Robust acoustic directional sensing enabled by synergy between resonator-based sensor and deep learning.

We demonstrate enhanced acoustic sensing arising from the synergy between resonator-based acoustic sensor and deep learning. We numerically verify that both vibration amplitude and phase are enhanced and preserved at and off the resonance in our compact acoustic sensor housing three cavities. In addition, we experimentally measure the response of our sensor to single-frequency and siren signals, based on which we train convolutional neural networks (CNNs). We observe that the CNN trained by using both amplitude and phase features achieve the best accuracy on predicting the incident direction of both types of signals. This is even though the signals are broadband and affected by noise thought to be difficult for resonators. We attribute the improvement to a complementary effect between the two features enabled by the combination of resonant effect and deep learning. This observation is further supported by comparing to the CNNs trained by the features extracted from signals measured on reference sensor without resonators, whose performances fall far behind. Our results suggest the advantage of this synergetic approach to enhance the sensing performance of compact acoustic sensors on both narrow- and broad-band signals, which paves the way for the development of advanced sensing technology that has potential applications in autonomous driving systems to detect emergency vehicles.

Impact of frailty on long-term mortality in older patients receiving intensive care via the emergency department.

The aim of this study was to evaluate whether frailty was associated with 6-month mortality in older adults who were admitted to the intensive care unit (ICU) with an illness requiring emergency care. The investigation was a prospective, multi-center, observational study conducted among the ICUs of 17 participating hospitals. Patients ≥ 65 years of age who were admitted to the ICU directly from an emergency department visit were assessed to determine their baseline Clinical Frailty Scale (CFS) scores before the illness and were surveyed 6 months after admission. Among 650 patients included in the study, the median age was 79 years old, and overall mortality at 6 months was as low as 21%, ranging from 6.2% in patients with CFS 1 to 42.9% in patients with CFS ≥ 7. When adjusted for potential confounders, CFS score was an independent prognostic factor for mortality (one-point increase in CFS, adjusted risk ratio with 95% confidence interval 1.19 [1.09-1.30]). Quality of life 6 months after admission worsened as baseline CFS score increased. However, there was no association between total hospitalization cost and baseline CFS. CFS is an important predictor of long-term outcomes among critically ill older patients requiring emergent admission.

Severe hypotension during junctional rhythm in a patient with multiple cerebral infarcts.

An 82-year-old woman with parkinsonism and Lewy body dementia was re-admitted to our hospital due to convulsions and the recurrence of cerebral infarction. Parasternal transthoracic echocardiography showed normal left ventricular wall thickness and wall motion. To treat marked bradycardia and hypotension, she underwent temporary pacing. However, she lost her consciousness, when her blood pressure could not be measured. Simultaneous electrocardiogram and blood pressure monitoring showed that systolic blood pressure decreased by almost 30 mmHg from sinus rhythm to junctional rhythm. In the present case of acute cerebral infarction, severe hypotension occurred during junctional rhythm possibly contributed by parkinsonism and Lewy body dementia. Learning objective: As patients with junctional rhythm usually have no or mild symptoms, there are no specific guidelines for its evaluation and treatment. However, severe symptoms such as hypotension, cerebral infarction, loss of consciousness, or breathlessness may occur in some cases. Holter electrocardiogram with 24-hour noninvasive blood pressure monitoring may be helpful in such severe cases.

Prevalence and Risk Factor Analysis of Post-Intensive Care Syndrome in Patients with COVID-19 Requiring Mechanical Ventilation: A Multicenter Prospective Observational Study.

