No evidence of carbon storage usage for seed production in 18 dipterocarp masting species in a tropical rain forest.

Most canopy species in lowland tropical rain forests in Southeast Asia, represented by Dipterocarpaceae, undergo mast reproduction synchronously at community level during a general flowering event. Such events occur at irregular intervals of 2-10 years. Some species do not necessarily participate in every synchronous mast reproduction, however. This may be due to a lack of carbohydrate resources in the trees for masting. We tested the hypothesis that interspecific differences in the time required to store assimilates in trees for seed production are due to the frequency of masting and/or seed size in each species. We examined the relationship between reproductive frequency and the carbon accumulation period necessary for seed production, and between the seed size and the period, using radiocarbon analysis in 18 dipterocarp canopy species. The mean carbon accumulation period was 0.84 years before seed maturation in all species studied. The carbon accumulation period did not have any significant correlation with reproductive frequency or seed size, both of which varied widely across the species studied. Our results show that for seed production, dipterocarp masting species do not use carbon assimilates stored for a period between the masting years, but instead use recent photosynthates produced primarily in a masting year, regardless of the masting interval or seed size of each species. These findings suggest that storage of carbohydrate resources is not a limiting factor in the masting of dipterocarps, and that accumulation and allocation of other resources is important as a precondition for participation in general flowering.

Thrombolysis With Alteplase at 0.6 mg/kg for Stroke With Unknown Time of Onset: A Randomized Controlled Trial.

Background and Purpose- We assessed whether lower-dose alteplase at 0.6 mg/kg is efficacious and safe for acute fluid-attenuated inversion recovery-negative stroke with unknown time of onset. Methods- This was an investigator-initiated, multicenter, randomized, open-label, blinded-end point trial. Patients met the standard indication criteria for intravenous thrombolysis other than a time last-known-well >4.5 hours (eg, wake-up stroke). Patients were randomly assigned (1:1) to receive alteplase at 0.6 mg/kg or standard medical treatment if magnetic resonance imaging showed acute ischemic lesion on diffusion-weighted imaging and no marked corresponding hyperintensity on fluid-attenuated inversion recovery. The primary outcome was a favorable outcome (90-day modified Rankin Scale score of 0-1). Results- Following the early stop and positive results of the WAKE-UP trial (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke), this trial was prematurely terminated with 131 of the anticipated 300 patients (55 women; mean age, 74.4±12.2 years). Favorable outcome was comparable between the alteplase group (32/68, 47.1%) and the control group (28/58, 48.3%; relative risk [RR], 0.97 [95% CI, 0.68-1.41]; P=0.892). Symptomatic intracranial hemorrhage within 22 to 36 hours occurred in 1/71 and 0/60 (RR, infinity [95% CI, 0.06 to infinity]; P>0.999), respectively. Death at 90 days occurred in 2/71 and 2/60 (RR, 0.85 [95% CI, 0.06-12.58]; P>0.999), respectively. Conclusions- No difference in favorable outcome was seen between alteplase and control groups among patients with ischemic stroke with unknown time of onset. The safety of alteplase at 0.6 mg/kg was comparable to that of standard treatment. Early study termination precludes any definitive conclusions. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT02002325.

Histopathologic features of an autopsied patient with cerebral small vessel disease and a heterozygous HTRA1 mutation.

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a hereditary cerebral small vessel disease (CSVD) caused by homozygous or compound heterozygous mutations of the high temperature requirement A serine peptidase 1 gene (HTRA1). Affected patients suffer from cognitive impairment, recurrent strokes, lumbago and alopecia. Recently, clinical studies have indicated that some patients with heterozygous mutations in HTRA1 may also suffer CSVD. Here, we report the histopathologic features of an autopsied 55-year-old male patient who had shown cognitive impairment and multiple cerebral infarcts, and was found to have a heterozygous missense mutation (p.R302Q) in the HTRA1 gene. Histologically, small vessels in the brain and spinal cord showed intimal proliferation, splitting of the internal elastic lamina, and degeneration of smooth muscle cells in the tunica media. Thus, although less severe, the features were quite similar to those of patients with CARASIL, indicating that patients with heterozygous mutations develop CSVD through underlying pathomechanisms similar to those of CARASIL.

