By breaking the time-reversal symmetry in three-dimensional topological insulators with the introduction of spontaneous magnetization or application of magnetic field, the surface states become gapped, leading to quantum anomalous Hall effect or quantum Hall effect, when the chemical potential locates inside the gap. Further breaking of inversion symmetry is possible by employing magnetic topological insulator heterostructures that host non-degenerate top and bottom surface states. Here we demonstrate the tailored-material approach for the realization of robust quantum Hall states in the bilayer system, in which the cooperative or cancelling combination of the anomalous and ordinary Hall responses from the respective magnetic and non-magnetic layers is exemplified. The appearance of quantum Hall states at filling factor 0 and +1 can be understood by the relationship of energy band diagrams for the two independent surface states. The designable heterostructures of magnetic topological insulator may explore a new arena for intriguing topological transport and functionality.
The transport properties of materials with topologically non-trivial band structures may be manipulated by an applied magnetic field or by magnetic doping. Here, the authors demonstrate quantum Hall states for temperatures up to 2 K in thin film bilayers comprising pristine and Cr-doped topological insulators.
The purpose of this study was to evaluate the efficacy of superselective cisplatin infusion with concomitant radiotherapy (RADPLAT) for previously untreated patients with the squamous cell carcinoma of maxillary sinus (SCC-MS).
Between 1999 and 2010, 54 patients were given superselective intra-arterial infusions of cisplatin (100–120 mg m−2 per week) with simultaneous intra-venous infusions of thiosulfate to neutralise cisplatin toxicity and conventional radiotherapy (65–70 Gy).
One patient (1.9%) was diagnosed with T2, 14 (25.9%) with T3, 27 (50%) with T4a, and 12 (22.2%) with T4b disease. Lymph-node involvement was present in 12 patients (22.2%). During the median follow-up period of 6.4 years, the 5-year local progression-free and overall survival rates were 65.8 and 67.9% for all patients, respectively. No patient died as a result of treatment toxicity or experienced a cerebrovascular accident. Osteonecrosis (n=5), brain necrosis (n=1), and ocular/visual problems (n=14) were observed as late adverse reactions.
We have shown excellent overall survival and local progression-free rate in SCC-MS patients treated by RADPLAT with acceptable rates of acute and late toxicity. A multi-institutional trial is needed to prove that this strategy is a feasible and effective approach for the treatment of SCC-MS.
intra-arterial; cisplatin; maxillary sinus; chemotherapy; radiotherapy
The skeletal elements of embryonic limb are prefigured by prechondrogenic condensation in which secreted molecules such as adhesion molecules and extracellular matrix have crucial roles. However, how the secreted molecules are controlled to organize the condensation remains unclear. In this study, we examined metabolic regulation of secretion in prechondrogenic condensation, using bioluminescent monitoring systems. We here report on ATP oscillations in the early step of chondrogenesis. The ATP oscillations depended on both glycolysis and mitochondrial respiration, and their synchronization among cells were achieved via gap junctions. In addition, the ATP oscillations were driven by Ca2+ oscillations and led to oscillatory secretion in chondrogenesis. Blockade of the ATP oscillations prevented cellular condensation. Furthermore, the degree of cellular condensation increased with the frequency of ATP oscillations. We conclude that ATP oscillations have a critical role in prechondrogenic condensation by inducing oscillatory secretion.
prechondrogenic condensation; ATP oscillations; Ca2+ oscillations; secretion; bioluminescence
Cortical surface evoked potentials (SEPs) are larger during sleep and characterize a sleep-like state in cortical columns. Since tumor necrosis factor alpha (TNF) may be involved in sleep regulation and is produced as a consequence of waking activity, we tested the hypothesis that direct application of TNF to the cortex will induce a sleep-like state within cortical columns and enhance SEP amplitudes. We found that microinjection of TNF onto the surface of the somatosensory cortex enhanced whisker stimulation-induced SEP amplitude relative to a control heat-inactivated TNF microinjection. We also determined if whisker stimulation enhanced endogenous TNF expression. TNF immunoreactivity (IR) was visualized after 2 h of bilateral deflection of a single whisker bilaterally. The number of TNF-IR cells increased in layers II–IV of the activated somatosensory barrel column. In two separate studies, unilateral deflection of multiple whiskers for 2 h increased the number of TNF-IR cells in layers II–V in columns that also exhibited enhanced Fos-IR. TNF-IR also colocalized with NeuN-IR suggesting that TNF expression was in neurons. Collectively these data are consistent with the hypotheses that TNF is produced in response to neural activity and in turn enhances the probability of a local sleep-like state as determined by increases in SEP amplitudes.