INTRODUCTION: Post-intensive care syndrome (PICS) is an emerging problem in critically ill patients and the prevalence and risk factors are unclear in patients with severe coronavirus disease 2019 (COVID-19). This multicenter prospective observational study aimed to investigate the prevalence and risk factors of PICS in ventilated patients with COVID-19 after ICU discharge. METHODS: Questionnaires were administered twice in surviving patients with COVID-19 who had required mechanical ventilation, concerning Barthel Index, Short-Memory Questionnaire, and Hospital Anxiety and Depression Scale scores. The risk factors for PICS were examined using a multivariate logistic regression analysis. RESULTS: The first and second PICS surveys were obtained at 5.5 and 13.5 months (mean) after ICU discharge, with 251 and 209 patients completing the questionnaires and with a prevalence of PICS of 58.6% and 60.8%, respectively, along with the highest percentages of cognitive impairment. Delirium (with an odds ratio of (OR) 2.34, 95% CI 1.1-4.9, and p = 0.03) and the duration of mechanical ventilation (with an OR of 1.29, 95% CI 1.05-1.58, and p = 0.02) were independently identified as the risk factors for PICS in the first PICS survey. CONCLUSION: Approximately 60% of the ventilated patients with COVID-19 experienced persistent PICS, especially delirium, and required longer mechanical ventilation.

Quick sequential organ failure assessment versus systemic inflammatory response syndrome criteria for emergency department patients with suspected infection.

Previous studies have shown inconsistent prognostic accuracy for mortality with both quick sequential organ failure assessment (qSOFA) and the systemic inflammatory response syndrome (SIRS) criteria. We aimed to validate the accuracy of qSOFA and the SIRS criteria for predicting in-hospital mortality in patients with suspected infection in the emergency department. A prospective study was conducted including participants with suspected infection who were hospitalised or died in 34 emergency departments in Japan. Prognostic accuracy of qSOFA and SIRS criteria for in-hospital mortality was assessed by the area under the receiver operating characteristic (AUROC) curve. Of the 1060 participants, 402 (37.9%) and 915 (86.3%) had qSOFA ≥ 2 and SIRS criteria ≥ 2 (given thresholds), respectively, and there were 157 (14.8%) in-hospital deaths. Greater accuracy for in-hospital mortality was shown with qSOFA than with the SIRS criteria (AUROC: 0.64 versus 0.52, difference + 0.13, 95% CI [+ 0.07, + 0.18]). Sensitivity and specificity for predicting in-hospital mortality at the given thresholds were 0.55 and 0.65 based on qSOFA and 0.88 and 0.14 based on SIRS criteria, respectively. To predict in-hospital mortality in patients visiting to the emergency department with suspected infection, qSOFA was demonstrated to be modestly more accurate than the SIRS criteria albeit insufficiently sensitive.Clinical Trial Registration: The study was pre-registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN000027258).

Shorter Interval from Witnessed Out-Of-Hospital Cardiac Arrest to Reaching the Target Temperature Could Improve Neurological Outcomes After Extracorporeal Cardiopulmonary Resuscitation with Target Temperature Management: A Retrospective Analysis of a Japanese Nationwide Multicenter Observational Registry.

Extracorporeal cardiopulmonary resuscitation (ECPR) with extracorporeal membrane oxygenation is a more promising treatment for out-of-hospital cardiac arrest (OHCA) than conventional cardiopulmonary resuscitation (CCPR). However, previous studies that compared ECPR and CCPR included mixed groups of patients with or without target temperature management (TTM). In this study, we compared the neurological outcomes of OHCA between ECPR and CCPR with TTM in all patients. We performed retrospective subanalyses of the Japanese Association for Acute Medicine OHCA registry. Witnessed adult cases of cardiogenic OHCA treated with TTM were eligible for this study. We used univariate and multivariable analyses in all eligible patients to compare the neurological outcomes after ECPR or CCPR. We also conducted propensity score analyses of all patients and according to the interval from witnessed OHCA to reaching the target temperature (IWT) of ≤600, ≤480, ≤360, ≤240, and ≤120 minutes. We analyzed 1146 cases. The propensity score analysis did not show a significant difference in favorable neurological outcomes (defined as a Glasgow-Pittsburgh Cerebral Performance Category of 1-2 at 1 month after collapse) between EPCR and CCPR (odds ratio: OR 4.683 [95% confidence interval: CI 0.859-25.535], p = 0.747). However, ECPR was associated with more favorable neurological outcomes in patients with IWT of ≤600 minutes (OR 7.089 [95% CI 1.091-46.061], p = 0.406), ≤480 minutes (OR 10.492 [95% CI 1.534-71.773], p = 0.0168), ≤360 minutes (OR 17.573 [95% CI 2.486-124.233], p = 0.0042), ≤240 minutes (OR 38.908 [95% CI 5.045-300.089], p = 0.0005), and ≤120 minutes (OR 200.390 [95% CI 23.730-1692.211], p < 0.001). This study revealed significant differences in the neurological outcomes between ECPR and CCPR in patients with TTM whose IWT was ≤600 minutes.

