Effect of influenza vaccine subsidies for older adults on vaccination coverage and mortality before and during the COVID-19 pandemic: an ecological study in Japan.

OBJECTIVE: We aimed to determine how municipal subsidies for seasonal influenza vaccines for the elderly affected vaccination coverage and health outcomes and how responses to vaccine prices changed during the COVID-19 pandemic. STUDY DESIGN AND METHODS: This ecological study includes 1245 municipalities in Japan between 2019 and 2020. Fixed-effects regression analysis was performed to evaluate the effect of influenza vaccine cost subsidy for people aged 65 years or older on vaccination coverage, all-cause mortality, and influenza-related mortality. RESULTS: The vaccination rate increased when patients' copayments decreased, and reducing the copayment by 1000 Japanese Yen (JPY) was estimated to increase the vaccination rate by 6.3% (95% confidence interval [CI] 4.5-8.2%) in the adjusted model. When examining the additional effect of a zero price compared to a nearly zero price, we found that a zero price increased the immunization rate by 6.4% (95% CI 1.4-11.5%). The effect of copayment on the increase in vaccination coverage was significantly lower during the pandemic than in the pre-pandemic period. The municipal and prefectural analyses found no association between influenza vaccine copayments and all-cause, influenza, or pneumonia mortality. CONCLUSION: Cost subsidies and the zero-price effect were shown to increase vaccination coverage but were not associated with relevant mortality measures. Although the impact was attenuated under pandemic conditions, cost subsidy effectively increases the vaccination rate.

Experience-dependent plasticity of mouse visual cortex in the absence of the neuronal activity-dependent marker egr1/zif268.

Neuronal activity elicits a rapid increase in the expression of several immediate early genes (IEGs). To clarify a role for IEG response in activity-dependent development, we examined the contribution of the egr1/zif268 gene during visual cortical processing and plasticity in mice. We first analyzed the expression of egr1 mRNA in wild-type (WT) mice using Northern blot hybridization. In the visual cortex, expression of egr1 mRNA increased dramatically after eye opening, systemic injection of kainate, or 30 min of photostimulation after a brief (5 d) period of dark adaptation. Thus, the expression of egr1 is regulated by synaptic activity in the mouse visual cortex, as it is in other species (e.g., monkeys, cats, and rats). To evaluate whether this transcription factor is directly involved in activity-dependent plasticity, mice lacking Egr1 were deprived of the use of one eye during the developmental critical period [postnatal day 24 (P24)-P34]. Extracellular in vivo single-unit recordings from the binocular zone of the visual cortex revealed that visual responses developed normally in egr1 knock-out (KO) mice. Moreover, a similarly significant shift of responsiveness in favor of the open eye was produced in both KO and WT mice by either brief (4 d) or long-term (>2 weeks) occlusion of one eye. There was no apparent compensation among egr2, egr3, or c-fos mRNA and protein expression in the visual cortex of egr1 KO mice. Taken together, these results indicate that egr1 is a useful marker of sensory input in mice but is not intrinsically necessary for the experience-dependent plasticity of the visual cortex. Our findings underscore a mechanistic distinction between sensory plasticity and long-lasting forms of synaptic potentiation in the hippocampus, for which egr1/zif268 was recently found to be essential.

Association between hyperinsulinemia and intima-media thickness of the carotid artery in normotensive men.

OBJECTIVES: To determine whether hyperinsulinemia is associated with early atherosclerosis in normotensive men of a work site population. DESIGN AND METHODS: Six hundred and seventeen subjects were screened from 8678 male transport workers for the further examination of cardiovascular disease and diabetes. Subjects aged less than 40 years, those with hypertension or diabetes, or both, and those being administered medications for hyperlipidemia were excluded. Finally, 164 normotensive, nondiabetic subjects were enrolled. The intima-media thickness (IMT) was measured by B-mode ultrasonography with a 7.5 MHz probe. Electrocardiography, a 75 g oral glucose-tolerance test (OGTT) and blood chemistry measurements were also performed. The sum of insulin values (sigmaIRI) and the ratio of the sum of insulin values to blood glucose levels (sigmaIRI/sigmaBG) in the 75 g OGTT were used as markers of hyperinsulinemia. RESULTS: The mean age of the subjects was 52 +/- 5 years (mean +/- SD). In a univariate analysis, IMT was associated with age, systolic blood pressure, body mass index, sigmaIRI, and sigmaIRI/sigmaBG. Multivariate analysis showed that age, total cholesterol, and sigmaIRI (or sigmaIRI/sigmaBG) were independent risk factors for IMT. CONCLUSIONS: These results suggest that, in addition to age and total cholesterol, hyperinsulinemia as assessed by an OGTT is associated with early atherosclerosis in normotensive, nondiabetic men of a work site population.

