Peak value of serum KL-6 may be useful for predicting poor prognosis of severe COVID-19 patients.

BACKGROUND: Serum Krebs von den Lungen 6 (KL-6), which reflects alveolar epithelial injury, was reported to be useful to predict the progression of pneumonitis induced by COVID-19 in the early phase. This study aimed to evaluate the peak value of serum KL-6 during hospitalization for COVID-19 to discover a more useful biomarker for predicting prognosis in COVID-19 patients. METHODS: In this retrospective, single-center, observational study, we analyzed the data of 147 hospitalized patients who required supplemental oxygen, high-flow oxygen therapy, or invasive mechanical ventilation for respiratory failure due to COVID-19 from March 2020 to February 2021. We extracted data on patient sex, age, comorbidities, treatment, and biomarkers including the initial and peak values of KL-6. Inclusion criteria were examination of the studied biomarkers at least once within 3 days of admission, then at least once a week, and at a minimum, at least twice during the entire hospitalization. Area under the receiver operating curve (AUC) was analyzed to determine the accuracy of several biomarkers including KL-6 and LDH for predicting poor prognosis defined as survivors requiring invasive mechanical ventilation for over 28 days or non-survivors of COVID-19. Univariable and multivariate logistic regression analyses were performed to investigate the prognostic value of the baseline characteristics and biomarkers. RESULTS: Among the 147 patients, 108 (73.5%) had a good prognosis and 39 (26.5%) had a poor prognosis. The AUC analysis indicated that peak KL-6 showed precise accuracy in the discrimination of patients with poor prognosis (AUC 0.89, p < 0.001). The best cut-off value for KL-6 concentration was 966 U/mL (sensitivity 81.6%, specificity84.3%). After adjustment, increasing peak values of KL-6 or LDH were associated with a high risk of poor prognosis, with an adjusted odds ratio of 1.35 for peak value of KL-6, per 100 U/mL increase (95% CI 1.17-1.57, p < 0.001) and 2.16 for peak value of LDH, per 100 U/L increase (95% CI 1.46-3.20, p < 0.001). CONCLUSIONS: Peak values of KL-6 and LDH measured during hospitalization might help to identify COVID-19 patients with respiratory failure who are at higher risk for a poor prognosis.

Relationship between cognitive function affecting motor Functional Independence Measure and hypnotics.

Otsubo H, Kishimoto K, Hirano I, Nakano H, Itaya K, Kumaki R, Osumi H. Relationship between cognitive function affecting motor Functional Independence Measure and hypnotics. Jpn J Compr Rehabil Sci 2022; 13: 4-11. Purpose: The purpose of this study was to examine the relationship between cognitive dysfunction affecting motor Functional Independence Measure (FIM) and hypnotics. Methods: This was a retrospective study involving 509 patients aged ≥ 65 years who were discharged from a convalescent rehabilitation ward. Results: Multiple regression analysis was performed with motor FIM efficiency and motor FIM effectiveness (motor FIM-e) as independent variables and the presence or absence of cognitive dysfunction as the dependent variable. The use of hypnotics in patients with cognitive dysfunction showed a positive relationship with motor FIM efficiency (ß = 0.147, P = 0.019) and motor FIM-e (ß = 0.141, P = 0.026). Multiple regression analyses were performed after further classifying hypnotics by therapeutic class into hypnotics with new mechanisms, non-benzodiazepine (BZ) hypnotics, and BZ hypnotics. Non-BZ hypnotics (ß = 0.141, P = 0.021) showed a positive relationship with motor FIM efficiency. Non-BZ hypnotics (ß = 0.158, P = 0.009) and BZ hypnotics (ß = 0.178, P = 0.003) showed a positive relationship with motor FIM-e, whereas hypnotics with new mechanisms of action did not. In contrast, none of the three combinations of hypnotics showed any significant relationship with either motor FIM efficiency or motor FIM-e in patients without cognitive dysfunction. Conclusion: The results suggested that the use of hypnotics in patients with cognitive dysfunction increases motor FIM efficiency and motor FIM-e.

Light-In-Flight Imaging by a Silicon Image Sensor: Toward the Theoretical Highest Frame Rate.

