Prior exposure to stress exacerbates neuroinflammation and causes long-term behavior changes in sepsis.

Background: Neuroinflammation can occur during sepsis and is now regarded as the main mechanism underlying various related central nervous system (CNS) disorders. Another well-known factor causing neuroinflammation is psychological stress. In the current study, we examined the effects of prior exposure to stress on sepsis-induced neuroinflammation and CNS symptoms. Experimental procedure: Balb/c mice were subjected to wet bedding stress for 2 days, then lipopolysaccharide (LPS) was intraperitoneally administered. For examining the neuroinflammation, the expression of proinflammatory cytokines and NF-κB activity in the brain was analyzed by RT-PCR and ELISA-based assay. Additionally, immunohistochemical study using Iba-1 was performed. Finally, behavior tests were examined one month after LPS treatment. Result and conclusion: Stress exposure induced the upregulation of IL-1ß, IL-6 and TNFα mRNA in the cerebral cortex 4 h after LPS administration. Suggesting an underlying mechanism, LPS-induced NF-κB activation was significantly upregulated with stress in the brain. Histologically, microglia in the cerebral cortex were reactive and became more abundant with stress, while these effects were further increased with LPS injection. Behavioral analysis conducted showed a significant increase of anxiety-like behaviors in the stressed mice. These results suggest that prior exposure to stress exacerbates neuroinflammation during sepsis and induces long-term behavior changes.

Japan Geriatrics Society "Statement for the use of telemedicine in geriatric care: Telemedicine as a complement to in-person medical practice": Geriatric Medical Practice Committee consensus statement.

Telemedicine has changed from a way to treat patients with limited access to hospitals to a necessary method of treatment for non-urgent conditions during the coronavirus disease 2019 pandemic. There are two styles of telemedicine, namely "hybrid medical care" and "gateway medical care," which take advantage of the characteristics of online medical care and might become important in the near future. During hybrid medical care, a patient and their primary care physician have face-to-face medical care while simultaneously being examined by a specialist physician through telemedicine, leading to an overall improvement in the level of local medical care and expansion in the number of treatable diseases. Gateway medical practice is a form of telemedicine used for patients who would otherwise refuse or not receive in-person medical care to engage in consultation with a physician. Telemedicine allows physicians to determine disease severity and triage patients, while reducing unnecessary home visits, emergency hospitalizations and the spread of infection. Telemedicine is less intense than in-person medical care, and allows for easier collaboration with other healthcare providers. However, telemedicine is not optimal for conditions requiring a definitive diagnosis and a comprehensive understanding of the patient's medical history. It is limited by the patient's ability to use telemedicine devices, and the risk of accidental treatments and fraud. The use of telemedicine might result in the development of new, online comprehensive geriatric assessment tools and technologies. Geriatr Gerontol Int 2022; 22: 913-916.

Sepsis-associated neuroinflammation in the spinal cord.

Septic patients commonly present with central nervous system (CNS) disorders including impaired consciousness and delirium. Today, the main mechanism regulating sepsis-induced cerebral disorders is believed to be neuroinflammation. However, it is unknown how another component of the CNS, the spinal cord, is influenced during sepsis. In the present study, we intraperitoneally injected mice with lipopolysaccharide (LPS) to investigate molecular and immunohistochemical changes in the spinal cord of a sepsis model. After LPS administration in the spinal cord, pro-inflammatory cytokines including interleukin (IL)-1ß, IL-6, and tumor necrosis factor alpha mRNA were rapidly and drastically induced. Twenty-four-hour after the LPS injection, severe neuronal ischemic damage spread into gray matter, especially around the anterior horns, and the anterior column had global edematous changes. Immunostaining analyses showed that spinal microglia were significantly activated and increased, but astrocytes did not show significant change. The current results indicate that sepsis induces acute neuroinflammation, including microglial activation and pro-inflammatory cytokine upregulation in the spinal cord, causing drastic neuronal ischemia and white matter edema in the spinal cord.

The inhibitory effects of Orengedokuto on inducible PGE2 production in BV-2 microglial cells.