Superacute phase blood pressure elevation may relate to massive hematoma in hypertensive putaminal hemorrhage.

A restrospective clinical investigation has been performed to elucidate the relationship between hematoma size in putaminal hemorrhage and blood pressure (BP) changes during the immediate post-hemorrhagic phase in the emergency room (ER). Thirty-seven adult patients brought to the emergency department by ambulance within 6 hours after onset of symptoms with a confirmed diagnosis of acute putaminal hemorrhage on CT have been involved. Two BP measurements during the superacute phase in the ER have been studied: immediately after arrival at the ER (BP-I), and immediately prior to CT examination (BP-II). Patients have been divided into 6 categories: 1) those whose BP decreased with treatment (D+), 2) those whose BP decreased without treatment (D-), 3) those whose BP increased in spite of treatment (I+), 4) those whose BP increased without treatment (I-), 5) those whose BP remained unchanged in spite of treatment (U+), and 6) those whose BP remained unchanged without treatment (U-). Hematoma size has been compared among 5 categories (D+, D-, I-, U+, U-) using factorial ANOVA (analysis of variance). The hematoma sizes have been found to be (D+) 54 +/- 44 ml, (D-) 22 +/- 25 ml, (I-) 102 +/- 58 ml, (U+) 11 +/- 5 ml, (U-) 21 +/- 9 ml (mean +/- S.D.), respectively. (I-) has been significantly larger than any of the other categories (p < 0.001 - 0.05). Additional ANOVA has shown that BP-II in category (I-) was significantly higher than that of the other categories. Patients with putaminal hemorrhage whose BP was elevating during the superacute phase in the ER were shown to have massive hematomas.

Diagnostic value of a bedside test for cardiac troponin T in the patient with chest pain presenting to the emergency room.

Identification of patients with acute chest pain due to acute coronary syndrome is a common and difficult challenge for emergency physicians. A prospective study was conducted to assess the diagnostic value of a bedside test of cardiac troponin T in the emergency room setting. Forty-nine consecutive patients, who visited the emergency room within 6 hours of the onset of acute chest pain, were enrolled. Of the 26 patients who were ultimately diagnosed as having acute coronary syndrome, seven patients (27%) had positive cardiac troponin T assay results, whereas none of the patients without acute coronary syndrome had positive results (0%). For patients with acute coronary syndrome who presented later than 3 hours after the onset (n = 4), the test was positive in all cases (positive predictive value: 100%, negative predictive value: 100%, p < 0.01). However, the positive rate was only 14% for those who presented earlier than 3 hours after the onset (n = 22) (positive predictive value: 100%, negative predictive value: 47%, p = 0.84). In conclusion, bedside troponin T test results should be evaluated considering the time interval from the onset of chest symptoms.

Percutaneous transluminal angioplasty attenuates day-night difference in ambulatory blood pressure in renovascular hypertension.

To evaluate whether the circadian rhythm of blood pressure (BP) was altered in renovascular hypertension (RVH), ambulatory BP was monitored using a noninvasive recorder in nine patients with RVH attributable to fibromuscular dysplasia before and after percutaneous transluminal angioplasty (PCTA). The circadian rhythm of BP was assessed by the day-night difference in BP and by the single cosinor method. The day-night difference in BP before PCTA was significantly greater than in age- and sex-matched normotensive subjects (n = 9, P < .01) and patients with essential hypertension (n = 9, P < .05). PCTA decreased significantly the 24-h BP as well as plasma renin activity (P < .01). In the chronogram, the BP reduction after PCTA was evident especially during the day. Accordingly, the day-night difference in BP decreased significantly after PCTA (P < .01). In the cosinor analysis, the mesor and the percent amplitude of BP decreased significantly after PCTA (P < .01). In summary, circadian rhythm of BP was preserved or rather exaggerated in RVH. The stimulated renin angiotensin system in RVH possibly contributes to the altered circadian rhythm of BP primarily by elevating the daytime BP.