Insights from the ganglionic acetylcholine receptor autoantibodies in patients with Sjögren's syndrome.

OBJECTIVE: It is not known whether autonomic neuropathy is a feature of Sjögren's syndrome (SS) or whether it is related to circulating antiganglionic acetylcholine receptor (gAChR) antibodies. The goal of the present study was to investigate the autonomic dysfunction in patients with SS and the associations between autonomic dysfunction, anti-gAChR antibodies, and clinical features of SS. METHODS: (1) The first observational study tested for the presence of gAChR antibodies in the serum samples from 39 patients with SS (absent information regarding autonomic symptoms) and healthy volunteers. (2) In the second study, serological and clinical data from 10 Japanese patients diagnosed with SS were reviewed. These patients showed autonomic dysfunction, and luciferase immunoprecipitation systems (LIPS) test was conducted to detect anti-α3 and anti-ß4 gAChR antibodies. (3) In the final analysis, we combined the data of seropositive SS patients with autonomic symptom from the first study with all of the patients from the second study, and analyzed the clinical features. RESULTS: (1) The LIPS assay revealed that anti-gAChRα3 and anti-gAChRß4 antibodies were detected in the sera from patients with SS (23.1%, 9/39). Five of nine SS patients had autonomic symptoms. (2) Anti-α3 and anti-ß4 gAChR antibodies were also detected in 80.0% (8/10) of patients with SS with autonomic symptoms. Six of the ten patients were diagnosed as having SS after neurological symptoms developed. These seropositive patients had predominant and severe autonomic symptoms and were diagnosed with autonomic neuropathy. (3) Thirteen of fifteen SS patients with autonomic symptoms (86.7%) were seropositive for anti-gAChR antibodies, and we confirmed sicca complex, orthostatic hypotension, upper and lower gastrointestinal (GI) symptoms, and bladder dysfunction at high rates. CONCLUSION: The present results suggest the possibility of anti-gAChR antibodies aiding the diagnostics of SS with autonomic dysfunction.

Coexistence of amyotrophic lateral sclerosis with neuro-Behçet's disease presenting as a longitudinally extensive spinal cord lesion: clinicopathologic features of an autopsied patient.

We report the clinical and autopsy features of a 65-year-old Japanese man who clinically exhibited overlap of both neuro-Behçet's disease (NBD) and amyotrophic lateral sclerosis (ALS). The patient had a HLA-B51 serotype, a recent history of uveitis and had suffered paraparesis, sensory and autonomic disturbance, frontal signs and tremor. A brain and spine MRI study revealed a longitudinally extensive thoracic cord (Th) lesion, but no apparent intracranial abnormalities. The lesion extended ventrally from Th4 to Th9, exhibiting low intensity on T1-weighted images, high intensity on T2-weighted and fluid-attenuated inversion recovery images and gadolinium enhancement. The patient's upper and lower motor neuron signs and sensory disturbance worsened and he died 16 months after admission. At autopsy, the spinal cord and brain exhibited characteristic histopathological features of both NBD and ALS, including chronic destruction of the ventral thoracic white and gray matter, perivascular lymphocytic infiltration, binucleated neurons, lower and upper motor neuron degeneration, Bunina bodies and skein-like inclusions. Although incidental coexistence of these rare disorders could occur in an individual, this case raises the possibility of a pathomechanistic association between NBD and ALS.

Intravenous Alteplase at 0.6 mg/kg for Unknown Onset Stroke with Prior Antithrombotic Medication: THAWS Randomized Clinical Trial.

