Clinical features and management of traumatic ophthalmic artery aneurysm: a case report and literature review.

We report a 52-year-old man with progressive disturbance of visual acuity following a head injury. Magnetic resonance imaging (MRI) showed an aneurysm of the internal carotid artery. Digital subtraction angiography (DSA) 57 days after onset found that the aneurysm originated in the proximal ophthalmic artery. We treated the patient with an intravascular coil embolization, partially filling the aneurysm. Follow-up DSA indicated that the aneurysm did not recur.

Role of Microelectrode Recording in Deep Brain Stimulation of the Pedunculopontine Nucleus: A Physiological Study of Two Cases.

BACKGROUND: Deep brain stimulation (DBS) of the pedunculopontine nucleus (PPN) has been reported to improve gait disturbances in Parkinson's disease (PD); however, there are controversies on the radiological and electrophysiological techniques for intraoperative and postoperative confirmation of the target and determination of optimal stimulation parameters. OBJECTIVES: We investigated the correlation between the location of the estimated PPN (ePPN) and neuronal activity collected during intraoperative electrophysiological mapping to evaluate the role of microelectrode recording (MER) in identifying the effective stimulation site in two PD patients. MATERIALS AND METHODS: Bilateral PPN DBS was performed in two patients who had suffered from levodopa refractory gait disturbance. They had been implanted previously with DBS in the internal globus pallidus and the subthalamic nucleus, respectively. The PPN was determined on MRI and identified by intraoperative MER. Neuronal activity recorded was analyzed for mean discharge rate, bursting, and oscillatory activity. The effects were assessed by clinical ratings for motor signs before and after surgery. RESULTS: The PPN location was detected by MER. Groups of neurons characterized by tonic discharges were found 9-10 mm below the thalamus. The mean discharge rate in the ePPN was 19.1 ± 15.1 Hz, and 33% of the neurons of the ePPN responded with increased discharge rate during passive manipulation of the limbs and orofacial structures. PPN DBS with bipolar stimulation at a frequency range 10-30 Hz improved gait disturbances in both patients. Although PPN DBS provided therapeutic effects post-surgery in both cases, the effects waned after a year in case 1 and three years in case 2. CONCLUSIONS: Estimation of stimulation site within the PPN is possible by combining physiological guidance using MER and MRI findings. The PPN is a potential target for gait disturbances, although the efficacy of PPN DBS may depend on the location of the electrode and the stimulation parameters.

Clinical features and prognostic factors in patients with cancer-associated multiple ischemic stroke: A retrospective observational study.

OBJECTIVES: To investigate the patient demographics, survival after diagnosis, and prognostic factors among patients with multiple-territory cerebral infarctions due to cancer-associated ischemic stroke (multiple CAIS). MATERIALS AND METHODS: We performed a retrospective review of the medical records from a 10-year period of consecutive patients with multiple CAIS, defined as (1) newly developed multiple cerebral infarctions involving two or more cerebrovascular territories, (2) association with active cancer diagnosed or treated <6 months before or after stroke, and (3) exclusion of obvious etiologies other than cancer-associated coagulopathy in routine screening. We extracted demographic features, stroke severity and characteristics, cancer characteristics, comorbidities, and laboratory data. Univariable Cox proportional hazards regression was used to idenify the prognostic factors. RESULTS: The median age was 74 years (interquartile range, 68.3-80.5), and the median survival after diagnosis was 44.5 (27.3-76.8) days in 26 patients with complete follow-up. The median National Institutes of Health Stroke Scale was 5.5 (2.0-9.0). Twenty (76.9%) patients had received a cancer diagnosis prior to the diagnosis of multiple CAIS, and most patients (25 patients, 96.2%) had stage IV cancer. Univariate analysis showed that high serum albumin (hazard ratio, 0.31; 95% confidence interval, 0.11-0.88) was significantly associated with prolonged survival, whereas stroke severity and comorbidities were not associated with survival. CONCLUSION: Multiple CAIS predominantly occurred in elderly patients with advanced cancer, and their survival was short. Serum albumin levels were significantly associated with prognosis, indicating the poor general condition associated with cancers may affect prognosis.

Evaluation of Disappearance Time and Palatability of Foams in the Oral Cavities of Healthy Volunteers, and Preparation of Drug-Containing Foam Formulations for Use in the Treatment of Oral Mucositis.