Troglitazone, an insulin sensitizer, increases forearm blood flow in humans.

To test whether troglitazone, a thiazolidinedione insulin sensitizer, increases the peripheral blood flow, the changes in forearm blood flow (FBF) were evaluated by venous occlusion plethysmography in 11 lean healthy male volunteers (age range, 24 to 39 years) after a single oral dose of 200 mg of troglitazone. Forearm vascular resistance (FVR) was calculated from FBF and blood pressure. Two hours after the dose, FBF increased from 3.66+/-0.31 to 4.81+/-0.57 mL/100 mL/min (P < .01), and FVR decreased from 24.7+/-2.2 to 20.2+/-2.2 units (P < .01), whereas both these values did not change during the control recordings obtained without troglitazone. Blood pressure, blood glucose levels, and serum immunoreactive insulin levels did not change significantly during the observation period. Serum concentrations of nitrate ions decreased from 27.0+/-3.5 mmol/L to 23.1+/-2.7 mmol/L (P < .01) after the administration. These results suggest that troglitazone increases muscular blood flow through vasodilation induced by a mechanism other than the correction of hyperinsulinemia or the increase in nitric oxide. The present study provides the first evidence that troglitazone dilates the vasculature in humans.

Neutrophil-mediated tissue injury and its modulation.

Neutrophils play a key role in the development of the systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS). Since the lungs are the main target in these syndromes, with adult respiratory distress syndrome (ARDS) as the outcome, extensive research has been undertaken to prevent or mitigate ARDS. As evidence of the involvement of neutrophils in ARDS has accumulated, modulation of their function has become a major goal in terms of a therapeutic approach. In this short review, we sought to update our knowledge about neutrophils. Firstly, we summarized the various stimuli which activate neutrophils. Secondly, we described the different mediators, including cytokines, which are released by neutrophils. Lastly, we discussed the possible modulation of their function. Although we cannot assess the clinical usefulness of biochemical substances merely on the basis of their in vitro effects, understanding these mechanisms is fundamental to the success of the new therapeutic approach which is currently under way.

Relationship between pupil size and acetylcholinesterase activity in patients exposed to sarin vapor.

OBJECTIVE: To elucidate the effect of sarin vapor on pupil size and erythrocyte acetylcholinesterase activity (AchE). DESIGN: Retrospective observational survey. SETTING: Emergency department of an urban teaching hospital. PATIENTS: 80 patients who were exposed to sarin in a terrorist attack in Tokyo subways. MEASUREMENTS AND RESULTS: Pupil size and AchE activity on the day of exposure were measured. Among the 80 patients, the pupils were miotic (< 3 mm) in 50 patients (62.5%), while AchE activity was below the normal range (< 1.2 U) in 34 patients (42.5%). AchE was significantly lower in the miotic group than in the group with normal pupils (1.0 +/- 0.5 U vs 1.5 +/- 0.3 U, p < 0.01). In the miotic group, AchE activity was lower than normal in 32 patients (64.0%) but was decreased in only 2 patients in the normal pupil group (6.7%) (p < 0.01). CONCLUSIONS: Miosis is a more sensitive index of exposure to sarin vapor than erythrocyte AchE. Systemic poisoning is apparently less likely to develop if the patient's pupil size is normal on arrival at the hospital.

A case of traumatic shock complicated by methamphetamine intoxication.

A case of a 38-year-old male with traumatic shock complicated by methamphetamine intoxication is presented. The patient was involved in an assault which resulted in cardiac tamponade and right ventricular outflow laceration. Pericardiocentesis was immediately performed. However, profound metabolic acidosis greatly in excess of that expected from the short duration of the shock was revealed by arterial blood gas analysis. Another cause of the metabolic acidosis was suspected. The patient subsequently admitted to intravenous use of methamphetamine. Following hemodynamic and metabolic stabilization by continuous pericardial drainage and intravenous administration of sodium bicarbonate, the patient underwent cardiac surgery. His postoperative course was uneventful. There is a substantial association between methamphetamine users and traumatic accidents. In such cases, early identification of drug use is important. Marked metabolic acidosis, which conflicts with the diagnosed cause of shock, may be a clinical clue to methamphetamine intoxication.