Clinical profiles of hyperglycemic crises: A single-center retrospective study from Japan.

AIMS/INTRODUCTION: The aim of the present study was to clarify the pathophysiologies of hyperglycemic crises in Japanese patients. MATERIALS AND METHODS: This was a retrospective study of patients with hyperglycemic crises admitted to Kumamoto Medical Center, Kumamoto, Japan, between 2012 and 2019. Patients were classified as having diabetic ketoacidosis (DKA), hyperglycemic hyperosmotic syndrome (HHS) or a mixed state of the two conditions (MIX), and laboratory data and levels of consciousness at hospital admission, as well as the rates of mortality and coagulation disorders, were compared. RESULTS: The diagnostic criteria for hyperglycemic crisis were met in 144 cases, comprising 87 (60.4%), 38 (26.4%) and 19 (13.2%) cases of DKA, HHS and MIX, respectively. Type 1 diabetes was noted in 46.0 and 26.3% of patients in the DKA and MIX groups, respectively. Fibrin degradation product and D-dimer levels were significantly higher in the HHS group than in the DKA group (DKA and HHS groups: fibrin degradation product 7.94 ± 8.43 and 35.54 ± 51.80 µg/mL, respectively, P < 0.01; D-dimer 2.830 ± 2.745 and 14.846 ± 21.430 µg/mL, respectively, P < 0.01). Mortality rates were 5.7, 13.2 and 5.3% in the DKA, HHS and MIX groups, respectively. Seven patients (4.9%), four of whom were in the MIX group, had acute arterial occlusive diseases. CONCLUSIONS: The low frequency of type 1 diabetes in DKA and MIX might be responsible for reduced insulin secretion in Japanese populations. Patients with hyperglycemic crises have increased coagulability, and acute arterial occlusion needs to be considered, particularly in MIX.

Extracorporeal cardiopulmonary resuscitation without target temperature management for out-of-hospital cardiac arrest patients prolongs the therapeutic time window: a retrospective analysis of a nationwide multicentre observational study in Japan.

BACKGROUND: Extracorporeal cardiopulmonary resuscitation (ECPR) with extracorporeal membrane oxygenation (ECMO) is a promising therapy for out-of-hospital cardiac arrest (OHCA) compared with conventional cardiopulmonary resuscitation (CCPR). The no and low-flow time (NLT), the interval from collapse to reperfusion to starting ECMO or to the return of spontaneous circulation (ROSC) in CCPR, is associated with the neurological outcome of OHCA. Because the effects of target temperature management (TTM) on the outcomes of ECPR are unclear, we compared the neurological outcomes of OHCA between ECPR and CCPR without TTM. METHODS: We performed retrospective subanalyses of the Japanese Association for Acute Medicine OHCA registry. Witnessed cases of adult cardiogenic OHCA without TTM were selected. We performed univariate, multivariable and propensity score analyses to compare the neurological outcomes after ECPR or CCPR in all eligible patients and in patients with NLT of > 30 min or > 45 min. RESULTS: We analysed 2585 cases. Propensity score analysis showed negative result in all patients (odds ratio 0.328 [95% confidence interval 0.141-0.761], P = 0.010). However, significant associated with better neurological outcome was shown in patients with NLT of > 30 min or > 45 min (odds ratio 2.977 [95% confidence interval 1.056-8.388], P = 0.039, odds ratio 5.099 [95% confidence interval 1.259-20.657], P = 0.023, respectively). CONCLUSION: This study revealed significant differences in the neurological outcomes between ECPR and CCPR without TTM, in patients with NLT of > 30 min.

Successful treatment with artificial pancreas for a patient who attempted suicide using a high-dose insulin s.c. injection.

