Impaired vertical phoria adaptation in patients with cerebellar dysfunction

PURPOSE: To determine whether phoria adaptation to a vertical prism disparity is altered in patients with cerebellar dysfunction. METHODS: With a computer-aided haploscope, adaptive responses of fusion-free eye position to a 10- or 30-minute period was measured in subjects wearing a 3-prism diopter vertical prism over one eye. Thirteen patients with well-documented cerebellar diseases who did not have manifest ocular misalignment or limited versional eye movement and age-matched healthy subjects participated. RESULTS: The mean +/- SD percentage of vertical phoria adaptation was 13% +/- 22% and 20% +/- 16% for the 10- and 30-minute adaptations, respectively. These levels were significantly smaller than the respective ones in the age-matched control group (P < 0.001, repeated measures MANOVA). Seven (54%) of 13 patients, including two with genetically confirmed pure cerebellar lesions (spinocerebellar ataxia type 6), showed markedly reduced responses to both the 10- and 30-minute adaptations. In all three patients with acute cerebellar ataxia, the adaptive response was improved at the same time as remission of cerebellum-associated neurologic deficits. CONCLUSIONS: Phoria adaptation to vertical binocular disparity is frequently impaired in patients with cerebellar dysfunction. These results bolster the hypothesis that phoria adaptation is a cerebellar-dependent response.     

Magnetic resonance imaging of the functional anatomy of the inferior oblique muscle in superior oblique palsy

PURPOSE: To study size and contractility of the normal inferior oblique (IO) muscle using high-resolution magnetic resonance imaging (MRI) and to evaluate abnormalities of the superior oblique (SO) and IO muscles in chronic SO palsy. DESIGN: Prospective, case control study. PARTICIPANTS: Thirteen patients with SO palsy and 17 orthotropic subjects. METHODS: High-resolution, surface coil MRI was used to obtain sets of contiguous, 2-mm thick coronal and sagittal images repeated in multiple gaze directions. Digital image analysis was used to measure IO and SO muscle cross-sectional areas for evaluation of size and contractility. Diagnosis of SO palsy in one bilateral and 12 unilateral cases was based on subnormal contractility and SO size less than the normal 95% confidence limit. Ipsilesional and contralesional oblique muscles were compared with controls and correlated with clinical characteristics. RESULTS: In all subjects, anterior movement and contractile thickening of the IO were observed in supraduction, with posterior movement and relaxational thinning in infraduction. The mean (+/- standard deviation) cross-sectional area of 15 normal control IO muscles was 13.4 +/- 3.9 mm(2), with mean contractile increase from infraduction to supraduction of 5.7 +/- 2.6 mm(2). Subjects with SO palsy had incomitant hypertropia with a wide range of overelevation and underelevation in adduction (i.e., upshoot, downshoot). SO atrophy correlated with underdepression in adduction (P < 0.0001). Contralesional SO cross-section was slightly greater than normal (P = 0.004). The IO cross-section ipsilesional and contralesional to SO palsy did not, however, differ significantly from normal and did not correlate with elevation in adduction (P > 0.2). CONCLUSIONS: Quantitative morphometry by MRI can demonstrate IO size and contractility. Even in cases of unequivocal SO palsy associated with ipsilesional SO atrophy and deficient contractility, the degree of elevation in adduction was not correlated with IO size. This finding suggests that the associated overelevation in adduction, commonly termed "inferior oblique overaction," actually arises from some other mechanism than IO hypertrophy or excess contractility. Revision of clinical terminology seems warranted.     

Restoration of BRAK / CXCL14 gene expression by gefitinib is associated with antitumor efficacy of the drug in head and neck squamous cell carcinoma

