Chronic activation of ß-adrenergic receptors leads to tissue water and electrolyte retention.

Beta-adrenergic receptors (ß-AR) are expressed on the membranes of various cell types and their activation affects body water balance by modulating renal sodium and water excretion, cardiovascular function and metabolic processes. However, ß-AR-associated body fluid imbalance has not been well characterised. In the present study, we hypothesized that chronic ß-AR stimulation increases electrolyte and water content at the tissue level. We evaluated the effects of isoproterenol, a non-selective ß-AR agonist, on electrolyte and water balance at the tissue level. Continuous isoproterenol administration for 14 days induced cardiac hypertrophy, associated with sodium-driven water retention in the heart, increased the total body sodium, potassium and water contents at the tissue level, and increased the water intake and blood pressure of the mice. There was greater urine output in response to the isoproterenol-induced body water retention. These isoproterenol-induced changes were reduced by propranolol, a non-selective beta-receptor inhibitor. Isoproterenol-treated mice even without excessive water intake had higher total body electrolyte and water contents, and this tissue water retention was associated with lower dry body mass, suggesting that ß-AR stimulation in the absence of excess water intake induces catabolism and water retention. These findings suggest that ß-AR activation induces tissue sodium and potassium retention, leading to body fluid retention, with or without excess water intake. This characterisation of ß-AR-induced electrolyte and fluid abnormalities improves our understanding of the pharmacological effects of ß-AR inhibitors. Significance Statement We have shown that chronic ß-AR stimulation causes cardiac hypertrophy associated with sodium-driven water retention in the heart and increases the accumulation of body sodium, potassium and water at the tissue level. This characterisation of the ß-AR-induced abnormalities in electrolyte and water balance at the tissue level improves our understanding of the roles of ß-AR in physiology and pathophysiology and the pharmacological effects of ß-AR inhibitors.

Comparative studies of hair shaft components between healthy and diseased donors.

Globally, the rapid aging of the population is predicted to become even more severe in the second half of the 21st century. Thus, it is expected to establish a growing expectation for innovative, non-invasive health indicators and diagnostic methods to support disease prevention, care, and health promotion efforts. In this study, we aimed to establish a new health index and disease diagnosis method by analyzing the minerals and free amino acid components contained in hair shaft. We first evaluated the range of these components in healthy humans and then conducted a comparative analysis of these components in subjects with diabetes, hypertension, androgenetic alopecia, major depressive disorder, Alzheimer's disease, and stroke. In the statistical analysis, we first used a student's t test to compare the hair components of healthy people and those of patients with various diseases. However, many minerals and free amino acids showed significant differences in all diseases, because the sample size of the healthy group was very large compared to the sample size of the disease group. Therefore, we attempted a comparative analysis based on effect size, which is not affected by differences in sample size. As a result, we were able to narrow down the minerals and free amino acids for all diseases compared to t test analysis. For diabetes, the t test narrowed down the minerals to 15, whereas the effect size measurement narrowed it down to 3 (Cr, Mn, and Hg). For free amino acids, the t test narrowed it down to 15 minerals. By measuring the effect size, we were able to narrow it down to 7 (Gly, His, Lys, Pro, Ser, Thr, and Val). It is also possible to narrow down the minerals and free amino acids in other diseases, and to identify potential health indicators and disease-related components by using effect size.

Ginsenosides in Panax ginseng Extract Promote Anagen Transition by Suppressing BMP4 Expression and Promote Human Hair Growth by Stimulating Follicle-Cell Proliferation.

Studies showing that Panax ginseng promotes hair growth have largely been conducted using mice; there are few reports on how P. ginseng affects human hair growth. In particular, little is known about its effect on the telogen to anagen transition. To determine the effect of P. ginseng on human hair growth and the transition from the telogen to the anagen phase. The effects of P. ginseng extract (PGE) and the three major ginsenoside components, Rb1, Rg1, and Re, on the proliferation of human dermal papilla cells (DPCs) and human outer root sheath cells (ORSCs) were investigated. The effects of these compounds on the cell expression of bone morphogenetic protein 4 (BMP4), fibroblast growth factor 18 (FGF18) and Noggin were assessed by real-time PCR. The effect of PGE on hair-shaft elongation was determined in a human hair follicle organ-culture system. PGE and the three ginsenosides stimulated the proliferation of DPCs and ORSCs and suppressed BMP4 expression in DPCs but did not affect FGF18 expression in ORSCs and Noggin expression in DPCs. PGE stimulated hair-shaft growth. PGE and the ginsenosides Rb1, Rg1, and Re stimulate the transition from the telogen phase to anagen phase of the hair cycle by suppressing BMP4 expression in DPCs. These compounds might be useful for promoting the growth of human hair.

