Impact of the Coronavirus Disease 2019 Outbreak on Activity and Exercise Levels among Older Patients.

OBJECTIVES: This study aimed to clarify the impact of the coronavirus disease 2019 outbreak on the levels of activity among older patients with frailty or underlying diseases. A total of 175 patients (79.0±7.0 years) undergoing outpatient or home-based rehabilitation, stratified into groups, based on frailty status. The percentage of patients who went out at least once a week decreased after the outbreak from 91% to 87%, from 65% to 46%, and from 47% to 36% in the non-frail, frail, and nursing care requirement groups, respectively. The proportion of older patients participating in exercise during the outbreak was 75%, 51%, and 41% in the non-frail, frail, and nursing care requirement groups, respectively. The proportion of older patients participating in voluntary exercise after instruction was lowest in the frail group (35%). Older patients with frailty are susceptible to the negative effects of refraining from physical activity and require careful management.

Usefulness of quantitative susceptibility mapping for the diagnosis of Parkinson disease.

BACKGROUND AND PURPOSE: Quantitative susceptibility mapping allows overcoming several nonlocal restrictions of susceptibility-weighted and phase imaging and enables quantification of magnetic susceptibility. We compared the diagnostic accuracy of quantitative susceptibility mapping and R2* (1/T2*) mapping to discriminate between patients with Parkinson disease and controls. MATERIALS AND METHODS: For 21 patients with Parkinson disease and 21 age- and sex-matched controls, 2 radiologists measured the quantitative susceptibility mapping values and R2* values in 6 brain structures (the thalamus, putamen, caudate nucleus, pallidum, substantia nigra, and red nucleus). RESULTS: The quantitative susceptibility mapping values and R2* values of the substantia nigra were significantly higher in patients with Parkinson disease (P < .01); measurements in other brain regions did not differ significantly between patients and controls. For the discrimination of patients with Parkinson disease from controls, receiver operating characteristic analysis suggested that the optimal cutoff values for the substantia nigra, based on the Youden Index, were >0.210 for quantitative susceptibility mapping and >28.8 for R2*. The sensitivity, specificity, and accuracy of quantitative susceptibility mapping were 90% (19 of 21), 86% (18 of 21), and 88% (37 of 42), respectively; for R2* mapping, they were 81% (17 of 21), 52% (11 of 21), and 67% (28 of 42). Pair-wise comparisons showed that the areas under the receiver operating characteristic curves were significantly larger for quantitative susceptibility mapping than for R2* mapping (0.91 versus 0.69, P < .05). CONCLUSIONS: Quantitative susceptibility mapping showed higher diagnostic performance than R2* mapping for the discrimination between patients with Parkinson disease and controls.

Which factors predict the recovery of natural heart function after insertion of a left ventricular assist system?

BACKGROUND: Recent reports have demonstrated that use of a left ventricular assist system (LVAS) can initiate recovery of cardiac function, and subsequent weaning from the LVAS has attracted considerable interest. In this study we investigated reliable predictors of LVAS weaning. METHODS: Eighty-two patients underwent LVAS implantation between April 1994 and July 2006 at our institution. Cardiac function was restored in 8 patients, who were weaned from LVAS after a mean of 5 months (Group R). Thirty-three patients remained on LVAS support for >1 year (Group N) because natural heart function did not show adequate improvement. We retrospectively evaluated the differences between these two groups. Group R was younger, and had a shorter duration of heart failure than Group N (23.4 vs 36.7 years and 13.3 vs 56.1 months, p < 0.01, respectively). Pathologic findings showed that the interstitial fibrosis score was lower in Group R (p < 0.01). Three months after LVAS insertion, B-type natriuretic peptide (BNP) and fractional shortening (FS) were more favorable (66.6 +/- 46 vs 264.5 +/- 170 pg/ml, p < 0.01, and 23 +/- 17.1 vs 12 +/- 9.1%, p < 0.05, respectively) in Group R. Furthermore, Group R received a higher dose of beta-blocker (15.4 +/- 8.4 vs 5.8 +/- 3.9 mg, p < 0.05). CONCLUSIONS: Younger age, shorter history of heart failure, and less interstitial fibrosis were effective predictors of weaning from LVAS. Restoration of natural heart function was more rapid and more persistent in candidates for LVAS explantation, and presence of beta-blocker played a prominent role in improving cardiac function after LVAS implantation.