BACKGROUND: Artificial pancreas is usually used to manage hyperglycemia. We controlled prolonged hypoglycemia induced by insulin overdose using artificial pancreas. CASE PRESENTATION: A 56-year-old female patient with type 2 diabetes mellitus was admitted to the emergency department after overdosing on 1,800 units each of insulin aspart and insulin degludec. She had also ingested 2 weeks of anti-anxiety medication. When the patient arrived at the hospital, her blood glucose level was 30 mg/dL and she was in a coma. Artificial pancreas (STG-55; Nikkiso, Tokyo, Japan) was used to control blood glucose levels because we were unable to predict the duration or degree of hypoglycemia. Blood glucose levels were safely controlled without the development of hypo- or hyperglycemia. Finally, the patient was discharged without any complications on day 7. CONCLUSION: The STG-55 artificial pancreas was very useful and convenient for controlling blood glucose levels in our insulin overdose patient.

Comparative study on quick sequential organ failure assessment, systemic inflammatory response syndrome and the shock index in prehospital emergency patients: single-site retrospective study.

AIM: The quick sequential organ failure assessment (qSOFA) score, shock index (SI), and systemic inflammatory response syndrome (SIRS) criteria are simple indicators for the mortality of patients in the emergency department (ED). These simple indicators using only vital signs might be more useful in prehospital care than in the ED due to their quick calculation. However, these indicators have not been compared in prehospital settings. The aim of the present study is to compare these indicators measured in prehospital care and verify whether the qSOFA score is useful for prehospital triage. METHODS: We undertook a single-site retrospective study on patients transferred by ambulance to the Kumamoto Medical Center ED (Kumamoto, Japan) between January 2015 and December 2016. We compared areas under the receiver operating characteristic (AUROC) curves of the qSOFA score, SI, and SIRS criteria measured in prehospital care. We also carried out sensitivity and specificity analyses using the Youden index. RESULTS: A total of 4,827 patients were included in the present study. The AUROC (95% confidence interval) of the qSOFA score for in-hospital mortality was 0.64 (0.61-0.67), which was significantly higher than those of the SIRS criteria (0.59 [0.56-0.62]) and SI (0.58 [0.54-0.62]). According to the optimal cut-off values (qSOFA ≥ 2) decided on as the Youden index, the sensitivity of the qSOFA score was 52.3% and its specificity was 69.9%. CONCLUSIONS: The qSOFA score had the highest AUROC among three indicators. However, it might not be practical in actual prehospital triage due to its low sensitivity.

One-hour oral glucose tolerance test plasma glucose at gestational diabetes diagnosis is a common predictor of the need for insulin therapy in pregnancy and postpartum impaired glucose tolerance.

AIMS/INTRODUCTION: Gestational diabetes mellitus (GDM) is a risk for adverse perinatal outcomes, and patients with a history of GDM have an increased risk of impaired glucose tolerance (IGT). Here, we carried out two non-interventional and retrospective studies of GDM patients in Japan. MATERIALS AND METHODS: In the first study, we enrolled 529 GDM patients and assessed predictors of the need for insulin therapy. In the second study, we enrolled 185 patients from the first study, and assessed predictors of postpartum IGT. RESULTS: In the first study, gestational weeks at GDM diagnosis and history of pregnancy were significantly lower, and pregestational body mass index, family history of diabetes mellitus, 1- and 2-h glucose levels in a 75-g oral glucose tolerance test (OGTT), the number of abnormal values in a 75-g OGTT, and glycated hemoglobin were significantly higher in participants receiving insulin therapy. In the second study, 1- and 2-h glucose levels in a 75-g OGTT, the number of abnormal values in a 75-g OGTT, glycated hemoglobin, and ketone bodies in a urine test were significantly higher in participants with OGT. Logistic regression analysis showed that gestational weeks at GDM diagnosis, 1-h glucose levels in a 75-g OGTT and glycated hemoglobin were significant predictors of the need for insulin therapy, and 1-h glucose levels in a 75-g OGTT at diagnosis and ketone bodies in a urine test were significant predictors for postpartum IGT. CONCLUSIONS: Antepartum 1-h glucose levels in a 75-g OGTT was a predictor of the need for insulin therapy in pregnancy and postpartum IGT.

