Nafamostat mesylate decreases skin flap necrosis in a mouse model of type 2 diabetes by protecting the endothelial glycocalyx.

The success rate of flap tissue reconstruction has increased in recent years owing to advancements in microsurgical techniques. However, complications, such as necrosis, are still more prevalent in diabetic patients compared to non-diabetic individuals, presenting an ongoing challenge. To address this issue, many previous studies have examined vascular anastomoses dilation and stability, primarily concerning surgical techniques or drugs. In contrast, in the present study, we focused on microvascular damage of the peripheral microvessels in patients with diabetes mellitus and the preventative impact of nafamostat mesylate. Herein, we aimed to investigate the effects of hyperglycemia on glycocalyx (GCX) levels in mice with type 2 diabetes. We examined the endothelial GCX (eGCX) in skin flap tissue of 9-12-week-old type 2 diabetic mice (db/db mice) using a perforator skin flap and explored treatment with nafamostat mesylate. The growth rates were compared after 1 week. Heterotype (db/+) mice were used as the control group. Morphological examination of postoperative tissues was performed at 1, 3, 5, and 7 days post-surgery. In addition, db/db mice were treated with 30 mg/kg/day of nafamostat mesylate daily and were evaluated on postoperative day 7. Seven days after surgery, all db/db mice showed significant partial flap necrosis. Temporal observation of the skin flaps revealed a stasis-like discoloration and necrosis starting from the contralateral side of the remaining perforating branch. The control group did not exhibit flap necrosis, and the flap remained intact. In the quantitative assessment of endothelial glycans using lectins, intensity scoring showed that the eGCX in the db/db group was significantly thinner than that in the db/+ group. These results were consistent with the scanning electron microscopy findings. In contrast, treatment with nafamostat mesylate significantly improved the flap engraftment rate and suppressed eGCX injury. In conclusion, treatment with nafamostat mesylate improves the disrupted eGCX structure of skin flap tissue in db/db mice, potentially ameliorating the impaired capillary-to-venous return in the skin flap tissue.

Local anesthetic lidocaine induces growth suppression of HeLa cells by decreasing and changing the cellular localization of the proliferation marker Ki-67.

Although surgery is a basic therapy for cancer, it causes inflammation and immunosuppression, often resulting in recurrence and metastasis. Previous studies have suggested that anesthetic management influences the prognosis of cancer surgery patients. Administration of local anesthetics, such as lidocaine, for pain control reportedly improves their clinical outcomes; however, the precise underlying mechanism has not been fully elucidated. The growth of human embryonic kidney (HEK) 293T and cervical cancer HeLa cells was inhibited by lidocaine treatment and these cell lines showed different sensitivities for lidocaine. Ki-67 is a significant prognostic marker of cancer because it is expressed in the nucleus of actively proliferating cells. In lidocaine-treated HeLa cells, Ki-67 was detected not only in the nucleus but also in the cytoplasm. In addition, lidocaine-induced cytoplasmic Ki-67 partly colocalized with the increased ER chaperone, glucose-regulated protein 78, which is crucial for protein folding and maintenance of cellular homeostasis. Furthermore, lidocaine decreased Ki-67 levels and increased the population of HeLa cells in the G0/G1 phase. These results indicate that lidocaine plays a significant role in growth suppression by regulating the expression and distribution of Ki-67.

Recombinant Antithrombin Attenuates Acute Respiratory Distress Syndrome in Experimental Endotoxemia.

Sepsis-induced endothelial acute respiratory distress syndrome is related to microvascular endothelial dysfunction caused by endothelial glycocalyx disruption. Recently, recombinant antithrombin (rAT) was reported to protect the endothelial glycocalyx from septic vasculitis; however, the underlying mechanism remains unknown. Here, we investigated the effect of rAT administration on vascular endothelial injury under endotoxemia. Lipopolysaccharide (LPS; 20 mg/kg) was injected intraperitoneally into 10-week-old male C57BL/6 mice, and saline or rAT was administered intraperitoneally at 3 and 24 hours after LPS administration. Subsequently, serum and/or pulmonary tissues were examined for inflammation and cell proliferation and differentiation by histologic, ultrastructural, and microarray analyses. The survival rate was significantly higher in rAT-treated mice than in control mice 48 hours after LPS injection (75% versus 20%; P < 0.05). Serum interleukin-1ß was increased but to a lesser extent in response to LPS injection in rAT-treated mice than in control mice. Lectin staining and ultrastructural studies showed a notable attenuation of injury to the endothelial glycocalyx after rAT treatment. Microarray analysis further showed an up-regulation of gene sets corresponding to DNA repair, such as genes involved in DNA helicase activity, regulation of telomere maintenance, DNA-dependent ATPase activity, and ciliary plasm, after rAT treatment. Thus, rAT treatment may promote DNA repair, attenuate inflammation, and promote ciliogenesis, thereby attenuating the acute respiratory distress syndrome caused by endothelial injury.