barrel field; evoked response potentials; surface evoked potentials; local sleep; cortical columns; cytokine
The termination of the superficial middle cerebral vein (SMCV) has been described as entering or being partially equivalent to the venous sinus coursing under the lesser sphenoid wing, which has classically been called the sphenoparietal sinus. However, the recent literature reports that the SMCV is not connected to the sphenoparietal sinus. In this study, the venous anatomy was evaluated to clarify the anatomy of the sphenoparietal sinus and the termination of the SMCV. Magnetic resonance imaging (MRI) was performed on 1.5-T superconductive units using a three-dimensional fast spoiled gradient-recalled acquisition in the steady state (3-D fast SPGR) sequence with fat suppression in a total of 48 sides of 24 patients. Coronal source images and reconstructed axial images were displayed on the Advantage Window Console, and connections to the cavernous sinus were then evaluated for the venous sinus coursing under the lesser sphenoid wing (hereafter called the sinus of the lesser sphenoid wing), the middle meningeal vein, and the SMCV.
The following findings were observed bilaterally in all patients. The sinus of the lesser sphenoid wing was connected medially with the cavernous sinus and laterally with the anterior branch of the middle meningeal vein near the pterion.
The anterior branch of the middle meningeal vein entered the bony canal laterally above the junction with the sinus of the lesser sphenoid wing and coursed along the inner table of the skull or emerged into the diploic vein, indicating its parietal portion. Although the termination of the SMCV had several patterns, the SMCV was not connected with the sinus of the lesser sphenoid wing in any of the patients. The sphenoparietal sinus is considered to consist of the sinus of the lesser sphenoid wing and the parietal portion of the anterior branch of the middle meningeal vein; these were identified as venous structures distinct to the SMCV.
sphenoparietal sinus, superficial middle cerebral vein, MRI
To evaluate the c-kit expression in breast cancer, 217 invasive ductal carcinomas of the breast were immunohistochemically stained for c-kit protein. The c-kit expression was positive in 59 (27%) of 217 tumours, while the c-kit expression was negative in 158 (73%) of 217 tumours. There was a significant correlation between a negative expression of the c-kit protein and lymph node metastasis (P<0.0001), and the incidence of a negative expression of the c-kit protein increased as the number of the metastatic lymph nodes increased (P=0.0003). The c-kit expression did not significantly correlate with the tumour size, nuclear grade, oestrogen receptor status, MIB-1 counts and p53 protein expression. A univariate analysis indicated the patients with the negative c-kit expression to have a worse disease-free survival (DFS) than those with the positive c-kit expression (P=0.0041), while a multivariate analysis determined lymph node metastases and the MIB-1 counts to be independently significant factors for DFS. In conclusion, a loss of the c-kit expression was found in about three-fourth of invasive ductal carcinoma of the breast and was associated with lymph node metastases. The prognostic implications of the c-kit expression seem to be due to fact that a loss of the c-kit expression is associated with an advanced stage of breast cancer.
breast cancer; c-kit; prognosis
Digital subtraction angiography (DSA) and magnetic resonance imaging (MRI) findings in 20 patients with carotid-cavernous fistula (CCF; 3 direct CCFs and 17 indirect CCFs) were retrospectively reviewed to evaluate venous drainage patterns that may cause intracerebral haemorrhage or venous congestion of the brain parenchyma.