Serum MIP-1 alpha and IL-8 in septic patients.

UNLABELLED: We studied blood MIP-1 alpha and IL-8 in 38 septic patients and 5 healthy volunteers. Both chemokines were undetectable in the healthy volunteers. In sepsis, serum MIP-1 alpha was detected in 45% of the patients and Il-8 in 84%. The levels of MIP-1 alpha, but not of IL-8, correlated with CRP, IL-6 and TNF alpha levels. Complications, including various organ failures and mortality, showed no correlation with serum MIP-1 alpha levels. In contrast, we found increased levels of serum IL-8 in septic patients with disseminated intravascular coagulation, central nervous system (CNS) dysfunction or renal failure, and the mortality rate was higher in the IL-8 detectable group than in the IL-8 undetectable group (50% vs 0%, p < 0.05). In conclusion, the production of both MIP-1 alpha and IL-8 was increased and initially detectable levels of circulating IL-8 predicted high mortality in sepsis. OBJECTIVE: To determine the significance of the C-C chemokine MIP-1 alpha and the C-X-C chemokine IL-8 in sepsis. DESIGN: Prospective study. SETTING: Clinical investigation, emergency department and general intensive care unit of university hospital. PATIENTS AND PARTICIPANTS: 38 septic patients and 5 healthy volunteers were studied. Sepsis was diagnosed following the criteria formulated by ACCP/SCCM. INTERVENTIONS: 10-20 ml of blood was drawn from each patient at the time of initial diagnosis of sepsis. MEASUREMENTS AND RESULTS: MIP-1 alpha and IL-8 were determined by sandwich ELISA. Both chemokines were undetectable in the healthy volunteers. In sepsis, serum MIP-1 alpha was detected in 45% of the patients and IL-8 was detected in 84%. The levels of MIP-1 alpha, but not of IL-8, correlated with CRP, IL-6 and TNF alpha levels. Complications, including various organ failures and mortality, showed no correlation with serum MIP-1 alpha levels. In contrast, we found increased levels of serum IL-8 in patients with disseminated intravascular coagulation (DIC) (p < 0.05), central nervous system (CNS) dysfunction (p < 0.05), renal failure (p < 0.01) and the mortality rates were higher in the IL-8 detectable group than in the IL-8 undetectable group (50% vs 0%, p < 0.05). CONCLUSIONS: The production of MIP-1 alpha and IL-8 was increased in sepsis. Furthermore, an initially detectable level of circulating IL-8, but not MIP-1 alpha, predicted a high mortality in sepsis diagnosed according to the ACCP/SCCM criteria.

Secondary exposure of medical staff to sarin vapor in the emergency room.

OBJECTIVE: To clarify the risk of secondary exposure of medical staff to sarin vapor in the emergency room, and to warn emergency room staffs of the hazard. DESIGN: Retrospective observational survey. SETTING: Emergency department of a university hospital in a metropolitan area of Japan. PARTICIPANTS: Fifteen doctors treating victims of a terrorist attack with sarin in the Tokyo subways on the day of the attack. MEASUREMENTS AND RESULTS: Of the 15 doctors who worked in the emergency room treating the victims, 13 became simultaneously aware of symptoms during the resuscitation of two victims who were exposed to sarin. Among 11 doctors (73%) who complained of dim vision, the pupils were severely miotic (<2 mm) in 8 (73%). Other symptoms included rhinorrhea in eight (53%), dyspnea or tightness of the chest in four (27%), and cough in two (13%). Atropine sulfate was given to six, and pralidoxime was given to one of these six doctors. To decontaminate the emergency room of sarin vapor, ventilation was facilitated and all belongings of the patients were sealed up. None of the doctors noticed worsening of their symptoms thereafter. CONCLUSIONS: Careful attention to the risks of secondary exposure to toxic gas in the emergency room and prompt decontamination if such exposure should occur are necessary in the case of large-scale disasters caused by sarin.

Effect of blood and albumin on pulmonary hypertension and edema in perfused rabbit lungs.

