Durvalumab plus carboplatin-etoposide treatment in a patient with small-cell lung cancer on hemodialysis: a case report and literature review.

Little is known about the efficacy and safety of durvalumab plus carboplatin-etoposide treatment in patients with extensive-disease (ED) small-cell lung cancer (SCLC) on hemodialysis. Here, we present a case of a 67-year-old man with pleuroperitoneal communication on continuous ambulatory peritoneal dialysis who was diagnosed with ED-SCLC based on a cytological analysis of the peritoneal fluid. He was switched from peritoneal dialysis to hemodialysis and received durvalumab (1500 mg/body on day 1) plus carboplatin (area under the concentration-time curve = 5, 125 mg on day 1) and etoposide (50 mg/m2 on days 1 and 3) as first-line therapy. During the first cycle, grade 2 anemia, grade 3 neutropenia, and grade 3 upper gastrointestinal bleeding occurred; therefore, durvalumab and reduced doses of carboplatin and etoposide were administered. No other severe adverse events occurred, and a partial response was observed after four cycles. Our findings indicate that durvalumab plus carboplatin-etoposide treatment is safe and effective even in patients on hemodialysis.

Additional Steroid Therapy for Delayed Facial Palsy in Miller Fisher Syndrome.

Miller Fisher syndrome (MFS) is a variant of Guillain-Barré syndrome. Delayed facial palsy (DFP) is a symptom that occurs after other neurological symptoms begin to recover within four weeks from the onset of MFS. As there have been few detailed reports about DFP in MFS cases treated with additional immunotherapy, we investigated three cases of DFP in MFS treated with additional steroid therapies. The duration of facial palsy in our cases was 12-24 days. No severe adverse effects were observed. Although adverse side effects should be carefully monitored, additional steroid therapy might be a treatment option for MFS-DFP.

Phenological shifts in lake stratification under climate change.

One of the most important physical characteristics driving lifecycle events in lakes is stratification. Already subtle variations in the timing of stratification onset and break-up (phenology) are known to have major ecological effects, mainly by determining the availability of light, nutrients, carbon and oxygen to organisms. Despite its ecological importance, historic and future global changes in stratification phenology are unknown. Here, we used a lake-climate model ensemble and long-term observational data, to investigate changes in lake stratification phenology across the Northern Hemisphere from 1901 to 2099. Under the high-greenhouse-gas-emission scenario, stratification will begin 22.0 ± 7.0 days earlier and end 11.3 ± 4.7 days later by the end of this century. It is very likely that this 33.3 ± 11.7 day prolongation in stratification will accelerate lake deoxygenation with subsequent effects on nutrient mineralization and phosphorus release from lake sediments. Further misalignment of lifecycle events, with possible irreversible changes for lake ecosystems, is also likely.

[Eclizumab in the treatment of myasthenia gravis crisis complicating invasive thymoma: a case study of efficacy].

A 40-year-old male patient was diagnosed with invasive thymoma and myasthenia gravis in 2015. In 2016 and 2017, he experienced myasthenic crises, with an increase in size of invasive thymoma. In 2018, he received chemotherapy for the invasive thymoma. After 2 months, his symptoms rapidly progressed to myasthenic crisis with severe bulbar and respiratory symptoms, despite the significant effect of chemotherapy for the thymoma. High-dose corticosteroid, multiple plasma exchanges, and intravenous immunoglobulin did not improve the symptoms. Thus, eculizumab was administered, resulting in an improvement in his conditions. To our knowledge, this is the first report showing that eculizumab may improve myasthenic crisis with invasive thymoma.

TDP-43 transports ribosomal protein mRNA to regulate axonal local translation in neuronal axons.