Light in flight was captured by a single shot of a newly developed backside-illuminated multi-collection-gate image sensor at a frame interval of 10 ns without high-speed gating devices such as a streak camera or post data processes. This paper reports the achievement and further evolution of the image sensor toward the theoretical temporal resolution limit of 11.1 ps derived by the authors. The theoretical analysis revealed the conditions to minimize the temporal resolution. Simulations show that the image sensor designed following the specified conditions and fabricated by existing technology will achieve a frame interval of 50 ps. The sensor, 200 times faster than our latest sensor will innovate advanced analytical apparatuses using time-of-flight or lifetime measurements, such as imaging TOF-MS, FLIM, pulse neutron tomography, PET, LIDAR, and more, beyond these known applications.

Immunological studies of cerebrospinal fluid from patients with CNS symptoms after human papillomavirus vaccination.

In 32 patients with prolonged central nervous system symptoms after human papillomavirus (HPV) vaccination, we measured conventional and immunological markers in cerebrospinal fluid (CSF) and compared with the levels in disease controls. Our studies revealed significantly decreased chloride and neuron-specific enolase (NSE) levels in CSF of patients with CNS symptoms after HPV vaccination compared to disease controls. IL-4, IL-13, and CD4(+) T cells increased significantly in patients, and IL-17 increased significantly from 12 to 24months after symptom onset. Chemokines (IL-8 and MCP-1) were also elevated, but CD8(+) T cells, PDGF-bb and IL-12 were reduced. Antibodies to GluN2B-NT2, GluN2B-CT and GluN1-NT increased significantly. These results suggest biological, mainly immunological, changes in the CSF of patients after HPV vaccination.

Imbalance in multiple sclerosis and neuromyelitis optica: association with deep sensation disturbance.

Abnormality in balance is one of the most important causes of gait disturbance which has a direct impact to disability and medical cost in multiple sclerosis (MS) and neuromyelitis optica (NMO). However, characteristics of imbalance in these two diseases have not been fully elucidated. The aim of this study was to evaluate the degree and features of imbalance using stabilography, the degree of deep sensation disturbance using tibial nerve somatosensory evoked potentials (SEP), and their association with clinical impairment, in patients with MS and NMO. Seven NMO patients and seven MS patients with balance disturbance were examined. The relationship among stabilography measurements representing the degree and features of imbalance, height-adjusted P38 peak latency of SEP, and neurological functional disability, were analyzed. Stabilography evaluation showed a significantly severer degree of imbalance in NMO than in MS. Romberg quotient of the patients with brainstem lesions was significantly larger than those without them. In all patients, length of excursion per second significantly correlated positively with anterio-posterior-axis power spectra at intermediate frequency band. In all patients and in NMO, P38 peak latency adjusted by height significantly correlated positively with anterio-posterior-axis power spectra at intermediate frequency band. These findings suggest that the degree of imbalance of MS and NMO possibly correlate with deep sensation disturbance, which could be evaluated by anterio-posterior-axis power spectra at intermediate frequency band by stabilography. Severer imbalance in NMO than MS may be associated with the severe longitudinally extensive spinal cord lesions.

A subtle case of tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is known to cause severe intractable epilepsy and mental retardation; however, diagnosis can be delayed in milder cases. We report a 26-year-old right-handed female patient who started having convulsions at age 7 days. She had several focal seizures per year that were intractable to treatment with carbamazepine or phenytoin. Her two sisters had several episodes of suspected epileptic seizures but had no symptoms related to TSC. Seizure semiology of the patient comprised of visual hallucination, loss of consciousness, and convulsive movements predominantly on the right. Physical examination revealed several small scattered angiofibromas over the nose that were histologically determined by skin biopsy. Hypomelanotic macules, shagreen patches, or periungual fibromas were not seen. Neurological examination showed mental retardation (MMSE: 23/30, WAIS-III: VIQ63, PIQ59, FIQ58) and decreased vibration sensation in both legs. Interictal EEG showed slow waves and epileptiform discharges broadly over the anterior quadrants bilaterally. Brain imaging showed multiple cortical tubers and malformation of cortical development but no subependymal nodules. Interictal IMP-SPECT showed hypoperfusion in the left frontal lobe. Cardiac rhabdomyoma was not noticed by cardiac echography. Truncal CT showed sclerosis of the bilateral lumbosacral joints. There was no abnormality in the lung, major arteries, liver, or kidneys. No hamartomas or retinal achromic patches were noticed by ophthalmologic evaluation. Administration of lamotrigine was effective for her seizures. This patient fulfilled two major features of diagnostic criteria for TSC and was diagnosed as definite TSC. Patients with mental retardation and epilepsy should be carefully evaluated for the possible diagnosis of TSC.

Ezetimibe ameliorates atherogenic lipids profiles, insulin resistance and hepatocyte growth factor in obese patients with hypercholesterolemia.