Oral mucositis is one of the most common adverse effects of radiation and chemotherapy in treatments of cancers. Some clinical guidelines have focused on the prevention and treatment of oral mucositis, and thus, a mouthwash containing drugs is often recommended. In this study, we aimed to evaluate the disappearance time and palatability in the oral cavities of healthy volunteers in foams prepared from different concentrations of the three viscosity grades of methylcellulose (SM-4, -100, -400). In addition, we prepared foam formulations of drugs (benzydamine, dexamethasone, allopurinol and rebamipide) for use as a prevention and treatment of oral mucositis. There was a significant relationship between the foam drainage ratios at 5-15 min and the disappearance time in the oral cavities. The significant relationship of foam densities to the foam disappearance time and overall palatability in a clinical study were observed. Thus, the foam density is considered an important parameter and reflects these clinically important properties. The foam from SM-4 has the longest disappearance time and the best palatability followed by foams from the 4 and 1% SM-4. Drug contents in drug-containing foam formulations which were prepared with 1-4% SM-4 represented 101-112% of the loaded drug contents, and the relative standard deviations of drug contents were <2.2%, which suggests that these formulations had pharmaceutically acceptable properties. This is the first report in regard to foam formulations containing drugs for the prevention and treatment of oral mucositis, and these formulations could be potentially useful for the prevention and treatment of oral mucositis.

Arterial spin labeling imaging correlates with the angiographic and clinical vascularity of vestibular schwannomas.

PURPOSE: Hypervascular vestibular schwannomas (HVSs) are a type of the vestibular schwannomas (VSs) that are extremely difficult to remove. We examined whether HVSs can be predicted by using arterial spin labeling (ASL) imaging. METHODS: A total of 103 patients with VSs underwent ASL imaging and digital subtraction angiography (DSA) before surgery. Regional cerebral blood flow (CBF) of gray matter and regional tumor blood flow (TBF) were calculated from ASL imaging, and we defined the ratio of TBF to CBF as the relative TBF (rTBF = TBF/CBF). Angiographic vascularity was evaluated by DSA, and clinical vascularity was evaluated by the degree of intraoperative tumor bleeding. Based on the angiographic and clinical vascularity, the VSs were divided into two categories: HVS and non-HVS. We compared rTBF with angiographic and clinical vascularities, retrospectively. RESULTS: The mean rTBFs of angiographic non-HVSs and HVSs were 1.29 and 2.58, respectively (p < 0.0001). At a cutoff value of 1.55, the sensitivity and specificity were 93.9% and 72.9%, respectively. The mean rTBFs of clinical non-HVS and HVSs were 1.45 and 2.22, respectively (p = 0.0002). At a cutoff value of 1.55, the sensitivity and specificity were 79.4% and 66.7%, respectively. CONCLUSION: The rTBF calculated from ASL imaging correlates well with tumor vascularity and may be useful for predicting HVSs before surgery.

[A Rebleeding Case of Carotid Blowout Syndrome after Endovascular Treatment with Covered Stent].

We present a case of a patient who survived carotid blowout syndrome(CBS)due to covered stent placement, but bled again 34 days later. A 67-year-old man with laryngeal cancer experienced cardiac arrest due to carotid blowout a day after he underwent the balloon occlusion test and abnormal feeder embolization of the tumor. After quick resuscitation, he was treated with endovascular therapy using a covered stent, since he had insufficient cerebral ischemic tolerance. We succeeded in stent placement and the bleeding stopped without any procedural complications. The patient survived after the procedure. However, bleeding recurred when a nasal endoscope was inserted 34 days later. The rupture point was immediately distal of the stent. We performed carotid artery occlusion with coils and n-butyl-cyanoacrylate. The patient survived, but his condition gradually weakened and died 97 days after stenting. Emergency hemostasis for carotid blowout using a covered stent is the only available treatment for patients who do not have sufficient cerebral ischemic tolerance. However, this procedure has a higher rate of re-bleeding than carotid artery occlusion. Moreover, it is an off-label treatment in Japan. Therefore, possible treatments for CBS including use of covered stent or treatments for non-ruptured CBS should be analyzed in the future.