Brain Diseases and Fall-Related Surgery in Older Persons.

BACKGROUND: It is known that age-related brain symptoms (gait difficulty and dementia) increase the likelihood of fall-related surgery. In contrast, it is not known which types of brain disease underlie such symptoms most. OBJECTIVE: The aim of this study was to correlate brain diseases with the types of surgeries performed at our hospital for patients who had fallen. METHODS: This was a retrospective study at a multifaculty university hospital in Japan, with a 12-month recruiting period, a follow-up period of 3.0 ± 2.5 weeks, and ≥1×/week visits. We assembled a neurogeriatric team to diagnose brain diseases with the use of brain imaging to the extent possible and correlated the diagnoses with types of fall-related surgery. RESULTS: Fall-related surgery was conducted by the orthopedics (OP) and neurosurgery (NS) faculties (total n = 124) at a ratio of about 2 to 1. The underlying brain diseases differed by faculty; for OP, surgery was most commonly performed in patients with a combination of white matter disease (WMD) and Alzheimer's disease (AD) (79%) followed by dementia with Lewy bodies. In contrast, for NS, the most common surgery was for patients with alcoholism (50%) followed by a combination of WMD and AD. CONCLUSION: Fall-related surgery was performed by the OP and NS faculties at a 2 to 1 ratio. The major underlying brain diseases were a combination of WMD and AD (79%) for OP and alcoholism (50%) for NS.

Conditional Ror1 knockout reveals crucial involvement in lung adenocarcinoma development and identifies novel HIF-1α regulator.

We previously reported that ROR1 is a crucial downstream gene for the TTF-1/NKX2-1 lineage-survival oncogene in lung adenocarcinoma, while others have found altered expression of ROR1 in multiple cancer types. Accumulated evidence therefore indicates ROR1 as an attractive molecular target, though it has yet to be determined whether targeting Ror1 can inhibit tumor development and growth in vivo. To this end, genetically engineered mice carrying homozygously floxed Ror1 alleles and an SP-C promoter-driven human mutant EGFR transgene were generated. Ror1 ablation resulted in marked retardation of tumor development and progression in association with reduced malignant characteristics and significantly better survival. Interestingly, gene set enrichment analysis identified a hypoxia-induced gene set (HALLMARK_HYPOXIA) as most significantly downregulated by Ror1 ablation in vivo, which led to findings showing that ROR1 knockdown diminished HIF-1α expression under normoxia and clearly hampered HIF-1α induction in response to hypoxia in human lung adenocarcinoma cell lines. The present results directly demonstrate the importance of Ror1 for in vivo development and progression of lung adenocarcinoma, and also identify Ror1 as a novel regulator of Hif-1α. Thus, a future study aimed at the development of a novel therapeutic targeting ROR1 for treatment of solid tumors such as seen in lung cancer, which are frequently accompanied with a hypoxic tumor microenvironment, is warranted.

Possible involvement of Syndecan-1 in the state of COVID-19 related to endothelial injury.

BACKGROUND: The coronavirus infection 2019 (COVID-19) is associated with microvascular endothelial injury. Here, we report that syndecan-1, a component of endothelial glycocalyx, may reflect the disease state of COVID-19 related to endothelial injury. CASE PRESENTATION: A patient with COVID-19 was transferred to the intensive care unit of our hospital. Computed tomography of the chest showed bilateral ground glass opacities, which was diagnosed as acute respiratory syndrome. The PaO2/FIO2 ratio gradually increased from 158 on hospitalization to 300 on Day 11, on which day the ventilator was withdrawn. However, serum syndecan-1 (SDC-1) level gradually decreased from 400.5 ng/ml at hospitalization to 165.1 ng/ml on Day 5. On Day 6, serum SDC-1 level increased to 612.9 ng/ml owing to a systemic thrombosis with an increase in D-dimer. Serum SDC-1 level then decreased until 206.0 ng/ml on Day 11 after a decrease in D-dimer. The patient was transferred to another hospital on Day 21 after hospitalization. CONCLUSIONS: In this case report, changes in serum SDC-1 level closely reflected the change in disease condition in a patient with COVID-19. Serum SDC-1 may be a useful biomarker for monitoring the disease state of critically ill patients with COVID-19.

