Reduction of APOE accounts for neurobehavioral deficits in fetal alcohol spectrum disorders.

A hallmark of fetal alcohol spectrum disorders (FASD) is neurobehavioral deficits that still do not have effective treatment. Here, we present that reduction of Apolipoprotein E (APOE) is critically involved in neurobehavioral deficits in FASD. We show that prenatal alcohol exposure (PAE) changes chromatin accessibility of Apoe locus, and causes reduction of APOE levels in both the brain and peripheral blood in postnatal mice. Of note, postnatal administration of an APOE receptor agonist (APOE-RA) mitigates motor learning deficits and anxiety in those mice. Several molecular and electrophysiological properties essential for learning, which are altered by PAE, are restored by APOE-RA. Our human genome-wide association study further reveals that the interaction of PAE and a single nucleotide polymorphism in the APOE enhancer which chromatin is closed by PAE in mice is associated with lower scores in the delayed matching-to-sample task in children. APOE in the plasma is also reduced in PAE children, and the reduced level is associated with their lower cognitive performance. These findings suggest that controlling the APOE level can serve as an effective treatment for neurobehavioral deficits in FASD.

Ninety-day mortality of extremely elderly patients undergoing hip fracture surgery and its association with preoperative cardiac function: a single-center retrospective study.

PURPOSE: We investigated the 90-day mortality rate in elderly patients who underwent hip fracture surgery and the association of preoperative cardiac function with mortality. METHODS: We retrospectively enrolled 133 consecutive patients aged 80 years or older who underwent hip fracture surgery. We obtained information for patient sex, age, comorbidities, medications, anesthesia method, left ventricular systolic and diastolic functions assessed by echocardiography, and preoperative brain natriuretic peptide (BNP) levels. Multivariate logistic regression analysis was performed. RESULTS: The 90-day mortality rate in patients with a mean age of 88.9 years was 7.5% (10/133). More than half of the patients had diastolic dysfunction of the left ventricle. There were no significant differences in preoperative cardiac systolic and diastolic functions between the mortality group and non-mortality group. The preoperative BNP level in the mortality group was significantly higher than that in the non-mortality group (p = 0.038). Preoperative BNP level was not an independent risk factor for 90-day mortality (p = 0.081) in the primary multivariate logistic regression analysis but was an independent risk factor (p = 0.039) with an odds ratio of 1.004 (95% CI 1.000-1.008) in the sensitivity analysis with different explanatory variables. CONCLUSION: The 90-day mortality rate in patients over 80 years old after hip fracture surgery was 7.5%. There were no significant differences in preoperative cardiac function assessed by echocardiography between the mortality and non-mortality groups. Our results suggest that there is no association or only a weak association of high BNP level with 90-day mortality in this age population.

Effects of anesthetics on nociceptive sensory evoked potentials by intraepidermal noxious electrical stimulation of A-δ fibers.

PURPOSE: Generation of nociceptive sensory evoked potentials (NEPs) by selective stimulation of nociceptive intraepidermal nerve fibers is a simple technique which could be used as intraoperative nociception monitor. We evaluated the effects of remifentanil, propofol and sevoflurane on NEPs by this technique. METHODS: Patients undergoing general anesthesia were assigned to groups in two studies. A-δ fiber selective NEPs were recorded. Study 1: NEPs were recorded at control, under anesthetics administration: remifentanil at an effect-site concentration (Ce) of 1.0 ng/mL (n = 10), propofol at Ce of 0.5 µg/mL (n = 10), or sevoflurane at 0.2 minimum alveolar concentration (MAC) (n = 10), and recovery from the anesthetics. Study 2: NEPs were recorded at control and under administration of higher dose anesthetics: propofol at Ce of 0.5 and 1.0 µg/mL (n = 10) or sevoflurane at 0.2 and 0.5 MAC (n = 10). A P-value < 0.016 was considered statistically significant in multiple analyses. RESULTS: Study 1: Remifentanil at Ce of 1.0 ng/mL significantly suppressed the amplitude of NEPs (mean amplitude (standard deviation) of control vs. remifentanil administration: 16.8 µV (3.8) vs. 10.1 µV (2.5), P < 0.001). Propofol and sevoflurane did not suppress the amplitude significantly. Study 2: Propofol at Ce of 0.5 and 1.0 µg/mL and sevoflurane at 0.2 and 0.5 MAC did not suppress the amplitude significantly. CONCLUSION: The amplitude of A-δ fiber selective NEPs was suppressed by remifentanil but not propofol or sevoflurane. NEPs with intraepidermal electrical stimulation can assess the analgesic effect of anesthetics. CLINICAL TRIAL NUMBER: UMIN000038214 REGISTRY URL: https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000043328.