Long-Term Suppression of Disabling Tremor by Thalamic Stimulation in a Patient with Spinocerebellar Ataxia Type 2.

The beneficial effect of thalamic deep brain stimulation (DBS) on action tremor has been reported in a few cases of spinocerebellar ataxia (SCA); however, several factors should be taken into account regarding the indication for DBS in advanced cases. We performed DBS of the ventral intermediate nucleus (Vim) of the thalamus for treatment of coarse action tremor in a patient with SCA2 (spinocerebellar ataxia type 2) in the wheelchair-bound stage. Although improvement of the tremor of the proximal part was incomplete, the patient regained substantial parts of daily functioning. The effect lasted for more than 6 years, and the suppression of tremor significantly contributed to maintaining the level of the patient's expression into the bedridden stage. Vim DBS can be a treatment option for tremor in SCA patients, even in the advanced stage, as long as the tremor is depriving the patient of behavioral expression. As residual proximal tremor may hamper functional recovery, DBS of other targets or multi-targets should be further explored to attain a better outcome.

Post-embolization neurological syndrome after embolization for intracranial and skull base tumors: transient exacerbation of neurological symptoms with inflammatory responses.

PURPOSE: Pre-operative embolization is an effective treatment strategy for hypervascular intracranial and skull base tumors. However, neurological complications resulting from tumor swelling, cranial nerve ischemia, or hemorrhage can occur after embolization. The purpose of this study was to examine the relationship between neurological complications following pre-operative embolization and minor adverse events including fever, headache, or increasing inflammation, which are common after embolization for abdominal tumors (i.e., post-embolization syndrome, PES). METHODS: We retrospectively reviewed 39 consecutive patients with pre-operative embolization for intracranial and skull base tumors. Neurological symptoms and minor adverse events were regularly observed after embolization. The degree of devascularization was evaluated using enhanced magnetic resonance imaging. We also evaluated changes in peritumoral edema. RESULTS: Neurological complications occurred in eight cases, five of whom had exacerbation of existing neurological symptoms, which occurred concurrent with a general inflammatory response. We termed this clinical condition post-embolization neurological syndrome (PENS). The mean time to neurological symptom onset was 37.2 h after embolization. PENS was self-limiting in all cases but one, which required emergency surgery. The remaining three cases were diagnosed with cranial nerve ischemia. CONCLUSIONS: PENS is an important neurological complication after pre-operative embolization, which should be distinguished from ischemic or hemorrhagic complications. PES is a minor complication with favorable prognosis, whereas PENS should be considered as a dangerous clinical sign that may require emergency treatment. Further experiments are needed to elucidate the pathology of PENS.

Clinico-Radiological Characteristics and Pathological Diagnosis of Cerebral Amyloid Angiopathy-Related Intracerebral Hemorrhage.

OBJECTIVE: We aim to clarify the clinico-radiological characteristics of cerebral amyloid angiopathy-related intracerebral hemorrhage and to investigate the efficacy of pathological diagnosis using biopsy specimens. METHOD: We retrospectively reviewed 253 consecutive patients with cortico-subcortical hemorrhage who had been admitted to Aizawa Hospital between January 2006 and July 2013. We had performed craniotomy and hematoma evacuation in 48 patients, as well as biopsy of the evacuated hematoma, cerebral parenchyma adjacent to the hematoma, or both, and they were classified according to the histological results (positive or negative for vascular amyloid deposition) and to the Boston criteria. We compared the clinico-radiological characteristics of cerebral amyloid angiopathy-related intracerebral hemorrhage. We also investigated the detection rate of cerebral amyloid angiopathy with respect to the origins of the specimens. RESULTS: Pathological examination revealed that 22 subjects were positive for vascular amyloid. The number of the cerebral microbleeds located in the deep or infratentorial region was significantly larger in the negative group than in the positive group (P <.05). There was no significant difference in the distribution of lobar cerebral microbleeds and in the prevalence of hypertension. In the probable cerebral amyloid angiopathy-related intracerebral hemorrhage patients, the probability of having vascular amyloid detected by biopsy of both hematoma and parenchyma was 100%. Rebleeding in the postoperative periods was observed in 2 cases (9.1%) of the positive group. CONCLUSIONS: Our results demonstrate the importance and safety of biopsy simultaneously performed with hematoma evacuation. Deep or infratentorial microbleeds are less correlated with cerebral amyloid angiopathy-related intracerebral hemorrhage than with noncerebral amyloid angiopathy-related intracerebral hemorrhage.