BACKGROUND: Ezetimibe ameliorates serum low-density lipoprotein cholesterol (LDL-c) and it has been approved for the treatment of hypercholesterolemia. However, the effects of ezetimibe on specific biomarkers have not been fully clarified in obese Japanese patients. METHODS: A total of 101 patients (47 males and 54 females) were registered in this study during 2011 and 2012. All patients were over 20 years old, were obese [body mass index (BMI) ≥ 25 kg/m(2)] and had hypercholesterolemia (LDL-c ≥ 120 mg/dl). After excluding 10 subjects (7 who dropped out and 3 with missing data), 91 patients (39 males and 52 females) were analyzed. They were treated with 10 mg ezetimibe once a day for 24 weeks and were evaluated at 12 and 24 weeks. RESULTS: Following 12 weeks of ezetimibe therapy, BMI (p < 0.001), waist circumference (p < 0.001), total cholesterol (p < 0.001), LDL-c (p < 0.001), non high-density lipoprotein cholesterol [HDL-c] (p < 0.001), triglycerides (p < 0.05) and remnant-like particle cholesterol (RLP-c; p < 0.001) were significantly decreased. Following 24 weeks of ezetimibe therapy, BMI (p < 0.05), waist circumference (p < 0.001), total cholesterol (p < 0.001), LDL-c (p < 0.001), non HDL-c (p < 0.001), triglycerides (p < 0.05), RLP-c (p < 0.001), insulin (p < 0.05) and hepatocyte growth factor (HGF; p < 0.05) were significantly decreased. In contrast, HDL-c (p < 0.001) was significantly increased. CONCLUSIONS: Ezetimibe ameliorated not only atherogenic lipid profiles but also anthropometric factors, insulin resistance and biomarkers such as HGF. Ezetimibe may have pleiotropic effects on obese patients with hypercholesterolemia.

[Epidemiology and cause of epilepsy].

Incidence of epilepsy was estimated at 24-53 per 100,000, while prevalence was varying between 2.7-40 per 1,000, in Japan 8.8 in children younger than 13 years. Higher incidence and prevalence were increasingly noted in aged population; even higher in the advanced aged than in children. Incidence of generalized seizures was indicated to be slightly higher than focal seizures, although this figure may change due to high incidence of aged epilepsy with increased cerebrovascular disorders or degenerative diseases as a cause of epilepsy. Mortality is higher in patients with epilepsy than in the general population, including SUDEP in intractable epilepsy.

Epileptic seizures in Japanese patients with multiple sclerosis and neuromyelitis optica.

PURPOSE: To examine the incidence and clinical features of epileptic seizures in Japanese patients with multiple sclerosis (MS) and neuromyelitis optica (NMO). METHODS: We reviewed medical records of all patients who visited the Neurology Clinic in Utano National Hospital between January and December, 2009, and enrolled 63 MS patients who fulfilled the McDonald criteria (2005) (mean age, 41.1 years) and 31 NMO patients who fulfilled the Wingerchuk criteria (2006) (mean age, 44.6 years). Patients with a history of epileptic seizures were selected and their clinical features were obtained. RESULTS: Four MS patients (6.3%; 2 men and 2 women; mean age, 32.5 years) and 4 NMO patients (12.9%; 4 women; mean age, 36.0 years) had epileptic seizures. Disease onset age of MS patients with seizures was significantly younger than those without seizures by 13.1 years, and Expanded Disability Status Scale of NMO patient with seizures was significantly higher than those without seizures by 2.2. All 8 patients showed brain lesions on magnetic resonance imaging and 2 MS patients had tumefactive demyelinating lesions. Electroencephalography showed interictal epileptiform discharges in 5 patients. Seizure types of 6 patients were recognized as partial seizures based on clinical semiology. All patients responded to antiepileptic therapy well. In both MS and NMO, there were both seizures with and without concurrent relapse. CONCLUSIONS: Similar to MS, NMO patients possibly have higher risk to develop epileptic seizures than general population.

Epizootic canine distemper virus infection among wild mammals.