Perfusate composition may alter pulmonary hemodynamics and edema formation in perfused lungs. Perfusion for 3 h with Krebs-Henseleit solution with 3% bovine serum albumin did not produce pulmonary hypertension, pulmonary edema (assessed by lung wet-to-dry wt ratio), or increased macromolecular permeability (assessed by 125I-albumin uptake). Addition of blood to hematocrit levels of 10 or 20% resulted in pulmonary hypertension during the final hour of perfusion but not pulmonary edema or increased macromolecular permeability. Pulmonary hypertension during blood perfusion was primarily due to increased precapillary resistance. Perfusion with buffer solution without albumin produced edema and increased macromolecular permeability but not pulmonary hypertension. In lungs perfused with blood (20% hematocrit), thromboxane B2 levels increased in parallel with the pulmonary hypertension, and inhibition of cyclooxygenase or thromboxane synthase with indomethacin or dazmegrel prevented pulmonary hypertension. Perfusion with leukopenic blood (from prior nitrogen mustard administration or from filtration) also prevented pulmonary hypertension. We conclude that blood perfusion produces pulmonary hypertension via thromboxane A2 generation, which depends on leukocyte activation, and that perfusion with buffer solutions without albumin produces edema and increased permeability without pulmonary hypertension.

Attenuation of hyperoxic lung injury by the 21-aminosteroid U-74389G.

Hyperoxic lung injury is attributable to oxygen radicals produced under hyperoxic conditions. The 21-aminosteroid (AS), U-74389G, is a potent antioxidant. We examined the effect of U-74389G on lung injury in guinea pigs during exposure to 90% O2 for 48 h. We injected either vehicle or 10 mg/kg of U-74389G 30 min before the O2 exposure and injected the same dose 12, 24, and 36 h later. We performed two series of experiments after exposure. In the first series, we measured the clearance rate of 99mTc-labeled dialdehyde starch (DAS) from the lungs as an index of pulmonary epithelial damage in three experimental groups consisting of 1) control (n = 6) O2 alone (n = 6), and 3) O2 + AS (n = 6). In the second series, pulmonary endothelial injury was estimated by using 28 guinea pigs divided into four experimental groups consisting of 1) control (n = 8), 2) AS alone (n = 5), 3) O2 alone (n = 6), and 4) O2 + AS (n = 9). In the second series, we measured the wet-to-dry weight ratio (W/D) as an index of lung water and the concentration ratio of 125I-labeled albumin in lung tissue and bronchoalveolar lavage (BAL) fluid compared with plasma (T/P and BAL/P, respectively) as indexes of pulmonary endothelial damage. Cell accumulation in BAL fluid and lung tissue samples was also assessed in the second series.(ABSTRACT TRUNCATED AT 250 WORDS)

Regional lung hematocrit variation and assessment of acute lung injury.

Estimating blood content in the lung remains a key step in calculating lung water volume and microvascular permeability. We studied the effect of regional lung hematocrit (Hct) variation on assessment of acute lung injury. Escherichia coli endotoxin was administered in guinea pigs intravenously. Lung injury was evaluated by measuring the wet-to-dry weight ratio (W/D) and transvascular 125I-labeled albumin leakage for 3 h [tissue-to-plasma 125I-albumin ratio (T/P)] in five tissue samples from each animal. Residual blood content was corrected using either 51Cr-red blood cells as a blood cell marker, 99mTc-albumin as a plasma marker, or both, injected 10 min before the guinea pigs were killed. Lung Hct, estimated from the marker counts of lung and peripheral blood samples, was lower than peripheral blood Hct; intraindividual variation, represented by the standard deviation in each subject, was 0.024 +/- 0.015 for the control group (coefficient of variation 8.0 +/- 5.1%) and 0.026 +/- 0.013 for the endotoxin group (coefficient of variation 8.5 +/- 4.1%). Uncorrected W/D for residual blood content was greater than the corrected W/D. 99mTc-albumin correction gave values closer to the W/D corrected by both markers. T/P corrected by 99mTc-albumin showed smaller data variations than the values obtained with 51Cr-red blood cell correction, which was affected by variations in lung Hct. We recommend using a plasma marker to correct for blood content in assessing acute lung injury by W/D and T/P.

