Olfactory and taste dysfunctions caused by COVID-19: a nationwide study.

BACKGROUND: Olfactory dysfunctions (OD) and taste dysfunctions (TD) are widely recognized as characteristic symptoms of COVID-19; however, the frequency and mode of occurrence has varied depending on the viral mutation. The prevalence and characteristics of OD/TD in Japan have not been definitively investigated. The purpose of this study is to assess the prevalence of OD/TD in Japan during the Alpha variant epidemic, and measure symptom prolongation at 6 months and 1 year later following initial infection. METHODS: Patients treated for COVID-19 between February to May 2021 were evaluated for OD/TD symptoms and provided with a QOL questionnaire. Olfactory tests and taste tests were performed using Open Essence and Taste Strips, respectively. RESULTS: Among the 251 COVID-19 patients who participated, 119 underwent both olfactory and taste tests. Prevalence of subjective OD and TD at the time of survey was 57.8% and 40.2%, respectively. After 12 months, the prevalence fell to 5.8% for OD and 3.5% for TD. Among the OD/TD patients, 36.6% experienced parosmia, and 55.4% experienced parageusia. Prevalence of parosmia and parageusia was higher at 6 and 12 months than at the time of survey. Patients with long-lasting disease reported qualitative dysfunctions and scored significantly higher in food-related QOL problems. Most patients who were aware of their hyposmia had low scores on the olfactory test (83.1%). In contrast, only 26.7% of patients who were aware of their hypogeusia had low scores on the taste test. CONCLUSIONS: The prevalence of COVID-19-related OD and TD at the time of survey was 57.8% and 40.2%, respectively. Subjective symptoms of OD and TD persisted for one year in 5.8% and 3.5% of patients, respectively. More than half of the patients with OD or TD complained of qualitative dysfunction and a decrease in their QOL related to eating and drinking. Most patients with TD did not have true TD, but rather developed flavour disorders associated with OD. This conclusion is supported by the finding that patients with subjective OD had low scores on the olfactory test, whereas most patients with subjective TD had normal scores on the taste test.

NUDT15 R139C causes thiopurine-induced early severe hair loss and leukopenia in Japanese patients with IBD.

The efficacy of thiopurines, including azathioprine (AZA) and 6-mercaptopurine (6MP), has been demonstrated for the treatment of inflammatory bowel disease (IBD). The most common and serious adverse event of treatment with thiopurines altered by doctors is leukopenia. Hair loss is also a serious event that could be a critical reason for patients to decline thiopurine treatment. Thiopurine-induced severe hair loss causes cosmetic problems, and it takes a long time to recover. In a recent study, NUDT15 R139C was strongly associated with thiopurine-induced leukopenia in Korean and Caucasian populations. In this study, we performed an association study to investigate and replicate the association of R139C with adverse events of thiopurines in Japanese patients. A total of 142 Japanese patients with IBD, with histories of thiopurine treatment, were examined. NUDT15 R139C was genotyped using a custom TaqMan genotyping assay. Adverse events including leukopenia were reviewed from medical records. The 6MP dose was adjusted to AZA equivalents by multiplying with 2 as a thiopurine dose. Five patients developed severe hair loss and all of them were risk homozygous (T/T) for R139C. No early severe hair loss was observed in patients with the C/T or C/C genotype (P=3.82 × 10(-16), odds ratio=212). The association of R139C with early (<8 weeks) leukopenia (white blood cells<3000 mm(-3)), which was previously reported in Korean patients, was replicated in our Japanese IBD cohort (P=1.92 × 10(-16), odds ratio=28.4). However, we could not confirm the association with late leukopenia in the Japanese subjects. Patients with the C/T genotype discontinued treatment or required thiopurine dose reduction significantly earlier than patients with the C/C genotype (P=1.45 × 10(-4)); however, on manipulating the doses, there was no significant difference in the thiopurine continuation rates between the groups. In the maintenance period, the frequencies of 6MP usage were higher, and the doses of thiopurines were significantly lower in patients with the C/T genotype than in those with the C/C genotype (0.574±0.316 mg kg(-1) per day vs 1.03±0.425 mg kg(-1) per day, P=6.21 × 10(-4)). NUDT R139C was significantly associated with early severe hair loss in Japanese patients with IBD. We also verified the previously reported association of R139C with early leukopenia in a different East Asian population. It is recommended that treatment with thiopurines should be avoided for patients with the T/T genotype. Low-dose 6MP (0.2-0.3 mg kg(-1) per day) could be used rather than AZA for the patients with C/T genotype to continue thiopurine treatments. However, late leukopenia and other several adverse events could not be completely predicted by R139C genotypes.