BACKGROUND AND AIM: Reactive microglia has been associated with neuroinflammation caused by the production of proinflammatory molecules such as cytokines, nitric oxide, and prostaglandins. The overexpression of these molecules may provoke neuronal damage that can cause neurodegenerative diseases. A traditional herbal medicine, Orengedokuto (OGT), has been widely used for treating inflammation-related diseases. However, how it influences neuroinflammation remains poorly understood. EXPERIMENTAL PROCEDURE: This study investigated the effects of OGT on inflammatory molecule induction in BV-2 microglial cells using real-time RT-PCR and ELISA. An in vivo confirmation of these effects was then performed in mice. RESULTS AND CONCLUSION: OGT showed dose-dependent inhibition of prostaglandin E2 (PGE2) production in BV-2 cells stimulated with lipopolysaccharide (LPS). To elucidate the mechanism of PGE2 inhibition, we examined cyclooxygenases (COXs) and found that OGT did not suppress COX-1 expression or inhibit LPS-induced COX-2 upregulation at either the transcriptional or translational levels. In addition, OGT did not inhibit COX enzyme activities within the concentration that inhibited PGE2 production, suggesting that the effect of OGT is COX-independent. The inhibitory effects of OGT on PGE2 production in BV-2 cells were experimentally replicated in primary cultured astrocytes and mice brains. OGT can be useful in the treatment of neuroinflammatory diseases by modulating PGE2 expression.

Determinants and impact of physical impairment in patient-reported outcomes among older patients with type 2 diabetes mellitus in Japan.

OBJECTIVE: To investigate the predictive factors associated with physical impairment among older patients with type 2 diabetes mellitus (T2DM) in Japan and to examine the potential impact of physical impairment on patient-reported health outcomes in this population. METHODS: A cross-sectional analysis was conducted using patient-reported data from the 2012-2014 Japan National Health and Wellness Survey. Physical impairment was measured using the Physical Component Summary (PCS) score of the Short-Form 36-Item Health Survey (SF-36) three-component model (using Japanese norms). Older T2DM patients (≥65 years old; n = 1511) were dichotomized into physically impaired (PCS ≤ 25th percentile; n = 378) and non-physically impaired (PCS > 25th percentile; n = 1133). Work productivity (absenteeism, presenteeism and overall work impairment), activity impairment and healthcare resource utilization were compared between these groups. RESULTS: Age, female sex, low and high body mass index (BMI), diabetes-related complications, cardiovascular events, unawareness of having hypoglycemic events in the past 3 months, and lack of regular exercise were significant factors associated with physical impairment in multivariable analysis. The physically impaired group reported significantly more regular outpatient visits (13.48 vs. 10.16, respectively, p < .001), 1% or greater absenteeism (16.7% vs. 4.1%, p = .005), greater presenteeism (27.8% vs. 12.2%, p = .001), overall work impairment (30.0% vs. 13.0%, p = .001) and overall activity impairment (39.5% vs. 17.2%, p < .001) than the non-physically-impaired group after adjusting for covariates. CONCLUSIONS: This study identified age, BMI, diabetes-related comorbidities, history of cardiovascular events and lack of exercise as key predictors associated with physical impairment in older patients with T2DM in Japan, which predicted low work productivity as well as activity impairment. This study provides support that physical impairment in patients with T2DM may lead to low work productivity and activity impairment.Supplemental data for this article is available online at https://doi.org/10.1080/03007995.2020.1846170.

Graft dysfunction immediately after reperfusion predicts short-term outcomes in living-donor lobar lung transplantation but not in cadaveric lung transplantation.

OBJECTIVES: Primary graft dysfunction (PGD) is a major cause of early morbidity and mortality after cadaveric lung transplantation (CLT). This study examined the incidence, time course and predictive value of PGD after living-donor lobar lung transplantation (LDLLT). METHODS: We retrospectively investigated 75 patients (42 with LDLLT and 33 with CLT) who underwent lung transplantation from January 2008 to December 2013. Patients were assigned PGD grades at six time points, as defined by the International Society for Heart and Lung Transplantation: immediately after final reperfusion, upon arrival at the intensive care unit (ICU), and 12, 24, 48 and 72 h after ICU admission. RESULTS: The incidence of severe (Grade 3) PGD at 48 or 72 h after ICU admission was similar for LDLLT and CLT patients (16.7 vs 12.1%; P = 0.581). The majority of the LDLLT patients having severe PGD first developed PGD immediately after reperfusion, whereas more than half of the CLT patients first developed severe PGD upon ICU arrival or later. In LDLLT patients, severe PGD immediately after reperfusion was significantly associated with fewer ventilator-free days during the first 28 postoperative days [median (interquartile range) of 0 (0-10) vs 21 (13-25) days, P = 0.001], prolonged postoperative ICU stay [median (interquartile range) of 20 (16-27) vs 12 (8-14) days, P = 0.005] and increased hospital mortality (27.3 vs 3.2%, P = 0.02). Severe PGD immediately after reperfusion was not associated with ventilator-free days during the first 28 postoperative days, time to discharge from ICU or hospital, or hospital mortality in CLT patients. CONCLUSIONS: Postoperative incidence of severe PGD was not significantly different between LDLLT and CLT patients. In LDLLT patients, the onset of severe PGD tended to be earlier than that in CLT patients. Severe PGD immediately after reperfusion was a significant predictor of postoperative morbidity and mortality in LDLLT patients but not in CLT patients.