Alkalized lidocaine in a tapered cuff suppresses endotracheal tube-induced hemodynamic changes: a randomized controlled trial.

PURPOSE: The use of an endotracheal tube (ET) cuff filled with alkalized lidocaine (AL) can suppress ET-induced emergence phenomena, such as hypertension, tachycardia and coughing, and postoperative sore throat (POST) and hoarseness (PH). The efficacy of intracuff lidocaine may vary depending on the cuff shape, but there has been no study on the effects of a tapered cuff filled with AL. We examined whether intracuff AL suppresses ET-induced emergence phenomena, POST and PH. METHODS: Sixty-two patients were enrolled in this study and the patients were randomly allocated to a group in which the tapered cuff was filled with AL (Group AL) and a group in which the tapered cuff was filled with normal saline (Group S). The primary outcomes of this study were changes in mean blood pressure (MBP) and heart rate (HR) at extubation. MBP, HR and the number of coughs were recorded before and up to 10 min after extubation. The degree of POST and the incidences of POST and PH were recorded at 15 min, 2 h and 24 h after extubation. RESULTS: Changes in MBP before extubation and HR before and after extubation were significantly lower in Group AL than in Group S (p < 0.025). The number of coughs at extubation and the incidence of PH at 2 h after extubation were significantly lower in Group AL than in Group S (p < 0.0001 and p = 0.014, respectively). CONCLUSION: AL in a tapered cuff significantly suppresses ET-induced cardiovascular changes in MBP and HR.

An unusual foreign body in the oral cavity: a case report from a patient safety point of view and literature review.

Accidental foreign bodies (FBs) in the oral cavity, airway, esophagus and breathing circuit associated with anesthetic procedures are rare but can cause serious and life-threatening complications. We here present a case in which an unusual FB in the oral cavity was found after emergence from general anesthesia. The FB was later identified as a melted cap of a felt-tip pen. We investigated the cleaning process for reusable materials and concluded that the FB was accidentally placed in the inner lumen of the reusable bite block during the cleaning process. We then performed a review of the literature on FBs other than those of dental origin which were entrapped in the oral cavity, pharynx, larynx, trachea, esophagus, and anesthetic breathing circuit due to anesthetic procedures. From our case and 53 cases found in the search, we concluded that 1) use of disposable medical devices is recommended, 2) FBs can easily migrate into the oral cavity and airway during anesthesia, 3) delayed FB recognition may be associated with difficult intubation situations, and 4) more attention should be paid to the possibility of any medical or non-medical device becoming an FB during anesthesia.

[Sequential development of mantle cell lymphoma following chronic lymphocytic leukemia].

Richter syndrome (RS) is the development of an aggressive lymphoma in patients with chronic lymphocytic leukemia (CLL). Most cases of diffuse large B-cell lymphoma variant of RS are clonally related to the original CLL. Here, we present a case of mantle cell lymphoma (MCL) that developed sequentially during the clinical course of CLL. A 72-year-old man had been diagnosed with CLL 16 years ago and was followed-up without treatment. He developed autoimmune hemolytic anemia 2 years ago, which resolved with rituximab and prednisolone treatment. Subsequently, he presented with fever, abdominal bloating, and fatigue. Progressive lymphocytosis and splenomegaly with elevated lactic dehydrogenase levels were suggestive of RS. Bone marrow examination revealed a small- to medium-sized lymphoid infiltrate, which was positive for CD5, CD20, CCND1, and SOX-11 and negative for CD23 and LEF1 on immunostaining. Fluorescence in situ hybridization analysis was positive for IgH/CCND1, which indicated MCL. Southern blot analysis showed that both the MCL and the previous CLL expressed different IgH gene rearrangement bands. At the time of relapse or progression of CLL, sequential development of MCL should be considered.