Comparability and reproducibility of the carotid-femoral pulse wave velocity measurements using a multi-element carotid tonometry sensor.

To evaluate the comparability and reproducibility of the carotid-femoral pulse wave velocity (PWV) measured by the newly developed device compared to that measured by the standard device and the validity of brachial-ankle PWV as a substitute of carotid-femoral PWV. We measured aortic PWV twice in 21 normotensive males by using the standard devices and the newly developed device. We also measured brachial-ankle PWV in the same subjects. There was a strong, significant correlation between aortic (carotid-femoral) PWV measured by using two different devices (r = 0.741, P = 0.00012). Interquartile range of the differences of carotid-femoral PWV measured by Form (0.75 m/s (-0.36, 0.39)) was smaller than that by Complior (1.67 m/s (-1.03, 0.63)). There was no correlation between carotid-femoral PWV, measured by either device, and brachial ankle PWV. Our present results suggest that carotid-femoral PWV measured by using Form was comparable to, and may be more reproducible than, that measured by Complior that has been widely used as a predictable marker for cardiovascular events. Our results also suggest brachial-ankle PWV may not be a substitute for carotid-femoral PWV.

Genotype-phenotype study of familial haemophagocytic lymphohistiocytosis due to perforin mutations.

BACKGROUND: PRF1 gene mutations are associated with familial haemophagocytic lymphohistiocytosis type 2 (FHL2). Genotype-phenotype analysis, previously hampered by limited numbers of patients, was for the first time performed by data pooling from five large centres worldwide. PATIENTS AND METHODS: Members of the Histiocyte Society were asked to report cases of FHL2 on specific forms. Data were pooled in a common database and analysed. RESULTS: The 124 patients had 63 different mutations (including 15 novel mutations): 11 nonsense, 10 frameshift, 38 missense and 4 in-frame deletions. Some mutations were found more commonly: 1122 G-->A (W374X), associated with Turkish origin, in 32 patients; 50delT (L17fsX22) associated with African/African American origin, in 21 patients; and 1090-91delCT (L364fsX), in 7 Japanese patients. Flow cytometry showed that perforin expression was absent in 40, reduced in 6 and normal in 4 patients. Patients presented at a median age of 3 months (quartiles: 2, 3 and 13 months), always with fever, splenomegaly and thrombocytopenia. NK activity was absent in 36 (51%), 5% in 4 (6%), "reduced" in 2 (3%) (not reported, n = 54). Nonsense mutations were significantly associated with younger age at onset (p<0.001) and absent natural killer activity (p = 0.008). CONCLUSION: PRF1 mutations are spread over the functional domains. Specific mutations are strongly associated with Turkish, African American and Japanese ethnic groups. Later onset and residual cytotoxic function are observed in patients with at least one missense mutation.

Local anesthetics facilitate ion transport across lipid planar bilayer membranes under an electric field: dependence on type of lipid bilayer.

In order to elucidate the role of structural change of lipid membrane bilayer in the mode of action of local anesthetic, we studied the effects of local anesthetics, charged tetracaine and uncharged benzocaine, on ion permeability across various lipid planar bilayers (PC, mixed PC/PS (4/1, mol/mol); mixed PC/PE (1/1, mol/mol); mixed PC/SM (4/1, mol/mol)) under a constant applied voltage. The membrane conductances increased in the order of PC<

Identification of novel MUNC13-4 mutations in familial haemophagocytic lymphohistiocytosis and functional analysis of MUNC13-4-deficient cytotoxic T lymphocytes.

BACKGROUND: Familial haemophagocytic lymphohistiocytosis (FHL) has an autosomal recessive mode of inheritance and consists of at least three subtypes. FHL2 subtype with perforin (PRF1) mutation accounts for 30% of all FHL cases, while FHL with MUNC13-4 mutation was recently identified and designated as FHL3 subtype. OBJECTIVE: To examine MUNC13-4 mutations and the cytotoxic function of MUNC13-4 deficient T lymphocytes in Japanese FHL patients METHODS: Mutations of MUNC13-4 and the cytotoxicity of MUNC13-4-deficient cytotoxic T lymphocytes (CTL) were analysed in 16 Japanese families with non-FHL2 subtype. RESULTS: Five new mutations of the MUNC13-4 gene were identified in six families. The mutations were in the introns 4, 9, and 18, and exons 8 and 19. Two families had homozygous mutations, while the remaining four had compound heterozygous mutations. Cytotoxicity of MUNC13-4 deficient CTL was low compared with control CTL, but was still present. Clinically, the onset of disease tended to occur late; moreover, natural killer cell activity was not deficient in some FHL3 patients. CONCLUSIONS: MUNC13-4 mutations play a role in the development of FHL3 through a defective cytotoxic pathway.