Clinical impact of monitoring frequency per day as a prospective audit and feedback strategy for patients receiving antimicrobial agents by injection.

BACKGROUND: Implementation of antimicrobial stewardship programmes improve antimicrobial therapies and thus result in better patient outcomes and safety. The impact of prospective audit and feedback (PAF) is likely dependent on how frequently it is conducted, and how quickly after antibiotic prescription it is initiated. To our knowledge, however, no report has yet investigated the impact of an increase in monitoring frequency per day on PAF strategy. Here, we evaluated the clinical impact of an increase in monitoring frequency per day as a PAF strategy in patients receiving antimicrobial injections. METHODS: We conducted a single-centre, retrospective observational pre-post study to evaluate the impact of increasing the frequency of monitoring from once daily (once daily review group) to twice daily (twice daily review group). Time to intervention and clinical outcomes were compared before and after implementation of twice daily review. RESULTS: Time to intervention for inappropriate antimicrobial therapy was significantly shorter in the twice daily review group than the once daily review group (5.1 ± 6.1 hours vs 29.9 ± 21.5 hours, HR: 4.53, 95% CI: 2.90-7.07, P < .001). The twice daily review group had a significantly lower rate of clinical failure (16.2% vs 38.3%, P = .004) and hepatotoxicity (4.1% vs 15.0%, P = .035) than the once daily review group. CONCLUSIONS: An increase in monitoring frequency from once daily to twice daily significantly shortened the time to intervention for inappropriate antimicrobial therapy, with a concomitant reduction in clinical failure and hepatotoxicity.

Elevated Membrane Cholesterol Disrupts Lysosomal Degradation to Induce ß-Amyloid Accumulation: The Potential Mechanism Underlying Augmentation of ß-Amyloid Pathology by Type 2 Diabetes Mellitus.

The endocytic membrane trafficking system is altered in the brains of early-stage Alzheimer disease (AD) patients, and endocytic disturbance affects the metabolism of ß-amyloid (Aß) protein, a key molecule in AD pathogenesis. It is widely accepted that type 2 diabetes mellitus (T2DM) is one of the strongest risk factors for development of AD. Supporting this link, experimentally induced T2DM enhances AD pathology in various animal models. Spontaneous T2DM also enhances Aß pathology with severe endocytic pathology, even in nonhuman primate brains. However, it remains unclear how T2DM accelerates Aß pathology. Herein, we demonstrate that cholesterol metabolism-related protein levels are increased and that membrane cholesterol level is elevated in spontaneous T2DM-affected cynomolgus monkey brains. Moreover, in vitro studies that manipulate cellular cholesterol reveal that elevated membrane cholesterol disrupts lysosomal degradation and enhances chemical-induced endocytic disturbance, resulting in great accumulation of Aß in Neuro2a cells. These findings suggest that an alteration of cerebral cholesterol metabolism may be responsible for augmentation of Aß pathology in T2DM-affected brains, which, in turn, may increase the risk for developing AD.

History of the development of antagonists for neuromuscular blocking agents.

Muscle relaxation induced by neuromuscular blocking agents (NMBAs) is necessary for tracheal intubation and immobilization during surgery. Although acetylcholinesterase inhibitors have been successfully used as antagonists for NMBAs, they have their limitations; their effects are transient and ineffective against profound neuromuscular blockade. In the past, alternative antagonists were developed, such as germine and 4-aminopyridine, which are effective for the treatment of diseases causing muscle weakness and could potentially be used as antagonists for NMBAs. Unfortunately, these drugs did not come into practical use due to unwanted side-effects. Sugammadex is an almost ideal antagonist because it rapidly forms a rigid complex with rocuronium and produces less adverse effects. The development of novel NMBAs and antagonists, especially sugammadex, has revolutionized anesthesia practice. Recently, novel short-acting NMBAs, such as gantacurium and CW002 have been developed. Their effects can be reversed by the amino-acid L-cysteine. More recently, calabadions have been developed, which can form complexes with both steroidal and bisbenzyl-isoquinolinium NMBAs, in a similar fashion as sugammadex. Understanding the history of the NMBA antagonist's development is interesting and useful for modern anesthesiologists since it enhances their knowledge about the mechanisms involved in neuromuscular transmission and might lead to the development of ideal NMBA antagonists.