Clinical efficacy of gefitinib (ZD1839, Iressa), which is an inhibitor specific for epidermal growth factor (EGF) receptor tyrosine kinase, has been shown in non-small-cell lung carcinoma patients with EGF receptor mutations, so these mutations are useful marker(s) to find a responder for the drug. Recent studies have shown that the EGF receptor gene mutation is rare in squamous cell carcinoma in the esophageal and head and neck regions. We previously reported that the expression of the chemokine BRAK/CXCL14 in head and neck squamous cell carcinoma (HNSCC) cells was down-regulated by EGF treatment, and that forced expression of BRAK in tumor cells decreased the tumorigenicity of the cells in xenografts. Thus, we investigated the relationship between restoration of BRAK expression by gefitinib and the efficacy of the drug for tumor suppression. We found that EGF down-regulated BRAK expression through the MEK–extracellular signal regulated kinase pathway and that this down-regulated expression was restored by gefitinib in vitro . Oral administration of gefitinib significantly ( P  <   0.001) reduced tumor growth of xenografts of three HNSCC cell lines (HSC-2, HSC-3, and HSC-4), in female athymic nude mice, accompanied by an increase in BRAK expression specifically in tumor tissue. This tumor-suppressing effect of the drug was not observed in the case of BRAK non-expressing cells. Furthermore introduction of BRAK shRNA vector reduced both the expression levels of BRAK in HSC-3 cells and the antitumor efficacy of gefitinib in vivo . Our data showing an inverse relationship between BRAK expression levels in tumor cells and the tumor growth rate indicate that the gefitinib-induced increase in BRAK expression is beneficial for tumor suppression in vivo. ( Cancer Sci 2009)     

Superior oblique muscle layers in monkeys and humans

PURPOSE: Rectus and the inferior oblique extraocular muscles (EOMs) consist of orbital layers (OLs), inserting on connective tissues, and global layers (GLs), inserting on the sclera. This study was performed to clarify the anatomic relationships of the corresponding layers of the superior oblique (SO) muscle. METHODS: Two whole human and two monkey orbits were serially sectioned en bloc at 10-mum thickness in the coronal plane and stained for collagen with Masson's trichrome and for elastin with van Gieson's stain. The SO muscles of one human and one monkey were sectioned longitudinally. The structure of the SO muscle was examined by light microscopy, and muscle fibers in the OL and GL of selected sections were counted. RESULTS: The deep SO muscle consisted of a central GL contiguous with the tendon, surrounded coaxially by a peripheral OL inserting on the SO sheath posterior to the trochlea. The maximum number of SO fibers was 14,400 to 19,200 in the human and 7,000 to 7,400 in the monkey. In the monkey, approximately 60% of total fibers were in the GL, and 40% in the OL. The SO sheath was in mechanical continuity with the superior rectus pulley. CONCLUSIONS: The primate SO has a substantial OL configured to contribute to positioning the superior rectus pulley in the coronal plane. Whereas the direction of application of the SO's GL force is determined by the rigid trochlea, the SO's OL influences the direction of application of rectus EOM forces. This insight extends the concept of active control of pulley positions to include a contribution from the SO muscle.     

Clinicopathologic study on an ALS family with a heterozygous E478G optineurin mutation

We investigated a family manifesting amyotrophic lateral sclerosis (ALS) with a heterozygous E478G mutation in the optineurin (OPTN) gene. Clinically, slow deterioration of motor function, mood and personality changes, temporal lobe atrophy on neuroimaging, and bizarre finger deformity were noted. Neuropathologically, TAR DNA-binding protein 43 (TDP-43)-positive neuronal intracytoplasmic inclusions were observed in the spinal and medullary motor neurons. In these cells, the immunoreactivity of nuclear TDP-43 was reduced. Consecutive sections revealed that the inclusions were also reactive with anti-ubiquitin and anti-p62 antibodies, but noticeably negative for OPTN. In addition, TDP-43/p62-positive glial cytoplasmic inclusions (GCIs) were scattered throughout the spinal cord and the medullary motor nuclei. Furthermore, Golgi fragmentation was identified in 70% of the anterior horn cells (AHCs). The presence of AHCs with preserved nuclear TDP-43 and a fragmented Golgi apparatus, which are unrecognizable in sporadic ALS, indicates that patients with the E4787G OPTN mutation would manifest Golgi fragmentation before loss of nuclear TDP-43. In the neocortex, GCIs were sparsely scattered among the primary motor and temporal cortices, but no neuronal TDP-43-positive inclusions were detected. In the amygdala and the ambient gyrus, argyrophilic grains and ballooned neurons were seen. The thorough neuropathologic investigations performed in this work demonstrated that OPTN-positive inclusion bodies, if any, were not prominent. We postulate that optineurinopathy is closely linked with TDP-proteinopathy and speculate that this heterozygous E478G mutation would cause ALS by acting through a dominant-negative mechanism.     