Mislocalization and abnormal deposition of TDP-43 into the cytoplasm (TDP-43 proteinopathy) is a hallmark in neurons of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). However, the pathogenic mechanism of the diseases linked to TDP-43 is largely unknown. We hypothesized that the failure of mRNA transport to neuronal axons by TDP-43 may contribute to neurodegeneration in ALS and FTLD, and sought to examine the function of TDP-43 by identifying its target mRNA for axonal transport. We found that mRNAs related to translational function including ribosomal proteins (RPs) were decreased by shRNA-based TDP-43 knock-down in neurites of cortical neurons. TDP-43 binds to and transports the RP mRNAs through their 5' untranslated region, which contains a common 5' terminal oligopyrimidine tract motif and a downstream GC-rich region. We showed by employing in vitro and in vivo models that the RP mRNAs were translated and incorporated into native ribosomes locally in axons to maintain functionality of axonal ribosomes, which is required for local protein synthesis in response to stimulation and stress to axons. We also found that RP mRNAs were reduced in the pyramidal tract of sporadic ALS cases harboring TDP-43 pathology. Our results elucidated a novel function of TDP-43 to control transport of RP mRNAs and local translation by ribosomes to maintain morphological integrity of neuronal axons, and proved the influence of this function of TDP-43 on neurodegeneration in ALS and FTLD associated with TDP-43 proteinopathy.

Satellite-measured water properties in high altitude Lake Tahoe.

It has been difficult in satellite remote sensing to derive accurate water optical, biological, and biogeochemical products over high-altitude inland waters due to issues in satellite data processing (i.e., atmospheric correction). In this study, we demonstrate that accurate normalized water-leaving radiance spectra nLw(λ) can be derived for a high-altitude lake, Lake Tahoe, using improved Rayleigh radiance computations (Wang, M., Opt. Express, 24, 12414-12429, 2016) which accurately account for water surface altitude effects in the Multi-Sensor Level-1 to Level-2 (MSL12) ocean color data processing system. Satellite observations from the Visible Infrared Imaging Radiometer Suite (VIIRS) onboard the Suomi National Polar-orbiting Partnership (SNPP) between 2012 and 2018 are used to evaluate and validate satellite-derived nLw(λ) spectra, and to quantitatively characterize water properties in the lake. Results show that VIIRS-derived nLw(λ) spectra are quite comparable with those from the in situ measurements. Subsequent retrievals of water biological and biogeochemical products show that chlorophyll-a (Chl-a) concentration and Secchi depth (SD) are reasonably well-estimated, and captured normal seasonal variations in the lake, e.g., the annual highest Chl-a and SD normally occur in the winter while the lowest occur in the summer, which is consistent with in situ measurements. Interannual variability of these water quality parameters is also observed. In particular, Lake Tahoe experienced a significant environmental anomaly associated with an extreme weather condition event in 2017, showing considerably decreased nLw(λ) at the spectral bands of 410, 443, and 486 nm, and significantly reduced SD values in the entire lake. The low SD measurements from VIIRS are consistent with in situ observations. Following the event in the 2017-2018 winter, Lake Tahoe recovered and returned to its typical conditions in spring 2018.

Changes in clinical features of multiple system atrophy in Japan.

INTRODUCTION: Multiple system atrophy (MSA) is an adult-onset progressive neurodegenerative disease that causes parkinsonism, cerebellar ataxia, and/or autonomic failure. MSA is categorized as MSA with predominant cerebellar ataxia (MSA-C) or MSA with predominant parkinsonism (MSA-P) according to the cardinal symptom at diagnosis. MSA-C has been reported to be the predominant presentation in Japan to date. However, major epidemiological studies regarding MSA in Japan were carried out before 2006; thus, the recent advancement of various imaging studies remains unclear. This study aimed to investigate the clinical characteristics of the recent MSA patients in Japan. METHODS: In this retrospective study, we divided 80 probable MSA patients into group A and group B and examined them to reveal whether the clinical features of MSA were different depending on the time periods of diagnosis (1989-2003 and 2004-2018, respectively). RESULTS: The age at onset was significantly higher in MSA-P patients than in MSA-C patients (p = 0.0039) and was also higher in group B than in group A (p = 0.013). Although MSA-C was the predominant type in both groups, MSA-P was significantly more frequent in group B than in group A (p = 0.039). Although not statistically significant, the early heart/mediastinum ratio in [123I]-meta-iodo benzylguanidine (MIBG) myocardial scintigraphy tended to be lower in patients with MSA-P than in those with MSA-C. CONCLUSION: The proportion of MSA-P was likely larger than previously recorded due to the aging population in Japan and the improvement of differential diagnosis between PD and MSA-P.

[Utility of the Predictive Score for Cisplatin-Induced Nephrotoxicity in Patients with Chemotherapy for Lung Cancer].