[The Present State of Inter-Laboratory Differences in Setting and Practicing Critical Values -Results of a Questionnaire Survey Performed to the Laboratories of Keio University-Associated Hospitals].

Presently we, Keio Endocrine and Metabolite Survey (KEMS) study group conducted a questionnaire sur- vey with respect to panic values in the laboratories belonging to Keio University-associated hospitals. As to the initial setting, most of the laboratories answered to play a leading role in preparing the necessary matters to implementation of panic values and revise them corresponding to physician's request on each occasion. In almost all laboratories, they did not verify whether the notification procedure does work to exert appropriate clinical action. The numbers of critical values answered by the 18 laboratories distributed widely in the test items (8-39) and their critical limits (10-68). As to the critical limits, the lower limits of serum K and blood glucose converged among the laboratories, however, the limits of other test items diverged. The results of the present survey regarding to critical values, although being in small scale, may submit the im- portant issue to be solved in near future. [Short Communication].

Assembly and stoichiometry of FliF and FlhA in Salmonella flagellar basal body.

The bacterial flagellar export apparatus is required for the construction of the bacterial flagella beyond the cytoplasmic membrane. The membrane-embedded part of the export apparatus, which consists of FlhA, FlhB, FliO, FliP, FliQ and FliR, is located in the central pore of the MS ring formed by 26 copies of FliF. The C-terminal cytoplasmic domain of FlhA is located in the centre of the cavity within the C ring made of FliG, FliM and FliN. FlhA interacts with FliF, but its assembly mechanism remains unclear. Here, we fused yellow fluorescent protein (YFP) and cyan fluorescent protein (CFP) to the C-termini of FliF and FlhA and investigated their subcellular localization by fluorescence microscopy. The punctate pattern of FliF-YFP localization required FliG but neither FliM, FliN, FlhA, FlhB, FliO, FliP, FliQ nor FliR. In contrast, FlhA-CFP localization required FliF, FliG, FliO, FliP, FliQ and FliR. The number of FlhA-YFP molecules associated with the MS ring was estimated to be about nine. We suggest that FlhA assembles into the export gate along with other membrane components during the MS ring complex formation in a co-ordinated manner.

Second-degree atrioventricular block induced by electrical stimulation of transcranial motor-evoked potential: a case report.

BACKGROUND: Although several complications of transcranial motor-evoked potentials (Tc-MEPs) have been reported, reports of arrhythmias during Tc-MEP are very rare. CASE PRESENTATION: A 71-year-old woman underwent transforaminal lumbar interbody fusion under general anesthesia, with intraoperative Tc-MEP monitoring. Preoperative electrocardiography showed an incomplete right bundle branch block but no cardiovascular events in her life. After induction of anesthesia, Tc-MEP was recorded prior to the surgery. During the Tc-MEP monitoring, electrocardiography and arterial blood pressure showed a second-degree atrioventricular block, but it improved rapidly at the end of the stimulation, and the patient was hemodynamically stable. Tc-MEP was recorded seven times during surgery; the incidence of P waves without QRS complexes was significantly higher than before stimulation. The surgery was uneventful, and she was discharged eight days postoperatively without complications. CONCLUSIONS: Our case suggests that electrical stimulation for Tc-MEP can cause arrhythmia. Electrocardiography and blood pressure must be closely monitored during Tc-MEP monitoring.

Exogenous and endogenous factors affecting stock market transactions: A Hawkes process analysis of the Tokyo Stock Exchange during the COVID-19 pandemic.

Transactions in financial markets are not evenly spaced but can be concentrated within a short period of time. In this study, we investigated the factors that determine the transaction frequency in financial markets. Specifically, we employed the Hawkes process model to identify exogenous and endogenous forces governing transactions of individual stocks in the Tokyo Stock Exchange during the COVID-19 pandemic. To enhance the accuracy of our analysis, we introduced a novel EM algorithm for the estimation of exogenous and endogenous factors that specifically addresses the interdependence of the values of these factors over time. We detected a substantial change in the transaction frequency in response to policy change announcements. Moreover, there is significant heterogeneity in the transaction frequency among individual stocks. We also found a tendency where stocks with high market capitalization tend to significantly respond to external news, while their excitation relationship between transactions is weak. This suggests the capability of quantifying the market state from the viewpoint of the exogenous and endogenous factors generating transactions for various stocks.

