Mental arithmetic modulates temporal variabilities of finger-tapping tasks in a tempo-dependent manner.

Background: Several psychiatric diseases impair temporal processing. Temporal processing is thought to be based on two domains: supra-second intervals and sub-second intervals. Studies show that temporal processing in sub-second intervals is mainly an automated process. However, the brain functions involved in temporal processing at each time scale remain unclear. We hypothesized that temporal processing in supra-second intervals requires several brain areas, such as the ventrolateral prefrontal cortex, intraparietal sulcus (IPS), and inferior parietal lobe, corresponding to various cognitions in a time scale-dependent manner. We focused on a dual-task paradigm (DTP) involving simultaneous performance of cognitive and motor tasks, which is an effective method for screening psychomotor functions; we then designed a DTP comprising finger tapping at various tempi as the temporal processing task and two cognitive tasks (mental arithmetic and reading) that might affect temporal processing. We hoped to determine whether task-dependent interferences on temporal processing in supra-second intervals differed depending on the cognitive tasks involved. Methods: The study included 30 participants with no history of neuromuscular disorders. Participants were asked to perform a DTP involving right index finger tapping at varying tempi (0.33, 0.5, 1, 2, 3, and 4 s inter-tapping intervals). Cognitive tasks comprised mental arithmetic (MA) involving three-digit addition, mental reading (MR) of three- to four-digit numbers, and a control (CTL) task without any cognitive loading. For comparison between tasks, we calculated the SDs of the inter-tapping intervals. Participants' MA abilities in the three-digit addition task were evaluated. Results: The MA and MR tasks significantly increased the SDs of the inter-tapping intervals compared to those of the CTL task in 2-3 s and 3-4 s for the MA and MR tasks, respectively. Furthermore, SD peaks in the finger-tapping tasks involving MA were normalized by those in the CTL task, which were moderately correlated with the participants' MA ability (r = 0.462, P = 0.010). Discussion: Our results established that DTP involving the temporal coordination of finger-tapping and cognitive tasks increased temporal variability in a task- and tempo-dependent manner. Based on the behavioral aspects, we believe that these modulations of temporal variability might result from the interaction between finger function, arithmetic processing, and temporal processing, especially during the "pre-semantic period". Our findings may help in understanding the temporal processing deficits in various disorders such as dementia, Parkinson's disease, and autism.

The relationship between spatiotemporal gait parameters and cognitive function in healthy adults: protocol for a cross-sectional study.

BACKGROUND: Motor dysfunctions, such as slower walking speed, precede the occurrence of dementia and mild cognitive impairment, suggesting that walking parameters are effective biomarkers for detecting early sub-clinical cognitive risk. It is often also concurrent with self-complained cognitive dysfunction, called motoric cognitive risk (MCR) syndrome. Our preliminary study found several walking parameters, obtained by a three-dimensional motion capture system, to be correlated with computer-based assessments of various cognitive function modalities, although the sample size was small. The Cognitive-Gait (CoGait) Database Project, described in the current protocol, aims to establish a database of multi-dimensional walking and cognitive performance data, collected from a large sample of healthy participants, crucial for detecting early sub-clinical cognitive risk. METHODS: We will recruit healthy volunteers, 20 years or older, without any neurological musculoskeletal or psychiatric disorders. The estimated sample size is 450 participants, including a 10% attrition rate. Using computer-based cognitive assessments, participants will perform six tasks: (i) the simple reaction time task, (ii) Go/No-Go task, (iii) Stroop Color-Word Test, (iv) N-back test, (v) Trail Making Test, and (vi) digit span test. We will also conduct paper-based cognitive assessments such as the Mini-Mental State Examination, Montreal Cognitive Assessment, and the Geriatric Depression Scale-15 for assessing MCR. Gait will be measured through joint kinematics and global positioning in participants' lower legs while walking at a comfortable and faster pace, using pants with an inertial measurement unit-based three-dimensional motion capture system. Finally, we will establish a prediction model for various cognitive performance modalities based on walking performance. DISCUSSION: This will be the first study to reveal the relationship between walking and cognitive performance using multi-dimensional data collected from a large sample of healthy adults, from the general population. Despite certain methodological limitations such as the accuracy of measurements, the CoGait database is expected to be the standard value for both walking and cognitive functions, supporting the evaluation of psychomotor function in early sub-clinical cognitive risk identification, including motoric-cognitive risk syndrome.