Predictors of short-term repetition of self-harm among patients admitted to an emergency room following self-harm: A retrospective one-year cohort study.

We conducted a retrospective chart-review study, examining predictors of the repetition of short-term self-harm (<1 month and <6 months) among the patients who were admitted to an emergency department in Japan following self-harm. A total of 405 patients were enrolled and were followed-up for a subsequent one year. The incidence of repeated self-harm within one- and six- months were 6.4% and 13.1%, respectively. Cox's proportional hazards model analyses demonstrated that history of self-harm and comorbid physical illness were associated with repeated self-harm within one month. The patients who lived alone and who were directly discharged from the emergency room after referral to a psychiatrist were at higher risk for repeated self-harm within both one and six months. Living on public assistance and having been discharged from psychiatric wards within the past 12 months were associated with repetition within six months. These risk factors should be incorporated into routine assessment at an emergency room, and elaborate follow-up plan should be provided to the patients with these risk factors upon discharge from the emergency room. Further prospective studies are warranted, addressing more comprehensive factors that are associated with short-term risk for self-harm and suicide.

New clinical decision rule to exclude subarachnoid haemorrhage for acute headache: a prospective multicentre observational study.

OBJECTIVE: To ensure good outcomes in the management of subarachnoid haemorrhage (SAH), accurate prediction is crucial for initial assessment of patients presenting with acute headache. We conducted this study to develop a new clinical decision rule using only objectively measurable predictors to exclude SAH, offering higher specificity than the previous Ottawa SAH Rule while maintaining comparable sensitivity. DESIGN: Multicentre prospective cohort study. SETTING: Tertiary-care emergency departments of five general hospitals in Japan from April 2011 to March 2014. PARTICIPANTS: Eligible patients comprised 1781 patients aged >15 years with acute headache, excluding trauma or toxic causes and patients who presented in an unconscious state. MAIN OUTCOME MEASURES: Definitive diagnosis of SAH was based on confirmation of SAH on head CT or lumbar puncture findings of non-traumatic red blood cells or xanthochromia. RESULTS: A total of 1561 patients were enrolled in this study, of whom 277 showed SAH. Using these enrolled patients, we reached a rule with mainly categorical predictors used in previous reports, called the 'Ottawa-like rule', offering 100% sensitivity when using any of age ≥40 years, neck pain or stiffness, altered level of consciousness or onset during exertion. Using the 1317 patients from whom blood samples were obtained, a new rule using any of systolic blood pressure >150 mm Hg, diastolic blood pressure >90 mm Hg, blood sugar >115 mg/dL or serum potassium <3.9 mEq/L offered 100% sensitivity (95% CI 98.6% to 100%) and 14.5% specificity (12.5% to 16.9%), while the Ottawa-like rule showed the same sensitivity with a lower specificity of 8.8% (7.2% to 10.7%). CONCLUSIONS: While maintaining equal sensitivity, our new rule seemed to offer higher specificity than the previous rules proposed by the Ottawa group. Despite the need for blood sampling, this method can reduce unnecessary head CT in patients with acute headache. TRIAL REGISTRATION NUMBER: UMIN 00004871.

[An autopsy case with progressive muscular atrophy: an subtype of lower motor predominant amyotrophic lateral sclerosis].

We report an autopsy case with progressive muscular atrophy of 6 years' duration. The patient was a Japanese woman without any hereditary predisposition to neuropathy. She developed muscle weakness of the upper extremities at 66 years of age, followed by muscle weakness of the lower extremities, fasciculation, and atrophy of the tongue. She died at 72 years of age from fat embolism of the lung. During the clinical course of her illness, neither Babinski sign nor hyperreflexia were present on neurological examination. No respirator support was necessary at any time throughout the clinical course. Neuropathological examinations on autopsy disclosed neuronal loss with gliosis in the hypoglossal nucleus and anterior horns of the spinal cord, but there was no apparent atrophy of the motor cortex or degeneration of the corticospinal tract. No Bunina bodies were detected. Skein-like neuronal cytoplasmic inclusions and glial cytoplasmic inclusions positive for phosphorylated TDP-43 were found in the anterior spinal horn. Grouped muscle fiber atrophy of the tongue indicated neurogenic changes. Based on these clinicopathological findings, our diagnosis for this woman was progressive muscular atrophy, which is defined by progressive degeneration of lower motor neurons. We and other experts believe this represents a lower motor neuron-predominant phenotype of ALS.