BACKGROUND: Cisplatin(CDDP)-induced nephrotoxicity(CIN)is a critical complication of chemotherapy. Among patients undergoing chemotherapy with CDDP, short-hydration, and magnesium supplementation for lung cancer, this study was conducted to evaluate the frequency of CIN and utility of the predictive score. METHODS: Patients who underwent chemotherapy with CDDP for lung cancer were retrospectively investigated. A multiple logistic regression analysis to detect the risk factors for CIN and receiver operating characteristic analysis to examine the discrimination of the predictive score were performed. RESULTS: A total of 111 patients were included, with a total count of chemotherapy courses of 402 and a median count of chemotherapy courses of 4. CIN occurred in 9.9% of the patients, with grade 2 and higher in 7.2% and 87% of the CIN cases detected in the initial course, respectively. The significantly independent risk factors for CIN included the number of chemotherapy courses, female gender, and predictive score. The discriminative power of the predictive score was moderate. CONCLUSION: The predictive score for CIN was simple and useful in patients undergoing chemotherapy for lung cancer with CDDP, short-hydration, and magnesium supplementation, even in late courses.

Histological characterisation of visceral changes in a patient with type 2 Gaucher disease treated with enzyme replacement therapy.

Gaucher disease is a lysosomal storage disease caused by deficiency of glucocerebrosidase and accumulation of glucocerebroside. Three major sub-types have been described, type 2 is an acute neurological form that exhibits serious general symptoms and poor prognosis, compared with the other types. This case was a girl diagnosed with type 2 Gaucher disease at 12months of age who presented with poor weight gain from infancy, stridor, hypertonia, hepatosplenomegaly, trismus and an eye movement disorder. Enzyme replacement therapy (ERT) was administered, but she had frequent myoclonus and developmental regression. She needed artificial ventilation because of respiratory failure. She died at 11years of age. An autopsy demonstrated infiltrating CD68-positive large cells containing abundant lipids in alveoli, while in the liver, kidney and bone marrow CD68-positive cells were small and round. In the bone marrow, myelodysplastic changes were present without Gaucher cells. The infiltration of Gaucher cells in alveoli was marked, suggesting that ERT was relatively ineffective in pulmonary involvement, particularly intra-alveolar. Additional treatments are necessary to improve the neurological and pulmonary prognosis of type 2Gaucher disease.

Streptococcus panodentis sp. nov. from the oral cavities of chimpanzees.

Three strains TKU9, TKU49 and TKU50(T) , were isolated from the oral cavities of chimpanzees (Pan troglodytes). The isolates were all gram-positive, facultative anaerobic cocci that lacked catalase activity. Analysis of partial 16S rRNA gene sequences showed that the most closely related species was Streptococcus infantis (96.7%). The next most closely related species to the isolates were S. rubneri, S. mitis, S. peroris and S. australis (96.6 to 96.4%). Based on the rpoB and gyrB gene sequences, TKU50(T) was clustered with other member of the mitis group. Enzyme activity and sugar fermentation patterns differentiated this novel bacterium from other members of the mitis group streptococci. The DNA G + C content of strain TKU50(T) was 46.7 mol%, which is the highest reported value for members of the mitis group (40-46 mol%). On the basis of the phenotypic characterization, partial 16S rRNA gene and sequences data for two housekeeping gene (gyrB and rpoB), we propose a novel taxa, S. panodentis for TKU 50(T) (type strain = CM 30579(T) = DSM 29921(T) ), for these newly described isolates.

Identification of the neural correlates of cyclothymic temperament using a working memory task in fMRI.

BACKGROUND: Recently, we reported a significantly negative association of cyclothymic temperament scores with activations of the left lingual gyrus during esthetic judgments of paintings, suggesting that cyclothymic temperament may be associated with the left lingual gyrus. In view of potential associations of cyclothymic temperament, bipolar disorder and dementia, this study examined the relationship of temperament to lingual gyrus activity using a working memory task as a new context. METHODS: N-back tasks (0-, 1-, 2- and 3-back tasks) were performed on 34 healthy subjects using functional MRI. Multiple regression analyses were applied to measure the association between cyclothymic temperament scores and each of 4 beta images corresponding to 0-, 1-, 2- and 3-back tasks with gender, age and the other temperament scores (depressive, hyperthymic, irritable and anxious) as covariates. RESULTS: The whole brain analysis corrected for multiple comparisons revealed a significant activation of the left lingual gyrus associated with cyclothymic temperament scores in a new context-working memory for both 2- and 3-back tasks. LIMITATIONS: The number of subjects was relatively small. The subjects were almost medical staff or students and the results should be interpreted with caution. CONCLUSIONS: The present findings reconfirm that cyclothymic temperament may be associated with the left lingual gyrus.