Risk factors for Clostridium difficile-associated diarrhea and the effectiveness of prophylactic probiotic therapy.

Measures for prevention of Clostridium difficile-associated diarrhea, a common nosocomial infection, in hospital settings are urgently needed. This study was conducted to identify the risk factors contributing to C. difficile-associated diarrhea and to evaluate the clinical benefit of probiotics in its prevention. The study included 2716 patients at least 20 years old who received an injected antibiotic at any time between February 2010 and February 2011; a total of 2687 patients (98.9%) were assigned to the non-C. difficile-associated diarrhea group, and 29 patients (1.1%) were assigned to the C. difficile-associated diarrhea group. Univariate analysis revealed a significant difference between the two groups for the following factors: antibiotic therapy for > or = 8 days; enteral nutrition; intravenous hyperalimentation; fasting; proton pump inhibitor use; H2 blocker use; and serum albumin < or = 2.9g/dL (p<0.05). Multivariate logistic regression analysis revealed a significant difference between the two groups for several factors. Antibiotic therapy for > or = 8 days, intravenous hyperalimentation, proton pump inhibitor use, and H2 blocker use were therefore shown to be risk factors for C. difficile-associated diarrhea. Prophylactic probiotic therapy was not shown to suppress the occurrence of C. difficile-associated diarrhea.

Risk factors contributing to urinary protein expression resulting from bevacizumab combination chemotherapy.

Proteinuria following administration of bevacizumab is reported to be a specific adverse effect, but the risk factors for proteinuria have not been elucidated. In this study, the risk factors for urinary protein expression resulting from bevacizumab combination chemotherapy were investigated. The subjects were 47 patients aged > or = 20 years who had received bevacizumab combination chemotherapy at Gifu Municipal Hospital between February 2010 and February 2011. A total of 13 patients were excluded based on exclusion criteria; of the remaining 34 patients, 24 (70.6%) were assigned to the urinary protein non-expression group, and 10 (29.4%) were assigned to the urinary protein expression group. The results of multivariate logistic regression analysis revealed a significant difference in systolic blood pressure (> or =130 mmHg) between the two groups (OR: 14.499, 95%CI: 1.326-158.577, p=0.028). This finding shows that systolic blood pressure (> or =130 mmHg) is a risk factor for urinary protein expression resulting from bevacizumab combination chemotherapy.

Relationship between pattern of masticatory path and state of lateral occlusal contact.

The purpose of this study is to clarify whether the state of occlusal contact on lateral excursion is related to the pattern of masticatory movement path. The masticatory movement during mastication of softened chewing gum and the occlusal contact on lateral sliding of the mandible by 1 mm (L1), 2 mm (L2) and 3 mm (L3) were recorded in 50 healthy subjects. The path of masticatory movement was classified into one of seven patterns. The number of teeth involved in the occlusal contact in each pattern was investigated and compared among different lateral occlusal positions. The occlusal contact was then classified into 15 types based on one or a combination of the following four regions; incisal region, canine region, premolar region and molar region. The number of occlusal contact type for each pattern was investigated and compared among patterns. The number of teeth involved in occlusal contact decreased as the degree of lateral excursion increased, and significant differences were observed among the lateral occlusal positions (P < 0.001). The occlusal contact tended to decrease in the molar region and increase in the canine or premolar regions as the degree of the lateral excursion increased. When comparing among patterns, significant differences were observed at L2 and L3 (L2; P < 0.001, L3; P = 0.030) but not at L1 (P = 0.318). The difference was remarkable at L2. It was suggested that the state of occlusal contact at L2 and L3, particularly at L2 was related to the masticatory path pattern.

GAP junctional channel inhibition alters actin organization and calcium propagation in rat cultured astrocytes.

