The grasp reflex in patients with idiopathic normal pressure hydrocephalus.

OBJECTIVE: To investigate the prevalence and intensity of grasp reflexes and to examine changes in these reflexes after shunt surgery in patients with idiopathic normal pressure hydrocephalus (iNPH). METHODS: We enrolled 147 patients with probable iNPH. A standard procedure was used to determine the presence of grasp reflexes, and the intensity of these reflexes was assessed using a four-category classification. Clinical rating scales and their correlation with grasp reflexes were also evaluated. Grasp reflexes were reassessed in 72 patients 1 year after surgery. RESULTS: We found that approximately 50.3% of patients with iNPH exhibited a positive grasp reflex. Among these patients, 69% exhibited bilateral positivity, while the remaining patients showed unilateral positivity. Furthermore, the intensity of the grasp reflex was significantly correlated with the severity of gait and with cognitive, urinary, motor, and behavioural symptoms. Surgical interventions led to a reduction (41.7%) or maintenance (30.6%) of the reflex intensity in 72.3% of iNPH patients. The changes in reflex intensity showed significant positive correlations with changes in the number of steps of the Timed Up and Go test and Trail Making Test-A scores but not with changes in total scores on the iNPH Grading Scale. CONCLUSION: This retrospective study identified grasp reflexes as a highly prevalent phenomenon in patients with iNPH. These reflexes can assist in evaluating the severity of various symptoms, including cognitive, gait, urinary, motor and emotional symptoms.

Tumor cell-derived spermidine is an oncometabolite that suppresses TCR clustering for intratumoral CD8+ T cell activation.

The activation and expansion of T cells that recognize cancer cells is an essential aspect to antitumor immunity. Tumors may escape destruction by the immune system through ectopic expression of inhibitory immune ligands typically exemplified by the PD-L1/PD-1 pathway. Here, we reveal another facet of tumor evasion from T cell surveillance. By secretome profiling of necrotic tumor cells, we identified an oncometabolite spermidine as a unique inhibitor of T cell receptor (TCR) signaling. Mechanistically, spermidine causes the downregulation of the plasma membrane cholesterol levels, resulting in the suppression of TCR clustering. Using syngeneic mouse models, we show that spermidine is abundantly detected in the tumor immune microenvironment (TIME) and that administration of the polyamine synthesis inhibitor effectively enhanced CD8+ T cell-dependent antitumor responses. Further, the combination of the polyamine synthesis inhibitor with anti-PD-1 immune checkpoint antibody resulted in a much stronger antitumor immune response. This study reveals an aspect of immunosuppressive TIME, wherein spermidine functions as a metabolic T cell checkpoint that may offer a unique approach for promoting tumor immunotherapy.

NRF3 activates mTORC1 arginine-dependently for cancer cell viability.

Cancer cells coordinate the mTORC1 signals and the related metabolic pathways to robustly and rapidly grow in response to nutrient conditions. Although a CNC-family transcription factor NRF3 promotes cancer development, the biological relevance between NRF3 function and mTORC1 signals in cancer cells remains unknown. Hence, we showed that NRF3 contributes to cancer cell viability through mTORC1 activation in response to amino acids, particularly arginine. NRF3 induced SLC38A9 and RagC expression for the arginine-dependent mTORC1 recruitment onto lysosomes, and it also enhanced RAB5-mediated bulk macropinocytosis and SLC7A1-mediated selective transport for arginine loading into lysosomes. Besides, the inhibition of the NRF3-mTORC1 axis impaired mitochondrial function, leading to cancer cell apoptosis. Consistently, the aberrant upregulation of the axis caused tumor growth and poor prognosis. In conclusion, this study sheds light on the unique function of NRF3 in arginine-dependent mTORC1 activation and the pathophysiological aspects of the NRF3-mTORC1 axis in cancer development.

Risk factors for unfavourable outcomes after shunt surgery in patients with idiopathic normal-pressure hydrocephalus.