[Recurrence of chronic active Epstein-Barr virus infection presenting with myelopathy after umbilical cord blood transplantation].

A 38-year-old man was admitted to our hospital with neck pain, dysesthesia of both hands, and weakness of the left upper limb. He had been diagnosed with a chronic active Epstein-Barr virus infection (CAEBV) at the age of 34 and had undergone umbilical cord blood transplantation at the age of 37. MRI of the spinal cord revealed an intramedullary hyperintense lesion on T2-weighted images with gadolinium enhancement. Because his laboratory tests revealed proliferation of CD19(+) lymphocytes in the peripheral blood, and EBV DNA was detected in both peripheral blood and CSF, he was diagnosed as having post-transplant EBV associated lymphoproliferative disease. However, chemotherapy did not alleviate his symptoms. At a later time, quantitative chimerism analysis of his CSF showed a higher proportion of lymphocytes that had originated from the recipient. Finally, he was diagnosed as having a recurrence of CAEBV in the central nervous system, and his symptoms were restored by intrathecal chemotherapy (methotrexate, cytosine arabinoside, and prednisolone). Quantitative chimerism analysis of CSF was useful for diagnosing the recurrence of CAEBV in the central nervous system.

Upregulation of store-operated Ca(2+) entry in the naïve CD4(+) T cells with aberrant cytokine releasing in active rheumatoid arthritis.

The regulated control of Ca(2+) influx is essential for the activation and function of the adaptive immune response, as Ca(2+) is a key regulator of important transcription factors. To determine whether Ca(2+) release-activated Ca(2+) (CRAC) channels contribute to the abnormal behaviour of T cells in patients with rheumatoid arthritis (RA), we performed a cross-sectional study to characterize the expression and functional status of CRACM1 channels in RA patients. Peripheral blood was obtained from 50 RA patients, 50 osteoarthritis (OA) patients and healthy donors. We measured Ca(2+) influx and CRAC currents in naïve and memory CD4(+) T cells. CRACM1 expression was evaluated in T cells from each of the three groups. These cells were further characterized by flow cytometric analysis of interleukin-4 (IL-4), IL-17, interferon-γ and tumour necrosis factor-α. These cytokines were also measured in naïve CD4(+) T cells following the lentivirus-mediated silencing of CRACM1.There was a significant positive correlation between Ca(2+) influx in naïve T cells and RA activity. Functionally aberrant naïve CD4(+) T cells from patients with active RA showed the different cytokine release pattern and exhibited increased Ca(2+) influx as well as increased CRACM1 protein expression and function. Specific lentiviral-induced gene silencing of CRACM1 reversed the alterations in T-cell cytokine production. The data presented here indicate that an upregulation of CRACM1 expression and function may be responsible for the abnormal cytokine release of naïve CD4(+) T cells in RA patients. CRACM1 might therefore represent a new molecular target for RA therapies.

Intracranial arachnoid cysts in a chimpanzee (Pan troglodytes).

An intracranial arachnoid cyst was detected in a 32-year-old, 44.6-kg, female chimpanzee at the Primate Research Institute, Kyoto University. Magnetic resonance imaging (MRI) and computed tomography (CT) were performed and the cognitive studies in which she participated were reviewed. MRI revealed that the cyst was present in the chimpanzee's right occipital convexity, and was located in close proximity to the posterior horn of the right lateral ventricle without ventriculomegaly. CT confirmed the presence of the cyst and no apparent signs indicating previous skull fractures were found. The thickness of the mandible was asymmetrical, whereas the temporomandibular joints and dentition were symmetrical. She showed no abnormalities in various cognitive studies since she was 3 years old, except a different behavioural pattern during a recent study, indicating a possible visual field defect. Detailed cognitive studies, long-term observation of her physical condition and follow-up MRI will be continued.

Irreversible neurological defects in the lower extremities after haploidentical stem cell transplantation: possible association with nelarabine.