In the spring of 2007, seven raccoon dogs and a weasel were captured near the city of Tanabe in Wakayama prefecture, Japan. The causative agent of the animals' death 1-2 days after capture was identified as canine distemper virus (CDV) by virus isolation, immunostaining with an anti-CDV polyclonal antibody, and a commercially available CDV antigen-detection kit. Sequence analysis of hemagglutinin genes indicated the isolated viruses belong to genotype Asia-1 and possess the substitution from tyrosine (Y) to histidine (H) at position 549 that is associated with the spread of CDV to non-canine hosts. A serosurvey for CDV was then conducted among wild animals in the region. The animals assayed consisted of 104 raccoons, 41 wild boars, 19 raccoon dogs, five Sika deer, two badgers, one weasel, one marten, one Siberian weasel and one fox. Virus-neutralization (VN) tests showed that, except for fox and weasel, all of the species assayed had VN antibodies to CDV. Interestingly, 11 of the 41 wild boars (27%) and two of the five Sika deer assayed possessed VN antibodies to CDV. These findings indicate that CDV infection was widespread among wild mammals during this epizootic.

[A case of neuromyelitis optica with varicella zoster virus meningitis during mitoxantrone treatment].

A 36-year-old woman with neuromyelitis optica had been treated with steroids for the prevention of relapse. However, her treatment was not effective and she showed adverse effects such as diabetes mellitus, osteoporosis, compression fractures, and Pneumocystis carinii pneumonia. Therefore, we started her on mitoxantrone treatment. After five courses of mitoxantrone injection, she developed a herpes zoster infection in her thigh followed by aseptic meningitis. PCR for varicella zoster virus (VZV)-DNA was positive in the cerebrospinal fluid. The mechanisms that caused VZV reactivation by mitoxantrone are not known. Opportunistic herpes virus reactivation may occur easily with increasing use of immunosuppressive drugs for both neuromyelitis optica and multiple sclerosis. These drugs must be used under careful supervision.

[Diffuse alveolar hemorrhage arising after use of a waterproofing spray].

A 33-year-old woman used waterproofing spray and subsequently developed cough, sputum and chest pain about 8 hours later accompanied by dyspnea, fever and general fatigue. She was admitted to our hospital 4 days after the symptoms appeared. A chest CT scan on the first visit revealed diffuse mild centrilobular nodular opacities and ground-glass opacities in both lung fields. Hemosiderin-laden macrophages accounted for 11% of the histiocytes found in her bronchoalveolar lavage fluid, which also contained blood. Based on these findings, the patient was given a diagnosis of diffuse alveolar hemorrhage. This is the first report in Japan of diffuse alveolar hemorrhage occurring after the use of a waterproofing spray.

A bright and long-pulse illumination for ultrahigh-speed microscopy of living specimens.

Ultrahigh-speed microscopy of living specimens requires ultrabright illumination. Moreover, the duration of illumination should be sufficiently long, on the order of at least several tens of milliseconds, in order to investigate the dynamic state of living specimens. However, specimens are exposed to a high risk of damage by the intense illumination. The brightness and pulse duration of illumination have to be continuously controlled for use in the ultrahigh-speed microscopy of living specimens. Commercial or laboratory-made illumination systems do not satisfy the abovementioned requirements. In this paper, the development of a bright and long-pulse illumination system for ultrahigh-speed microscopy of living specimens is presented. A xenon flashlamp with an arc length of 1.5 mm has been used as the light source. The electrical power supply consists of a voltage-regulated circuit, a capacitor bank, and a control circuit including an insulated-gate bipolar transistor as a gating device, which provides a large rectangular current pulse with the duration in the range to the order of several tens of milliseconds. The brightness, pulse duration, and repetition rate can be easily and continuously controlled. The illumination developed in the present study is installed in an inverted fluorescence microscope equipped with a high-speed camera in order to evaluate the performance as an illumination source. A fluorescent image of the living spermatozoa of a mouse obtained at a frame rate of 8 kHz shows good contrast. Such an image cannot be obtained using a commercial illumination system.

Chronic inflammatory demyelinating polyneuropathy after treatment with interferon-alpha.

Interferon-alpha (IFN-alpha), though widely used for the treatment of chronic viral hepatitis, may be associated with the occurrence of autoimmune disorders. In this case report, a patient with chronic hepatitis C virus infection had chronic inflammatory demyelinating polyneuropathy (CIDP) after the initiation of IFN-alpha therapy. The neurological symptoms of this patient continued to progress even though the treatment with IFN-alpha had been withdrawn; the symptoms improved dramatically following treatment with intravenous immunoglobulin. This case may therefore provide an important clue to understand the immune mechanism of CIDP and IFN-alpha.

Detection of antibody to canine distemper virus in wild raccoons (Procyon lotor) in Japan.