[A Case of an Elderly Diabetic Patient Developing Wernicke Encephalopathy without Alcohol Abuse or an Unbalanced Diet].

A 70-year-old man with a 28-year history of type 2 diabetes mellitus was admitted due to persistent vomiting and neurological abnormalities in Nov 2012. He had developed gait disturbance and diplopia for six months during antiplatelet therapy, which was initiated following the diagnosis of a cerebellar infarction in June 2012. He had nystagmus, truncal ataxia and an ocular motility disorder, and the MRI study showed increased FLAIR and DWI signals in the peri-third ventricle and periaqueductal region, in addition to the cerebellar vermis. Wernicke encephalopathy was suspected according to his symptoms, and thiamine administration dramatically improved his condition. He did not have a history of alcohol abuse or poor eating habits; however, various coexisting factors, including diabetes mellitus, pyloric stenosis and the use of antiulcer drugs and insulin, were considered to be responsible for Wernicke encephalopathy. This case demonstrates the importance of distinguishing Wernicke encephalopathy from cerebrovascular disease in elderly patients.

[A case of an elderly diabetic patient with dementia effectively treated with weekly exenatide].

A 74-year-old man with diabetes mellitus since 64 years of age had been treated with glimepiride, metformin and alogliptin; however, his glycemic control remained poor, i.e., a casual blood glucose level of 318 mg/dl, HbA1c level of 10.6% and glycated albumin level of 24.9%. Although his blood glucose level improved with intensive insulin therapy, he exhibited dementia with an MMSE score of 9/30 and was unable to continue insulin injections by himself, thus rejecting his family's help. The extended-release form of the GLP-1 agonist exenatide (Bydureon(®)) was recently introduced in Japan. This new anti-diabetic agent enables the administration of once-weekly type 2 diabetes treatment that delivers a continuous dose of exenatide in a single weekly injection. We employed weekly exenatide therapy in combination with oral hypoglycemic agents in this case. The patient visited our outpatient clinic for injections every week, showing a remarkable improvement in his HbA1c level, from 10.7% to 7.1% in five months. Subcutaneous induration was the only side effect of weekly exenatide injection. Weekly exenatide therapy can be easily managed by other caregivers and is expected to be a useful treatment approach in elderly diabetic patients with dementia.

[Acyclovir-induced neurotoxicity and acute kidney injury in an elderly diabetic patient treated with valacyclovir: report of a case].

An 83-year-old Japanese man had a 29-year history of well-controlled diabetes mellitus. His HbA1c level was approximately 6.0%, with no microalbuminuria and a serum creatinine level seven days before admission of 0.8 mg/dl (eGFR: 69.67 ml/min/1.73 m(2)). Five days before admission, he visited an ophthalmologist with inflammation of the right palpebra and conjunctiva and began taking valacyclovir at a dose of 3,000 mg for the treatment of herpes zoster. Two days before admission, he was prescribed loxoprofen at a dose of 180 mg for a headache. One day prior to admission, he developed dysarthria, wandering and loss of appetite. He was subsequently admitted to our hospital with progressive deterioration of consciousness (Japan Coma Scale: II-20). On admission, he exhibited renal dysfunction, with a serum creatinine level of 5.11 mg/dl (eGFR: 9.16 ml/min/1.73 m(2)). Based on his diverse symptoms and current treatment with valacyclovir, the patient was diagnosed with acyclovir-induced neurotoxicity and his symptoms rapidly improved after hemodialysis. The serum acyclovir level on admission was found to be 9.25 µg/ml. Although acyclovir-induced neurotoxicity is commonly seen in elderly patients with renal dysfunction, there are also reports of this condition in patients with a normal renal function. Valacyclovir is frequently prescribed to the elderly to treat diseases such as herpes zoster. As valacyclovir induces renal dysfunction, which raises the serum acyclovir level to the toxic range, special attention must be paid when administering this drug in elderly subjects.