Treatment with edaravone, initiated at symptom onset, slows motor decline and decreases SOD1 deposition in ALS mice

Edaravone is a free-radical scavenger, an agent being widely used for cerebral ischemia in Japan. To evaluate its efficacy for possible treatment of amyotrophic lateral sclerosis (ALS), we performed a randomized blind trial in ALS model mice. After identification of the clinical onset in each female G93A mutant SOD1 transgenic mouse, we intraperitoneally administered multiple doses of edaravone to the mice and observed their motor symptoms. We also counted the number of lumbar motoneurons, determined the 3-nitrotyrosine/tyrosine ratio, and evaluated the abnormal SOD1 aggregation in the spinal cord at the 10th day after the edaravone injection. Edaravone significantly slowed the motor decline of the transgenic mice. The remaining motoneurons were significantly preserved in the higher-dose edaravone-administered group, and the 3-nitrotyrosine/tyrosine ratios were reduced dose-dependently. Intriguingly, the area of abnormal SOD1 deposition in the spinal cord was significantly decreased in the higher-dose edaravone-administered group. Our results indicate that edaravone was effective to slow symptom progression and motor neuron degeneration in the ALS model mice. These favorable actions might be attributable to the yet unidentified mechanism responsible for reducing the deposition of mutant SOD1.     

The first Japanese patient with variant Creutzfeldt‐Jakob disease (vCJD)

Eleven years after a brief visit to some European countries, a 48‐year‐old Japanese man developed writing difficulty, irritability and general fatigue. Then he complained of dysesthetic pains in his legs, for which benzodiazepines were prescribed. However, at the time pulvinar sign was retrospectively confirmed on brain MRI. Eighteen months after the onset, his gait became ataxic with rapid deterioration of mental status over the following several months. Thirty‐one months after the onset, he became akinetic and mute with periodic synchronous discharges on EEG, and died at the age of 51. The total clinical course was approximately 43 months. Pathological examination revealed the characteristic alterations of spongiform encephalopathy, severe in the thalamus, moderate but widely spread in the cerebral cortices, and moderate in the cerebellum. Abundant amyloid plaques were easily identified in the cerebral cortex and the cerebellum on HE staining. Immunohistochemistry for abnormal prion protein (PrP^sc) confirmed amyloid plaques in several forms, such as florid, uni‐ and multi‐centric plaques as well as perineuronal and periaxonal deposits in the basal ganglia and synaptic patterns in the thalami. A Western blotting study identified type 2B protease‐resistant PrP. This is the first Japanese patient who was definitely diagnosed as variant Creutzfeldt‐Jakob disease (vCJD). The pathological findings were similar to those of previous reports of vCJD in the UK. However, the changes were much more severe both in degree and distribution, probably due to a longer duration of the illness than those in the UK.     

Opaciniols A–C, new terpenoids from Garcinia opaca

Three new terpenoids, opaciniols A–C (1–3), were isolated from the barks of Garcinia opaca, together with malabarica-17,21-dien-3β,14-diol (4) and 13βH-malabarica-14,17,21-trien-3β-ol (5). Their structures were determined on the basis of NMR spectroscopic data. 3 and 4 showed moderate cytotoxicity against HL-60 cells.     

Systemic sclerosis complicated by arrhythmogenic right ventricular dysplasia that was misinterpreted as pulmonary arterial hypertension

A 58-year old Japanese woman who had been diagnosed with and managed for systemic sclerosis (SSc) with pulmonary arterial hypertension died suddenly. However, the autopsy revealed marked right ventricular dilatation, and the myocardium had been replaced by fatty tissue. These findings were consistent with arrhythmogenic right ventricular dysplasia (ARVD). A literature search identified nine cases of SSc with ARVD in Japan, including this case; this number is significantly higher than the value estimated from the prevalences of ARVD and SSc in Japan, suggesting an association between these two rare diseases.