Human metapneumovirus-associated community-acquired pneumonia in adults during the first wave of COVID-19.

Objective: The clinical course of human metapneumovirus (hMPV) infection is similar to that of coronavirus 2019 disease (COVID-19). However, community-acquired hMPV infections in adults have not yet been sufficiently investigated. We examined the detection status of hMPV antigens and the clinical features of positive patients during the first wave of COVID-19, which coincided with the epidemic season of hMPV infection in Japan. Methods: In this cross-sectional, observational, and single-center study, we recruited consecutive individuals who visited the Japan Agricultural Cooperatives Kochi Hospital due to fever, respiratory symptoms, or close contact with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infected persons during the period from January to May 2020. Results: The positive rate of immunochromatography for hMPV antigens from nasopharyngeal swabs was 9.5% (4/42), and four positive cases were community-acquired pneumonia (CAP) (5.3% of all CAP). The positive rate of hMPV antigens in the CAP group (30.8%, 4/13) was higher than that in the non-pneumonia group (0.0%, 0/19) (p < 0.05). The average age of the four adult patients with CAP was 69.8 years (range 35-93). Mean white blood cell counts and C-reactive protein blood levels were 6,250 cells/µL (3,500-12,180) and 4.30 mg/dL (4.05-7.04), respectively. Chest computed tomography images were diverse and two patients showed dense consolidation. No multi-organ disorder was noted during the clinical course in any of the four cases, and their prognoses were good. Conclusion: hMPV infection may be considered in the differential diagnosis of COVID-19 and CAP in Japan under the preventive measures for SARS-CoV-2 infection, at least during the epidemic season of hMPV infection.

Topical Management of Peristomal Pyoderma Gangrenosum: A Report of 3 Case Studies.

BACKGROUND: Peristomal pyoderma gangrenosum (PPG) presents multiple challenges for healthcare providers. The diagnosis of PPG may be delayed, and it may be mistaken for an irritant dermatitis or an infection. Patients with ostomies secondary to inflammatory bowel disease (IBD) may experience PPG. Issues related to PPG include difficulty maintaining a seal of the ostomy pouching system and preventing contamination of the painful, necrotic ulcerations characteristic of this condition. Treatment focuses on the appropriate assessment of the ulcers, successful pouch application, and proper management of IBD through a collaborative effort of both dermatologists and certified WOC nurses (CWOCN). CASES: We treated 3 patients diagnosed with Crohn's disease (CD) who developed refractory PPG. All 3 were treated with a topical steroid lotion, prednisone, and adalimumab or a combination of these agents. Ostomy products and application were tailored to prevent leakage and protect areas of ulceration. All ulcers were healed within 6 months of our initial consultation. CONCLUSION: We successfully managed 3 patients with CD and PPG with appropriate ostomy care, including revision of the ostomy pouching techniques, topical steroid treatment, and treatment based on assessment of ulcer status by the dermatologist and the WOC nurse.

Evaluation of therapeutic effects of FAK inhibition in murine models of atherosclerosis.

OBJECTIVE: Therapeutic effects of focal adhesion kinase (FAK) inhibition using a small molecule inhibitor was evaluated in apolipoprotein E (apoE) knockout (KO) and low-density lipoprotein receptor (LDLr) KO mouse atherosclerosis models. RESULTS: The prevention trial consisted of an 8-week treatment with an FAK inhibitor concurrent treatment with a high fat (HF)/high cholesterol (HC) diet. The intervention trial consisted of 6- and 8-week treatment after 6- and 8-week pre-loading, respectively, of a HF/HC diet in apoE KO and LDLr KO mice, respectively. The inhibitor was admixed with a HF/HC diet and mice were given free access to the admixture. The FAK inhibitor exhibited marked inhibition against the development of the atherosclerosis in both of prevention and intervention trials at a dose of 0.03% without showing any remarkable toxic properties in biochemical examinations. These results indicated that FAK inhibition might be a possible candidate for novel therapeutic targets against atherosclerosis.

Case of Subarachnoid Hemorrhage from Ruptured Oncotic Fusiform Aneurysms from Choriocarcinoma Metastasis Treated with Aneurysmectomy and Vessel Reconstruction.