AIM: This study aimed to assess the potential effect of prior antithrombotic medication for thrombolysis in an unknown onset stroke. METHODS: This was a predefined sub-analysis of the THAWS trial. Stroke patients with a time last known well ＞4.5 h who had a DWI-fluid-attenuated inversion recovery mismatch were randomly assigned (1:1) to receive alteplase at 0.6 mg/kg (alteplase group) or standard medical treatment (control group). Patients were dichotomized by prior antithrombotic medication. RESULTS: Of 126 patients (intention-to-treat population), 40 took antithrombotic medication (24 with antiplatelets alone, 13 with anticoagulants alone, and 3 with both), and the remaining 86 did not before stroke onset. Of these, 17 and 52 patients, respectively, received alteplase, and 23 and 34, respectively, had standard medical treatment. Antithrombotic therapy was initiated within 24 h after randomization less frequently in the alteplase group (12% vs. 86%, p＜0.01). Both any intracranial hemorrhage within 22-36 h (26% vs. 14%) and a modified Rankin Scale score of 0-1 at 90 days (good outcome) (47% vs. 48%) were comparable between the two groups. A good outcome was more common in the alteplase group than in the control group in patients with prior antithrombotic medication [relative risk (RR) 2.25, 95% confidence interval (CI) 1.02-4.99], but it tended to be less common in the alteplase group in those without (RR 0.69, 95% CI 0.46-1.03) (p＜0.01 for interaction). The frequency of any intracranial hemorrhage did not significantly differ between the two groups in any patients dichotomized by prior antithrombotic medication. CONCLUSION: Alteplase appears more beneficial in patients with prior antithrombotic medication.

p53 mediates cellular dysfunction and behavioral abnormalities in Huntington's disease.

We present evidence for a specific role of p53 in the mitochondria-associated cellular dysfunction and behavioral abnormalities of Huntington's disease (HD). Mutant huntingtin (mHtt) with expanded polyglutamine (polyQ) binds to p53 and upregulates levels of nuclear p53 as well as p53 transcriptional activity in neuronal cultures. The augmentation is specific, as it occurs with mHtt but not mutant ataxin-1 with expanded polyQ. p53 levels are also increased in the brains of mHtt transgenic (mHtt-Tg) mice and HD patients. Perturbation of p53 by pifithrin-alpha, RNA interference, or genetic deletion prevents mitochondrial membrane depolarization and cytotoxicity in HD cells, as well as the decreased respiratory complex IV activity of mHtt-Tg mice. Genetic deletion of p53 suppresses neurodegeneration in mHtt-Tg flies and neurobehavioral abnormalities of mHtt-Tg mice. Our findings suggest that p53 links nuclear and mitochondrial pathologies characteristic of HD.

Aprataxin, causative gene product for EAOH/AOA1, repairs DNA single-strand breaks with damaged 3'-phosphate and 3'-phosphoglycolate ends.

Aprataxin is the causative gene product for early-onset ataxia with ocular motor apraxia and hypoalbuminemia/ataxia with oculomotor apraxia type 1 (EAOH/AOA1), the clinical symptoms of which are predominantly neurological. Although aprataxin has been suggested to be related to DNA single-strand break repair (SSBR), the physiological function of aprataxin remains to be elucidated. DNA single-strand breaks (SSBs) continually produced by endogenous reactive oxygen species or exogenous genotoxic agents, typically possess damaged 3'-ends including 3'-phosphate, 3'-phosphoglycolate, or 3'-alpha, beta-unsaturated aldehyde ends. These damaged 3'-ends should be restored to 3'-hydroxyl ends for subsequent repair processes. Here we demonstrate by in vitro assay that recombinant human aprataxin specifically removes 3'-phosphoglycolate and 3'-phosphate ends at DNA 3'-ends, but not 3'-alpha, beta-unsaturated aldehyde ends, and can act with DNA polymerase beta and DNA ligase III to repair SSBs with these damaged 3'-ends. Furthermore, disease-associated mutant forms of aprataxin lack this removal activity. The findings indicate that aprataxin has an important role in SSBR, that is, it removes blocking molecules from 3'-ends, and that the accumulation of unrepaired SSBs with damaged 3'-ends underlies the pathogenesis of EAOH/AOA1. The findings will provide new insight into the mechanism underlying degeneration and DNA repair in neurons.

