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Coronavirus disease 2019 (COVID-19) presents a complex pathology including inflammation, endothelial damage, thrombus formation, and acute respiratory failure [2,3,4] This syndrome requires complex treatment to reduce viral genome amounts, anti-inflammatory drugs, and anticoagulation. COVID-19 was diagnosed with real-time reverse transcriptase-polymerase chain reaction in approved laboratories from nasopharyngeal and throat swabs and with lung computed tomography. The treatment protocol was completed without any clinically important change in 2 patients with bronchial asthma, one with rheumatoid arthritis (early-stage steroid administration) and one with bleeding complication (without heparin).

Septic encephalopathy (SE) is characterized by symptoms such as coma, delirium, and cognitive dysfunction, and effective therapeutic interventions for SE remain elusive. In this study, we aimed to investigate the potential alleviating effects of vagal nerve stimulation (VNS) on SE-associated signs. To evaluate our hypothesis, we utilized a mouse model of SE induced by intraperitoneal injection of lipopolysaccharide (0.3 mg per mouse) and administered noninvasive, high-frequency ultrasound VNS. To assess the efficacy of ultrasound VNS, we measured inflammation-related molecules, including the α7 nicotinic acetylcholine receptor (α7nAChR) expression in peritoneal macrophages and plasma interleukin 1β (IL-1β) levels. Consistent with our hypothesis, SE mice exhibited reduced α7nAChR expression in macrophages and elevated IL-1β levels in the blood. Remarkably, VNS in SE mice restored α7nAChR expression and IL-1β levels to those observed in control mice. Furthermore, we evaluated the effects of VNS on survival rate, body temperature, and locomotor activity. SE mice subjected to VNS demonstrated a modest, yet significant, improvement in survival rate, recovery from hypothermia, and increased locomotor activity. To investigate the impact on the brain, we examined the hippocampus of SE mice. In control mice, VNS increased the expression of c-fos, a marker of neuronal electrical excitability, in the hippocampus. In SE mice, VNS led to the restoration of aberrant firing patterns in hippocampal neurons. Additionally, proteomic analysis of hippocampal tissue in SE mice revealed abnormal increases in two proteins, tissue factor (TF) and acyl-CoA dehydrogenase family member 9 (ACAD9), which returned to control levels following VNS. Collectively, our findings support the value of exploring the beneficial effects of ultrasound VNS on SE.

This study was performed to gain insights into novel therapeutic approaches for the treatment of heatstroke. The central nervous system regulates peripheral immune responses via the vagus nerve, the primary neural component of the cholinergic anti-inflammatory pathway. Electrical vagus nerve stimulation (VNS) reportedly suppresses pro-inflammatory cytokine release in several models of inflammatory disease. Here, we evaluated whether electrical VNS attenuates severe heatstroke, which induces a systemic inflammatory response. Anesthetized rats were subjected to heat stress (41.5°C for 30 minutes) with/without electrical VNS. In the VNS-treated group, the cervical vagus nerve was stimulated with constant voltage (10 V, 2 ms, 5 Hz) for 20 minutes immediately after completion of heat stress. Sham-operated animals underwent the same procedure without stimulation under a normothermic condition. Seven-day mortality improved significantly in the VNS-treated group versus control group. Electrical VNS significantly suppressed induction of pro-inflammatory cytokines such as tumor necrosis factor-α and interleukin-6 in the serum 6 hours after heat stress. Simultaneously, the increase of soluble thrombomodulin and E-selectin following heat stress was also suppressed by VNS treatment, suggesting its protective effect on endothelium. Immunohistochemical analysis using tissue preparations obtained 6 hours after heat stress revealed that VNS treatment attenuated infiltration of inflammatory (CD11b-positive) cells in lung and spleen. Interestingly, most cells with increased CD11b positivity in response to heat stress did not express α7 nicotinic acetylcholine receptor in the spleen. These data indicate that electrical VNS modulated cholinergic anti-inflammatory pathway abnormalities induced by heat stress, and this protective effect was associated with improved mortality. These findings may provide a novel therapeutic strategy to combat severe heatstroke in the critical care setting.