BACKGROUND: Oncotic aneurysm is a rare condition with a high mortality rate. Because no consensus has been reached regarding therapeutic strategy for ruptured oncotic aneurysm, treatment remains challenging. CASE DESCRIPTION: A 35-year-old woman developed sudden onset of severe headache. Computed tomography showed subarachnoid hemorrhage and cerebral angiography revealed 2 fusiform aneurysms in the distal portion of the left middle cerebral artery. Aneurysmectomy with vessel reconstruction using a superficial temporal artery graft was performed to maintain blood flow to the distal middle cerebral artery. Pathologic examination of the aneurysm and wall of the resected recipient middle cerebral artery showed infiltrating trophoblasts. Immunostaining for human chorionic gonadotropin was positive in the aneurysm specimen. On the basis of an elevated concentration of serum human chorionic gonadotropin, choriocarcinoma with ruptured intracranial oncotic aneurysms was diagnosed. After further systemic examination for carcinoma, chemotherapy was initiated. CONCLUSIONS: Aneurysmectomy, resection of the parent artery with irregular walls and reconstruction to the distal recipient artery with normal intima should be considered to secure patency of the anastomosis and prevent the recurrence of oncotic aneurysm. Subsequent chemotherapy is essential to prevent carcinomatous meningitis and disease progression.

Association between leptin gene expression in subcutaneous adipose tissue and circulating leptin levels in obese patients with psoriasis.

Numerous reports have shown that psoriasis is associated with obesity and leptin. However, few reports are available on the association between serum leptin levels and leptin gene expression in SAT of psoriasis patients. To clarify this point, we examined serum leptin levels and expression levels of leptin messenger RNA (mRNA) in subcutaneous adipose tissue (SAT) of psoriasis patients. 17 psoriasis vulgaris patients and 6 non-obese control patients who underwent skin surgery were enrolled in this study. We measured serum leptin levels. SAT samples in psoriasis patients were taken from beneath the lesional psoriatic skin at the time of skin biopsy. Leptin mRNA expression in SAT was measured using quantitative real-time reverse transcription polymerase chain reaction (real-time RT-PCR) amplification. Leptin mRNA expression showed a positive correlation with serum leptin levels and BMI. We classified psoriasis patients into two groups according to BMI: the group of non-obese psoriasis patients (BMI < 25, n = 7), and the group of obese psoriasis patients (BMI ≥ 25, n = 10). PASI score, serum leptin levels and Leptin mRNA expression in SAT were significantly higher in the obese psoriasis patients than in the non-obese psoriasis patients. Leptin mRNA expression in SAT was correlated with circulating levels of leptin, the severity of psoriasis, and obesity in psoriasis patients. Serum leptin levels and leptin mRNA expression levels in SAT of non-obese psoriasis patients were not significantly different from those of non-obese controls. The altered secretion of leptin by SAT may be related to the severity of psoriasis.

Determination of the structure of {31}ne by a fully microscopic framework.

We perform the first quantitative analysis of the reaction cross sections of {28-32}Ne by {12}C at 240 MeV/nucleon, using the double-folding model with the Melbourne g matrix and the deformed projectile density calculated by antisymmetrized molecular dynamics. To describe the tail of the last neutron of {31}Ne, we adopt the resonating group method combined with antisymmetrized molecular dynamics. The theoretical prediction excellently reproduces the measured cross sections of {28-32}Ne with no adjustable parameters. The ground state properties of {31}Ne, i.e., strong deformation and a halo structure with spin parity 3/2{-}, are clarified.

Feature on erythropoiesis in dietary restricted rats.

We attempted to characterize the influence of undernutrition on erythropoiesis in toxicity studies. Male rats were divided into the following 5 groups: dietary restriction groups in which feeding was restricted by 33% or 66% for 14 days (R33 and R66); phlebotomy groups in which 1% or 4% of total blood volume was removed by serial phlebotomy for 14 days (PB01 and PB04); and a nontreated group (NT). Toxicological parameters such as hematology and blood chemistry were evaluated. The body weight gains in the R33 and phlebotomy groups (PB01 and PB04) were similar and were less than that observed in the NT group. Decreases in peripheral blood reticulocytes, bone marrow erythroids and the unsaturated iron binding capacity (UIBC) were observed as changes that suppressed erythropoiesis in the R33 and R66 groups. However, increases in reticulocytes and UIBC were observed as opposite changes in the phlebotomy groups. In addition, an increase in the blood urea nitrogen level and a decrease in the serum alkaline phosphatase level were observed as changes reflecting poor nutrition in the phlebotomy groups. Decreased reticulocytes which are related to poor nutrition were not observed. However, increases in those cells as reflected by a loss of blood were observed in the phlebotomy groups. Even if undernutrition suppresses erythropoiesis, the ability of erythropoiesis to respond to a demand appears to be retained. In repeated dose toxicity studies, decreased food consumption is often observed in the drug administration groups. Our study results provide useful information for hematological evaluations in toxicity studies.

Evaluation of Short-term Myelotoxicity Study in Dietary Reduced Rats.