Astrocytes are connected by gap junctions, which provide intercellular pathways that allow a direct exchange of ions and small metabolites including second messengers and the propagation of electric currents. The roles of gap junctional communication on whole-cell morphology, cytoskeletal organization, and intercellular communication in astrocytes are not yet clear even in vitro, though there are many studies that have examined the active relation between gap junctions and actin filaments in astrocytes. Here we examined the effects of gap junction inhibitors, which do not interrupt the formation but rather the function of gap junctions, on whole-cell morphology, cytoskeletal organization, and intercellular communication in rat cultured astrocytes. Functional blockade of gap junctions during the formation of an astrocytic monolayer resulted in discordance of actin stress fibers between neighboring cells, even though whole-cell morphology of these cells did not change by such treatment. Mechanical stimulation-induced calcium wave propagation was significantly reduced in these actin-discordance cells even after thorough wash out. Differentiation of astrocytes in the presence of gap junction inhibitors was associated with morphological disarrangement among neighboring cells due to disordered alignment of actin stress fibers between cells.Our results indicate that gap junctional communication enables cell-to-cell coordination of actin stress fibers in astrocytes, thus enhancing intercellular communication through calcium spread.

Current topics on cytokine removal technologies.

It has been widely accepted that cytokines play important roles in the development of organ failure in various pathophysiological conditions of critically ill patients. Various new technologies, including continuous renal replacement therapy, have been developed for the removal of causative humoral mediators in sepsis or other critical conditions. Nonselective blood purification technologies, such as hemofiltration and plasma exchange, are applied in cytokine removal technology. However, the more selective blood purification technologies, such as adsorption, and the combination of those technologies, should be considered in future applications. Only through a prospective randomized controlled study can it be elucidated whether or not these technologies have efficacy in the treatment of sepsis and critically ill patients with hypercytokinemia. We should join and discuss the design of future clinical trials with a standardized strategy for the evaluation of the technologies.

Heated scallop-shell powder slurry treatment of shredded cabbage.

The main component of scallop-shell powder is calcium carbonate (CaCO3). Through heat treatment, CaCO3 in the shell is converted to CaO, which exhibits antibacterial activity. The disinfecting effect of heated scallop-shell powder on shredded cabbage was investigated for various powder concentrations (0.1 to 1.0 g dm(-3)) and treatment temperatures (10 to 40 degrees C). Scallop-shell powder treatment was found to reduce the aerobic bacteria count in cabbage, with increasing effectiveness at higher powder concentrations and treatment temperatures. Coliforms were completely eliminated within 5 min with as little as 0.1 g dm(-3) powder treatment. During storage at 4 degrees C, aerobic bacterial counts did not increase after powder treatment, whereas counts increased with water-washing or sodium hypochlorite treatment at 200 microg dm(-3). The inactivation pattern of bacterial cells in shredded cabbage involved an accelerated decline followed by an extended tail at powder concentrations of 0.1 and 0.5 g dm(-3). We postulate that a fraction of bacterial cells in the initial population becomes tolerant to the shell powder. A proposed model accurately predicts the reducing bacterial counts on shredded cabbage by scallop-shell powder treatment. The decrease in the L-ascorbic acid content of shredded cabbage was approximately 20 to 30% for scallop-shell powder treatment at 0.1 and 0.5 g dm(-3) (20 degrees C), which is almost identical to that by sodium hypochlorite treatment at 200 micorg dm(-3).

Ca2+ signaling regulated by an ATP-dependent autocrine mechanism in astrocytes.

Although the mechanisms of Ca2+ wave propagation in astrocytes induced by mechanical stimulation have been well studied, it is still not known how the [Ca2+]i increases in the stimulated cells. Here, we have analyzed the mechanisms of [Ca2+]i increase in single, isolated astrocytes. Our results showed that there was an autocrine mechanism of Ca2+ regulation mediated by ATP in mechanically stimulated astrocytes. This autocrine mechanism induced the activation of phospholipase C via a G-protein, resulting in Ca2+ release from intracellular Ca2+ stores. A second pathway mediating a [Ca2+]i increase was via a Ca2+ influx from the extracellular space, which, interestingly, suppressed an intracellular Ca2+ oscillation. These two different Ca2+ cascades are involved in signal transduction and may function separately during intercellular communication.

Usefulness of plasma exchange plus continuous hemodiafiltration to reduce adverse effects associated with plasma exchange in patients with acute liver failure.