Trends in prescription of anti-seizure medicines for Japanese pediatric outpatients during 2013-2019.

Temporal trends in prescriptions of anti-seizure medicines (ASMs) for children, including newer ASMs, are unclear. We investigated ASM prescription trends for pediatric outpatients in Japan. The MDV analyzer® was used to analyze the MDV database containing de-identified hospital administrative data. Administrative data as of June 2021 including pediatric outpatients (0-17 years) with epilepsy, visiting 123 acute diagnostic procedure combination hospitals during 2013-2019, were used. Annual ASMs prescription trends were calculated, based on proportions. The Cochran-Armitage trend test evaluated the proportion of prescriptions for each ASM. ASMs most often prescribed were valproic acid, carbamazepine, and levetiracetam, regardless of sex. In girls, the proportion of valproic acid and carbamazepine prescriptions decreased from 37.93% to 26.84%, and from 24.80% to 15.78%, respectively (p < 0.0001). Conversely, the proportion of levetiracetam prescriptions increased from 6.40% to 28.18% (p < 0.0001). In boys, the proportion of valproic acid and carbamazepine prescriptions decreased, from 36.58% to 32.20% and from 26.42% to 16.85%, respectively (p < 0.0001). The proportion of levetiracetam prescriptions increased from 5.64% to 23.02% (p < 0.0001). Overall, the proportion of valproic acid and carbamazepine prescriptions declined, whereas levetiracetam prescriptions increased. Trends in ASM prescriptions among pediatric outpatients with epilepsy in Japan have shifted towards more recently available ASMs.

Intestinal Perforation in a Patient with Colon Cancer during Treatment with Regorafenib: A Case Report and Review of the Literature.

The multikinase inhibitor, regorafenib, is known to exert its antitumor effects by targeting several kinases, inhibiting interstitial intracellular signaling and suppressing tumor cell proliferation. Regorafenib causes gastrointestinal perforation and gastrointestinal fistula as adverse events, and discontinuation is recommended if these adverse events occur during administration. However, there are no prescribed standards for re-administration after discontinuation and for administration in patients with a history of gastrointestinal perforation. Herein, we report a case of gastrointestinal perforation in a patient, with a history of gastrointestinal microperforation, undergoing bevacizumab therapy, within a few days of starting regorafenib; this had a significant effect on the prognosis. The site of gastrointestinal perforation was consistent with previously reported sites around the tumor and at the anastomotic site. Based on a review of literature and our experience with the case presented here, we recommend that administration of regorafenib to patients with a history of gastrointestinal perforation should be avoided to the extent possible. Moreover, in case of prior administration of a drug reported to cause gastrointestinal perforation, such as an anti-VEGFR drug, the risk of gastrointestinal perforation should be considered during the administration of regorafenib. In the event of complaints, such as abdominal pain, gastrointestinal perforation should be considered as a differential diagnosis and appropriate tests and treatments should be initiated at an early stage.

Spinal movement variability associated with low back pain: A scoping review.

OBJECTIVE: To identify suggestions for future research on spinal movement variability (SMV) in individuals with low back pain (LBP) by investigating (1) the methodologies and statistical tools used to assess SMV; (2) characteristics that influence the direction of change in SMV; (3) the methodological quality and potential biases in the published studies; and (4) strategies for optimizing SMV in LBP patients. METHODS: We searched literature databases (CENTRAL, Medline, PubMed, Embase, and CINAHL) and comprehensively reviewed the relevant papers up to 5 May 2020. Eligibility criteria included studies investigating SMV in LBP subjects by measuring trunk angle using motion capture devices during voluntary repeated trunk movements in any plane. The Newcastle-Ottawa risk of bias tool was used for data quality assessment. Results were reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews. RESULTS: Eighteen studies were included: 14 cross-sectional and 4 prospective studies. Seven linear and non-linear statistical tools were used. Common movement tasks included trunk forward bending and backward return, and object lifting. Study results on SMV changes associated with LBP were inconsistent. Two of the three interventional studies reported changes in SMV, one of which was a randomized controlled trial (RCT) involving neuromuscular exercise interventions. Many studies did not account for the potential risk of selection bias in the LBP population. CONCLUSION: Designers of future studies should recognize that each of the two types of statistical tools assesses functionally different aspects of SMV. Future studies should also consider dividing participants into subgroups according to LBP characteristics, as three potential subgroups with different SMV characteristics were proposed in our study. Different task demands also produced different effects. We found preliminary evidence in a RCT that neuromuscular exercises could modify SMV, suggesting a rationale for well-designed RCTs involving neuromuscular exercise interventions in future studies.