This study attempted to prove our hypothesis that a short-term toxicity study, using a 4-day dosing regimen as an example, is suitable for evaluating myelotoxicity in rats. We compared the hematological, bone marrow cytological and histopathological results of 5-fluorouracil (5-FU) treated and pair-feeding groups after a 4-day administration period. Several experimental groups were defined for this 4-day study as well as for our previously reported 14-day study (Miyata et al., 2009); these included 5-FU treated groups receiving 12, 15 and 18 mg/kg/day (FU12, FU15 and FU18), pair-feeding groups (R12, R15 and R18 receiving the same amount of food as the FU12, FU15 and FU18 groups, respectively) and a nontreated control group. Although severe reductions in body weight gain and food consumption were reported in the 14-day study, only slight reductions were observed in the 4-day study. In the 4-day study, a decrease in blood reticulocytes and a decreasing trend of marrow erythroid cells were only observed in the FU18 group, and no effects were observed in the pair-feeding groups. The erythroblastic changes observed in this 4-day study were thought to reflect the direct influence of 5-FU administration. Since concerns regarding the influence of secondary changes related to undernutrition were minimized in the 4-day study, it was thought to clarify the direct influence of 5-FU administration on erythroblastic cells. Thus, a 4-day study protocol might be helpful for distinguishing secondary changes related to undernutrition.

[Circadian rhythms and effects of anesthesia on plasma natriuretic peptide levels in rats].

Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are circulating hormones secreted predominantly in patients with hypertension or congestive heart failure. To obtain background data on plasma ANP and BNP levels in rats, we investigated the circadian rhythms and effects of anesthesia on these peptides. To determine the circadian rhythms, plasma samples from thirty rats were collected by non-anesthesia (decapitation) at six time points every fourth hour. To determine the effects of anesthesia, plasma samples from thirty-two rats were collected under diethyl ether, pentobarbital or urethane anesthesia. The plasma ANP and BNP levels were determined using a radioimmunoassay. The plasma ANP levels were high from the evening to early morning, while the plasma BNP levels were relatively low at 2:30 AM. The difference in the BNP levels was statistically significant. The plasma BNP levels were relatively high when the rats were anesthetized using urethane. These results suggest that blood collection should be performed between 10:30 AM to 2:30 PM to determine plasma ANP and BNP. The use of pentobarbital is also recommended for toxicological studies in rats.

Evaluation of myelotoxicity in dietary restricted rats.

The purpose of this study was to clarify the effect of decreased food consumption on evaluation of myelotoxicity in routine general toxicity studies. Male rats were divided into the following 7 groups: 12, 15, and 18 mg/kg 5-fluorouracil (5-FU) treatment groups (FU12, FU15 and FU18); dietary restriction groups (R12, R15 and R18 receiving the same amount of food as the rats in the FU12, FU15 and FU18 groups, respectively); and a nontreated control group (NT). We compared the changes in body weight, hematology and the results of cytological analyses of bone marrow and histopathology among the groups after administration and recovery periods of 14 and 7 days, respectively. At the end of the administration period, the FU15 and FU18 groups showed decreases in many hematologic and bone marrow parameters that were all similar to those in the corresponding dietary restriction groups (R15 and R18). A granulocyte abnormality (polyploidy: frequency of 1% or less) was also observed in all 5-FU treated groups. At the end of the recovery period, increases in the reticulocyte and platelet counts and extramedullary hematopoiesis of the spleen were observed in the 5-FU treated groups. These results indicate that the results of general toxicity studies in rats should be evaluated in consideration of dietary restriction effects when food consumption is decreased at about 30-40% or more. Careful morphological observation of hemocytes would be helpful in distinguishing the effect of a drug from that of dietary restriction in relation to hematological and bone marrow parameters. Performance of a recovery test to determine the reactive response of hematopoiesis is also recommended.

Importance of starting age for myelotoxicity study in dietary restricted rats.

The aim of this study was to prove our hypothesis that adult rats with lowering of body weight gain, rats at 12 weeks of age as an example, are suitable for evaluation of myelotoxicity. Age-related differences between young rats (6-week-old study) and adult rats (12-week-old study) were analyzed in hematological examination values. The data of the young rats were reprinted from our previous report (Miyata et al., 2009) since our hypothesis was verified by comparison with that previous report. Several experimental groups were defined for the 12-week-old study as well as for the 6-week-old study; these included 5-fluorouracil (5-FU) treated groups receiving 12, 15 and 18 mg/kg/day (FU12, FU15 and FU18), pair-feeding groups (R12, R15 and R18 receiving the same amount of food as in the FU12, FU15 and FU18 groups, respectively) and a nontreated control group. Numerous hematologic and bone marrow parameters in the 5-FU treated groups were comparable to those in the corresponding pair-feeding groups in both age studies. Generally, the influences of undernutrition were more apparent in the young rats than in the adult rats. Histopathological examinations showed a decrease in hematopoiesis in the bone marrow in the 5-FU treated and pair-feeding groups. No apparent differences were observed in the decreased hematopoiesis between the 5-FU treated and pair-feeding groups in the 6-week-old study, but a difference between these groups was noted in the 12-week-old study; decreased hematopoiesis was more frequently noted in the 5-FU treated groups. These facts suggest that adult rats are more suitable than young rats for evaluation of 5-FU-induced myelotoxicity.