Feasibility study of immediate pharyngeal cooling initiation in cardiac arrest patients after arrival at the emergency room.

AIM: Cooling the pharynx and upper oesophagus would be more advantageous for rapid induction of therapeutic hypothermia since the carotid arteries run in their vicinity. The aim of this study was to determine the effects of pharyngeal cooling on brain temperature and the safety and feasibility for patients under resuscitation. METHODS: Witnessed non-traumatic cardiac arrest patients (n=108) were randomized to receive standard care with (n=53) or without pharyngeal cooling (n=55). In the emergency room, pharyngeal cooling was initiated before or shortly after return of spontaneous circulation by perfusing physiological saline (5 °C) into a pharyngeal cuff for 120 min. RESULTS: There was a significant decrease in tympanic temperature at 40 min after arrival (P=0.02) with a maximum difference between the groups at 120 min (32.9 ± 1.2°C, pharyngeal cooling group vs. 34.1 ± 1.3°C, control group; P<0.001). The return of spontaneous circulation (70% vs. 65%, P=0.63) and rearrest (38% vs. 47%, P=0.45) rates were not significantly different based on the initiation of pharyngeal cooling. No post-treatment mechanical or cold-related injury was observed on the pharyngeal epithelium by macroscopic observation. The thrombocytopaenia incidence was lower in the pharyngeal cooling group (P=0.001) during the 3-day period after arrival. The cumulative survival rate at 1 month was not significantly different between the two groups. CONCLUSIONS: Initiation of pharyngeal cooling before or immediately after the return of spontaneous circulation is safe and feasible. Pharyngeal cooling can rapidly decrease tympanic temperature without adverse effects on circulation or the pharyngeal epithelium.

Prevalence of metabolic syndrome in stroke patients: a prospective multicenter study in Japan.

AIMS: The fact that Metabolic Syndrome (MetS) increases the risk of atherosclerosis has been epidemiologically studied and proven; however, a prospective study on the prevalence of MetS in stroke patients has never been conducted because of the difficulty in diagnosis under critical illness in the acute phase. Therefore, we conducted a prospective multicenter study to investigate the prevalence of MetS in stroke patients with modified diagnostic criteria for MetS. METHODS: Stroke patients admitted in the seven participating Emergency and Critical Care Centers within the two years from April 2007 were registered in this study as a prospective multicenter study. Inclusion criteria were 50 to 89 year-old stroke patients who presented within three days from the onset of symptoms. A total of 992 subjects were classified according to the stroke type and the prevalence of MetS and the associated risk factors were investigated. The participants in a medical checkup without any history of a stroke were enrolled as the control group, and compared between the two groups. RESULTS: The prevalence of MetS as well as hyperglycemia and dyslipidemia in the infarction group was significantly higher than that in the non-stroke group. While the hemorrhage group showed no significant difference in the prevalence of MetS, only hypertension was significantly high. According to a subtype analysis, there is a significant correlation between waist circumference increment of the stroke patients and the prevalence of the risk factors of hypertension, hyperglycemia and dyslipidemia. CONCLUSIONS: Different risk factors are significantly related to the type of stroke.

Effects of combined treatment with eldecalcitol and alendronate on bone mass, mechanical properties, and bone histomorphometry in ovariectomized rats: a comparison with alfacalcidol and alendronate.