Effects of intra-arterial infusion of insulin on forearm vasoreactivity in hypertensive humans.

We previously demonstrated that intra-arterial infusion of insulin attenuates vasoreactivity to phenylephrine and angiotensin II in the forearm of normotensive humans, which suggests that the pressor effects of insulin via sympathetic activation may be offset in peripheral arteries. In the present study, we investigated the effects of insulin on vasoreactivity in hypertensive humans. Seven male patients with essential hypertension (age, 26 +/- 2 yr; blood pressure, 159 +/- 4/103 +/- 4 mmHg; mean +/- SEM) were studied. We measured forearm blood flow by a strain gauge plethysmograph while infusing phenylephrine (1, 4, 12 nmol/min) and angiotensin II (5, 10, 20 pmol/min) locally into the brachial artery before and during simultaneous intra-arterial infusion of human insulin (0.15 mU/kg/min). Forearm vascular resistance was calculated from directly measured arterial pressure and forearm blood flow. Intra-arterial infusion of insulin raised the local plasma insulin level without changing the blood glucose level, basal forearm blood flow, or forearm vascular resistance. Phenylephrine and angiotensin II increased forearm vascular resistance dose-dependently before and during insulin infusion. In contrast to the previous results in normotensive subjects, locally infused insulin did not attenuate vasoconstrictive responses to phenylephrine and angiotensin II in patients with essential hypertension. These results suggest that the balance between the pressor and depressor effects of insulin might be altered in favor of a pressor effect in patients with hypertension.

Transcranial doppler sonography and ambulatory blood pressure monitoring in patients with hypertension.

To appraise the value of transcranial Doppler sonography (TCD) for assessment of hypertensive cerebrovascular damage, the relationship between ambulatory blood pressure (BP) and indices of cerebral circulation determined by TCD was investigated. Subjects were 55 inpatients with or without hypertension, including 13 patients with histories of cerebrovascular attacks. Mean flow velocity (MFV) in the middle cerebral artery was measured by TCD, then the cerebrovascular resistance index (CVRI; mean BP/MFV) and the Fourier PI1 (pulsatility index of the first Fourier harmonic of the flow-velocity waveform) were determined as indices of cerebrovascular resistance. CO2 reactivity of MFV was estimated as an index of cerebrovascular flow reserve. CVRI positively correlated with both daytime and nighttime BP as well as with age (p<0.01). Fourier PI1 positively correlated with nighttime BP and age (p<0.01). CO2 reactivity did not correlate with any of the ambulatory BP parameters, but negatively correlated with age (p<0.01). LV mass index significantly correlated with ambulatory BP parameters, CVRI, and Fourier PI1 but did not correlate with CO2 reactivity. Multiple regression analyses showed that nighttime systolic BP was a significant correlate for CVRI and Fourier PI1, but not for CO2 reactivity, and that history of cerebrovascular attack was significant for CVRI and CO2 reactivity. We conclude that cerebrovascular resistance determined by TCD accords with the results of ambulatory BP and LVMI, and thus could be successfully used to detect the early stage of hypertensive cerebrovascular change. Cerebrovascular flow reserve would be relatively preserved in hypertensive patients without cerebrovascular diseases.

Clinical significance of measuring myeloperoxidase, thiobarbituric acid reactive material and 7S collagen in plasma of patients with adult respiratory distress syndrome.

We measured myeloperoxidase (MPO), thiobarbituric acid reactive material (TBARM), and Type IV collagen 7S domain (7S collagen) in the plasma of 21 patients with acute lung injury (ALI). Sixteen healthy subjects served as a control group. There was no significant difference in MPO between the control and ALI groups. The TBARM and 7S collagen concentrations in ALI (TBARM; 3.05 +/- 0.65 nMol/ml, 7S collagen 9.06 +/- 5.96 ng/ml: Mean +/- SD) were significantly higher than those in the control group (2.54 +/- 0.33 and 3.43 +/- 1.05, p < 0.05). TBARM and 7S collagen levels of deceased ALI patients were higher than those of surviving ALI patients (p < 0.05). There were significant correlations between the plasma levels of these two parameters and the lung injury scores. Our findings suggest that plasma TBARM and 7S collagen are useful markers for the assessment of the severity of ARDS.