OBJECTIVE: To efficiently remove middle-molecular-weight substances such as hepatic toxins and minimize adverse effects associated with plasma exchange implementation, we have performed plasma exchange slowly in combination with continuous hemodiafiltration. This study was designed to determine the usefulness of plasma exchange with continuous hemodiafiltration in reducing the adverse effects associated with implementation of plasma exchange alone. DESIGN: A retrospective clinical study. SETTING: University teaching hospital. PATIENTS: The study involved 90 patients with liver failure who had been treated with plasma exchange in our department over the past 12 yrs. We examined these patients by dividing them into two groups (48 patients treated with plasma exchange alone and 42 patients treated with plasma exchange plus continuous hemodiafiltration at the time of plasma exchange implementation). MEASUREMENTS AND MAIN RESULTS: Baseline blood Na+ concentration, HCO3- concentration, and colloid osmotic pressure were followed after implementation of plasma exchange to compare the frequency of development of three adverse effects (hypernatremia, metabolic alkalosis, and sharp decrease in colloid osmotic pressure) in the two groups. Hypernatremia was found in 26.7% of treatments in the group with plasma exchange alone and 3.3% in the group of plasma exchange plus continuous hemodiafiltration, and metabolic alkalosis was found in 30.6% of treatments in the group with plasma exchange alone and 4.9% in the group of plasma exchange plus continuous hemodiafiltration; both percentages were significantly higher in the group with plasma exchange alone (p <.001). A sharp decrease in colloid osmotic pressure occurred in 13.3% of treatments in the group with plasma exchange alone but was not observed at all in the patients treated with plasma exchange plus continuous hemodiafiltration. CONCLUSIONS: We conclude that adverse effects associated with plasma exchange for artificial liver support for liver failure can be alleviated with use of plasma exchange plus continuous hemodiafiltration instead of plasma exchange alone.

Kinetic analysis of the bactericidal action of heated scallop-shell powder.

Shell powder of scallop (Patinopecten yessoensis) was exposed to heat treatment at between 200 and 1000 degrees C, and the bactericidal action of the powder slurry was investigated. Shell powder heated at 700 degrees C or higher exhibited bactericidal action against Escherichia coli, Salmonella typhimurium, Staphylococcus aureus and Bacillus subtilis (vegetative cells). The death of bacteria in the shell powder slurry followed first-order reaction kinetics, and the apparent death rate constant (k) was determined. An increase in exposure temperature enhanced the bactericidal action. The bactericidal action is due to calcium oxide that is converted from calcium carbonate, which is the main component of the shell powder, by heat treatment. The slurry temperature is found to significantly affect the bactericidal action of the shell powder. The slope of the Arrhenius plot of k for E. coli and S. aureus that were grown at 37 degrees C exhibited a discontinuous point at approximately 22 degrees C, at which the values of activation energy for the death of bacteria in the powder slurry changed. This temperature corresponds to that of the phase transition of cell membrane lipids. The bactericidal action of the shell powder is greater than that of a NaOH solution of identical pH. Although the pH of the shell powder slurry is high, the slurry was considered to possess other antibacterial mechanisms in addition to that of alkalinity.

The effect of bolus size on the chewing cycle in humans.

No general agreement exists regarding the effect that bolus size has on masticatory movement, probably because both the size and texture of food change during mastication. In this experiment, in order to clarify the effect of bolus size on masticatory movement, a food that does not change in size and texture--chewing gum--was chosen, and the relationship between bolus size and the chewing cycle was analyzed. Ten healthy subjects in their twenties were asked to chew pieces of softened chewing gum of four different sizes. For ten cycles, beginning with the fifth cycle of mastication, gape and masticatory width were calculated for the spatial parameter of the chewing cycle, and cycle time was calculated as the temporal parameter. The relationship between these parameters and the bolus size was investigated. As the bolus size increased, the spatial and temporal parameters increased. In addition, there was a positive correlation between the bolus size and each parameter. The influence of the bolus size was as follows: gape, r = 0.91; masticatory width, r = 0.79; and cycle time, r = 0.74 (all, P < 0.001). From these results it was concluded that the shape of the chewing cycle was altered by the size of the food bolus, and that the changes in sensory input from the peripheries greatly affected the masticatory movement.

Quantitative analyses of topography and elasticity of living and fixed astrocytes.

The topography and elasticity of living and fixed astrocytes cultured from the rat cerebra were studied quantitatively by atomic force microscopy (AFM). Ridge-like structures reflecting F-actin beneath the cell membrane were prominent in the contact-mode images of living astrocytes. Many of these ridges became unclear after fixation (2% glutaraldehyde). In addition, the ridge-like structures were invisible in the topography of living cells observed at zero-loading force in the force mapping mode, which is considered to show the real cell surface not pressed down by an AFM tip. The topography of fixed cells observed both in the contact mode and at zero-loading force in the force mapping mode was similar to that of living cells observed at zero-loading force in the force mapping mode, although some deformed areas were detected in the fixed cells. The elasticity map images of living astrocytes showed that the cell membrane above the nucleus was softer (2-3 kPa) than the surroundings, and that the cell membrane above F-actin was stiffer (10-20 kPa) than the surroundings. In the elasticity map images of fixed astrocytes, on the other hand, the elasticity of the cells was found to be relatively uniform (200-700 kPa) irrespective of the inner structures of cells. These results show that images observed by AFM should be carefully examined in consideration of the force introduced to specimens and the elasticity of specimens to find out the real surface topography.