Atypical Parkinsonism in distal myopathy with rimmed vacuoles.

A patient with distal myopathy with rimmed vacuoles (DMRV) exhibited Parkinsonism with a severe writing tremor that responded poorly to levodopa. Molecular genetic analysis revealed that the patient had the D176V/V572L compound heterozygous mutation in the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene. Histopathological examination of a biopsied muscle specimen yielded findings compatible with those of DMRV, which is characterized by the presence of rimmed vacuoles without inflammatory cell infiltration in muscle fibers. The finding of normal cardiac meta-iodobenzylguanide uptake makes the possibility of incidental Parkinson's disease in this patient unlikely. These observations raise the possibility that atypical Parkinsonism is a rare complication of DMRV associated with GNE mutation.

[An Adult Case of Enterovirus D68 Encephalomyelitis Presenting as Bilateral Facial Nerve Palsy and Dysphagia].

A 33-year-old man was admitted to our hospital with bilateral facial nerve paralysis, dysphagia, and muscle weakness in the neck and trunk following fever, headache and throat pain. T2-weighted brain magnetic resonance imaging (MRI) showed hyperintense lesions in the tegmentum of the brain stem and the ventral region of the superior cervical cord. Based on the characteristic findings on the brain MRI, we diagnosed the patient with enteroviral encephalomyelitis. Steroid therapy was administered; however, his bilateral facial nerve paralysis and dysphagia were refractory to this therapy. Subsequently, enterovirus D68 was detected in the serum using polymerase chain reaction (PCR) analysis. At that time, an outbreak of enteroviral D68 infection was reported in Japan. Finally, we diagnosed encephalomyelitis caused by enteroviral D68 infection. Characteristic MRI findings were very useful in narrowing down the differential diagnosis in this patient. (Received March 3, 2017; Accepted April 20, 2017; Published August 1, 2017).

Long-term therapeutic efficacy and safety of low-dose tacrolimus (FK506) for myasthenia gravis.

OBJECTIVE: To elucidate the long-term therapeutic efficacy and safety of low-dose FK506 (tacrolimus) in patients with myasthenia gravis (MG). PATIENTS AND METHODS: We treated nine patients with MG (all women: age range: 35-83 years (mean: 51.1 years); MGFA classification: 4 type IIa, 4 type IIb, and 1 type IVb patients) with FK506 for more than 24 months (observation period: 24-46 months). All the patients had undergone extended thymectomy before FK506 treatment; two patients (22.2%) had noninvasive thymoma and six (66.7%) had thymic hyperplasia. We evaluated total Quantitative MG (Q-MG) score, anti-acetylcholine receptor (AChR) antibody titer in the blood, interleukin 2 (IL-2) production in peripheral blood mononuclear cells (PBMCs), administration dosage of prednisolone (PSL), and adverse effects of FK506. RESULTS: A reduction in steroid dosage of 50% without worsening of the symptoms was observed 1 year after FK506 administration in three out of six steroid-dependent MG patients (50.0%). The total Q-MG scores (range: 0-39 points) at 6 months and 1 year after FK506 administration improved by 3 points or more in six (66.7%) and seven (77.8%) out of nine patients, respectively. The efficacy of FK506 was maintained for more than 2 years. Although adverse effects were observed in three patients (33.3%), these were not serious. CONCLUSIONS: Our study indicates that low-dose FK506 treatment may be efficacious not only in controlling intractable myasthenic symptoms, but also in reducing steroid dosage, and that FK506 is safe as an adjunctive drug to PSL for MG treatment for a maximum of 3 years.

[A pedigree of Charcot-Marie-Tooth disease type 4F (Periaxin mutation)].