Dog-specific hemorrhagic changes induced by liposomal formulations, in the liver and the gallbladder.

Although several liposomal drugs, including liposomal doxorubicin, have been approved, the etiology of the pathological responses caused by their physicochemical properties remains unknown. Herein, we investigated the pathological changes in the liver and the gallbladder of dogs following a single injection of liposomal doxorubicin (1 or 2.5 mg/kg) or an empty liposomal formulation (i.e., liposomal formulation without doxorubicin, ca. 21 mg/kg as lipid content). Injection of liposomal doxorubicin or the empty liposomal formulation induced hemorrhagic changes in the liver and the gallbladder. These changes were accompanied by minimal cellular infiltration with no obvious changes in the blood vessels. As there were no differences in the incidence and severity of hemorrhage between the groups administered comparable amounts of total lipid, the physicochemical properties of the liposomal formulation rather than an active pharmacological ingredient, doxorubicin, were associated with the hemorrhagic changes. Furthermore, decreased cytoplasmic granules with low electron density in mast cells beneath the endothelium of the hepatic vein were observed in the liver of dogs treated with liposomal doxorubicin or empty liposomal formulation. Injection of compound 48/80, a histamine releaser induced comparable hemorrhage in dogs, implying that hemorrhage caused by injection of liposomal doxorubicin or the empty liposomal formulation could be attributed to the histamine released from mast cells. The absence of similar hemorrhagic lesions in other species commonly used in toxicology studies (i.e., rats and monkeys), as well as humans, is due to the lack of mast cells beneath the endothelium of the hepatic vein in these species.

Clinical impact of a prospective audit with intervention and feedback without carbapenem restriction in patients receiving carbapenem injection.

BACKGROUND: Antimicrobial stewardship is required to ensure the appropriate use of antimicrobials. However, few reports have shown the impact of antimicrobial stewardship on clinical outcomes. METHODS: To evaluate the clinical outcomes of implementing a prospective audit with intervention and feedback without carbapenem pre-authorisation, we conducted a single-centre, prospective cohort study in patients who received carbapenem injection. Subjects were allocated to groups receiving antimicrobial agents before (non-intervention group) or after (intervention group) the implementation of an antimicrobial stewardship programme in the clinical setting. RESULTS: The intervention facilitated the rate of choice of effective antimicrobials on day 2 from the onset of infection (from 63.2% to 90.2%; P < 0.001). Moreover, the rates of clinical failure-free survival (hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.47-0.89; P = 0.008) and re-infection-free survival (HR, 0.35; 95% CI, 0.18-0.68; P = 0.002) were significantly higher in the intervention group than in the non-intervention group. A multivariate Cox proportional hazard analysis indicated that non-implementation of antimicrobial stewardship was a significant risk factor for clinical failure in patients receiving carbapenem injection (HR, 1.56; 95% CI, 1.11-2.19; P = 0.010). CONCLUSIONS: Our prospective audit with intervention and feedback strategy without carbapenem restriction facilitated the choice of optimal antimicrobials at an early stage of infection and improved clinical outcomes in patients who received carbapenem.

Clinical impact of matrix-assisted laser desorption ionization-time of flight mass spectrometry combined with antimicrobial stewardship interventions in patients with bloodstream infections in a Japanese tertiary hospital.