Prognostic value of c-erbB2 and other markers in patients treated with chemotherapy for recurrent head and neck cancer.

BACKGROUND: Chemotherapy is widely used in patients with recurrent head and neck cancer, but no clear markers are available that can predict response to treatment or survival in these patients. METHODS: Twenty-nine patients evaluated in this study had recurrent head and neck squamous carcinomas, previously treated with surgery and/or radiotherapy. Patients received either cisplatin and 5-fluorouracil (5-FU) (n = 15) or cisplatin and paclitaxel (Taxol) (n = 14). Expression of c-erbB2, p53, glutathione S-transferase pi, multidrug resistance-associated protein, thymidylate synthase, and glutathione synthetase were evaluated in biopsy tissues. RESULTS: Response to chemotherapy was significantly correlated with improved survival (progression-free survival, p =.0005; overall survival, p =. 007). Of the factors examined, expression of c-erbB2 was associated with significantly decreased progression-free survival (p =.023) and overall survival (p =.029). This was seen in patients treated with cisplatin/taxol but not in patients treated with cisplatin/5-FU. CONCLUSION: Expression of c-erbB2 may be a clinically useful predictor of survival in this group of patients.

Comparison of Sepsis-related Organ Failure Assessment (SOFA) score and CIS (cellular injury score) for scoring of severity for patients with multiple organ dysfunction syndrome (MODS).

OBJECTIVE: To evaluate the usefulness of cellular injury score (CIS) and Sepsis-related Organ Failure Assessment (SOFA) score for determination of the severity of multiple organ dysfunction syndrome (MODS). DESIGN: A prospective observational study. SETTING: A medical and surgical intensive care unit (ICU) of a teaching hospital. PATIENTS: Forty-seven consecutive MODS patients. MEASUREMENTS AND RESULTS: SOFA score and CIS were measured every day for 12 months for 47 MODS patients. Comparison was made of the SOFA score and CIS for usefulness in the scoring of severity of MODS in 26 survivors and 21 non-survivors. In addition, receiver operating characteristics (ROC) analysis was used to determine the usefulness of these two indexes as predictors of prognosis. No significant differences were found on admission between the survivors and non-survivors, but significant differences between the two subgroups (p < 0.001) were found in maximum value within 1 week after admission and maximum value during the course of treatment for both indexes. Analysis of changes after admission indicated that significant differences between survivors and non-survivors began to appear on day 3 of admission for both indexes; at that time SOFA score began to deteriorate in the non-survivors while CIS began to improve in the survivors. ROC analysis demonstrated that the area under the ROC curve was 0.769 for SOFA scores and 0.760 for CIS. CONCLUSIONS: Both SOFA score and CIS sequentially reflected the severity of MODS. Furthermore, they were comparable in diagnostic value as predictors of prognosis. These findings may indicate the possibility that MODS is a summation of effects of cellular injury. In addition, sequential evaluation of both SOFA score and CIS would provide a more accurate prediction of prognosis than conventional methods.

Dynamics of astrocyte adhesion as analyzed by a combination of atomic force microscopy and immuno-cytochemistry: the involvement of actin filaments and connexin 43 in the early stage of adhesion.

We observed the time-dependent morphological alteration of astrocytes during their adhesion by atomic force microscopy (AFM) and investigated the relationships between this morphological alteration and the localization of actin filaments and connexin 43 by immunocytochemistry. The fine processes observed as fine ridge-like structures by AFM were closely concerned with actin filaments by immunocytochemistry. During the adhesion of astrocytes, actin filaments appeared to be aligned regularly beyond the borders among different cells. Detectable connexin immunoreactivity was changed in the following regions: 1) the tips of fine cell processes and the cell margin when astrocytes started to adhere; 2) the border of cells when astrocytes tightly adhered; and 3) non-specific sites when astrocytes became a cluster. In the former two cases, the immunopositive spots for connexin were observed to colocalize with the tips of cell processes with actin filaments. These results strongly suggest that connexin associated with actin filaments at the tip of cell processes plays an important role in the early stage of the adhesion of astrocytes. These observations afford valuable clues for understanding the glial communication.