Highly efficient Runx1 enhancer eR1-mediated genetic engineering for fetal, child and adult hematopoietic stem cells.

A cis-regulatory genetic element which targets gene expression to stem cells, termed stem cell enhancer, serves as a molecular handle for stem cell-specific genetic engineering. Here we show the generation and characterization of a tamoxifen-inducible CreERT2 transgenic (Tg) mouse employing previously identified hematopoietic stem cell (HSC) enhancer for Runx1, eR1 (+24 m). Kinetic analysis of labeled cells after tamoxifen injection and transplantation assays revealed that eR1-driven CreERT2 activity marks dormant adult HSCs which slowly but steadily contribute to unperturbed hematopoiesis. Fetal and child HSCs that are uniformly or intermediately active were also efficiently targeted. Notably, a gene ablation at distinct developmental stages, enabled by this system, resulted in different phenotypes. Similarly, an oncogenic Kras induction at distinct ages caused different spectrums of malignant diseases. These results demonstrate that the eR1-CreERT2 Tg mouse serves as a powerful resource for the analyses of both normal and malignant HSCs at all developmental stages.

Eosinophilic cystitis mimicking hemorrhagic cystitis in relapsed follicular lymphoma.

Eosinophilic cystitis (EC) is a rare and non-infectious inflammatory disorder characterized by transmural infiltration of eosinophils in the bladder wall. The diagnosis of EC is made only by the pathophysiological findings. Because the urinary symptoms of EC are quite similar to other urinary tract disorders including hemorrhagic cystitis (HC), it can be misdiagnosed or left undiagnosed. A 49-year-old woman with relapsed and refractory follicular lymphoma presented with sudden-onset gross hematuria after the chemo-immunotherapy. The patient was initially treated as HC with continuous bladder irrigation, resulting in recurrent and refractory hematuria. Corticosteroid dramatically resolved hematuria after the bladder biopsy revealed EC. It is important to suspect EC and perform bladder biopsy in patients with recurrent episodes of hematuria or refractory to conservative treatment for HC.

Non-valvular Infective Endocarditis Caused by Sarocladium kiliense in an Immunocompromised Patient with Aplastic Anemia.

Sarocladium kiliense is ubiquitous in the human environment and is an emerging opportunistic pathogen, especially among immunocompromised hosts. A 77-year-old man diagnosed with aplastic anemia suffered from non-valvular endocarditis. After he passed away, fungal hyphae were observed in several lesions on a postmortem examination. Polymerase chain reaction (PCR) and a DNA sequence analysis revealed S. kiliense as the causative organism. This is the first case report of non-valvular fungal endocarditis caused by S. kiliense identified by PCR and a DNA sequence analysis in an immunocompromised patient. Although rare, invasive fungal infection caused by S. kiliense should be considered in immunocompromised hosts.

Resection of liver metastasis from submandibular gland carcinoma five years after the primary operation: A case.

INTRODUCTION: Liver metastasis of submandibular gland carcinoma is not uncommon, yet its optimal management is still unclear. We report a case of resection of liver metastasis from submandibular gland carcinoma five years after the primary operation. CASE PRESENTATION: The patient was a 76-year-old male who had undergone resection of primary adenoid cystic carcinoma of the submandibular gland in 2012. On follow-up computed tomography (CT) five years after the initial operation, a tumor was found incidentally in hepatic segment 6. Magnetic resonance imaging (MRI) confirmed the lesion's presence. Based on imaging findings and medical history, the lesion was suspected to be a liver metastasis of the previous submandibular gland carcinoma. The patient underwent hepatic posterior sectionectomy. His postoperative course was uneventful except for minor bile leakage that subsided without surgical intervention, and he was discharged on postoperative day 25. Postoperative pathological examinations of the hepatic tumor showed exactly the same features seen in the primary submandibular gland carcinoma, and the diagnosis as metastasis from this carcinoma was confirmed. DISCUSSION: Liver resection may be a reasonable choice of treatment for liver metastasis of submandibular gland carcinoma. Further evidence from studies with larger patient populations must be accumulated to confirm this. CONCLUSION: We report our experience with a case of liver metastasis from submandibular gland carcinoma, which was resected five years after the primary operation.

The segment IV approach: a useful method for achieving the critical view of safety during laparoscopic cholecystectomy in patients with anomalous bile duct.