Clinical features and a mutation with late onset of limb girdle muscular dystrophy 2B.

OBJECTIVE AND METHODS: Dysferlin encoded by DYSF deficiency leads to two main phenotypes, limb girdle muscular dystrophy (LGMD) 2B and Miyoshi myopathy. To reveal in detail the mutational and clinical features of LGMD2B in Japan, we observed 40 Japanese patients in 36 families with LGMD2B in whom dysferlin mutations were confirmed. RESULTS AND CONCLUSIONS: Three mutations (c.1566C>G, c.2997G>T and c.4497delT) were relatively more prevalent. The c.2997G>T mutation was associated with late onset, proximal dominant forms of dysferlinopathy, a high probability that muscle weakness started in an upper limb and lower serum creatine kinase (CK) levels. The clinical features of LGMD2B are as follows: (1) onset in the late teens or early adulthood, except patients homozygous for the c.2997G>T mutation; (2) lower limb weakness at onset; (3) distal change of lower limbs on muscle CT at an early stage; (4) impairment of lumbar erector spinal muscles on muscle CT at an early stage; (5) predominant involvement of proximal upper limbs; (6) preservation of function of the hands at late stage; (7) preservation of strength in neck muscles at late stage; (8) lack of facial weakness or dysphagia; (9) avoidance of scoliosis; (10) hyper-Ckaemia; (11) preservation of cardiac function; and (12) a tendency for respiratory function to decline with disease duration. It is important that the late onset phenotype is found with prevalent mutations.

Casting votes of antecedents play a key role in successful sequential decision-making.

Aggregation of opinions often results in high decision-making accuracy, owing to the collective intelligence effect. Studies on group decisions have examined the optimum weights for opinion aggregation to maximise accuracy. In addition to the optimum weights of opinions, the impact of the correlation among opinions on collective intelligence is a major issue in collective decision-making. We investigated how individuals should weigh the opinions of others and their own to maximise their accuracy in sequential decision-making. In our sequential decision-making model, each person makes a primary choice, observes his/her predecessors' opinions, and makes a final choice, which results in the person's answer correlating with those of others. We developed an algorithm to find casting voters whose primary choices are determinative of their answers and revealed that decision accuracy is maximised by considering only the abilities of the preceding casting voters. We also found that for individuals with heterogeneous abilities, the order of decision-making has a significant impact on the correlation between their answers and their accuracies. This could lead to a counter-intuitive phenomenon whereby, in sequential decision-making, respondents are, on average, more accurate when less reliable individuals answer earlier and more reliable individuals answer later.

Fatty acid metabolism changes in association with neurobehavioral deficits in animal models of fetal alcohol spectrum disorders.

Fetal alcohol spectrum disorders (FASD) show behavioral problems due to prenatal alcohol exposure (PAE). A previous study reports changes in gene expressions linked to fatty acid (FA) metabolism in the cerebral cortex of the PAE mouse model. We find an increase of palmitic acid and arachidonic acid in phospholipid in the cerebral cortex of PAE at postnatal day 30. The increase of palmitic acid is consistent with increase of the producing enzyme, Fasn (fatty acid synthase). Decrease of 26:6 FA is also consistent with the increase of the enzyme which uses 26:6 as a substrate for making very long chain FAs, Elovl4 (elongation of very long chain fatty acids protein 4). However, there is no increase in the elongated products. Rather, lipid droplets (LDs) accumulated in the brain. Although FA-associated metabolic measurements are not affected by PAE, the abundance of FA-related gut microbiota is altered. This suggests that the gut microbiome could serve as a tool to facilitate uncovering the brain pathophysiology of FASD and a potential target to mitigate neurobehavioral problems.

Fluctuations in the Number of Stores by Industry During the COVID-19 Pandemic Based on Japanese Phone Book Entries.