A number of vascular risk factors (VRFs) have been reported to be associated with idiopathic normal-pressure hydrocephalus (iNPH), but it remains unclear whether these VRFs are related to patient outcomes after shunt surgery. Therefore, we investigated the risk factors for unfavourable outcomes after shunt surgery in iNPH patients using two samples from Tohoku University Hospital and from a multicentre prospective trial of lumboperitoneal (LP) shunt surgery for patients with iNPH (SINPHONI-2). We enrolled 158 iNPH patients. We compared the prevalence of VRFs and clinical measures between patients with favourable and unfavourable outcomes and identified predictors of unfavourable outcomes using multivariate logistic regression analyses. The presence of hypertension, longer disease duration, more severe urinary dysfunction, and a lower Evans' index were predictors of unfavourable outcomes after shunt surgery. In addition, hypertension and longer disease duration were also predictors in patients with independent walking, and a lower Evans' index was the only predictor in patients who needed assistance to walk or could not walk. Our findings indicate that hypertension is the only VRF related to unfavourable outcomes after shunt surgery in iNPH patients. Larger-scale studies are needed to elucidate the reason why hypertension can affect the irreversibility of symptoms after shunt placement.

Polarity protein SCRIB interacts with SLC3A2 to regulate proliferation and tamoxifen resistance in ER+ breast cancer.

Estrogen receptor (ER) positive breast cancer represents 75% of all breast cancers in women. Although patients with ER+ cancers receive endocrine therapies, more than 30% develop resistance and succumb to the disease, highlighting the need to understand endocrine resistance. Here we show an unexpected role for the cell polarity protein SCRIB as a tumor-promoter and a regulator of endocrine resistance in ER-positive breast cancer cells. SCRIB expression is induced by estrogen signaling in a MYC-dependent manner. SCRIB interacts with SLC3A2, a heteromeric component of leucine amino acid transporter SLC7A5. SLC3A2 binds to the N-terminus of SCRIB to facilitate the formation of SCRIB/SLC3A2/LLGL2/SLC7A5 quaternary complex required for membrane localization of the amino acid transporter complex. Both SCRIB and SLC3A2 are required for cell proliferation and tamoxifen resistance in ER+ cells identifying a new role for the SCRIB/SLC3A2 complex in ER+ breast cancer.

Effects of Four-Week Kayak Training on Three-Dimensional Paddling Kinetics, Body Kinematics, and Electromyography Activity in a Novice Paddler: A Case Study.

From a biomechanical viewpoint, no longitudinal quantitative studies have been conducted on inexperienced paddlers. The present study aimed to investigate changes in three-dimensional paddling kinetics and kinematics, whole-body kinematics, and muscle activity with four-week on-water kayak training in a novice paddler. The participant practiced kayak paddling on river for four weeks. Before and after training, paddling kinetics and kinematics, body kinematics, and electromyography (EMG) activity were measured using a kayak ergometer. After the four-week training, the time required for on-water paddling for 270 m was reduced by 7.3% from pre to post training, while the average impulse in the x-direction significantly (P < 0.001, partial eta squared [η2] = 0.82) increased from 71.9 ± 1.9 to 91.1 ± 5.4 N kg-1 s-1. Furthermore, with training, the stroke rate and stroke length in the x-direction significantly (P < 0.001, partial η2 = 0.80 and 0.79, respectively) increased from 62.8 ± 1.2 to 81.0 ± 2.9 spm and from 1.53 ± 0.04 to 1.71 ± 0.02 m, respectively. After training, the transition time significantly (P < 0.001, partial η2 = 0.32) decreased (from 0.04 ± 0.01 to 0.01 ± 0.01 s), and there was an increase in paddle catch position (from -0.88 ± 0.01 to -1.04 ± 0.03 m). The pull time was not significantly changed (P = 0.077, partial η2 = 0.08) because of the increasing stroke length after training, meaning that substantial pull time, which defined as pull time relative to the stroke displacement, was shorter in post-training than in pre-training. The relative change in average impulse in the x-direction with training was significantly (r = 0.857, P = 0.014) correlated with that of vastus lateralis EMG. These results indicated that after four-week kayak training of the novice paddler, the key mechanism underlying time reduction to perform on-water paddling for 270 m was associated with (1) increased average impulse along the propulsive direction caused by an increase in vastus lateralis EMG and (2) a higher stroke rate, which was attributed to a reduction in the pull and transition times.