We evaluated the relationship between cortical venous reflux and abnormal signal intensity of the brain parenchyma on MRI. Cortical venous reflux was identified on DSA in 12 of 20 patients (60.0%) into the superficial middle cerebral vein (SMCV; n=4), the uncal vein (n=2), the petrosal vein (n=2), the lateral mesencephalic vein (LMCV; n=1), the anterior pontomesencephalic vein (APMV; n=1), both the APMV and the petrosal vein (n=1) and both the uncal vein and the SMCV (n=1). Features of venous congestion, such as tortuous and engorged veins, focal staining and delayed appearance of the veins, were demonstrated along the region of cortical venous reflux in the venous phase of internal carotid or vertebral arteriography in six of 20 patients (30.0%). These findings were not observed in the eight CCF patients who did not demonstrate cortical venous reflux. MRI revealed abnormal signal intensity of the brain parenchyma along the region with cortical venous reflux in four of 20 indirect CCF patients (20%). Of these four patients, one presented with putaminal haemorrhage, while the other three presented with hyperintensity of the pons, the middle cerebellar peduncle or both on T2-weighted images, reflecting venous congestion. The venous drainage routes were obliterated except for cortical venous reflux in these four patients and the patients without abnormal signal intensity on MRI had other patent venous outlets in addition to cortical venous reflux.
CCF is commonly associated with cortical venous reflux. The obliteration or stenosis of venous drainage routes causes a converging venous outflow that develops into cortical venous reflux and results in venous congestion of the brain parenchyma or intracerebral haemorrhage. Hyperintensity of brain parenchyma along the region of cortical venous reflux on T2-weighted images reflects venous congestion and is the crucial finding that indicates concentration of venous drainage into cortical venous reflux.
carotid-cavernous fistula, cortical venous reflux, venous congestion
OBJECTIVES—To examine the pathophysiology of
"stress induced urinary incontinence" (urinary incontinence evoked
by abdominal straining) in patients with spinocerebellar degeneration.
METHODS—Micturitional symptoms of 184 patients
with spinocerebellar degeneration who were admitted to hospital were
studied repeatedly. Urodynamic studies were made in symptomatic
patients, and consisted of uroflowmetry, measurement of residual urine,
urethral pressure profilometry, medium fill water cystometry, and
external sphincter EMG
RESULTS—Twenty nine (15.8%) patients with
spinocerebellar degeneration showed stress induced urinary
incontinence. Twenty of the 29patients had detrusor overactivity, low
compliance detrusor, or residual urine, resembling urgency and overflow
types of incontinence (complicated form). The other nine had none of
these findings (pure form), but showed decreased maximum urethral
closure pressure in four, absence of bulbocavernosus reflex in two,
absence of voluntary sphincter contraction in one, incompetent urinary
storage even at the first sensation in two, and high amplitude and
polyphasic neurogenic changes in three of five patients studied,
indicative of neurogenic sphincter dysfunction.
CONCLUSIONS—Stress induced urinary incontinence in
spinocerebellar degeneration had various underlying mechanisms. Some of
the patients only showed evidence of pudendal denervation, which can
cause external sphincter weakness and may reflect lesions of the sacral Onuf's nucleus and the pudendal nerve. Urodynamic studies are necessary to evaluate stress induced urinary incontinence in patients with spinocerebellar degeneration, to prescribe appropriate therapies.
Micturitional disturbance is rarely mentioned in human herpetic
brainstem encephalitis although the pontine tegmentum, called the
pontine micturition centre, seems to regulate the lower urinary tract
in experimental animals. The case of a 45 year old man, who developed
subacute coma and hiccup-like dysrhythmic breathing, and needed
assisted ventilation is reported. Examination of CSF showed mononuclear
pleocytosis and antibody against herpes simplex virus type 1, but the
opening pressure was 90 cm H2O. Brain CT showed brain
swelling, predominantly in the posterior fossa, and bilateral subdural
effusion. Herpetic brainstem encephalitis was diagnosed, and he
received 900 mg/day vidarabine. On regaining consciousness, he had left
trochlear nerve palsy, left corectopia, ageusia, and urinary retention.
Brain MRI showed right side dominant, bilateral pontine segmental
lesions extending slightly to the midbrain and medulla. After two weeks
he was able to urinate but showed nocturnal urinary frequency, urinary
incontinence, and voiding difficulty. Urodynamic studies showed a
residual urine volume of 350 ml and detrusor hyporeflexia on voiding.