We report a 51-year-old man genetically diagnosed as Charcot-Marie-Tooth disease type 4F. The patient was the first child of healthy, consanguineous parents. He had two sisters and one of them showed similar but milder symptoms. He had gait disturbance since childhood. Then he noticed muscle weakness of his hands at the age of early forties, and more difficulties in gait at the age of late forties. On examination at age 51, he showed absence of all deep tendon reflexes, weakness of the hand and distal leg muscles, pes cavus and decreased sensitivity to touch and vibration in the lower extremities. Electrophysiological studies of the median nerve showed delayed motor nerve conduction velocity and undetectable sensory nerve action potentials. The histology of his sural nerve revealed moderate loss of large myelinated fibers and the diameters of residual fibers shifted to small shown as size-frequency histogram. Many fibers are thinly myelinated and some of the Schwann cells looked as wrapping around the myelinate fibers with their processes. On gene analyses, we identified an Arg 1070 Stop homozygous mutation in the Periaxin, known to be a causative gene for CMT type 4F. Based on these observations, we emphasized that broad genetic analyses are necessary for diagnosis of CMT disease, including so far unidentified mutations among the Japanese populations.

Inducible PC12 cell model of Huntington's disease shows toxicity and decreased histone acetylation.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by the abnormal expansion of a polyglutamine tract in the huntingtin protein. We have developed PC12 cell lines in which the expression of an N-terminal truncation of huntingtin (N63) with either wild type (23Q) or expanded polyglutamine (148Q) can be induced by the removal of doxycycline. Differentiated PC12 cells induced to express N63-148Q showed cellular toxicity reaching up to 50% at 6 days post-induction. Histone acetyltransferase (HAT) activity and global histone acetylation was significantly decreased in cells expressing truncated huntingtin with mutant but not normal huntingtin. These data suggest that altered chromatin modification via reduction in coactivator activity may cause neuronal transcriptional dysregulation and contribute to cellular toxicity.

[A case of multiple sclerosis with pathological laughing caused by pontine base lesions].

We report a case of multiple sclerosis (MS) with pathological laughing for which lesions in pontine bases are considered to be responsible. A 30-year-old man was diagnosed as having MS based on left hemiparesis, and pathological laughing, and MRI findings showing a plaque in the right pontine base as well as several plaques in the bilateral periventricular deep white matter. After remission for 6 years, his pathological laughing exacerbated in association with development of right hemiparesis. A new lesion in the left pontine base was demonstrated by MRI studies in addition to a few supratentorial lesions. Steroid pulse therapy was effective for both pathological laughing and right hemiparesis. We speculate that the anatomical lesion responsible for the pathological laughing is located in the pontine base.

[An autopsy case of amyotrophic lateral sclerosis with prominent muscle cramps, fasciculation, and high titer of anti-voltage gated potassium channel (VGKC) complex antibody].

The patient was a 55-year-old male who had prominent fasciculation and muscle cramps. Muscle weakness and atrophy of the trunk, respiratory system, and extremities gradually progressed. On the basis of these features, we diagnosed this patient as having amyotrophic lateral sclerosis (ALS), however, the upper motor neuron signs were not significant. Following the detection of the anti-voltage gated potassium channel (VGKC) complex antibody at 907.5 pM (normal < 100 pM) and repetitive discharge in a nerve conduction study, immunotherapy with intravenous immunoglobulin, methylprednisolone (mPSL), double filtration plasmapheresis (DFPP), ciclosporin, and rituximab was introduced. mPSL and DFPP showed only tentative effectiveness for fasciculation and muscle cramps, respectively. Thereafter, muscle weakness progressed. The patient died of type II respiratory failure at the age of 57 years, about 2 years after the onset of the disease. At autopsy, a histopathological diagnosis of ALS with lower-motor-predominant degeneration was made. Characteristic cellular features, including Bunina bodies in the remaining lower motor neurons and phosphorylated TAR DNA-binding protein 43-kDa (pTDP-43)-immunopositive inclusions in both upper and lower motor neuron systems, were evident. At present, an immunological role of the anti-VGKC complex antibody in the development of cramp-fasciculation syndrome has been speculated. In this ALS patient, the antibodies might be associated with pathomechanisms underlying the characteristic symptoms.