The effectiveness of a desensitization technique for mitigating oral and facial tactile hypersensitivity in institutionalized older persons: A randomized controlled trial.

BACKGROUND/PURPOSE: Oral health care provision in long-term care settings is often limited by specific behaviors exhibited by residents, which may be interpreted as a refusal of care. Such behaviors can be attributed to oral tactile hypersensitivity (TH), which is characterized by aberrations in the perception of oral stimuli. TH is also associated with a decline in ingestion and swallowing function. The purpose of this study was to examine the effectiveness of a technique for mitigating TH (TMH) among institutionalized older persons. MATERIALS AND METHODS: In this study, 18 institutionalized older persons (Mean age, 90.6 ±â€¯4.5 years; 92.9% females) with TH were randomized to a control group or an intervention group. Pre- and post-intervention assessments were conducted for seven participants in each group. Routine oral care was provided by the facility's staff in both groups. TMH in the intervention group was performed by a dental hygienist over a 3-month period. RESULTS: In the intervention group, the number of areas with TH was significantly reduced (P = 0.027). No significant change was observed in the control group. CONCLUSION: The results of this study suggest that TMH can effectively mitigate TH. Our findings provide clinicians with an additional treatment option for hypersensitivity in older patients. Additional long-term studies with larger sample sizes are required to confirm the effectiveness of this technique.

Echolalia in patients with primary progressive aphasia.

OBJECTIVE: This study aimed to examine echolalia and its related symptoms and brain lesions in primary progressive aphasia (PPA). METHODS: Forty-five patients with PPA were included: 19 nonfluent/agrammatic variant PPA (nfvPPA), 5 semantic variant PPA, 7 logopenic variant PPA, and 14 unclassified PPA patients. We detected echolalia in unstructured conversations. An evaluation of language function and the presence of parkinsonism, grasp reflex, imitation behaviour, and disinhibition were assessed. We also measured regional cerebral blood flow (rCBF) using single-photon emission computed tomography. RESULTS: Echolalia was observed in 12 nfvPPA and 2 unclassified PPA patients. All patients showed mitigated echolalia. We compared nfvPPA patients with echolalia (echolalia group) to those without echolalia (non-echolalia group). The median age of the echolalia group was significantly lower than that of the non-echolalia group, and the echolalia group showed a significantly worse auditory comprehension performance than the non-echolalia group. In contrast, the performance of repetition tasks was not different between the two groups. The prevalence of imitation behaviour in the echolalia group was significantly higher than that in the non-echolalia group. The rCBFs in the bilateral pre-supplementary motor area and bilateral middle cingulate cortex in the echolalia group were significantly lower than those in the non-echolalia group. CONCLUSIONS: These findings suggest that echolalia is characteristic of nfvPPA patients with impaired comprehension. Reduced inhibition of the medial frontal cortex with release activity of the anterior perisylvian area account for the emergence of echolalia.

Logopenic aphasia due to Lewy body disease dramatically improved with donepezil.

•Pathological basis of primary progressive aphasia is heterogeneous.•Logopenic primary progressive aphasia can precede dementia with Lewy bodies (DLB).•Cholinesterase inhibitor can improve logopenic aphasia with DLB.

Survey on the oral health status of community-dwelling older people with visual impairment.

AIMS: Little is known about the impact of low vision (LV) on dental care in the elderly population. The present study aimed to clarify the oral health status and oral health behavior of older people with LV. METHODS AND RESULTS: We surveyed community-dwelling older people (age ≥ 65 years, non-LV = 35, LV = 23); and collected data on sex, age, systemic diseases, oral health status, and oral health behavior. Although there was no difference in dental clinic visits within one year, the LV group received significantly lesser oral health instructions by dental hygienists and dentists than the non-LV (60.9% vs 85.7%, P < 0.05) group. Additionally, the LV group was more than twice as aware of the "8020 Campaign," written by the Ministry of Health, Labor and Welfare in Japan than the non-LV group. The non-LV group had higher awareness of thickening agents and denture cleaners, both of which may require visual input. Although we had assumed that LV would lead to poor results for the oral health status, there were no demonstrable differences between both groups. CONCLUSION: Older individuals with LV require suitable forms of nonvisual communication to receive oral health instruction and literacy.