Micturitional disturbance gradually disappeared together with the
neurological signs. The bilateral pontine tegmental lesions in this
patient are similar to those in previous findings on brainstem strokes, evidence of the presence of a pontine micturition centre
OBJECTIVES—To examine the frequency and
pathophysiology of micturitional disturbance in patients with
METHODS—Micturitional symptoms were noted
and neurological examinations made repeatedly during admission to
hospital of patients with clinical and neurophysiologically definite
Guillain-Barré syndrome. Urodynamic studies consisted of
uroflowmetry, measurement of residual urine, urethral pressure
profilometry, medium fill water cystometry, and external sphincter EMG.
RESULTS—Seven of 28 (25%) patients with
Guillain-Barré syndrome showed micturitional disturbance. The
symptoms included voiding difficulty in six, urinary retention in
three, nocturnal urinary frequency in three, and urge incontinence in
two. These micturitional symptoms appeared after weakness occurred, and
improved gradually along with the neurological signs. All three
patients who showed retention became able to urinate. Urodynamic
studies were made on four symptomatic patients two of whom underwent
repeated study. Disturbed bladder sensation was noted in one patient,
bladder areflexia in one, and absence of the bulbocavernosus reflex in
one. Cystometry showed decreased bladder volume in two and bladder
overactivity in two, one of whom had urge urinary incontinence and the
other urinary retention.
CONCLUSIONS—A quarter of the patients with
Guillain-Barré syndrome tend to have micturitional disturbance. The
patients studied had evacuation and storage disorders, as well as
bladder areflexia and disturbed bladder sensation indicative of
peripheral types of parasympathetic and somatic nerve dysfunction.
Decreased bladder volume with bladder overactivity but no evidence of
CNS involvement was also found, evidence that bladder overactivity also
occurs in peripheral nerve lesions with probable pelvic nerve irritation.
Non-insulin-dependent diabetes mellitus (NIDDM) is considered a polygenic disorder in which insulin resistance and insulin secretory defect are the major etiologic factors. Homozygous mice with insulin receptor substrate-1 (IRS-1) gene knockout showed normal glucose tolerance associated with insulin resistance and compensatory hyperinsulinemia. Heterozygous mice with beta cell glucokinase (GK) gene knockout showed impaired glucose tolerance due to decreased insulin secretion to glucose. To elucidate the interplay between insulin resistance and insulin secretory defect for the development of NIDDM, we generated double knockout mice with disruption of IRS-1 and beta cell GK genes by crossing the mice with each of the single gene knockout. The double knockout mice developed overt diabetes. Blood glucose levels 120 min after intraperitoneal glucose load (1.5 mg/g body wt) were 108 +/- 24 (wild type), 95 +/- 26 (IRS-1 knockout), 159 +/- 68 (GK knockout), and 210 +/- 38 (double knockout) mg/dl (mean +/- SD) (double versus wild type, IRS-1, or GK; P < 0.01). The double knockout mice showed fasting hyperinsulinemia and selective hyperplasia of the beta cells as the IRS-1 knockout mice (fasting insulin levels: 0.38 +/- 0.30 [double knockout], 0.35 +/- 0.27 [IRS-1 knockout] versus 0.25 +/- 0.12 [wild type] ng/ml) (proportion of areas of insulin-positive cells to the pancreas: 1.18 +/- 0.68%; P < 0.01 [double knockout], 1.20 +/- 0.93%; P < 0.05 [IRS-1 knockout] versus 0.54 +/- 0.26% [wild type]), but impaired insulin secretion to glucose (the ratio of increment of insulin to that of glucose during the first 30 min after load: 31 [double knockout] versus 163 [wild type] or 183 [IRS-1 knockout] ng insulin/mg glucose x 10(3)). In conclusion, the genetic abnormalities, each of which is nondiabetogenic by itself, cause overt diabetes if they coexist. This report provides the first genetic reconstitution of NIDDM as a polygenic disorder in mice.