BACKGROUND: The critical view of safety (CVS) method can be achieved by avoiding vasculo-biliary injury resulting from misidentification during laparoscopic cholecystectomy (LC). Although achieving the CVS has become popular worldwide, there is no established standardized technique to achieve the CVS in patients with an anomalous bile duct (ABD). We recently reported our original approach for securing the CVS using a new landmark, the diagonal line of the segment IV of the liver (D-line). The D-line is an imaginary line that lies on the right border of the hilar plate. The cystic structure can be securely isolated along the D-line without any misidentification, regardless of the existence of an ABD. We named this approach the segment IV approach in LC. METHODS: In this study, we adopted the segment IV approach in patients with an ABD. RESULTS: From October 2015 to June 2020, 209 patients underwent LC using the segment IV approach. Among them, three (1.4%) were preoperatively diagnosed with an ABD. The branching point of the cystic duct was the posterior sectional duct, anterior sectional duct, or left hepatic duct in each patient. The CVS was achieved in all cases without any complications. CONCLUSION: It is a promising technique, especially even for patients with an ABD during LC.

Exploration of an odorous aldehydes and ketones produced by Uroglena americana using high resolution mass spectrometry, GC-Olfactometry, and multivariate analysis.

Off-flavor events in tap water have been reported from various regions of Japan. Fishy smell is the second most common off-flavor in Japan and Uroglena americana (U. americana) is known to be a major contributor to the smell. However, the causative compound of the smell it produces still remains unrevealed to the best of our knowledge. In this study, an exploration of odorous aldehydes and ketones originating from U. americana was performed with a view to discovering a possible candidate substance of causative compounds. Environmental samples containing U. americana colony and cultured media with U. americana were analyzed with two high resolution mass spectrometers, one of them is coupled with liquid chromatography (LC-HRMS), and the other is with gas chromatography and a sniffing port (GC-O-HRMS). Multivariate analyses (MVA) were utilized to explore a compound that is likely to be odorous aldehydes or ketones with a reduced time of exploration. A combination of LC-HRMS and MVA resulted in the selection of one candidate substance and its formula was determined to be C13H20O3 on the basis of its accurate mass and natural isotopic pattern. The candidate substance underwent GC-O-HRMS analyses and milk-like smell was detected at around its retention time. Although the detected smell was different from fishy smell, it is expected that the fishy smell is caused by multiple compounds to which the candidate substance belongs. First generation product ion spectra of the candidate substance suggested that it contains a hydroxyl group, a cyclohexene ring, and a ketone moiety.

Segment IV approach for difficult laparoscopic cholecystectomy.

Although achieving the critical view of safety (CVS) is useful for avoiding vasculobiliary injury during laparoscopic cholecystectomy (LC), the CVS cannot always be achieved in cases of severe cholecystitis because of technical difficulties. Herein, we focused on segment IV of the liver and its diagonal line (D-line) as a feasible landmark for carrying out difficult LC. The D-line connects the right dorsal and left ventral corners of segment IV and is used as the vectoral landmark, which is where the gallbladder is first dissected to achieve CVS without misidentification. Conversion to subtotal cholecystectomy along the D-line is also feasible when gallbladder wall scarring is severe. We named this procedure the segment IV approach for LC. Sixty-two consecutive difficult LC (including 27 scheduled LC after percutaneous transhepatic gallbladder drainage [PTGBD] and 35 conservatively treated cases of Tokyo Guidelines [TG] grade II cholecystitis) were managed by the segment IV approach. Successful gallbladder extraction along the D-line was achieved in 44 (71%) cases; all of these cases also achieved CVS following total cholecystectomy. The other 18 (29%) cases were converted to subtotal cholecystectomy because gallbladder extraction along the D-line failed as a result of severe cholecystitis with inflammatory adhesion with surrounding structures. Median operative time and intraoperative blood loss were 135 (range, 54-290) min and 10 (range, 0-100) mL, respectively. No intra- or postoperative complications were observed. The segment IV approach is feasible for achieving CVS and for considering subtotal cholecystectomy in difficult LC cases where scarring of the gallbladder wall is present.

Venue of catheter insertion does not significantly impact the event of central line-associated bloodstream infection in patients with haematological diseases.