Novel ABHD12 mutations in PHARC patients: the differential diagnosis of deaf-blindness.

OBJECTIVE: This study examines ABHD12 mutation analysis in 2 PHARC patients, originally thought to be Usher syndrome. METHODS: The ABHD12 gene of 2 patients, who suffered from deaf-blindness and dysfunctional central and peripheral nervous systems, were sequenced. RESULTS: We identified that both cases carried the same novel splice site mutation in the ABHD12 gene. However, 1 had epilepsy and the other had peripheral neuropathy. Based on haplotype analysis, the mutation is likely not a hot spot, but rather could be attributable to a common ancestor. CONCLUSION: This study shows that PHARC has phenotypic variability, even within a family, which is consistent with previous reports. Differential diagnosis of "deaf-blindness" diseases is crucial. Confirming the presence of associated symptoms is necessary for differentiating some deaf-blindness syndromes. In addition, mutation analysis is a useful tool for confirming the diagnosis.

Case of tizanidine withdrawal showing hallucination, decorticate posture and tremor, with hypersympathetic vital signs.

Tizanidine, an α2-adrenergic receptor agonist commonly prescribed as a muscle relaxant, has been associated with limited cases of acute intoxication or withdrawal. Here, we present a case of tizanidine withdrawal in a woman in her 40s who presented with an unusual combination of systemic and neurological symptoms. These included hallucinations, decorticate posture, limb and eyelid tremors, along with hypertension, tachycardia and tachypnoea. The diagnosis of tizanidine withdrawal was established by a comprehensive assessment of the patient's medical history and the systematic exclusion of other potential diseases. Our approach to managing the withdrawal symptoms was to initiate symptomatic treatment with a combination of a beta-blocker and a calcium channel blocker. Remarkably, this intervention successfully resolved both vital signs and neurological manifestations by the following day. In conclusion, tizanidine withdrawal is associated with a distinct and diagnostically significant neurological syndrome characterised by hallucinations, decorticate posture, tremors and hypersympathetic vital signs.

A Cerebral Embolism Caused by a Malignant Peripheral Nerve Sheath Tumor in a Patient with Neurofibromatosis Type 1.

A 31-year-old man with neurofibromatosis type 1 (NF-1) had undergone resection of a malignant peripheral nerve sheath tumor (MPNST) on the buttock 3 months previously. He subsequently underwent mechanical thrombectomy for a hyperacute left middle cerebral artery embolism. Histopathologically, the emboli comprised neurofilament-positive pleomorphic tumor cells with geographic necrosis and conspicuous mitosis and were identified as MPNST. The patient died of respiratory failure due to lung MPNST metastasis on day 15 of hospitalization. To our knowledge, this is the first report of a spontaneous cerebral embolism due to MPNST in a NF-1 patient.

ON and OFF channels in human retinal ganglion cells.

The ON and OFF channels are basic functional elements in parallel processing in the visual system in vertebrates including primates. We analysed the responses of the optic tract fibre activity in response to switching a flashlight on or off in 25 awake patients with Parkinson's disease who underwent stereotactic surgery targeting the internal globus pallidus. The responses were evoked in a darkened room by a light with a luminance of approximately 4 × 10(4) cd m(-2) at the eye and a wide-spectrum wavelength. Most of the responses at the light on event were excitatory (38 out of 41 sites, 93%). Thirty-five sites with increase in activity at the light on event showed reciprocal responses or no responses to light off, and these sites were classified as containing ON fibres. In single-fibre analysis, all of 14 ON fibres were recorded at the sites of multi-fibre excitatory responses. Six sites showed multi-fibre excitatory responses at the light off event; three sites showed sustained reduction in activity at the light on event, and these three sites were classified as containing OFF fibres. In single-fibre analysis, two OFF fibres were recorded at the sites of multi-fibre suppressive responses at the light on event, and the other two OFF fibres were recorded at the sites of multi-fibre excitatory responses at the light on event. We found that all excitatory responses to light on were transient, while all but one excitatory responses to light off were sustained. Reduction in activity tended to be smaller than increase in activity at the light on event. These results demonstrate that the ON and OFF channels, and their transient and sustained features function in visual processing in humans.