Phosphoethanolamine Accumulation Protects Cancer Cells under Glutamine Starvation through Downregulation of PCYT2.

Tolerance to severe tumor microenvironments, including hypoxia and nutrient starvation, is a common feature of aggressive cancer cells and can be targeted. However, metabolic alterations that support cancer cells upon nutrient starvation are not well understood. Here, by comprehensive metabolome analyses, we show that glutamine deprivation leads to phosphoethanolamine (PEtn) accumulation in cancer cells via the downregulation of PEtn cytidylyltransferase (PCYT2), a rate-limiting enzyme of phosphatidylethanolamine biosynthesis. PEtn accumulation correlated with tumor growth under nutrient starvation. PCYT2 suppression was partially mediated by downregulation of the transcription factor ELF3. Furthermore, PCYT2 overexpression reduced PEtn levels and tumor growth. In addition, PEtn accumulation and PCYT2 downregulation in human breast tumors correlated with poor prognosis. Thus, we show that glutamine deprivation leads to tumor progression by regulating PE biosynthesis via the ELF3-PCYT2 axis. Furthermore, manipulating glutamine-responsive genes could be a therapeutic approach to limit cancer progression.

Perioperative serum and urine metabolome analyses in patients with hepatocellular carcinoma undergoing partial hepatectomy.

OBJECTIVES: Perioperative nutritional management is essential for early recovery after liver surgery. The aim of this study was to assess changes in amino acid levels in serum and urine after hepatectomy. METHODS: Serum samples were collected from 16 patients with hepatocellular carcinoma before and 1, 3, and 14 d after hepatectomy (S0, S1, S3, and S14, respectively). Spot urine samples were collected before and 3 d after the hepatectomy (U0 and U3). Metabolites in the serum and urine were analyzed. RESULTS: Compared with S0, insulin levels significantly increased in the S1 and S3 samples. Valine levels significantly decreased in S1 and S14, and leucine levels significantly decreased in S14. Phenylalanine levels significantly increased in S1 and S3, and tyrosine levels significantly increased in S1. The Fischer ratio (branched-chain/aromatic amino acids) significantly decreased in S1 and S3. In multiple regression analysis, changes in serum taurine levels were related to the white blood cell count in S1 and S3, and inversely related to alanine aminotransferase levels in S14. Changes in serum glutamine levels were negatively related to C-reactive protein levels in S3. Serum glutamine levels decreased in S3 and S14, and tended to increase in U3, suggesting a deficiency of glutamate resulting from the invasive surgical procedure. CONCLUSIONS: These findings highlight the usefulness of metabolome analysis for characterizing perioperative patterns after liver resection. The observed amino acid pattern, including the reduction in Fischer ratio, underscores the need for specialized nutritional support.

Oral function and nutritional status among the elderly with facial and oral tactile hypersensitivity who are under long-term care.

Objective　In oral health care, a refusal action can cause difficulties, and tactile hypersensitivity (TH) may be a contributing factor. People with TH of the face and mouth clench their jaws. Despite numerous reports on TH among children with disabilities, reports on TH in the elderly who are under long-term care are scarce. The purpose of this study was to investigate TH among the elderly who are under long-term care.Methods　We selected 80 residents (8 men and 72 women; mean age: 91.1±6.2y) in a Tokyo nursing home and investigated the presence of TH in them. We also obtained patients' (1) basic information (sex, age, stage of long-term care needs (SCN), and the degree of independent living (IL)); (2) oral information (swallowing status, choking tendency, and intraoral residue); and (3) nutritional information (serum albumin (Alb) levels and body mass index (BMI)). We assessed the face (the forehead, cheek, and perioral area) and the intraoral environment (buccal mucosa, buccal cavity, and palate) as testing sites for TH, using the tester's palm and forefinger. We confirmed the presence of TH when the tested areas reacted partially or fully by shuddering. We classified the subjects into 2 groups based on the presence or absence of TH and analyzed our results using a chi-square test and Mann-Whitney U test. This investigation was approved by the Dentistry Ethics Screening Committee, Tokyo Medical and Dental University.Results　A total of 18 residents were diagnosed with TH (22.5%). Significant differences in SCN, IL, choking tendency, intraoral residue, swallowing status, serum Alb levels, and BMI (P<0.05) were reported between this group and the non-TH group.Conclusion　We demonstrated that residents with TH were in an advanced SCN and had a lower IL score and a decreased swallowing and nutritional status. Therefore, oral health care, promotion of nutritional status, and meal support are particularly important for the elderly with TH.