Canine distemper virus (CDV) causes a lethal disease among members of the Carnivora. To clarify the distribution of CDV in wild animals, we examined 106 raccoon sera collected from two prefectures in Japan, Hyogo and Osaka, from 2005 to 2007. Among them, 34 raccoons (32.1%) possessed a virus-neutralizing (VN) antibody to KDK-1 strain (genotype Asia-1). There was no significant difference in seroprevalence of CDV regardless of places, gender, and body weights. In Hyogo, a geometric mean of VN titers to KDK-1 was significantly higher than that to Onderstepoort (vaccine strain), indicating that KDK-1-like CDV different from vaccine strain might have spread among raccoon population in Hyogo. In conclusion, CDV is epidemic among feral raccoons in Japan, suggesting that CDV might have been spreading among Japanese wild animals.

Establishment of canine and feline cells expressing canine signaling lymphocyte activation molecule for canine distemper virus study.

Signaling lymphocyte activation molecule (SLAM) is one of the receptors for canine distemper virus (CDV). In this study, canine and feline cells expressing canine SLAM, designated A-72/cSLAM and CRFK/cSLAM, were established for the in vitro study of canine distemper. Recent CDV isolates, KDK-1 and 246, which belong to genotypes Asia/H1 and Asia/H2, respectively, rapidly grew and produced distinct syncytia in both the SLAM-expressing cells. The virus-neutralizing (VN) test was successfully performed using these cells, and the results indicated that sera from dogs experimentally infected with KDK-1 had higher VN titers for homologous strain KDK-1 than for heterologous strain 246 and the vaccine Onderstepoort. These newly established cells expressing canine SLAM would help virological and serological analyses of canine distemper.

Adenosinergic modulation of ventilation in obese zucker rats.

OBJECTIVES: The goal of our study was to determine whether altered adenosinergic mechanisms contribute to the depressed ventilatory response observed in obese Zucker rats. RESEARCH METHODS AND PROCEDURES: Eight lean and eight obese Zucker rats were studied at 7 to 8 weeks of age. Ventilation (V(E)) during room air, during 5-minute hypercapnic (7% CO(2), balance O(2)), and during 30-minute sustained hypoxic (10% O(2)) exposures were sequentially measured by the barometric method on three separate occasions after the randomized blinded administration of equal volumes of either saline (control), 8-(p-sulfophenyl)-theophylline (8-PST, 7 mg/kg, peripheral adenosine antagonist), or aminophylline (AMPH, 15 mg/kg, peripheral and central adenosine antagonist). RESULTS: During room air and hypercapnic exposures, AMPH (but not 8-PST) significantly (p < 0.05) increased V(E) in both lean and obese rats. During acute (2 minute) hypoxic exposure, 8-PST (but not AMPH) significantly depressed V(E) in lean rats. In contrast, AMPH (but not 8-PST) selectively increased V(E) in obese rats. During sustained (10 to 30 minutes) hypoxic exposure, neither AMPH nor 8-PST administration altered V(E) in lean rats. In contrast, AMPH (but not 8-PST) selectively increased V(E) during the late response in obese rats. DISCUSSION: Our findings indicate that obese rats possess altered adenosinergic modulation of ventilatory responses to acute and sustained hypoxia in two opposite ways. We conclude that the reduced hypoxic ventilatory response observed in obese Zucker rats is attributed to depressed adenosinergic peripheral excitatory mechanisms and to enhanced adenosinergic central depression mechanisms, both of which contribute to the blunted ventilatory response in obesity.

Doxapram stimulates the carotid body via a different mechanism than hypoxic chemotransduction.

To determine if doxapram stimulates the carotid body through the same mechanism as hypoxia, we compared the effects of doxapram and hypoxia on isolated-perfused carotid bodies in rabbits. Doxapram stimulated the carotid body in a dose-dependent manner. In Ca(2+)-free solution, neither doxapram nor hypoxia stimulated the carotid body. Although, doxapram had an additive effect on the carotid body chemosensory response to hypercapnia, a synergistic effect was not observed. Also, we investigated the various K(+) channel activators on the response to doxapram and hypoxia: pinacidil and levcromakalim as ATP-sensitive K(+) channel activators; NS-1619 as a Ca(2+)-sensitive K(+) channel activator; and halothane as a TASK-like background K(+) channel activator. The hypoxic response was partially reduced by halothane only, while pinacidil, levcromakalim and NS-1619 had no effect. Interestingly, the effect of doxapram was partially inhibited by NS-1619. Neither pinacidil nor levcromakalim affected the stimulatory effect of doxapram. We conclude that doxapram stimulates the carotid body via a different mechanism than hypoxic chemotransduction.