Severe peripheral neuropathy and myelopathy are rare complications after stem cell transplantation (SCT). In our institution, seven patients of precursor T lymphoblastic leukemia/lymphoma without the central nervous involvement who had been treated by nelarabine to control their diseases received SCT from HLA-haploidentical familial donor (HLA-haploidentical SCT) with the conditioning regimen including high-dose cytarabine (HDAC). Three of evaluable six patients developed irreversible paresthesia and muscle weakness in both lower extremities after neutrophil engraftment. The results of nerve conduction studies and short latency somatosensory evoked potentials suggested axonal neuropathy of both lower extremities in all three patients and myelopathy in two patients. Negative findings of PET-CT, and analyses of repeated cerebrospinal fluid samples and the bone marrow also indicated that tumor involvement was improbable. In all three patients, the symptoms worsened or persisted despite administration of corticosteroid and intravenous immunoglobulin. The high frequency of the neurological symptoms in our patients previously treated by nelarabine strongly suggested the association of the nelarabine use. Furthermore, the HLA-haploidentical SCT setting and the use of a potentially neurotoxic agent, HDAC might augment the neurotoxicity of nelarabine. It may be desirable that HLA-haploidentical SCT candidates avoid receiving nelarabine.

Behavioral recovery from tetraparesis in a captive chimpanzee.

An adult male chimpanzee living in a captive social group at the Primate Research Institute of Kyoto University developed acute tetraparesis. He was paralyzed and received intensive care and veterinary treatment as previously reported in Miyabe-Nishiwaki et al. (J Med Primatol 39:336-346, 2010). The behavioral recovery of the chimpanzee was longitudinally monitored using an index of upright posture between 0 and 41 months after the onset of tetraparesis. Four phases were identified during the course of behavioral recovery. During Phase 0 (0-13 months), the chimpanzee remained lying on his back during the absence of human caretakers. An increase in upright posture occurred in Phase I (14-17 months), then remained at a stable level of around 50-70 % in Phase II (18-29 months). During Phases I and II, the subject's small treatment cage represented a spatial limitation. Thus, behavioral recovery was mainly mediated by arm muscle strengthening caused by raising the body trunk with the aid of materials attached to the cage walls as environmental enrichment. When the chimpanzee was moved to a larger rehabilitation room in Phase III (30-41 months), the percentage of upright posture constantly exceeded 80 %, except in the 40th month when he injured his ankle and was inactive for several days. The enlargement of the living space had a positive effect on behavioral recovery by increasing the types of locomotion exhibited by the subject, including the use of legs during walking. Rehabilitation works were applied in face-to-face situations which enabled the use of rehabilitation methods used in humans. The process of behavioral recovery reported in this study provides a basic data set for planning future rehabilitation programs and for comparisons with further cases of physical disability in non-human primates.

Streptococcus troglodytae sp. nov., from the chimpanzee oral cavity.

Six strains, TKU 25, TKU 28, TKU 30, TKU 31(T), TKU 33 and TKU 34, were isolated from the oral cavity of a chimpanzee (Pan troglodytes). Colonies of strains grown on Mitis-Salivarius agar were similar in morphology to that of Streptococcus mutans. The novel strains were Gram-stain-positive, facultatively anaerobic cocci that lacked catalase activity. Analysis of the partial 16S rRNA gene sequences of these isolates showed that the most closely related strain was the type strain of S. mutans (96.4 %). The next closely related strains to the isolates were the type strains of Streptococcus devriesei (94.5 %) and Streptococcus downei (93.9 %). These isolates could be distinguished from S. mutans by inulin fermentation and alkaline phosphatase activity (API ZYM system). The peptidoglycan type of the novel isolates was Glu-Lys-Ala(3). Strains were not susceptible to bacitracin. On the basis of phenotypic characterization, partial 16S rRNA gene and two housekeeping gene (groEL and sodA) sequence data, we propose a novel taxon, Streptococcus troglodytae sp. nov.; the type strain is TKU 31(T) ( = JCM 18038(T) = DSM 25324(T)).

Efficient synthesis of oxygenated terphenyls and other oligomers: sequential arylation reactions through phenol oxidation-rearomatization.

One by one: starting from simple phenols, a diverse series of oxygenated terphenyl compounds can be prepared in a concise and practical manner using sequential arylation reactions involving phenol oxidation/rearomatization and quinone monoacetal intermediates. Many of the terphenyl products can be used for preparing well-defined oligomers and, furthermore, contain valuable functional groups that can be transformed for further diversification.