Maternal Gaze Behaviors During Latching-On for Breastfeeding.

BACKGROUND: Studies in various fields have demonstrated that experts use specific gaze strategies to achieve better performance. Therefore, we hypothesized that mothers familiar with breastfeeding would use a specific gaze strategy to achieve better latching-on. METHODS: A head-mounted eye tracker was used to record pupil positions from 14 breastfeeding mothers with 1-month-old infants. Eye gazes were analyzed during the latching-on and assessment phases. RESULTS: During the latching-on phase, participants tended to fixate on their breast, the infant's lower face, an intermediate region between the infant's face and the breast, and the region of contact between the infant's mouth and the breast. Once the infant latched onto the breast, mothers typically assessed the latch by fixating on their breast or the region of contact between the infant's mouth and the breast. The gaze patterns were generally maintained without being influenced by the subtask properties of each phase. CONCLUSION: Similar to previous studies, we found that mothers fixated on specific locations that were relevant to the current breastfeeding subtask, suggesting that the gaze behavior contributes to the execution of latching-on. Therefore, it is important to consider that successful latching-on is influenced by maternal physical movements and efficient gazing behaviors.

An Inter- and Intraprofessional Education Program in Which Dental Hygiene Students Instruct Medical and Dental Students.

The aim of this study was to develop, implement, and evaluate an inter- and intraprofessional education program with a peer support joint practice in which dental hygiene students teach medical and dental students about oral health care for older people requiring long-term care. In 2015 at Tokyo Medical and Dental University, 22 dental hygiene students in their third year at the School of Oral Health Care Sciences (OH3), 110 students in their third year at the School of Medicine (M3), and 52 students in their third year at the School of Dentistry (D3) participated in this program. The OH3 students practiced with a whole-body-type simulator to learn oral health care for older people and then taught the methods to the M3 and D3 students according to their self-designed teaching plan. All M3 and D3 students experienced being both practitioner and patient. The number of respondents and response rates on the questionnaires after the training were 22 (100%), 102 (92.7%), and 52 (100%) for the OH3, M3, and D3 students, respectively. Self-assessment by the OH3 students indicated that they could supervise other students sufficiently (77-86%), and 91% of them found the preclinical practice with the simulator efficient for the peer support joint practice. Almost all the M3 and D3 students reported that they gained understanding of the methods (99%), significance (100%), and important points of oral health care for older people (97%) in addition to the jobs and roles of dental hygienists (93%) because of this program. The M3 students understood the methods and significance of oral health care more deeply than did the D3 students (p<0.05). This study found that an interprofessional program with a peer support joint practice to cultivate practical clinical ability aided in increasing understanding and cooperation between medicine and dentistry.

p62/Sqstm1 promotes malignancy of HCV-positive hepatocellular carcinoma through Nrf2-dependent metabolic reprogramming.

p62/Sqstm1 is a multifunctional protein involved in cell survival, growth and death, that is degraded by autophagy. Amplification of the p62/Sqstm1 gene, and aberrant accumulation and phosphorylation of p62/Sqstm1, have been implicated in tumour development. Herein, we reveal the molecular mechanism of p62/Sqstm1-dependent malignant progression, and suggest that molecular targeting of p62/Sqstm1 represents a potential chemotherapeutic approach against hepatocellular carcinoma (HCC). Phosphorylation of p62/Sqstm1 at Ser349 directs glucose to the glucuronate pathway, and glutamine towards glutathione synthesis through activation of the transcription factor Nrf2. These changes provide HCC cells with tolerance to anti-cancer drugs and proliferation potency. Phosphorylated p62/Sqstm1 accumulates in tumour regions positive for hepatitis C virus (HCV). An inhibitor of phosphorylated p62-dependent Nrf2 activation suppresses the proliferation and anticancer agent tolerance of HCC. Our data indicate that this Nrf2 inhibitor could be used to make cancer cells less resistant to anticancer drugs, especially in HCV-positive HCC patients.