Currently in Japan, summaries of the number of bankruptcies due to the spread of COVID-19 can only be obtained from surveys conducted by a few research firms targeting particular companies. In this study, we used Japanese telephone directory data containing detailed information on the location and industrial category of stores/facilities nationwide in an effort to infer the influence of COVID-19 on businesses in Japan. We analyzed the temporal change in the number of stores before and after the COVID-19 outbreak. Among other findings, the analysis revealed that the number of travel agencies and facilities offering karaoke and other forms of entertainment declined significantly after the outbreak in some prefectures, with the largest declines in Ibaraki, Osaka, and Hyogo prefectures, and a relatively small decline in Tochigi prefecture. Among the stores and facilities categorized as restaurants and travel-related services, the decline was particularly significant in urban areas such as Tokyo and Osaka prefectures.

A randomized, double-blinded, placebo-controlled, crossover study of the HCN channel blocker ivabradine in a capsaicin-induced pain model in healthy volunteers.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels have been focused on as a potential therapeutic target for inflammatory and neuropathic pain in rodent models. However, roles of HCN channels in human pain states have been scarcely investigated. We evaluated analgesic effects of 2-day administration of ivabradine, the only clinically available HCN channel blocker, on a capsaicin pain model in a randomized, double-blinded, placebo-controlled, crossover study. Twenty healthy adult subjects (18 males, 2 females) received ivabradine (5-7.5 mg) or a placebo 3 times in 2 days. Then capsaicin (0.5%) was topically applied on the volar forearm for 30 min. The primary outcome was capsaicin-induced spontaneous pain. The secondary outcomes included heat-pain threshold (HPT), flare size, and areas of secondary punctate mechanical hyperalgesia (PMH) and secondary dynamic mechanical allodynia (DMA). There was no significant difference in spontaneous pain (p = 0.7479), HPT (p = 0.7501), area of PMH (p = 0.1052) or flare size (p = 0.5650) at 30 min after capsaicin application between the groups. In contrast, the area of DMA in the ivabradine group was significantly smaller (p < 0.001) than that in the placebo group. HCN channels may be differentially involved in the various pain signal transmission pathways in humans.

Hairy Cell Leukemia-Japanese Variant: Report of a Patient and Literature Review.

Hairy cell leukemia-Japanese variant (HCL-jv) shares some features with, but differs in other features from, HCL variant. Recently, it has been pointed out that HCL-jv and splenic diffuse red pulp small B-cell lymphoma (SDRPL) possibly constitute the same disease. We report a patient with HCL-jv, in which the neoplastic cells in the resected spleen were positive for CD11c, CD103, tartrate-resistant acid phosphatase (by immunohistochemistry), and weakly positive for cyclin D3. They were negative for CD25, CD123, annexin A1, and BRAF V600E-derived protein. Meta-analysis of HCL-jv cases in the literature showed considerable variation in the expression of HCL-related molecules. Although the clinical features and pattern of splenic involvement of HCL-jv are similar to those of SDRPL, some cytomorphological and phenotypical differences can be pointed out. To confirm whether the weak expression of cyclin D3 in our case suggests a spectrum from HCL-jv to SDRPL or one of the characteristics of HCL-jv, further studies on a large number of cases are necessary.

The parabrachial-to-amygdala pathway provides aversive information to induce avoidance behavior in mice.

The neuronal circuitry for pain signals has been intensively studied for decades. The external lateral parabrachial nucleus (PB) was shown to play a crucial role in nociceptive information processing. Previous work, including ours, has demonstrated that stimulating the neuronal pathway from the PB to the central region of the amygdala (CeA) can substitute for an actual pain signal to drive an associative form of threat/fear memory formation. However, it is still unknown whether activation of the PB-CeA pathway can directly drive avoidance behavior, escape behavior, or only acts as strategic freezing behavior for later memory retrieval. To directly address this issue, we have developed a real-time Y-maze conditioning behavioral paradigm to examine avoidance behavior induced by optogenetic stimulation of the PB-CeA pathway. In this current study, we have demonstrated that the PB-CeA pathway carries aversive information that can directly trigger avoidance behavior and thereby serve as an alarm signal to induce adaptive behaviors for later decision-making.

Successful Management of a Patient with Intraoperative Bleeding of More than 80,000 mL and Usefulness of QTc Monitoring for Calcium Correction.