Measurements of cosmic-ray low-energy antiproton and proton spectra in a transient period of solar field reversal.

The energy spectra of cosmic-ray low-energy antiprotons ( *p's) and protons ( p's) have been measured by BESS in 1999 and 2000, during a period covering reversal at the solar magnetic field. Based on these measurements, a sudden increase of the *p/p flux ratio following the solar magnetic field reversal was observed, and it generally agrees with a drift model of the solar modulation.

Activation of connexin-43 hemichannels can elevate [Ca(2+)]i and [Na(+)]i in rabbit ventricular myocytes during metabolic inhibition.

ATP depletion due to ischemia or metabolic inhibition (MI) causes Na(+) and Ca(2+) accumulation in myocytes, which may be in part due to opening of connexin-43 hemichannels. Halothane (H) has been shown to reduce conductance of connexin-43 hemichannels and to protect the heart against ischemic injury. We therefore investigated the effect of halothane on [Ca(2+)]i and [Na(+)]i in myocytes during MI. Isolated rabbit left ventricular myocytes were loaded with 4 microM fluo-3 AM for 30 min, or with 5 microM sodium green AM for 60 min at 37 degrees C. After washing, the myocytes were exposed to: (1) Normal HEPES solution; (2) MI solution (2 mM NaCN, 20 mM 2-deoxy-D-glucose and 0-glucose); or (3) MI+H (0.95 mM, 4.7 mM) for 60 min. Propidium iodide (PI, 25 microM) was added to all samples before data acquisition. The fluorescence intensity was measured by flow cytometry with 488 nm excitation and 530 nm emission for fluo-3 or sodium green, and 670 nm for PI. The [Ca(2+)]i and [Na(+)]i were then calculated by calibration. In some experiments, the effect of 10 microM tetrodotoxin (TTX) and 20 microM nifedipine (NIF) were studied. Metabolic inhibition for 60 min caused a significant increase in [Ca(2+)]i and [Na(+)]i in myocytes when compared to controls, which was significantly reduced by halothane in a dose-dependent fashion. In the presence of TTX and NIF, halothane also significantly reduced the rise in the [Ca(2+)]i and [Na(+)]i in myocytes subjected to MI. 1-heptanol, another gap junction blocker, had similar effects. Thus, halothane reduced [Ca(2+)]i and [Na(+)]i overload produced by MI in myocytes. This effect is not solely due to block of voltage-gated Na(+) and Ca(2+) channels, and is likely mediated by inhibiting the opening of connexin-43 hemichannels.

ATP synthase F(1) sector rotation. Defective torque generation in the beta subunit Ser-174 to Phe mutant and its suppression by second mutations.

Subunit gamma of the ATP synthase F(1) sector is located at the center of the alpha(3)beta(3) hexamer and rotates unidirectionally during ATP hydrolysis, generating the rotational torque of approximately 45 pN.nm. A mutant F(1) with the betaSer-174 to Phe substitution (betaS174F) in the beta subunit generated lower torque ( approximately 17 pN.nm), indicating that betaS174F is mechanically defective, the first such mutant reported. The defective rotation of betaS174F was suppressed by a second-site mutation, betaGly-149 to Ala, betaIle-163 to Ala, or betaIle-166 to Ala in the same subunit, but not by betaLeu-238 to Ala. These results suggest that the region between betaGly-149 and betaSer-174 plays an important role in the coupling between ATP hydrolysis and mechanical work.

Volumetric study on the protein-anesthetic binding.