Predictors of outcome in hypoglycemic encephalopathy.

AIMS: The aim of this study was to investigate factors predicting poor prognosis in patients with hypoglycemic encephalopathy. METHODS: We retrospectively analyzed data on 165 consecutive patients with hypoglycemic encephalopathy. We evaluated their outcome 1 week after hypoglycemia onset using the Glasgow outcome scale (GOS) and compared the clinical features of patients with good outcomes (GOS = 5) and poor outcomes (GOS ≤ 4). RESULTS: The poor-outcome group included 38 patients (23%). The initial blood glucose level in the poor-outcome group was lower than that in the good-outcome group (p = 0.002). The duration of hypoglycemia in the poor-outcome group was longer than that in the good-outcome group (p < 0.001). Body temperature during hypoglycemia in the poor-outcome group was higher than that in the good-outcome group (p < 0.001). Furthermore, lactic acid level in the poor-outcome group was lower than in the good-outcome group (p = 0.032). There was no significant difference in the frequency of posttreatment hyperglycemia between the good-outcome and poor-outcome groups (p = 0.984). CONCLUSION: Profound and prolonged hypoglycemia, normal or higher body temperature, and a low lactic acid level during hypoglycemia may be predictors of a poor outcome in patients with hypoglycemic encephalopathy.

[Amyloid beta-related angiitis: brain lesions showing leptomeningeal gadolinium enhancement on MRI and characteristic surgical pathologic features].

Amyloid-ß-related angiitis (ABRA) of the CNS occurs in association with vasculitis of small-and medium-sized leptomeningeal arteries. Here, we describe the clinicopathological features of a 76-year-old man with ABRA. The patient suffered progressive truncal oscillation, aphasia, and recent memory disturbance with a subacute disease onset. His cerebrospinal fluid showed a mild increase in protein levels (101 mg/dL) and pleocytosis (8/mm(3)). High-intensity brain lesion were detected on T(2)-weighted and FLAIR MRI scans, and prominent spread of gadolinium enhancement spreading was observed through the sulci of the left occipital and temporal lobes and left cerebellar hemisphere. A biopsy of the left temporal lesion showed a granulomatous and angiodestructive inflammation with infiltration of many CD4(+) T-lymphocytes and multinucleated giant cells and with fibrinoid necrosis of the arterial walls in the subarachnoid space. Immunolabeling for Aß(1-40) revealed the abundant deposition of this protein in the affected arteries. On the basic of the diagnosis of ABRA, immunosuppressive therapy was conducted, and it ameliorated the clinical course.

[Case of Lemierre syndrome associated with infectious cavernous sinus thrombosis and septic meningitis].

A 33-year-old man was admitted to our hospital because of right exophthalmos, diplopia and left neck pain. Neurological examination revealed lateral and inferior disturbance of his right eye movement and the meningeal irritation sign. Cerebrospinal fluid showed elevated polynuclear cells. Enhanced CT and MRI revealed thrombophlebitis of the left internal jugular vein and bilateral cavernous sinuses. On the basis of these findings, he was diagnosed as having Lemierre syndrome associated with cavernous sinus thrombophlebitis and bacterial meningitis. After administration of antibiotics, his symptoms disappeared and the data of laboratory analyses also improved. However, after his discharge, he was required re-antibiotics therapy because of septic embolus- induced multiple lung abscesses. Lemierre syndrome is characterized by disseminated abscesses and thrombophlebitis of the internal jugular vein after infection of the oropharynx. Because Lemierre syndrome is potentially life-threatening, early diagnosis and initiation of appropriate therapy are important.