The infectivity of progeny adenovirus in the presence of neutralizing antibody.

Human adenoviruses (Ads), common pathogens that cause upper respiratory and gastrointestinal infections, are blocked by neutralizing antibodies (nAbs). However, Ads are not fully eliminated even in hosts with nAbs. In this study, we assessed the infectivity of progeny Ad serotype 5 (Ad5) in the presence of nAb. The infectivity of Ad5 was evaluated according to the expression of the Ad genome and reporter gene. Infection by wild-type Ad5 and Ad5 vector continued to increase until 3 days after infection even in the presence of nAb. We established an assay for determining the infection levels of progeny Ad5 using a sorting system with magnetic beads and observed little difference in progeny Ad5 counts in the presence and absence of nAb 1 day after infection. Moreover, progeny Ad5 in the presence of nAb more effectively infected coxsackievirus and adenovirus receptor (CAR)-positive cells than CAR-negative cells. We investigated the function of fiber proteins, which are the binding partners of CAR, during secondary infection, observing that fibre proteins spread from infected cells to adjacent cells in a CAR-dependent manner. In conclusion, this study revealed that progeny Ad5 could infect cells even in the presence of nAb, differing from the common features of the Ad5 infection cycle. Our findings may be useful for developing new therapeutic agents against Ad infection.

The apex angle of the rocker sole affects the posture and gait stability of healthy individuals.

BACKGROUND: Rocker sole (RS) shoes have been linked to impaired postural control. However, which features of RS design affect balance is unclear. RESEARCH QUESTION: Which RS design features affect standing balance and gait stability? METHODS: This study utilized an intervention and cross-over design. Twenty healthy young adults (10 males and 10 females) participated in this study. Standing balance and gait stability were measured using a single force platform and three-dimensional motion analysis system, respectively. The experimental conditions included the control shoe and five RS shoes in the combination of apex position (%) and apex angle (degree) for RS50-95, RS60-95, RS70-95, RS60-70, and RS60-110. The main outcome measures were the area surrounding the maximal rectangular amplitude, mean path length, average displacement of the center of pressure along the lateral and anterior/posterior directions, and maximal center of pressure excursion as the standing balance and lateral margin of stability as the gait stability. Statistical analyses were conducted using a two-way split-plot analysis of variance with repeated measures (with RS design as the within-subject factor and sex as the between-subject factor) and the Bonferroni post hoc test (α = .05). RESULTS: Regarding the mean path length, RS60-70 was significantly longer than the control shoe, and it showed a significantly increased lateral margin of stability. Thus, RS60-70 was shown to affect standing balance, limit of stability, and gait stability of the frontal plane during gait. SIGNIFICANCE: These results suggest that the apex angle of the RS design feature affects standing balance and gait stability, and RS60-70 is detrimental to stability. Therefore, when RS with a small apex angle is prescribed, it is necessary to consider the patient's balance ability.

Drug prescription for attention deficit hyperactivity disorder drugs in pediatric outpatients: A retrospective survey of Japanese administrative data (2012-2018).

We aimed to clarify the prescription trend of ADHD drugs in Japanese pediatric outpatients. From January 2012 to December 2018, we evaluated the trends of prescribing methylphenidate-osmotic-controlled release oral delivery system (OROS), atomoxetine, and guanfacine as monotherapy. In boys, methylphenidate-OROS and atomoxetine prescriptions decreased from 46.5 % to 37.2 % and 18.6 % to 15.6 %, respectively. Prescriptions of guanfacine increased from 0.0 % to 12.3 %. In girls, the methylphenidate-OROS prescriptions was not significantly different (37.0 % to 26.4 %); however, atomoxetine decreased from 23.1 % to 16.3 %, and guanfacine increased from 0.0 % to 12.8 %. Methylphenidate-OROS and atomoxetine prescriptions changed to guanfacine between 2012 and 2018.

Characteristics of an Emulsion Obtained Using Hydrophobic Hydroxypropyl Methylcellulose as an Emulsifier and a High-Pressure Homogenizer.