Thermodynamic equations describing the volume behavior of protein-ligand mixtures in water were derived. In order to estimate the volume and binding parameters, the equations were combined with a Langmuir-type binding isotherm. Densities of aqueous solutions of mixtures of bovine serum albumin (BSA) and octanol (C8OH) were measured as a function of total BSA molality, m(M)(T), at constant total C8OH molalities, m(X)(T). The data were analyzed by the equations. The partial molar volumes at infinite dilution of BSA and C8OH, V(M)(T,0) and V(X)(T,0), respectively, were estimated. It was seen that V(M)(T,0) decreases by the addition of C8OH to the solution and that V(X)(T,0) decreases gradually with increasing m(M)(T) and approaches asymptotically to a certain value at high m(M)(T). From the concentration dependence of V(M)(T,0) and V(X)(T,0), the values of the association constant K=392 kg mol(-1), the maximum binding number b(max)=1.9, and the volume change DeltaV=-109 cm(3) mol(-1) were obtained for BSA-C8OH interaction in water. The negative value of DeltaV indicates that the hydrophobic interaction reduces the protein volume and elevation of pressure promotes BSA-C8OH binding. These results is inconsistent with the pressure reversal of anesthesia.

Molecular mechanisms of anesthesia.

Anesthesia was a blessing to humankind. It is a miracle that simple molecules such as chloroform (CHCl3), diethyl ether (CH3.CH2.O.CH2.CH3), or nitrous oxide (N2O) induce a state of unconsciousness where patients can tolerate surgery. The diversity of the structures of these molecules indicates that there are no common receptors. The action of anesthetics is nonspecific and physical. After the demonstration by Meyer and Overton that anesthetic potencies correlate to their solubility into olive oil, the nonspecific lipid theories monopolized anesthesia theories for almost a century. The dominance of lipid theories invited repulsions against the nonspecificity idea. Protein theories that stress receptor bindings became the top mode. Nevertheless, the wide varieties of anesthetic molecules and the wide varieties of responding systems are difficult to reconcile with the specific interaction concept. This article discusses the recent progress and controversies on the molecular mechanisms of anesthesia. Anesthetics are unique drugs in pharmacology. They affect all macromolecules. The only comparable drugs are disinfectants. Both are nonspecific drugs. We use alcohols and phenols to wipe off the injection sites. We do not use penicillin or any other antibiotics for this purpose, because they are specific binders. Interestingly, these two nonspecific drugs opened the window for the modern medicine.

Cardiovascular effects of medetomidine, detomidine and xylazine in horses.

The cardiovascular effects of medetomidine, detomidine, and xylazine in horses were studied. Fifteen horses, whose right carotid arteries had previously been surgically raised to a subcutaneous position during general anesthesia were used. Five horses each were given the following 8 treatments: an intravenous injection of 4 doses of medetomidine (3, 5, 7.5, and 10 microg/kg), 3 doses of detomidine (10, 20, and 40 microg/kg), and one dose of xylazine (1 mg/kg). Heart rate decreased, but not statistically significant. Atrio-ventricular block was observed following all treatments and prolonged with detomidine. Cardiac index (CI) and stroke volume (SV) were decreased with all treatments. The CI decreased to about 50% of baseline values for 5 min after 7.5 and 10 microg/kg medetomidine and 1 mg/kg xylazine, for 20 min after 20 microg/kg detomidine, and for 50 min after 40 microg/kg detomidine. All treatments produced an initial hypertension within 2 min of drug administration followed by a significant decrease in arterial blood pressure (ABP) in horses administered 3 to 7.5 microg/kg medetomidine and 1 mg/kg xylazine. Hypertension was significantly prolonged in 20 and 40 microg/kg detomidine. The hypotensive phase was not observed in 10 microg/kg medetomidine or detomidine. The changes in ABP were associated with an increase in peripheral vascular resistance. Respiratory rate was decreased for 40 to 120 min in 5, 7.5, and 10 microg/kg medetomidine and detomidine. The partial pressure of arterial oxygen decreased significantly in 10 microg/kg medetomidine and detomidine, while the partial pressure of arterial carbon dioxide did not change significantly. Medetomidine induced dose-dependent cardiovascular depression similar to detomidine. The cardiovascular effects of medetomidine and xylazine were not as prolonged as that of detomidine.

Caenorhabditis elegans senses protons through amphid chemosensory neurons: proton signals elicit avoidance behavior.