BACKGROUND: Central line-associated bloodstream infection (CLABSI) is a serious complication of central venous catheter (CVC) placement in patients with haematological diseases associated with neutropenia and immunosuppression. However, whether the venues where CVC are inserted influence CLABSI development remains unclear. METHODS: We investigated whether CVC insertion at venues with different standards of cleanliness altered the occurrence of CLABSI. We evaluated data from 279 patients (545 CVC insertions) with haematological diseases including age, sex, underlying disease, reason for insertion, insertion site, number of lumens, venue, dates of insertion and removal, complete blood counts, percentage of neutrophils and serum albumin concentrations at the time of CVC insertion. FINDINGS: Overall, 55 CLABSI events occurred during a period of 23,434 catheter days (2.35 per 1,000 catheter days). In total, 153 and 190 patients underwent 226 and 305 CVC insertions, respectively in a ward and in an operating room, respectively. Univariate analysis identified the operating room (P = 0.017), allogeneic haematopoietic stem cell transplantation (P < 0.001), triple lumen catheter (P = 0.002), haemoglobin (P = 0.019), white blood cell count (P = 0.012) and percentage of neutrophils (P = 0.012) as significant factors for the development of CLABSI. However, multivariate analysis adjusted for age, reason for insertion, insertion site, number of lumens, haemoglobin, percentage of neutrophils and platelet counts found no significant differences between the venue where CVC were inserted and CLABSI development (P = 0.158). CONCLUSION: The venue of CVC insertion is unlikely to influence CLABSI development in patients with haematological diseases.

New Concept Air Conditioning System for the Operating Room to Minimize Patient Cooling and Surgeon Heating: A Historical Control Cohort Study.

BACKGROUND: Intraoperative hypothermia is a common adverse event. For avoiding the complication due to hypothermia, many warming devices and methods have been used in perioperative period. It has been reported that more patients undergoing laparoscopic surgery tend to have hypothermia than with open surgery. To avoid intraoperative hypothermia, many kinds of warming tools have been used. But, it was also reported that some warming methods increased perceptions of distraction and physical demand. METHODS: To achieve both patients' normothermia and surgeons' comfort, new air conditioning (AC) system was designed with considering the characteristics of laparoscopic surgery. The temperature of the airflows to the patient and to the surgeons can be adjusted independently in this new system. The new system has two parts. One controls the temperature of the central area over the operation table. The air from this part falls on the patients. The other part is the lateral area beside the operating table; the air from this part falls on the surgeons. The subjects of this study were 160 gastric cancer patients and 316 colorectal cancer patients undergoing laparoscopic surgery. The temperature of the central flow was set 23.5 °C, and the temperature of the lateral flow was set 22 °C just after the anesthesia. The number of timepoints the patient spent in hypothermic state, defined as a temperature cooler by 0.5 °C or more than that at the starting point of surgery, was determined in each patient. RESULTS: In the results, the rate of hypothermic state in old operation rooms was 23.8% and that in new operation rooms was 2.7% in male gastric cancer patients (p < 0.01). And those were 37.1% in old operation rooms and 0.9% in new operation rooms in female gastric cancer patients (p < 0.01). The rate of hypothermic state in old operation rooms was 30.0% and that in new operation rooms was 9.5% in male colorectal cancer patients (p < 0.01). And those were 41.6% in old operation rooms and 8.9% in new operation rooms in female colorectal cancer patients (p < 0.01). The similar results were showed in the study, which subjects were limited the patients undergoing surgery in 2015 and 2016; which were the last year the old operation rooms were used and the first year the new operation rooms were used. CONCLUSIONS: Thus, the usefulness of the new air conditioning system for achieving both patients' normothermia and comfort of surgeons could be verified in this study.

Clinical Significance of Tumor-Infiltrating T Cells and Programed Death Ligand-1 in Patients with Pancreatic Cancer.

The associations of the immunological status of the pancreatic ductal adenocarcinoma (PDA) microenvironment with prognosis were assessed. A high tumor-infiltrating lymphocyte (TIL) density was associated with a better prognosis. Importantly, even with a high density of TILs, the PDA cells with programed cell death-ligand 1 (PD-L1) expression showed a worse prognosis than the patients with negative PD-L1 expression. A significant association between a better prognosis and a tumor microenvironment with a high TIL density/negative PD-L1 expression was observed. Assessments of a combined immunological status in the tumor microenvironment may predict the prognosis of PDA patients following surgical resection.

Impact of Bile Exposure Time on Organ/space Surgical Site Infections After Pancreaticoduodenectomy.

BACKGROUND/AIM: Organ/space surgical site infections (SSIs) are critical complications of pancreaticoduodenectomy. We investigated the impact of the time between division of the common hepatic duct and completion of biliary reconstruction [bile exposure (BE) time] on the occurrence of post-pancreaticoduodenectomy organ/space SSI. PATIENTS AND METHODS: Sixty-one patients who underwent pancreaticoduodenectomy were retrospectively studied. The impact of perioperative variables and BE time on organ/space SSI occurrence was analyzed. RESULTS: Organ/space SSIs occurred in 17 patients (28%). Patients were divided into two groups according to BE time. The incidence of organ/space SSIs was significantly higher in the long BE time group than in the short BE time group (42% versus 13%, p=0.0127). Multivariate analysis revealed that long BE times [odds ratio (OR)=4.8; p=0.0240] and soft pancreatic texture (OR=16.5; p=0.0106) were independent risk factors for organ/space SSIs. CONCLUSION: Long BE time is a risk factor for post-pancreaticoduodenectomy organ/space SSIs. Shortening BE time may reduce organ/space SSI occurrence.