Hydrophobically modified hydroxypropyl methylcellulose (HM-HPMC), a polymer in which a small amount of HPMC is stearoxyl substituted, was used as an emulsifier of emulsion-type lotion. A high-pressure homogenizer (microfluidizer) was used. The viscosity of the 1% HM-HPMC aqueous gel decreased after passing through the microfluidizer from 5.5 to 2.7 Pa·s. When liquid paraffin (LP) was used as the oil phase, a stable emulsion was obtained with an LP ratio of 1-40%. The apparent viscosity decreased with LP ratios up to 20%, and then increased with increasing LP concentration. The emulsions with an LP ratio <20% presented a pseudo-viscous flow, similar to that of the diluted polymer solution. HM-HPMC likely adsorbed onto the oil with a stearoxyl group; thus, the interaction between the stearoxyl group, which explained the high viscosity of HM-HPMC, decreased, reducing the viscosity of the emulsion. The LP ratio was 40%, and the emulsion presented a plastic flow, which is typical of concentrated emulsions. The size of the droplet in the emulsion was approximately 1 µm regardless of the LP ratio. When low-viscosity LPs or monoester-type oils such as isopropyl myristate were used, some of the emulsions presented creaming. An emulsion using HM-HPMC as an emulsifier and an appropriate oil homogenized with a microfluidizer is stable, has low viscosity, and can be easily spread on skin.

Amantadine intoxication despite moderate renal dysfunction: A case of combined use with donepezil.

Amantadine intoxication occurred despite moderate renal dysfunction. This may have been affected by the use of donepezil, and we require careful attention to these combinations.

Characteristics of dynamic standing balance with and without an insole in patients with spastic diplegia cerebral palsy.

[Purpose] This study examined characteristics of dynamic standing balance, with an without an insole, in patients with spastic diplegia cerebral palsy (CP). [Participants and Methods] This cross-sectional study used a crossover design. Eleven patients with spastic diplegia CP and gross motor levels between I and III with spastic diplegia CP (according to the Gross Motor Function Classification System expanded and revised version) were randomly allocated to either the barefoot or insole groups. The Index of postural stability (IPS) was evaluated while each patient was barefoot and while wearing insoles. The Pediatric Evaluation of Disability Inventory (PEDI) was used to measure functional self-care and mobility domains. [Results] While wearing the insoles, the center movement distance between right and left positions was significantly higher. While barefoot, IPS and area of postural sway correlated with the PEDI subscales for mobility and self-care. [Conclusion] Insoles promote standing balance and dynamic balance to move the center of pressure within the base of support. Such improvements may enhance activities of daily living in patients with spastic diplegia CP.

Nedaplatin as a Single-Agent Chemotherapy May Support Palliative Therapy for Patients with Adenoid Cystic Carcinoma: A Case Report.

Adenoid cystic carcinoma (ACC) is a rare form of adenocarcinoma, which is a broad term describing any cancer that begins in the glandular tissues. It can be found in the head and neck. We report a patient with recurrent ACC arising from the submandibular gland, treated with 100 mg/m2 nedaplatin every 4 weeks. Although our patient's lactate dehydrogenase levels, which is produced by ACC, showed a rising trend throughout the treatment, the level decreased for approximately 2 weeks immediately after administration of nedaplatin every 4 weeks. Thus, there is a possibility that the agent may be effective. Complications such as anorexia and nausea were observed, but they were tolerated and manageable. Nedaplatin may be considered as a supportive agent during palliative therapy for patients with ACC. More clinical trials regarding nedaplatin are necessary, as this study may indicate that a medical approach works well for ACC.

[A Case of Merkel Cell Carcinoma Complicated with Severe Thrombocytopenia Treated with Carboplatin/Etoposide Regimen after Surgery].

Thrombocytopenia is often caused by myelosuppression during chemotherapy. However, when platelet transfusions are required, pathological conditions such as idiopathic thrombocytopenic purpura(ITP)and thrombotic thrombocytopenic purpura( TTP)also occur. We report a case of Merkel cell carcinoma complicated with severe thrombocytopenia treated with carboplatin/etoposide regimen after surgery. The patient's platelet count did not increase in spite of platelet transfusions. However, the platelet count increased after steroid treatment was chosen under the diagnosis of ITP. Subsequent examinations revealed that the patient had HLA antibody, which caused the platelet transfusion refractoriness. When the platelet count does not increase in spite of platelet transfusions during chemotherapy, the possibility that the platelet transfusion refractoriness is due to the presence of HLA antibody should be considered.