Highly multiplexed immune profiling throughout adulthood reveals kinetics of lymphocyte infiltration in the aging mouse prostate.

Aging is a significant risk factor for disease in several tissues, including the prostate. Defining the kinetics of age-related changes in these tissues is critical for identifying regulators of aging and evaluating interventions to slow the aging process and reduce disease risk. An altered immune microenvironment is characteristic of prostatic aging in mice, but whether features of aging in the prostate emerge predominantly in old age or earlier in adulthood has not previously been established. Using highly multiplexed immune profiling and time-course analysis, we tracked the abundance of 29 immune cell clusters in the aging mouse prostate. Early in adulthood, myeloid cells comprise the vast majority of immune cells in the 3-month-old mouse prostate. Between 6 and 12 months of age, there is a profound shift towards a T and B lymphocyte-dominant mouse prostate immune microenvironment. Comparing the prostate to other urogenital tissues, we found similar features of age-related inflammation in the mouse bladder but not the kidney. In summary, our study offers new insight into the kinetics of prostatic inflammaging and the window when interventions to slow down age-related changes may be most effective.

A conserved mechanism for JNK-mediated loss of Notch function in advanced prostate cancer.

Dysregulated Notch signaling is a common feature of cancer; however, its effects on tumor initiation and progression are highly variable, with Notch having either oncogenic or tumor-suppressive functions in various cancers. To better understand the mechanisms that regulate Notch function in cancer, we studied Notch signaling in a Drosophila tumor model, prostate cancer-derived cell lines, and tissue samples from patients with advanced prostate cancer. We demonstrated that increased activity of the Src-JNK pathway in tumors inactivated Notch signaling because of JNK pathway-mediated inhibition of the expression of the gene encoding the Notch S2 cleavage protease, Kuzbanian, which is critical for Notch activity. Consequently, inactive Notch accumulated in cells, where it was unable to transcribe genes encoding its target proteins, many of which have tumor-suppressive activities. These findings suggest that Src-JNK activity in tumors predicts Notch activity status and that suppressing Src-JNK signaling could restore Notch function in tumors, offering opportunities for diagnosis and targeted therapies for a subset of patients with advanced prostate cancer.

Microwell-based flow culture increases viability and restores drug response in prostate cancer spheroids.

3D cancer spheroids represent a highly promising model for study of cancer progression and therapeutic development. Wide-scale adoption of cancer spheroids, however, remains a challenge due to the lack of control over hypoxic gradients that may cloud the assessment of cell morphology and drug response. Here, we present a Microwell Flow Device (MFD) that generates in-well laminar flow around 3D tissues via repetitive tissue sedimentation. Using a prostate cancer cell line, we demonstrate the spheroids in the MFD exhibit improved cell growth, reduced necrotic core formation, enhanced structural integrity, and downregulated expression of cell stress genes. The flow-cultured spheroids also exhibit an improved sensitivity to chemotherapy with greater transcriptional response. These results demonstrate how fluidic stimuli reveal the cellular phenotype previously masked by severe necrosis. Our platform advances 3D cellular models and enables study into hypoxia modulation, cancer metabolism, and drug screening within pathophysiological conditions.

Prostate lineage-specific metabolism governs luminal differentiation and response to antiandrogen treatment.

Lineage transitions are a central feature of prostate development, tumourigenesis and treatment resistance. While epigenetic changes are well known to drive prostate lineage transitions, it remains unclear how upstream metabolic signalling contributes to the regulation of prostate epithelial identity. To fill this gap, we developed an approach to perform metabolomics on primary prostate epithelial cells. Using this approach, we discovered that the basal and luminal cells of the prostate exhibit distinct metabolomes and nutrient utilization patterns. Furthermore, basal-to-luminal differentiation is accompanied by increased pyruvate oxidation. We establish the mitochondrial pyruvate carrier and subsequent lactate accumulation as regulators of prostate luminal identity. Inhibition of the mitochondrial pyruvate carrier or supplementation with exogenous lactate results in large-scale chromatin remodelling, influencing both lineage-specific transcription factors and response to antiandrogen treatment. These results establish reciprocal regulation of metabolism and prostate epithelial lineage identity.