Acidic pH is known to cause pain sensation through nociceptive neurons as well as taste transduction in mammals. Caenorhabditis elegans avoids an acidic environment (pH lower than approximately 4.0) formed by organic or inorganic acids. This avoidance behavior was dependent on multiple amphid chemosensory neurons, and inhibited by a mutation of capsaicin receptor homologue, and by the addition of amiloride and ruthenium red (inhibitors of proton-gated Na+ channels and capsaicin receptors, respectively). These results indicate that C. elegans recognizes protons as a nociceptive stimulus, through multiple neurons, which elicits avoidance behavior. It is of special interest that a system similar to that of mammalian signal transduction is responsible for this nematode's acid avoidance.

Cycloaromatization and DNA cleavage of novel non-conjugated aromatic enetetrayne systems.

The novel, non-conjugated aromatic enetetrayne (2) underwent thermal cycloaromatization reaction to give polyphenylene derivative 6, forming a methyl cation as an active intermediate, and showed DNA-cleaving activity.

Porphyromonas gingivalis fimbriae induce adhesion of monocytic cell line U937 to endothelial cells.

This study used the human monocytic cell line U937 to examine whether or not Porphyromonas gingivalis fimbriae could induce the adhesion of monocytes to endothelial cells. An in vitro adhesion assay was used to investigate the effects of the fimbriae on U937 cell adhesion to human umbilical vein endothelial cells (HUVEC). The fimbriae enhanced U937 cell adhesion to HUVEC in a dose-dependent manner. U937 cells adhered better to HUVEC pretreated with the fimbriae for a minimum of 2 hr than to untreated HUVEC. The enhanced adhesion was inhibited by a monoclonal antibody against P. gingivalis 381 fimbriae. Pretreatment of U937 cells with the fimbriae for 24 hr enhanced U937 cell adhesion to HUVEC approximately 4-fold. This phenomenon was inhibited by an anti-CD11b antibody, suggesting the involvement of CD11b. These results indicate that P. gingivalis fimbriae can induce monocyte adhesion to the endothelial cell surface. They also suggest that the fimbriae may be involved in the initial event for infiltration of monocytes into the periodontal tissues of individuals with adult periodontitis.

[Centennial for the Meyer-Overton rule: anesthetics and receptors].

As a backlash to the dominance of lipid theories of anesthesia for almost a century, protein theories are prevalent at present. Lipid theories assume nonspecific interaction with membranes. Protein theories assume specific interaction with specific receptors in specific proteins. The Meyer-Overton rule does not specify the anesthetic action site to lipid membranes. The correlation between the olive oil solubility to the anesthetic potency means that the action sites have similar physical properties to olive oil. It does not discriminate between lipids and proteins. Olive oil is homogeneous (isotropic) liquid whereas membranes and proteins are structured (anisotropic). The physical properties of proteins and membranes are not uniform throughout the structure. The rule shows that the anesthetics bind multiple areas in nonspecific proteins and membranes. The diversity of anesthetic structures is difficult to reconcile with the idea that there is a specific receptor on specific proteins.

A biological molecular motor, proton-translocating ATP synthase: multidisciplinary approach for a unique membrane enzyme.

Proton-translocating ATP synthase (F(o)F(1)) synthesizes ATP from ADP and phosphate, coupled with an electrochemical proton gradient across the biological membrane. It has been established that the rotation of a subunit assembly is an essential feature of the enzyme mechanism and that F(o)F(1) can be regarded as a molecular motor. Thus, experimentally, in the reverse direction (ATP hydrolysis), the chemical reaction drives the rotation of a gammaepsilonc(10-14) subunit assembly followed by proton translocation. We discuss our very recent results regarding subunit rotation in Escherichia coli F(o)F(1) with a combined biophysical and mutational approach.

Mechanical rotation of the c subunit oligomer in ATP synthase (F0F1): direct observation.

F0F1, found in mitochondria or bacterial membranes, synthesizes adenosine 5'-triphosphate (ATP) coupling with an electrochemical proton gradient and also reversibly hydrolyzes ATP to form the gradient. An actin filament connected to a c subunit oligomer of F0 was able to rotate by using the energy of ATP hydrolysis. The rotary torque produced by the c subunit oligomer reached about 40 piconewton-nanometers, which is similar to that generated by the gamma subunit in the F1 motor. These results suggest that the gamma and c subunits rotate together during ATP hydrolysis and synthesis. Thus, coupled rotation may be essential for energy coupling between proton transport through F0 and ATP hydrolysis or synthesis in F1.