutated L1 allele. From postnatal day 7 onward into adulthood, L1+/? female mice show an increased density of neurons in the neocortex and basal ganglia in comparison to wild-type (L1+/+) mice, correlating with enhanced metabolic parameters as measured in vivo. The densities of astrocytes and parvalbumin immunoreactive interneurons were not altered. No significant differences between L1+/? and L1+/+ mice were seen for cell proliferation in the cortex during embryonic days 11.5–15.5. Neuronal differentiation as estimated by analysis of doublecortin-immunoreactive cortical cells of embryonic brains was similar in L1+/? and L1+/+ mice. Interestingly, at postnatal days 3 and 5, apoptosis was reduced in L1+/? compared to L1+/+ mice. We suggest that reduced apoptosis leads to increased neuronal density in adult L1+/? mice. In conclusion, L1+/? mice display an unexpected phenotype that is not an intermediate between L1+/+ mice and mice deficient in L1 (L1?/y), but a novel phenotype which is challenging to understand regarding its underlying molecular and cellular mechanisms.     

The results of pylorus-preserving resection of the stomach]

The functional results of pylorus-preserving resection of a stomach (PRS) in 68 patients with gastric ulcer disease were studied. According to the data of gastroscintigraphy and hepatoscintigraphy, it was established that number of patients with decreased motor-evacuatory function (MEF) of the stomach reduced from 31% before the operation to 11% at the long-term period after PRS. Duodenogastric reflux was noted in 10% of the patients as compared with 47% before the operation. MEF of the stomach normalized within 3-6 mos after the operation. Acid-producing function of the stomach after PRS steadily decreased until the development of a hypoacidic state. Basal pH of gastric, body at the long-term period was 3.39 +/- 0.59. An excellent and good result according to Visick scale was noted in 67 (98.5%) patients, a satisfactory one--in 1 (1.5%).     

Difficult mammographic needle localizations: use of alternate orthogonal projections

Lesions deep within the breast are occasionally visible on only one standard mammographic projection and are therefore difficult to localize preoperatively. Such abnormalities can often be visualized on two orthogonal 45 degrees oblique views. In these cases, needle localizations may be performed in a routine manner without computed tomography or stereotactic methods.