[Role of androgen in the elderly. Gender sensitive medicine and androgen - role of androgen in women - ].

From gender sensitive medicine aspect, sex hormones play most important roles in men and women's health. Both estrogen role in women and androgen role in men are well established recently. On the other hand, the effect of androgen on women's health has not been elucidated. Androgen is synthesized in the adrenal gland and the ovary. Androgen receptors (ARs) are found in many tissues. Androgen acts on numerous tissues, including bone (increased mineral density) , muscle (increased muscle mass) , adipose tissue (stimulation lipolysis) , bone marrows (stimulation of enzymatic metabolism) but not so well known. Testosterone provides dual action in breast tissues, stimulation with being converted into estrogen and suppressant effect as testosterone. In addition, women with hyperandrogenism have higher risk for cardiovascular disease and insulin resistance. Currently the testosterone replacement therapy for the woman is provided mainly on a sexual dysfunction, but the long-term safety with non-physiological concentrations is not confirmed without the standard direction for uses being established. The effects of androgens on well-being, quality of life, positive effects for body composition and cognitive function are currently the subject of increased attention. Much developmental work has to be done about testosterone for women's health.

[A case of severe hypokalemia caused by a Chinese herbal remedy (Yokukansan) in an 81-year-old woman with dementia].

An 81-year-old woman had been visiting 2 hospitals for hypertension and dementia, prior to admission to our emergency room for nausea, hypertension, severe hypokalemia (K 1.29 mEq/l) and abnormal electrocardiography findings. She had been taking a Chinese herbal remedy (Yokukansan, 7.5 g/day) for the behavioral and psychological symptoms of dementia (BPSD) for 6 months before admission. On admission, she presented with metabolic alkalosis with hypokalemia, a high urinary excretion of potassium, low plasma rennin activity and hypoaldosteronism. We diagnosed pseudoaldosteronism caused by the Chinese herbal remedy Yokukansan (which includes licorice). Discontinuation of Yokukansan and the administration of potassium supplements normalized her serum potassium level within 2 weeks. However, we could not successfully control her BPSD by drugs such as tiapride hydrochloride or risperidone. BPSD is a serious problem in an aging society, with the ever-increasing incidence of dementia. The use of Yokukansan has recently been receiving attention as a new treatment modality for BPSD. Because this agent has relatively few adverse effects compared with typical antipsychotic agents, the use of Yokukansan is continuing to increase sharply. Pseudoaldosteronism, if caused by Yokukansan, may cause death by severe hypokalemia, but the early identification of hypokalemia is sometimes difficult because drug-induced hypokalemia is not dose-dependent. We think it is important to create awareness of the possible adverse effects of Yokukansan, such as hypertension and electrolyte abnormalities to make the most of this commonly used drug for the treatment of BPSD among dementia patients.

[Thiazide diuretics for hypertensive treatment induced severe hyponatremia with consciousness disturbance in two elderly cases].

The salt intake of the Japanese is among the highest in the world, leading to a high prevalence of salt-sensitive hypertension. To prevent this, salt restriction, suppression of the rennin-angiotensin-aldosterone system, and natriuresis are important. Therefore, the use of a combination of an angiotensin II receptor blocker and thiazide diuretics is used for antihypertensive treatment. Some randomized controlled studies suggested that thiazide diuretics are useful not only to lower blood pressure, but also to prevent cardiovascular events and improve prognosis in the elderly, who are prone to being salt-sensitive. We encountered 2 elderly patients referred to our emergency room because of severe hyponatremia and consciousness disturbance, who had been treated with thiazide diuretics for 1 and 2 months, respectively. In both, hypernatriuria despite hyponatremia, slight dehydration, and refractory antidiuretic hormone (ADH) excess were observed, but activation of the rennin-angiotensin-aldosterone system was absent. Thyroid and adrenal functions were unremarkable. Theses phenomena have much in common with the condition called mineralcorticoid-responsive hyponatremia of the elderly (MRHE). Several weeks after discontinuation of diuretics, serum sodium values returned to normal levels, but transtubular potassium concentration gradient (TTKG) values were depleted despite slight hyperkalemia, and relative ADH excess was sustained, which suggested mineralocorticoid dysfunction and distal renal tubulointerstitial injury. Distal tubulointerstitial dysfunction is one of the most important causes of MRHE. On the basis of these 2 cases, we speculated whether distal tubulointerstitial injury may accelerate hyponatremia in the elderly. We need to check not only serum potassium, but also sodium levels, especially in elderly persons with suspected tubulointerstitial injury.