MYC is a regulator of androgen receptor inhibition-induced metabolic requirements in prostate cancer.

Advanced prostate cancers are treated with therapies targeting the androgen receptor (AR) signaling pathway. While many tumors initially respond to AR inhibition, nearly all develop resistance. It is critical to understand how prostate tumor cells respond to AR inhibition in order to exploit therapy-induced phenotypes prior to the outgrowth of treatment-resistant disease. Here, we comprehensively characterize the effects of AR blockade on prostate cancer metabolism using transcriptomics, metabolomics, and bioenergetics approaches. The metabolic response to AR inhibition is defined by reduced glycolysis, robust elongation of mitochondria, and increased reliance on mitochondrial oxidative metabolism. We establish DRP1 activity and MYC signaling as mediators of AR-blockade-induced metabolic phenotypes. Rescuing DRP1 phosphorylation after AR inhibition restores mitochondrial fission, while rescuing MYC restores glycolytic activity and prevents sensitivity to complex I inhibition. Our study provides insight into the regulation of treatment-induced metabolic phenotypes and vulnerabilities in prostate cancer.

Use of a chemically induced-colon carcinogenesis-prone Apc-mutant rat in a chemotherapeutic bioassay.

BACKGROUND: Chemotherapeutic bioassay for colorectal cancer (CRC) with a rat model bearing chemically-induced CRCs plays an important role in the development of new anti-tumor drugs and regimens. Although several protocols to induce CRCs have been developed, the incidence and number of CRCs are not much enough for the efficient bioassay. Recently, we established the very efficient system to induce CRCs with a chemically induced-colon carcinogenesis-prone Apc-mutant rat, Kyoto Apc Delta (KAD) rat. Here, we applied the KAD rat to the chemotherapeutic bioassay for CRC and showed the utility of the KAD rat. METHODS: The KAD rat has been developed by the ENU mutagenesis and carries a homozygous nonsense mutation in the Apc gene (S2523X). Male KAD rats were given a single subcutaneous injection of AOM (20 mg/kg body weight) at 5 weeks of age. Starting at 1 week after the AOM injection, they were given 2% DSS in drinking water for 7 days. Tumor-bearing KAD rats were divided into experimental and control groups on the basis of the number of tumors observed by endoscopy at week 8. The 5-fluorouracil (5-FU) was administrated intravenously a dose of 50 or 75 mg/kg weekly at week 9, 10, and 11. After one-week interval, the 5-FU was given again at week 13, 14, and 15. At week 16, animals were sacrificed and tumor number and volume were measured macroscopically and microscopically. RESULTS: In total 48 tumors were observed in 27 KAD rats with a 100% incidence at week 8. The maximum tolerated dose for the KAD rat was 50 mg/kg of 5-FU. Macroscopically, the number or volume of tumors in the 5-FU treated rats was not significantly different from the control. Microscopically, the number of adenocarcinoma in the 5-FU treated rats was not significantly different (p < 0.02) from that of the control. However, the volume of adenocarcinomas was significantly lower than in the control. Anticancer effect of the 5-FU could be obtained only after the 16 weeks of experimental period. CONCLUSION: The use of the AOM/DSS-treated tumor-bearing KAD rats could shorten the experimental period and reduce the number of animals examined in the chemotherapeutic bioassay. The efficient bioassay with the AOM/DSS-treated tumor-bearing KAD rats would promote the development of new anti-tumor drugs and regimens.

Paramedian Midbrain Infarction Presenting with Bilateral Ptosis and Unilateral Median Longitudinal Fasciculus Syndrome: A Peculiar Midbrain Syndrome.

We report a case of bilateral ptosis due to paramedian midbrain infarction, which was associated with ipsilateral impaired adduction of the eye and contralateral ataxia. T2-weighted magnetic resonance imaging of the brain revealed a right paramedian midbrain infarction. The ptosis rapidly improved without a difference between the left and right sides, while the other symptoms mostly resolved within a month following treatment with antiplatelet agents and rehabilitation. An infarction of the paramedian dorsocaudal portion of the midbrain can involve both the central caudal nucleus and the median longitudinal fasciculus (MLF), causing a peculiar combination of symptoms, bilateral ptosis, and unilateral MLF syndrome.