Crush injury patients often have systemic inflammatory response syndrome that leads to multiple organ failure. Receptor for advanced glycation endproducts (RAGE) functions as a pattern recognition receptor that regulates inflammation. We evaluated the effects of anti-RAGE antibody in a crush injury model. Pressure was applied to both hindlimbs of rats for 6 h by 3.0-kg blocks and then released. Animals were randomly divided into the sham (RAGE-Sh) group, crush (RAGE-Ctrl) group or anti-RAGE antibody-treated crush (RAGE-Tx) group. Samples were collected at 3, 6 and 24 h after releasing pressure. In the RAGE-Ctrl group, fluorescent immunostaining in the lung showed upregulated RAGE expression at 3 h. The serum soluble RAGE (sRAGE) level, which reflects the amount of RAGE expression in systemic tissue, increased at 6 h. Serum interleukin 6 (IL-6; systemic inflammation marker) increased immediately at 3 h. Histological analysis revealed lung injury at 6 and 24 h. Administration of anti-RAGE antibody before releasing compression inhibited upregulated RAGE expression in the lung alveoli, suppressed RAGE-associated mediators sRAGE and IL6, attenuated the lung damage and improved the 7-day survival rate. Collectively, our results indicated that the use of anti-RAGE antibody before releasing compression is associated with a favourable prognosis following crush injury.

Cases Case 1: A 63‐year‐old woman was referred for coughing blood. Although cardiorespiratory dynamics were stabilized by artificial respiration under sedation, severely poor ventilation developed from asphyxia associated with massive respiratory tract hemorrhage. One‐lung ventilation was temporarily secured by endotracheal tube insertion into the left main bronchus just prior to cardiopulmonary arrest. Case 2: A 72‐year‐old man was referred for massive hemoptysis after coughing, then intubated and placed on a respirator. During angiography, blood clots collected with bronchoscopy confirmed extravascular leakage into the right main bronchus. Outcomes Both showed no hemoptysis recurrence after bronchial artery embolization and were discharged. Case 1 required intensive treatment for 6 days, including artificial respiratory management. Conclusion Emergency one‐lung ventilation was required for asphyxia in Case 1, and we had difficulties with bleeding point identification and hemostatic therapy. From that experience, we noted hemoptysis during angiography using bronchoscopy in Case 2, enabling prompt bronchial artery embolization.

Obesity and metabolic diseases tend to go together, and humans who become obese are also prone to type 2 diabetes and cardiovascular problems. Starting with the observation that offspring of germ-free mice tended to become obese on high-fat diets, Kimura et al. investigated how the presence of the microbiota might be protective in mice (see the Perspective by Ferguson). Short-chain fatty acids (SCFAs) from the microbiota are known to suppress insulin signaling and reduce fat deposition in adipocytes. Further experiments showed that SCFAs in the bloodstream were able to pass from a non–germ-free mother's gut microbiota across the placenta and into the developing embryos. The authors found that in the embryos, the SCFA propionate mediates not only insulin levels through GPR43 signaling but also sympathetic nervous system development through GPR41 signaling. A high-fiber diet promoted propionate production from the maternal microbiota, and maternal antibiotic treatment resulted in obese-prone offspring. Science , this issue p. eaaw8429 ; see also p. 978 The mother’s gut microbiota during pregnancy tunes energy homeostasis and sympathetic nervous system development in offspring. Antibiotics and dietary habits can affect the gut microbial community, thus influencing disease susceptibility. Although the effect of microbiota on the postnatal environment has been well documented, much less is known regarding the impact of gut microbiota at the embryonic stage. Here we show that maternal microbiota shapes the metabolic system of offspring in mice. During pregnancy, short-chain fatty acids produced by the maternal microbiota dictate the differentiation of neural, intestinal, and pancreatic cells through embryonic GPR41 and GPR43. This developmental process helps maintain postnatal energy homeostasis, as evidenced by the fact that offspring from germ-free mothers are highly susceptible to metabolic syndrome, even when reared under conventional conditions. Thus, our findings elaborate on a link between the maternal gut environment and the developmental origin of metabolic syndrome.