Synthesis and structure-activity relationship of novel RXR antagonists: orally active anti-diabetic and anti-obesity agents.

A series of diazepinylbenzoic acid derivatives were synthesized and tested in the inhibition assay of the transactivation of RXR. Oral treatment of cyano derivatives (16f) was found to show anti-diabetic and anti-obesity effects in KK-A(y) mice.

Synthesis and structure-activity relationship of RXR antagonists based on the diazepinylbenzoic acid structure.

Synthesis and structure-activity relationship of RXR antagonists employing a diazepinylbenzoic acid scaffold are described. Of those antagonists, sulfonamide derivatives (6v and 6w) reveal a high antagonistic activity and good pharmacokinetic properties.

Full-field ERGs obtained using a contact lens electrode with built-in high intensity white light-emitting diodes in beagle dogs can be applied to toxicological assessments.

We investigated full-field ERGs in beagle dogs using a contact lens electrode with built-in LED. Experiment 1 was performed to determine the appropriate conditions for stimulus intensity and background illumination. We found that full-field ERGs could be recorded under the following conditions: stimulus intensity: -2.5logcd*s/m(2) in rod responses (RRs), 1.2logcd*s/m(2) in maximal responses (MRs), oscillatory potentials (OPs), cone responses (CRs), 30-Hz flicker responses (FRs), and background illumination: more than 25cd/m(2) in CRs and FRs. Experiment 2 was performed to apply full-field ERGs in beagle dogs to the detection of retinal toxicities. A dog was given one 30mg/kg dose of sodium iodate (NaIO(3)) intravenously. ERGs were recorded before administration and 1, 3, 5, 8, 24h, 7 and 14 days after administration of NaIO(3). The RRs disappeared completely at 1h when MRs and OPs decreased. On the other hand, CRs and FRs were recorded even at 8h. All responses disappeared at 24h. These findings indicate that retinal toxicity by NaIO(3) is first expressed in rods, followed by cones. These results suggest that full-field ERGs in beagle dogs using an LED contact lens can be used to evaluate toxic effects on rods and cones separately, with the potential to prove more useful than conventional methods for toxicological assessments of developing pharmaceuticals, and can be applied to it.

Cerebrospinal fluid taurine after traumatic brain injury.

In the experimental setting, taurine is known to be released from swollen cells to reestablish their normal volume. However, its clinical relevance has not been fully understood. This study was undertaken to reveal changes in cerebrospinal fluid (CSF) amino acids concentration in patients with severe traumatic brain injury (TBI). The study included eight patients, in whom a ventricular catheter was inserted to measure intracranial pressure and obtain CSF samples for 5 days. CSF obtained from patients with normal pressure hydrocephalus served as a control. CSF taurine concentration increased 1.8 times control (P < 0.05) after TBI and returned to control value approximately 67 h after injury. Taurine decreased further and remained lower than control thereafter. Phosphoethanolamine showed similar increase, whereas glutamine decreased transiently and arginine remained close to control value. The present data support the period of astrocytic swelling observed after TBI in other morphological studies. The mechanism and consequences of CSF taurine decrease in the subacute stage of TBI need to be elucidated.

Mutations induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in the lacZ and cII genes of Muta Mouse.

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) found in chewing tobacco, snuff, cigarettes, and cigars is a tobacco-specific nitrosamine and classified as a possible human carcinogen (Class 2B) by the International Agency for Research on Cancer (IARC). NNK given intraperitoneally was seen to induce lung and liver adenomas. To evaluate the genotoxicity of NNK in vivo, NNK was intraperitoneally administered to Muta Mouse at two concentrations (125 and 250 mg/kg, once a week for 4 weeks) followed by the measurement of mutant frequencies in the lacZ and cII genes from lung and liver in the same mice. Characterization of the types of the mutation was determined by sequencing the cII genes from mutant plaques. The mutant frequencies in both target genes from both organs dose-dependently increased up to 10 times compared to those of the control group. For the types of mutations, the ratio of the G:C to A:T mutation in the total number of mutants was less than the ratio of A:T to T:A and A:T to C:G transversion, contrary to a previous report. The A:T to T:A transversion was the most highly induced mutation both in the lung and liver cII genes. The increasing rate of mutant frequencies in lung and liver over the vehicle control was 55 and 56 times, respectively, while the increasing rate of G:C to A:T transition was only 1.9 and 2.8 times, respectively. These observations show that NNK predominantly induces DNA adducts leading to A:T to T:A and/or A:T to C:G mutations in the transgene.