Effect of alcohol on skin permeation and metabolism of an ester-type prodrug in Yucatan micropig skin.

We studied the effect that three alcohols, ethanol (EA), propanol (PA), and isopropanol (IPA), have on the skin permeation of p-hydroxy benzoic acid methyl ester (HBM), a model ester-type prodrug. HBM was applied to Yucatan micropig skin in a saturated phosphate buffered solution with or without 10% alcohol, and HBM and related materials in receptor fluid and skin were determined with HPLC. In the absence of alcohol, p-hydroxy benzoic acid (HBA), a metabolite of HBM, permeated the skin the most. The three alcohols enhanced the penetration of HBM at almost the same extent. The addition of 10% EA or PA to the HBM solution led to trans-esterification into the ethyl ester or propyl ester of HBA, and these esters permeated skin as well as HBA and HBM did. In contrast, the addition of 10% IPA promoted very little trans-esterification. Both hydrolysis and trans-esterification in the skin S9 fraction were inhibited by BNPP, an inhibitor of carboxylesterase (CES). Western blot and native PAGE showed the abundant expression of CES in micropig skin. Both hydrolysis and trans-esterification was simultaneously catalyzed by CES during skin permeation. Our data indicate that the alcohol used in dermal drug preparations should be selected not only for its ability to enhance the solubility and permeation of the drug, but also for the effect on metabolism of the drug in the skin.

Functional Modulation of Tight Junction to Enhance the Permeability of Biological Products (Biologics) in Biomembranes.

In recent years, biological products (biologics), including blood components, recombinant therapeutic proteins, antibodies, gene therapeutic materials, and so on, have been produced by biotechnology methods and other novel technologies. These products are essential therapeutic materials in progressive medicine. However, we often encounter the lower permeability of these biologics through biomembranes, due to their high molecular mass. In the last three decades, we have investigated drug delivery systems, including several enhancement methods for the permeability of biologics such as recombinant therapeutic proteins and viral vectors in epithelial cells. This review focuses the development of novel delivery systems for biologics in rectal and nasal administration, and includes an interesting observation of modulators of the tight junction (TJ) function. From cellular biology perspective, the interaction between permeability enhancing materials and targeted molecules in the TJ of epithelial cells was investigated. We elucidated that a TJ modulator will interact with a major constituent protein, for instance claudins, in playing an essential role in the tissue-specific barrier function of the TJ. Furthermore, useful enhancement of gene transfer in cells (for instance, in Caco-2 cells) was found in the combination of an adenovirus vector and capric acid sodium salt (C10), a TJ modulator.

Identification of Adenovirus-Derived Cell-Penetrating Peptide.

Cell-penetrating peptides (CPPs) have been highly anticipated as an efficient delivery system due to their ability to cross biological membranes and transport various cargoes into cells. In the present study, we have identified adenovirus-derived CPPs using various capsid-mutant adenovirus (Ad) vectors. First, we examined the endocytosis-inducing ability of these vectors. A fiber-shaft substituted Ad vector, Ad type 5 vector with the fiber shaft domain replaced by that derived from Ad type 35, induced the highest fluorescein isothiocyanate (FITC)-dextran uptake into a human liver cell line, HepG2 cells. In contrast, the FITC-dextran uptake in HepG2 cells was not significantly different between coxsackievirus and adenovirus receptor (CAR)-binding-ablated Ad vector, integrin-binding-ablated Ad vector or conventional Ad vector. Next, we produced a recombinant Ad type 35 shaft protein using the Escherichia coli recombinant system. The recombinant Ad type 35 shaft protein retained the ability for FITC-dextran uptake and efficient gene delivery by plasmid transfection reagent. Furthermore, we identified 26 C-terminal amino acids in the Ad type 35 shaft protein as the cell membrane binding domain. The 26 amino-acid peptides also have the potential to be internalized into cultured cells. The internalization ability of the peptide was dependent on degree and was inhibited by an actin polymerization inhibitor (Latrunculin B) and by a lipid raft formation inhibitor (methyl-ß-cyclodextrin). The results of the present study indicate that Ad type 35-derived peptides induce endocytosis in cultured cells and have the ability to cross biological membranes. This report is the first paper to identify Ad-derived CPPs.