Eldecalcitol (ELD), a 2ß-hydroxypropyloxy derivative of 1α,25 (OH) 2D3, inhibits bone resorption more potently than alfacalcidol (ALF) while maintaining osteoblastic function in an ovariectomized (OVX) osteoporosis rat model. Alendronate (ALN), which is the most common bisphosphonate used for the treatment of osteoporosis, increases the bone mineral density (BMD) by suppressing bone resorption. In this study, we investigated the effects of combination treatments with ELD and ALN or with ALF and ALN on bone mass and strength in OVX rats. Seventy female rats, 32 weeks old, were assigned to seven groups: (1) a sham-operated control group; (2) an OVX-control group; (3) an ELD group; (4) an ALF group; (5) an ALN group; (6) an ELD+ALN group; and (7) an ALF+ALN group. OVX rats were orally treated with ELD (0.015 µg/kg), ALF (0.0375 µg/kg), or ALN (0.2mg/kg) daily for 12 weeks. In both the lumbar spine and the femur, ELD and ALF monotherapy significantly increased the BMD, and ELD+ALN and ALF+ALN significantly increased the BMD, compared with ALN monotherapy, as an additive effect. In particular, ELD+ALN resulted in a significantly higher BMD than ALF+ALN in the femur. On mechanical testing of the lumbar spine, ELD and ALF monotherapy significantly increased the ultimate load, and ELD+ALN and ALF+ALN significantly increased the ultimate load compared with ALN monotherapy. In the femur, ELD, ELD+ALN, and ALF+ALN treatment significantly increased the ultimate load, compared with the OVX-control group, and ELD+ALN resulted in a significantly higher ultimate load than ALN monotherapy. A histomorphometric analysis showed that ELD monotherapy and ELD+ALN combination therapy had a potent inhibitory effect on bone resorption parameters (osteoclast surface and eroded surface), while maintaining bone formation parameters (osteoblast surface and osteoid surface). By contrast, ALF and ALF+ALN significantly lowered the histological parameters of both bone resorption and formation. These results suggested that ELD or ALF used in combination with ALN has therapeutic advantages over ALN monotherapy, with ELD+ALN combination treatment producing an especially beneficial anti-osteoporotic effect by inhibiting osteoclastic bone resorption and maintaining osteoblastic function, compared with ALF+ALN combination treatment.

Preparation and evaluation of biodegradable films containing the potent osteogenic compound BFB0261 for localized delivery.

To achieve sustained release of 3-ethyl-4-(4-methylisoxazol-5-yl)-5-(methylthio) thiophene-2-carboxamide (BFB0261), a new potent osteogenic compound for treating bone disorders, we prepared film formulations containing BFB0261 and the following newly synthesized biodegradable polymers by a solvent casting technique: poly(D,L-lactic acid) (PLA), poly(D,L-lactic acid-co-glycolic acid) (PLGA), poly(D,L-lactic acid)-block-poly(ethylene glycol) (PLA-PEG), and poly(D,L-lactic acid-co-trimethylene carbonate) (PLA-TMC) polymers or copolymers. Powder X-ray diffractometry (PXRD), differential thermal analysis (DTA), scanning electron microscopy (SEM), and tensile testing were performed to examine the physicochemical properties of these films. Almost all the films exhibited a smooth and homogeneous surface, as observed by SEM. In addition, PXRD and DTA revealed that BFB0261 existed in an amorphous state in the films. The in vitro release of BFB0261 from PLA100 (M(w): 251 kDa), PLAPEG9604H (PLA/PEG ratio: 96:4; M(w): 181 kDa), PLAPEG8515H (PLA/PEG ratio: 85:15; M(w): 51.5 kDa), or PLAPEG8020 (PLA/PEG ratio: 80:20; M(w): 33.7 kDa) films followed zero-order kinetics with slow release up to 12 weeks following incubation. Although release of BFB0261 from PLA-TMC films followed first-order kinetics, sustained release of BFB0261 for 12 weeks was still observed for PLATMC8416 (PLA/TMC ratio: 84:16; M(w): 170 kDa) films. Furthermore, when the BFB0261-loaded films constructed from various polymers were implanted subcutaneously on rat backs, the PLAPEG8515H and PLATMC8416 films were capable of achieving sustained release of BFB0261 at the administrated site for 12 weeks. Therefore, the present data indicate that films constructed from PLAPEG8515H or PLATMC8416 may be applicable to bone or tissue engineering.