Intraoperative massive bleeding is associated with high rates of mortality and anesthetic management of massive bleeding is challenging because it is necessary to achieve volume resuscitation and electrolyte correction simultaneously during massive transfusion. We report a case of life-threatening bleeding of more than 80,000 mL during liver transplantation in which real-time QTc monitoring was useful for an extremely large amount of calcium administration for treatment of hypocalcemia. A 47-year-old female with a giant liver due to polycystic liver disease was scheduled to undergo liver transplantation. During surgery, life-threatening massive bleeding occurred. The maximum rate of blood loss was approximately 15,000 mL/hr and the total amount of estimated blood loss was 81,600 mL. It was extremely difficult to maintain blood pressure and a risk of cardiac arrest continued due to hypotension. In addition, even though administration of insulin and calcium was performed, electrolyte disturbances of hyperkalemia and hypocalcemia with prolongation of QTc interval occurred. At that time, we visually noticed that the QT interval was shortened in response to bolus calcium administration, and we used the change of real-time QTc interval as a supportive indicator for calcium correction. This monitoring allowed for us to administer calcium at an unusually high rate, by which progression of hypocalcemia was prevented. Levels of hemoglobin and coagulation factors were preserved both by restriction of crystalloid infusion and by a massive transfusion protocol. The patient was extubated without pulmonary edema or cardiac overload and was finally discharged without any sequelae. Intensive and cooperative management for massive transfusion and electrolyte correction using QTc monitoring was considered to be a key for successful management.

Regression of viral pathogen indicators due to improvement of hygiene protocols on boots in a bovine farm.

Rotavirus A (RVA), bovine torovirus (BToV), bovine enterovirus (BEV) and bovine coronavirus (BCV) at a bovine farm in Ibaraki prefecture were monitored by one-step multiplex reverse transcription polymerase chain reaction (RT-PCR), with the aim of confirming the reduction of "viral pathogen indicators". A total of 960 bovine fecal samples were collected from calves less than 2 month-old within the period from October 2016 to October 2018 every 2 months at the bovine farm. In each sampling, 40 samples were taken from calves 3 week-old or less, and 40 samples from calves over 3 week-old, in principle. At the end of September 2017, the farm introduced improvement of hygiene protocols on boots by exchanging boots and appropriate usage of a footbath at the entrance of calf sheds. In the comparison of the virus detection by RT-PCR, prevalence of all 4 viruses was significantly reduced (P<0.01) in calves 3 week-old or less after the improvement. The mortality of calves less than 2 month-old was also significantly reduced after the improvement of hygiene protocols. These data suggest that the proper control of boots at calf sheds is important, perhaps even vital, for rearing hygiene measures at bovine farms so as to attain substantial decrease in the prevalence of pathogens.

Bactericidal efficacies of food additive grade calcium hydroxide toward Legionella pneumophila.

Food additive grade calcium hydroxide (FdCa(OH)2) in the solution of 0.17% was evaluated for its bactericidal efficacies toward Legionella pneumophila with or without sodium hypochlorite (NaOCl) at a concentration of 200 ppm total residual chlorine, at room temperature (RT) (25°C ± 2°C) and 42°C, either with or without 5% fetal bovine serum (FBS). Besides, FdCa(OH)2 in different concentration solutions were prepared in field water samples (hot spring and bath tab water) and evaluated for their bactericidal efficacies at 42°C. FdCa(OH)2 (0.17%) inactivated the L. pneumophila to the undetectable level (<2.6 log CFU/ml) within 5 min and 3 min, respectively, at RT and 42°C, with 5% FBS. At RT and 42°C, NaOCl inactivated L. pneumophila to the undetectable level within 5 min, without 5% FBS, but with 5% FBS, it could only inactivate this bacterium effectively (≥3 log reductions). Conversely, at RT and 42°C, the mixture of 0.17% FdCa(OH)2 and 200 ppm NaOCl could inactivate L. pneumophila to the undetectable level, respectively, within 3 min and 1 min, even with 5% FBS, and it was elucidated that FdCa(OH)2 has a synergistic bactericidal effect together with NaOCl. FdCa(OH)2 0.05% solution prepared in hot spring water could inactivate L. pneumophila to the undetectable within 3 min at 42°C. So, FdCa(OH)2 alone could show nice bactericidal efficacy at 42°C, even with 5% FBS, as well as in field water samples.