BACKGROUND: Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) has the potential to permit early organism identification and optimization of antibiotic therapy. However, MALDI-TOF MS combined with antimicrobial stewardship is available at only a limited number of institutions. Here, we evaluated the clinical impact of implementing MALDI-TOF MS combined with antimicrobial stewardship intervention in patients with bloodstream infections. METHODS: We conducted a single-centre, prospective cohort study to evaluate the clinical impact of implementing MALDI-TOF MS combined with antimicrobial stewardship intervention in patients with bloodstream infections. Processes and clinical outcomes in patients with bloodstream infections were compared before and after implementation of MALDI-TOF MS. RESULTS: Compared with the conventional identification method, MALDI-TOF MS combined with antimicrobial stewardship intervention significantly decreased the time to organism identification (48.6 ± 46.0 hours vs 78.1 ± 38.9 hours, P < 0.001), effective antimicrobial therapy (12.9 ± 19.0 hours vs 26.2 ± 44.8 hours, P < 0.001) and optimal antimicrobial therapy (53.3 ± 55.0 hours vs 91.7 ± 88.7 hours, P < 0.001. Moreover, the rate of clinical failure (14.0% vs 33.3%, P < 0.001) and incidence of adverse events (7.5% vs 23.9%, P < 0.001) was lower in the MALDI-TOF MS group than in the conventional identification group. A multivariate Cox proportional hazard analysis indicated that implementation of MALDI-TOF MS was a protective factor against clinical failure in patients with bloodstream infections (hazard ratio, 0.61; 95% confidence interval, 0.38-0.99; P = 0.047). CONCLUSIONS: Implementation of the MALDI-TOF MS combined with antimicrobial stewardship intervention facilitated early optimization of antimicrobial therapy with a remarkable concomitant reduction in clinical failure and adverse events in patients with bloodstream infections.

The impact of implementing an antifungal stewardship with monitoring of 1-3, ß-D-glucan values on antifungal consumption and clinical outcomes.

WHAT IS KNOWN AND OBJECTIVE: Implementation of an antifungal stewardship programme is a recognized need. However, there is insufficient information to confirm the impact of antifungal stewardship interventions. Further, few studies have evaluated the clinical effects of an antifungal stewardship intervention using 1-3, ß-D-glucan (ßDG) testing. The aim of the present study was to evaluate the impact of implementing an antifungal stewardship with monitoring of ßDG values on antifungal use and clinical outcomes. METHODS: A single institutional prospective cohort study was conducted to evaluate the impact of implementing daily reviews of antifungal agents and monitoring patients who measured ßDG values since August 2013. Antifungal consumption and clinical outcomes in patients with Candida bloodstream infection were compared before and after the intervention. RESULTS: After implementation of the programme, parental antifungal use was significantly reduced compared to that before intervention (P = 0.006). In the after-intervention group, the rate of 60-day clinical failure in patients with Candida bloodstream infection was significantly reduced, from 80.0% (28/35) to 36.4% (8/22) (P < 0.001), and the rate of 60-day mortality associated with Candida bloodstream infection tended to be reduced, from 42.9% (15/35) to 18.2% (4/22) (P = 0.081) compared to the before-intervention group. The incidence of adverse events associated with antifungal agents was significantly lower in the after-intervention group than in the before-intervention group (51.4% [18/35] vs 13.6% [3/22], P = 0.004). WHAT IS NEW AND CONCLUSION: Our findings suggest that daily review of the use of antifungal agents and monitoring of measured ßDG values was highly effective in reducing antifungal consumption and improving the clinical outcomes of patients with Candida bloodstream infection.

Petunidin, a B-ring 5'-O-Methylated Derivative of Delphinidin, Stimulates Osteoblastogenesis and Reduces sRANKL-Induced Bone Loss.

Several lines of evidence suggest that oxidative stress is one of the key pathogenic mechanisms of osteoporosis. We aimed to elucidate the bone protective effects of petunidin, one of the most common anthocyanidins, considering its potent antioxidative activity. Petunidin (>5 µg/mL) significantly inhibited osteoclastogenesis and downregulated c-fos, Nfatc1, Mmp9, Ctsk, and Dc-stamp mRNA expression in RAW264.7 cells. Conversely, petunidin (>16 µg/mL) stimulated mineralized matrix formation and gene expression of Bmp2 and Ocn, whereas it suppressed Mmp13, Mmp2, and Mmp9 mRNA expression and proteolytic activities of MMP13 and MMP9 in MC3T3-E1 cells. Micro-CT and bone histomorphometry analyses of sRANKL-induced osteopenic C57BL/6J mice showed that daily oral administration of petunidin (7.5 mg/kg/day) increased bone volume to tissue volume (BV/TV), trabecular thickness (Tb.Th), trabecular number (Tb.N), the ratio of osteoid volume to tissue volume (OV/TV), osteoid thickness (O.Th), the ratio of osteoid surface to bone surface (OS/BS), the ratio of osteoblast surface to bone surface (Ob.S/BS), and the number of osteoblast per unit of bone surface (N.Ob/BS), and decreased trabecular separation (Tb.Sp), the ratio of eroded surface to bone surface (ES/BS), the ratio of osteoclast surface to bone surface (Oc.S/BS), and number of osteoclast per unit of bone surface (N.Oc/BS), compared to untreated mice. Furthermore, histological sections of the femurs showed that oral administration of petunidin to sRANKL-induced osteopenic mice increased the size of osteoblasts located along the bone surface and the volume of osteoid was consistent with the in vitro osteoblast differentiation and MMP inhibition. These results suggest that petunidin is a promising natural agent to improve sRANKL-induced osteopenia in mice through increased osteoid formation, reflecting accelerated osteoblastogenesis, concomitant with suppressed bone resorption.