A new highly sensitive real-time quantitative-PCR method for detection of BCR-ABL1 to monitor minimal residual disease in chronic myeloid leukemia after discontinuation of imatinib.

Tyrosine kinase inhibitors (TKIs) targeting the BCR-ABL1 fusion protein, encoded by the Philadelphia chromosome, have drastically improved the outcomes for patients with chronic myeloid leukemia (CML). Although several real-time quantitative polymerase chain reaction (RQ-PCR) kits for the detection of BCR-ABL1 transcripts are commercially available, their accuracy and efficiency in laboratory practice require reevaluation. We have developed a new in-house RQ-PCR method to detect minimal residual disease (MRD) in CML cases. MRD was analyzed in 102 patients with CML from the DOMEST study, a clinical trial to study the rationale for imatinib mesylate discontinuation in Japan. The BCR-ABL1/ABL1 ratio was evaluated using the international standard (IS) ratio, where IS < 0.1% was defined as a major molecular response. At enrollment, BCR-ABL1 transcripts were undetectable in all samples using a widely-applied RQ-PCR method performed in the commercial laboratory, BML (BML Inc., Tokyo, Japan); however, the in-house method detected the BCR-ABL1 transcripts in five samples (5%) (mean IS ratio: 0.0062 ± 0.0010%). After discontinuation of imatinib, BCR-ABL1 transcripts were detected using the in-house RQ-PCR in 21 patients (21%) that were not positive using the BML method. Nineteen samples were also tested using a commercially available RQ-PCR assay kit with a detection limit of IS ratio, 0.0032 (ODK-1201, Otsuka Pharmaceutical Co., Tokyo, Japan). This method detected low levels of BCR-ABL1 transcripts in 14 samples (74%), but scored negative for five samples (26%) that were positive using the in-house method. From the perspective of the in-house RQ-PCR method, number of patients confirmed loss of MMR was 4. These data suggest that our new in-house RQ-PCR method is effective for monitoring MRD in CML.

Laparoscopic treatment of a solitary fibrous tumor originating in the cystic plate.

BACKGROUND: Solitary fibrous tumor (SFT) is a rare mesenchymal tumor originating from the tissue underlying the mesothelial layer of the pleura or mediastinum. Other reported sites include the upper respiratory tract, orbit, thyroid, peritoneum, and central nervous system. CASE PRESENTATION: We describe a case of a 7 cm SFT that originated in the cystic plate. A liver tumor was an incidental finding in a 49-year-old woman during a regular radiological checkup for uterine fibroids. Imaging revealed a well-circumscribed solid mass between the gallbladder and liver. Intraoperative laparoscopy identified a soft tumor that had progressively expanded behind the gallbladder which was easily separated from the Laennec's capsule of the liver. Hematoxylin and Eosin and immunohistochemical staining of the tumor tissue found both tangled and patterned arrangements of spindle cells consistent with a SFT derived from the subserosal layer of the gallbladder. CONCLUSIONS: To the best of our knowledge, this is the first report of a SFT originating in the cystic plate.

A case of portal vein thrombosis caused by blunt abdominal trauma in a patient with low protein C activity.

Portal vein thrombosis (PVT) is caused by several conditions including infection, malignancies, surgery, medications, and coagulation disorders. However, PVT caused by low-energy injury is very rare. A 51-year-old man visited a clinic with a 2-day history of abdominal pain following blunt abdominal trauma. Contrast-enhanced computed tomography (CT) revealed thrombosis in both the portal vein and splenic vein, and he was transferred to our hospital with a diagnosis of PVT. Anticoagulant therapy was initiated using unfractionated heparin. A repeat CT scan revealed enlargement of the thrombus, which occluded the main trunk and first right branch of the portal vein. Laboratory data before heparin administration suggested low protein C activity. Anticoagulation therapy was continued with intermittent assessment of the size of the thrombus and degree of coagulation. On day 23, enhanced CT showed marked shrinkage of the thrombus compared with that on day 8. On day 30, the patient was discharged with a therapeutic prothrombin time-international normalized ratio. Here we present a case of PVT caused by low-energy trauma of the upper abdomen in a patient with a background of low protein C activity that was successfully treated without invasive surgery.