Sudden cardiac arrest secondary to cardiac amyloidosis in a young woman with cryopyrin-associated periodic syndrome.

Cryopyrin-associated periodic syndrome (CAPS) is caused by NLRP3 mutations, which result in dysregulated interleukin 1ß (IL-1ß) production and inflammation. Some patients with CAPS develop systemic amyloidosis via an inflammatory reaction. We describe a case of a 39-year-old woman who experienced cardiopulmonary arrest secondary to ventricular fibrillation complicated by cardiac amyloidosis as well as by CAPS. She was diagnosed with renal amyloidosis at 32 years of age. At 34 years of age, genetic sequencing of the NLRP3 gene demonstrated that she was heterozygous for the p.E304 K mutation, and she was subsequently diagnosed with CAPS. After treatment with canakinumab (human anti-IL-1ß monoclonal antibody) for CAPS, the inflammatory reaction was improved. However, she eventually developed cardiac arrest with ventricular fibrillation and was successfully resuscitated. Echocardiography demonstrated mildly reduced left ventricular systolic function (left ventricular ejection fraction of 48%). Coronary angiography revealed no stenosis, but a cardiac biopsy demonstrated cardiac amyloidosis. She received an implantable cardioverter defibrillator.

Hydroxyproline, a serum biomarker candidate for gastric ulcer in rats: a comparison study of metabolic analysis of gastric ulcer models induced by ethanol, stress, and aspirin.

Gastrointestinal symptoms are a common manifestation of adverse drug effects. Non-steroid anti-inflammatory drugs (NSAIDs) are widely prescribed drugs that induce the serious side effect of gastric mucosal ulceration. Biomarkers for these side effects have not been identified and ulcers are now only detectable by endoscopy. We previously identified five metabolites as biomarker candidates for NSAID-induced gastric ulcer using capillary electrophoresis-mass spectrometry (CE-MS)-based metabolomic analysis of serum and stomach from rats. Here, to clarify mechanism of changes and limitations of indications of biomarker candidates, we performed CE-MS-based metabolomic profiling in stomach and serum from rats with gastric ulcers induced by ethanol, stress, and aspirin. The results suggest that a decrease in hydroxyproline reflects the induction of gastric injury and may be useful in identifying gastric ulcer induced by multiple causes. While extrapolation to humans requires further study, hydroxyproline can be a new serum biomarker of gastric injury regardless of cause.

Reconstruction of insulin signal flow from phosphoproteome and metabolome data.

Cellular homeostasis is regulated by signals through multiple molecular networks that include protein phosphorylation and metabolites. However, where and when the signal flows through a network and regulates homeostasis has not been explored. We have developed a reconstruction method for the signal flow based on time-course phosphoproteome and metabolome data, using multiple databases, and have applied it to acute action of insulin, an important hormone for metabolic homeostasis. An insulin signal flows through a network, through signaling pathways that involve 13 protein kinases, 26 phosphorylated metabolic enzymes, and 35 allosteric effectors, resulting in quantitative changes in 44 metabolites. Analysis of the network reveals that insulin induces phosphorylation and activation of liver-type phosphofructokinase 1, thereby controlling a key reaction in glycolysis. We thus provide a versatile method of reconstruction of signal flow through the network using phosphoproteome and metabolome data.

[Relationship between oral health status and life behavior in junior and senior high school students in Japan].

A survey of dental diseases carried out by the Ministry of Health, Labour and Welfare in 2003 revealed that more than 40% of people aged between 5 and 25 suffer from periodontal diseases and the average number of DMFT has been decreasing. The lifestyle of junior and senior high school students in particular has changed drastically. This study investigated the relationship between dietary habits and oral diseases in junior and senior high school students in Tokyo. Survey responses were received from 813 of 848 students. There was a significant correlation between the presence of untreated teeth and student's dietary habits, or the presence of periodontal diseases. These results suggest that dental hygienists need to consider providing advice on appropriate eating habits during dental hygiene instruction to students.