A patient with peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and severe hypoganglionosis associated with a novel SOX10 mutation.

In this report, we present the case of a female infant with peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease (PCWH) associated with a novel frameshift mutation (c.842dupT) in exon 5, the last exon of SOX10. She had severe hypoganglionosis in the small intestine and entire colon, and suffered from frequent enterocolitis. The persistence of ganglion cells made both the diagnosis and treatment difficult in the neonatal period. She also showed hypopigmentation of the irises, hair and skin, bilateral sensorineural deafness with hypoplastic inner year, severe demyelinating neuropathy with hypotonia, and diffuse brain hypomyelination. The p.Ser282GlnfsTer12 mutation presumably escapes from nonsense-mediated decay and may generate a dominant-negative effect. We suggest that hypoganglionosis can be a variant intestinal manifestation associated with PCWH and that hypoganglionosis and aganglionosis may share the same pathoetiological mechanism mediated by SOX10 mutations.

Time-Dependent Decline in Serum Phenytoin Concentration With Heightened Convulsive Seizure Risk by Prolonged Administration of Fosphenytoin in Japanese: A Retrospective Study.

BACKGROUND: Because clinical data to confirm the safety and effectiveness of fosphenytoin, a prodrug of phenytoin, are insufficient, the length of administration of fosphenytoin is restricted. Nevertheless, some cases require fosphenytoin administration for more than a few days. The aim of this study was to retrospectively investigate the serum concentration of phenytoin in adult Japanese patients who received intravenous fosphenytoin therapy for more than 3 days. METHODS: Patients injected with intravenous fosphenytoin for more than 3 days at Gifu University Hospital between January 2012 and September 2014 were enrolled. Individual pharmacokinetic parameters were predicted by Bayesian estimation using NONMEM software, and the maintenance dose of fosphenytoin required to maintain the therapeutic trough concentration (10-20 mcg/mL) was calculated from the parameters. RESULTS: Among a total of 8 patients, the serum trough concentration of phenytoin decreased with each day after repeated injection of fosphenytoin. The incidence rate of significant convulsive seizures was increased time dependently (0% on day 1, 12.5% on day 2, 25% on day 3, and 66.7% on day 4 and after). Phenytoin clearance showed a time-dependent increase. The maintenance dose of fosphenytoin required to maintain the therapeutic trough concentration was simulated to be 779.8 ± 316.8 mg/d, a dose that was markedly higher than the actual maintenance dose (414.1 ± 55.7 mg/d). CONCLUSIONS: Prolonged use of fosphenytoin, for such patients as those with autoimmune-mediated encephalopathy accompanied with reflux disease and/or ileus, time dependently decreased the serum concentration of phenytoin and increased the risk of convulsion. Therefore, the maintenance dose should be increased to maintain the therapeutic serum concentration.

Antimicrobial stewardship intervention for the clinical pathways improves antimicrobial prophylaxis in surgical or non-surgical invasive therapies.

BACKGROUND: The standard duration of administration of antimicrobial prophylaxis in surgery and non-surgical invasive therapy was shortened according to the promotion of appropriate use. Here, we conducted an intervention to optimise antimicrobial prophylaxis by revising all relevant clinical pathways based on the most recent guidelines. METHODS: We conducted a single-centre, prospective cohort study in patients who received antimicrobial prophylaxis to evaluate outcomes following revision of the clinical pathways for antimicrobial prophylaxis. Antibiotic consumption and the duration of antibiotic administration were compared before and after revising the clinical pathways. RESULTS: Thirty-five of 171 clinical pathways were considered inappropriate for antimicrobial use and were optimised. After this revision, the duration of antibiotic administration was significantly shortened (before revision: 3 [1-5] days vs after revision: 2 [1-3] days, median [interquartile range], P < 0.001). The rate of discontinuation of antibiotics within 48 h after surgery or non-surgical invasive therapy was significantly higher after the revision (62.4% vs 81.8%, P < 0.001). In contrast, the incidence of surgical site infection (SSI) was not significantly different before and after the revision (5.7% vs 4.3%, P = 0.177). A multivariate Cox proportional analysis indicated that revision of the clinical pathways was one of the prognostic factors associated with the discontinuation of antibiotics within 48 h after surgery or non-surgical invasive therapy (hazard ratio, 0.69; 95% confidence interval, 0.63-0.76, P < 0.001). CONCLUSIONS: Our findings suggest that revising all relevant clinical pathways was highly effective in reducing antibiotic consumption and shortening the antibiotic administration period without increasing the incidence of SSIs.