Preparation and evaluation of biodegradable microspheres containing a new potent osteogenic compound and new synthetic polymers for sustained release.

In order to achieve the sustained release of 3-ethyl-4-(4-methylisoxazol-5-yl)-5-(methylthio) thiophene-2-carboxamide (BFB0261), a new potent osteogenic compound for the treatment of bone disorders, we prepared microspheres containing BFB0261 and newly synthesized three poly (D, L-lactic acid) (PLA), four poly (D, L-lactic acid-co-glycolic acid) (PLGA), and eight poly (D, L-lactic acid)-block-poly(ethylene glycol) (PLA-PEG) biodegradable polymers or copolymers, and evaluated the release pattern of BFB0261 from the microspheres in vitro and in vivo. The mean particle size of the microspheres, except for the microspheres constructed from PLA-PEG with a greater than 20% PEG component, was in the range of approximately 10-50 microm, and the preparations showed a spherical shape with a smooth surface. In an in vitro release study, the release of BFB0261 from PLA-1 (Mw: 36 kDa), PLAPEG9604H (PLA/PEG ratio: 96:4, Mw: 181 kDa), or PLAPEG8317 (PLA/PEG ratio: 83:17, Mw: 106 kDa) microspheres occurred in a zero-order manner with a slow release, and more than 50% of BFB0261 remained in each type of microsphere at 12 weeks after incubation. When the BFB0261 microspheres constructed from various polymers were intramuscularly administered to the rat femur, the microspheres constructed from PLA-1 or PLAPEG9604H were able to achieve a sustained release of BFB0261 at the injection site for 6 weeks. The present information indicates that microspheres constructed from PLA-1 or PLAPEG9604H may be feasible for bone engineering.

The importance of brain PGE2 inhibition versus paw PGE2 inhibition as a mechanism for the separation of analgesic and antipyretic effects of lornoxicam in rats with paw inflammation.

OBJECTIVES: Lornoxicam is a non-selective cyclooxygenase inhibitor that exhibits strong analgesic and anti-inflammatory effects but a weak antipyretic effect in rat models. Our aim was to investigate the mechanism of separation of potencies or analgesic and antipyretic effects of lornoxicam in relation to its effect on prostaglandin E2 (PGE2) production in the inflammatory paw and the brain. METHODS: A model of acute or chronic paw inflammation was induced by Freund's complete adjuvant injection into the rat paw. Lornoxicam (0.01-1 mg/kg), celecoxib (0.3-30 mg/kg) or loxoprofen (0.3-30 mg/kg) was administered orally to the rats and the analgesic and antipyretic effects were compared. The paw hyperalgesia was assessed using the Randall-Selitto test or the flexion test. Dorsal subcutaneous body temperature was measured as indicator of pyresis. After the measurement of activities, the rats were sacrificed and the PGE2 content in the paw exudate, cerebrospinal fluid or brain hypothalamus was measured by enzyme-immunoassay. KEY FINDINGS: In a chronic model of arthritis, lornoxicam, celecoxib and loxoprofen reduced hyperalgesia with an effective dose that provides 50% inhibition (ED50) of 0.083, 3.9 and 4.3 mg/kg respectively, whereas the effective dose of these drugs in pyresis was 0.58, 0.31 and 0.71 mg/kg respectively. These drugs significantly reduced the PGE2 level in paw exudate and the cerebrospinal fluid. In acute oedematous rats, lornoxicam 0.16 mg/kg, celecoxib 4 mg/kg and loxoprofen 2.4 mg/kg significantly reduced hyperalgesia to a similar extent. On the other hand, lornoxicam did not affect the elevated body temperature, whereas celecoxib and loxoprofen significantly reduced the pyrexia to almost the normal level. These drugs significantly reduced the PGE2 level in inflamed paw exudate lo almost the normal level. On the other hand, lornoxicam did not change PGE2 level in the brain hypothalamus, whereas celecoxib and loxoprofen strongly decreased it. CONCLUSIONS: Lornoxicam exhibits strong analgesic but weak antipyretic effects in rats with paw inflammation. Such a separation of effects is related to its efficacy in the reduction of PGE2 levels in the paw and brain hypothalamus.