Pituitary apoplexy during general anesthesia in beach chair position for shoulder joint arthroplasty.

Pituitary apoplexy is a rare but potentially life-threatening clinical syndrome caused by the sudden enlargement of pituitary adenoma secondary to infarction and/or hemorrhage. It may be the first presentation of previously undiagnosed pituitary adenoma. Although various precipitating factors of pituitary apoplexy are indicated, the pathogenesis remains unknown. In this report, we describe for the first time a case of pituitary apoplexy developed explicitly during general anesthesia supplemented with interscalene brachial plexus block in beach chair or barbershop position for shoulder joint arthroplasty.

Age-related changes in plasma androgen levels and their association with cardiovascular risk factors in male Japanese office workers.

AIM: To assess the age-related change in plasma androgen levels in healthy middle-aged men and whether any clinical parameters are associated with the hormonal change. METHODS: The study was comprised of male Japanese office-workers aged 40-64 years, who had undergone an annual health check-up in 2002 and 2007 (96 and 76 men, respectively). Body mass index and blood pressure were measured, and serum concentration of lipids, glucose and uric acid in addition to plasma total testosterone, free testosterone and dehydroepiandrosterone sulfate (DHEA-S) levels were determined in the morning after an overnight fast. The 5-year hormonal changes and their associations with clinical parameters were analyzed in 33 men who repeated the examination at both check-ups. The cross-sectional associations of hormonal levels with clinical parameters were also investigated. RESULTS: Age was negatively associated with free testosterone (r = -0.399, P < 0.001 in 2002; r = -0.458, P < 0.001 in 2007) and DHEA-S (r = -0.233, P = 0.02 in 2002; r = -0.336, P < 0.01 in 2007) but not with total testosterone, while the 5-year changes of free testosterone and DHEA-S levels were not significant and showed no associations with major cardiovascular risk factors. Cross-sectionally, after adjustment for age, linear regression analysis showed a positive association between free testosterone and blood hemoglobin and a negative association between total testosterone and serum uric acid. CONCLUSION: In Japanese middle-aged men, 5-year androgen decline is too subtle to detect, and endogenous androgen levels seem to have relatively weak association with cardiovascular risk profiles.

Pituitary abscess with panhypopituitarism showing T1 signal hyperintensity of the marginal pituitary area: a non-invasive differential diagnosis of pituitary abscess and pituitary apoplexy.

A 53-year-old man was hospitalized with general fatigue, headache, dizziness and polyuria. The laboratory findings revealed anterior hypopituitarism and central diabetes insipidus. He also showed eye movement disorder and facial sensory impairment. These symptoms were treated successfully with conservative medical treatment. Concurrently, abnormal pituitary MR imaging findings were revealed. Pituitary abscess was primarily suspected on MR imaging findings, although it was difficult to differentiate pituitary apoplexy by MR imaging findings, alone. In this report, we propose a new diagnostic approach of pituitary abscess, using a combination of CT, MR imaging and clinical manifestations, without either pituitary surgery or pituitary biopsy.

Evaluation of high-performance liquid chromatography and mass spectrometry method for pharmacokinetic study of local anesthetic ropivacaine in plasma.

We studied the viability of high-performance liquid chromatography and mass spectrometry (LC/MS) as a selective and sensitive analytical method for measuring blood concentrations of the local anesthetic ropivacaine. Ropivacaine was effectively separated using a reverse-phase column and monitored at 275 m/z ion. The LC/MS method allowed measurement of concentrations of ropivacaine of lower than 75 ng/mL. The standard curve was linear and in the range of <1.5 microg/mL. Recovery of ropivacaine in plasma samples was over 90% after precipitation of plasma protein with trichloroacetic acid. The method was tested on the pharmacokinetics of plasma ropivacaine after single intravenous or subcutaneous administration in rabbits. The pharmacokinetic parameters showed a one-compartment model and a mean elimination half-life of 0.54+/-0.05 h and 2.83+/-0.51 h after administration at doses of 0.4 mg/kg, i.v. and 5 mg/kg, s.c., respectively. These values were in approximate agreement with previously obtained results in dogs. The results of the present study demonstrated that the LC/MS method was highly selective and sensitive for the measurement of ropivacaine, indicating that it offers a useful tool for monitoring the therapeutic effects and determining the pharmacokinetic parameters of this drug in blood.