This study was aimed to investigate the association of restriction fragment length polymorphisms (RFLPs) for pepsinogen genes with peptic ulcer disease. Eighty unrelated controls, 61 patients with gastric ulcer, and 57 patients with duodenal ulcer were studied. No genetic polymorphisms for pepsinogen A were detected by EcoRI digestion in Japanese subjects but a 100 base pairs insertion-deletion RFLP for the pepsinogen C gene was observed. The allele frequencies of the large (3.6 kilobase EcoRI fragment) and the small fragment (3.5 kilobase EcoRI fragment) were 80.6% and 19.4% respectively in controls, 55.4% and 44.6% in patients with gastric body ulcer, 79.4% and 20.6% in patients with gastric angular ulcer, 71.4% and 28.6% in patients with gastric antral ulcer, and 75.4% and 24.6% in patients with duodenal ulcer. The allele frequency of the small fragment was significantly higher in patients with gastric body ulcer than in controls and in patients with gastric angular or antral ulcer. The genotypes which possessed the small fragment were significantly more frequent in patients with gastric body ulcer (78.4%) than in controls (33.8%) and in patients with gastric angular or antral ulcer (37.5%). These results suggest that there is a significant association between the genetic polymorphism at the pepsinogen C gene locus and gastric body ulcer, and that the pepsinogen C RFLP is a useful marker of the genetic predisposition to this disorder. These results also indicate genetic heterogeneity of gastric ulcer disease, and suggest that the pepsinogen C RFLP may be a useful subclinical marker to explain the differences in genetic aetiologies of gastric body ulcer and gastric angular or antral ulcer.
1. Erythema induced by topically applied timolol, a non-selective beta-adrenoceptor blocker, was assessed in six male volunteers. Intensity of erythema developed on the inner surface of the left forearm where timolol free base was applied for 10 h was measured by a visual score, laser doppler flowmeter and reflectance spectrophotometry. Plasma timolol concentrations collected from the left and right arms were also measured. 2. The mean values for blood volume and blood flow per unit volume of tissue both of which were assessed by a laser doppler flowmeter, haemoglobin index measured by reflectance spectrophotometry, and magnitude of erythema graded by a visual score significantly increased after the application of an acrylic co-polymer adhesive patch containing 20% (w/v) timolol free base. 3. Plasma timolol concentrations collected from the left antecubital vein were 2.4 to 10.7 times greater than those from the right arm and had significant correlations (rs = 0.55 to 0.76) with the parameters indicating the extent of erythema developed where a patch containing timolol was applied. 4. The inter-individual variation of timolol was attributed to that of the diffusivity of timolol through skin rather than that of the skin reactivity to topically applied timolol because the plasma timolol concentrations drawn from the left arm in the subjects who did not develop erythema were very low.(ABSTRACT TRUNCATED AT 250 WORDS)
Lymphocytes are not present in normal brain but are known to infiltrate malignant gliomas. The reasons for this infiltration and the signals involved are not understood. The lymphocyte content of 15 malignant gliomas removed at time of surgery was studied, using monoclonal antibodies to T and B cell surface antigens and immunofluorescence. An average of 41% of infiltrating cells possessed surface Ig, with 21% bearing the common T cell marker. There was no evidence of oligoclonal restriction of light chain types.
Double-stranded DNA was synthesized from delta-crystallin mRNA prepared from lens fibers of 15-day-old chick embryos and cloned at the Pst I site of the plasmid pBR322. Using the cloned cDNA and single-stranded cDNA as hybridization probes, a number of genomic DNA fragments containing delta-crystallin gene sequences have been cloned from the partial and complete EcoRI digests of chick brain DNA. One of the clones from the partial digests contains a DNA fragment that consists of four EcoRI fragments of 7.6 kb, 4.0 kb, 2.6 kb, and 0.8 kb. The gene sequences reside in the (5')7.6 kb - 0.8 kb - 4.0 kb (3') fragments. Electron microscopy has provided evidence that the cloned DNA fragment includes the entire gene sequences complementary to delta-crystallin mRNA except for the 3' terminal poly(A) tail, and that the delta-crystallin gene is interrupted by at least 13 intervening sequences. Another clone contains a genomic fragment that consists of two EcoRI fragments of 3.0 kb and 11 kb. The DNA fragment in the latter clone represents a different delta-crystallin gene, as judged by restriction endonuclease mapping and by electron microscopy.