Dynein Dysfunction Reproduces Age-Dependent Retromer Deficiency: Concomitant Disruption of Retrograde Trafficking Is Required for Alteration in ß-Amyloid Precursor Protein Metabolism.

It is widely accepted that ß-amyloid (Aß) protein plays a pivotal role in Alzheimer disease pathogenesis, and accumulating evidence suggests that endocytic dysfunction is involved in Aß pathology. Retromer, a conserved multisubunit complex, mediates the retrograde transport of numerous kinds of cargo from endosomes to the trans-Golgi network. Several studies have found that retromer deficiency enhances Aß pathology both in vitro and in vivo. Cytoplasmic dynein, a microtubule-based motor protein, mediates minus-end-directed vesicle transport via interactions with dynactin, another microtubule-associated protein that also interacts with retromer. Aging attenuates the dynein-dynactin interaction, and dynein dysfunction reproduces age-dependent endocytic disturbance, resulting in the intracellular accumulation of beta-amyloid precursor protein (APP) and its ß-cleavage products, including Aß. Here, we report that aging itself affects retromer trafficking in cynomolgus monkey brains. In addition, dynein dysfunction reproduces this type of age-dependent retromer deficiency (ie, the endosomal accumulation of retromer-related proteins and APP. Moreover, we found that knockdown of Rab7, Rab9, or Rab11 did not alter endogenous APP metabolism, such as that observed in aged monkey brains and in dynein-depleted cells. These findings suggest that dynein dysfunction can cause retromer deficiency and that concomitant disruption of retrograde trafficking may be the key factor underlying age-dependent Aß pathology.

[Surgical Treatment for Synchronous Double Cancer of the Thoracic Esophagus and Lung].

We herein report 2 cases of radical operation for synchronous double cancer of the thoracic esophagus and each side of the lung. Case 1:A 71-year-old woman with synchronous double cancer of the thoracic esophagus (Mt, T3N2M0, Stage III) and right lung (M, T2aN0M0, Stage I B) underwent esophagectomy concomitantly with right middle lobectomy through right thoracotomy (single-stage operation) after 2 courses of systemic chemotherapy with docetaxel, cisplatin and 5-fluorouracil( DCF regimen). Case 2:A 72-year-old man with synchronous double cancer of the thoracic esophagus( MtLt, T3N2M0, Stage III) and left lung( U, T1aN0M0, Stage I A) underwent 2-stage operation after 2 courses of the DCF therapy. Esophagectomy through right thoracotomy was performed followed by left upper lobectomy through left thoracotomy 3 months later. Treatment strategy for synchronous double cancer of the thoracic esophagus and lung is discussed based on our experiences and previous reports.

[A Case of Rapidly Advancing G-CSF Producing Pleomorphic Carcinoma of the Breast Appearing as an Inflammatory Breast Cancer].

We report a rare case of pleomorphic carcinoma of the breast, suspected of being a granulocyte-colony stimulating factor (G-CSF)producing tumor, in a 75-year-old woman. She presented with a red and swollen breast, 3 weeks after undergoing core needle biopsy(CNB). Her leukocyte counts and C-reactive protein(CRP)levels were markedly high. At first, she was suspected to have an abscess and was initiated on a course of antibiotics. However, her condition rapidly deteriorated; therefore, she underwent an emergency mastectomy. Despite undergoing postoperative radiation therapy, 2 months after the operation, multiple metastatic foci were found in the lungs and liver, and she died of the disease 3 months after her first visit. After the operation, her leukocyte count had quickly returned to normal, but it increased as the disease progressed. These findings support the conclusion that this carcinoma was producing G-CSF. The final pathological diagnosis was G-CSF producing pleomorphic carcinoma of the breast.