Background: Small bowel adenocarcinoma (SBA) is a rare malignancy that accounts for 1–2% of gastrointestinal tumours. We investigated the clinical characteristics, outcomes, and prognostic factors of primary SBA. Methods: We retrospectively analysed the characteristics and clinical courses of 205 SBA patients from 11 institutions in Japan between June 2002 and August 2013. Results: The primary tumour was in the duodenum and jejunum/ileum in 149 (72.7%) and 56 (27.3%) patients, respectively. Sixty-four patients (43.0%) with duodenal adenocarcinoma were asymptomatic and most cases were detected by oesophagogastroduodenoscopy (EGD), which was not specifically performed for the detection or surveillance of duodenal tumours. In contrast, 47 patients (83.9%) with jejunoileal carcinoma were symptomatic. The 3-year survival rate for stage 0/I, II, III, and IV cancers was 93.4%, 73.1%, 50.9%, and 15.1%, respectively. Multivariate analysis revealed performance status 3–4, high carcinoembryonic antigen, high lactate dehydrogenase (LDH), low albumin, symptomatic at diagnosis, and stage III/IV disease were independent factors for overall survival (OS). Ten patients (18.5%) with stage IV disease were treated with a combination of resection of primary tumour, local treatment of metastasis, and chemotherapy; this group had a median OS of 36.9 months. Conclusions: Although most SBA patients were diagnosed with symptomatic, advanced stage disease, some patients with duodenal carcinoma were detected in early stage by EGD. High LDH and symptomatic at diagnosis were identified as novel independent prognostic factors for OS. The prognosis of advanced SBA was poor, but combined modality therapy with local treatment of metastasis might prolong patient survival.

Lung cancer, the leading cause of cancer death worldwide, is most frequently detected through imaging tests. In this study, we investigated serum microRNAs (miRNAs) as a possible early screening tool for resectable lung cancer. First, we used serum samples from participants with and without lung cancer to comprehensively create 2588 miRNAs profiles; next, we established a diagnostic model based on the combined expression levels of two miRNAs (miR-1268b and miR-6075) in the discovery set (208 lung cancer patients and 208 non-cancer participants). The model displayed a sensitivity of 99% and specificity of 99% in the validation set (1358 patients and 1970 non-cancer participants) and exhibited high sensitivity regardless of histological type and pathological TNM stage of the cancer. Moreover, the diagnostic index markedly decreased after lung cancer resection. Thus, the model we developed has the potential to markedly improve screening for resectable lung cancer. Asakura, Kadota et al. demonstrate the diagnostic potential of serum microRNAs for resectable lung cancer. Their diagnostic model based on the combined expression levels of two miRNAs predicts resectable lung cancer with 99% sensitivity, regardless of histological types and pathological stages of cancer, suggesting its promising, diagnostic utility.

Purpose Thin endometrium is often observed after clomiphene citrate (CC) administration for follicular development and is one of the reasons for embryo transfer (ET) cancelation or implantation failure. We retrospectively analyzed whether the endometrial thickness (EMT) on the days of the maturation trigger and ET are predictive factors of pregnancy outcomes after fresh cleaved ET in a CC‐based minimal stimulation cycle (CC‐cycle). Methods A total of 746 CC‐cycles in vitro fertilization (IVF), followed by fresh cleaved ET, from November 2018 to March 2019 were analyzed. Associations between the pregnancy outcomes and EMT on the days of the trigger and ET were statistically evaluated. Results Although the EMT on the day of ET was not significantly associated with the ongoing pregnancy rate (adjusted odds ratio [AOR], 1.043; P = .3251), a decreased EMT on the day of the trigger was significantly associated with a low ongoing pregnancy rate (AOR, 1.154; P = .0042). Furthermore, the clinical pregnancy rate was significantly lower when the EMT was <7 mm on the day of the trigger during the CC‐cycle. Conclusions These results suggest that measurement of the EMT on the day of the trigger could be effective for predicting the pregnancy outcomes after fresh cleaved ET during the CC‐cycle.

This study aimed to investigate the effect of a rehabilitation program combined with pain management targeting pain perception and activity avoidance on multifaceted outcomes in older patients with acute vertebral compression fractures (VCFs). We randomised 65 older adults with acute VCFs to either an intervention group (n = 32), involving usual rehabilitation combined with pain management that targeted pain perception and activity avoidance, or a control group (n = 33), involving only usual rehabilitation. The usual rehabilitation was initiated immediately after admission. All patients were treated conservatively. Pain management aimed to improve the patients’ daily behaviour by increasing their daily activities despite pain, rather than by focusing on eliminating the pain. Pain intensity and psychological statuses such as depression, pain catastrophising, and physical activity levels were assessed on admission. Two weeks postadmission and at discharge, physical performance measures were assessed along with the above-given measurements. A significant main effect of the group was observed for the intensity of lower back pain, favouring the intervention group (F = 5.135, p=0.027). At discharge, it was significantly better in the intervention group than in the control group (p=0.011). A time-by-group interaction emerged for magnification of the pain catastrophising scale (p=0.012), physical activity levels (p<0.001), and six-minute walking distance (p=0.006), all favouring the intervention group. Rehabilitation programs combined with pain management targeting pain perception and activity avoidance could be an effective conservative treatment for older patients with acute VCFs.