Cefroxadine (GCP-9000; CXD), 7 beta[D-2-amino-2-(1,4-cyclohexadienyl)-acetamido]-3-methoxy-ceph-3-em-carboxylic acid, is a new orally active cephalosporin derivative. The spectrum of antibacterial activity of CXD is identical with that of cephalexin (CEX), but CXD was twofold more effective than CEX against Escherichia coli and Klebsiella pneumoniae, CXD was as stable to penicillinase as CEX, but it was hydrolyzed by cephalosporinase, with a relative rate of hydrolysis similar to that of CEX. The affinities of CXD and CEX to penicillin-binding proteins of E. coli were estimated; the affinity of CXD to penicillin-binding protein 1Bs was higher than that of CEX. Consistent with this, CXD had more intensive lytic activity than CEX. In vivo antibacterial activities of CXD and CEX were compared using systemic infections of mice with E. coli and K. pneumoniae; CXD was consistently more active than CEX.
An 84 bp element located between nucleotides -162 and -79 of the chicken alpha A-crystallin gene exhibits lens-specific enhancer activity. Transient transfection experiments using 5' deletion and linker scanner mutants has indicated that the 84 bp enhancer element is composed of three motifs, alpha CE1 (-162 to -134), alpha CE3 (-135 to -121) and alpha CE2 (-119 to -99). Neither alpha CE1 or alpha CE3 motif alone can exhibit enhancer activity even when trimerized, whereas together they can direct some degree of lens-specific expression. alpha CE2 alone shows low transcriptional activity when trimerized. A combination of alpha CE1 with alpha CE2 exerts full lens-specific enhancer activity comparable with that of the 84 bp enhancer element, indicating that alpha CE1 and alpha CE2 motifs are sufficient to confer lens-specific expression. Transcriptional activation by these two motifs from a distance required the additional presence of either or both motifs adjacent to the beta-actin basal promoter. Gel shift experiments indicated that the alpha CE1, alpha CE2 and alpha CE3 motifs specifically bind nuclear proteins. alpha CE1 binds a protein predominantly present in lens cells, whereas alpha CE2- and alpha CE3-binding proteins differ between lens and lung cells. Mutations within the alpha CE1 and alpha CE2 motifs that failed to bind nuclear factors in vitro resulted in loss of transcriptional activation, indicating that these nuclear factors play a key role in controlling lens-specific expression.
We have determined the complete nucleotide sequence of one of the two non-allelic delta-crystallin genes in the chicken, arbitrarily designated delta-gene 1, using a genomic clone (lambda g delta 106) containing the entire gene sequence. By comparison of the genomic sequence and the delta-crystallin cDNA sequence previously determined, we have identified exon sequences in the genomic sequence. Thus, the presence of 17 exons and 16 introns in the gene has been clarified. The delta-crystallin polypeptide deduced from the exon sequences consists of 465 amino acids which is larger, by 19 amino acid residues, than the polypeptide deduced from the cDNA sequence previously reported. Re-examination of the cDNA sequence using the same cDNA clone previously used shows that the present exon sequences are correct and the molecular weight of the deduced delta-crystallin polypeptide is 50,615 daltons instead of the previously reported value of 48,447 daltons. In addition, some structural features of the delta-crystallin gene including putative expression signals are discussed.
The main histological change in rheumatoid arthritis (RA) is the villous proliferation of synovial lining cells, an important source of cytokines and chemokines, which are associated with inflammation. The aim of this study was to evaluate gene expression in the microdissected synovial lining cells of RA patients, using those of osteoarthritis (OA) patients as the control.
Samples were obtained during total joint replacement from 11 RA and five OA patients. Total RNA from the synovial lining cells was derived from selected specimens by laser microdissection (LMD) for subsequent cDNA microarray analysis. In addition, the expression of significant genes was confirmed immunohistochemically.
The 14 519 genes detected by cDNA microarray were used to compare gene expression levels in synovial lining cells from RA with those from OA patients. Cluster analysis indicated that RA cells, including low- and high-expression subgroups, and OA cells were stored in two main clusters. The molecular activity of RA was statistically consistent with its clinical and histological activity. Expression levels of signal transducer and activator of transcription 1 (STAT1), interferon regulatory factor 1 (IRF1), and the chemokines CXCL9, CXCL10, and CCL5 were statistically significantly higher in the synovium of RA than in that of OA. Immunohistochemically, the lining synovium of RA, but not that of OA, clearly expressed STAT1, IRF1, and chemokines, as was seen in microarray analysis combined with LMD.
Our findings indicate an important role for lining synovial cells in the inflammatory and proliferative processes of RA. Further understanding of the local signalling in structural components is important in rheumatology.