Gastrointestinal stromal tumors (GISTs) are rare gastrointestinal malignancies. They are rarely seen near the urinary tract. In a literature review, only one case of GIST presenting as a left adrenal tumor was reporte...Gastrointestinal stromal tumors (GISTs) are rare gastrointestinal malignancies. They are rarely seen near the urinary tract. In a literature review, only one case of GIST presenting as a left adrenal tumor was reported. We report two documented cases of gastric GISTs mimicking left adrenal tumors which were successfully treated with pure laparoscopic adrenalectomy and wedge resection of the stomach by excising the tumor from the stomach with serial fi ring of endoscopic gastrointestinal staplers. The surgical margins were clear, and the patients recovered smoothly. No adjuvant therapy with imatinib was prescribed. During the surveillance for 9 mo and 44 mo respectively, no tumor recurrence and metastasis were documented. Laparoscopic tumor excision, when adhering to the principles of surgical oncology, seems feasible and the prognosisis favorable for such tumors.展开更多
The aim of this editorial is to evaluate the evidence for using pimavanserin for the treatment of Parkinson's disease psychosis(PDP)from randomized controlled trials(RCTs).We only identified two published trials t...The aim of this editorial is to evaluate the evidence for using pimavanserin for the treatment of Parkinson's disease psychosis(PDP)from randomized controlled trials(RCTs).We only identified two published trials that evaluated the use of pimavanserin among individuals with PDP.Both studies found that pimavanserin improved psychotic symptoms among individuals with PDP when compared to placebo.Pimavanserin was fairly well tolerated in both studies and did not appear to cause significant sedation or worsen motor symptoms among individuals with PDP.However,given the limited data,additional confirmatory studies are required before pimavanserin can be considered as a first line agent for the treatment of psychotic symptoms among individuals with PD.展开更多
Objective: To validate the hypothesis that camel pericardium could be more protected than bovine pericardium against calcification process according to the huge difference in their respective lifestyle and lifetime. M...Objective: To validate the hypothesis that camel pericardium could be more protected than bovine pericardium against calcification process according to the huge difference in their respective lifestyle and lifetime. Methods: Glutaraldehyde (GA) fixed bovine and camel pericardium samples (BP and CP respectively) were both implanted in 30 New Zealand white rats (2 BP and 2 CP matched specimens in each animal) and explanted after 60 days. Unimplanted GA-fixed samples of both species served as control. Matched implanted samples and unimplanted samples were randomly submitted to elemental analysis by spectroscopy, phospholipid extraction, macroscopic and X-ray examination and histology. Results: At 60 days, calcium and phosphorus content were respectively 9.54% ± 3.1% and 4.79% ± 1.4% of tissue dry weight in BP, and 12.52% ± 2.7% and 6.14% ± 1.3% of tissue dry weight in CP (ns). In X-ray analysis, the calcification score was 1.28 ± 0.45 and 2.14 ± 0.98 in BP and CP samples respectively without significant difference (p < 0.08). In histology, calcifications were lower in BP than in CP: 1.37 ± 0.85 vs 2.28 ± 0.83 (ns);collagen fibers were better conserved in BP than in CP: 2.4 ± 0.48 vs 1.87 ± 0.78 (ns), and less disoriented: 25% vs 62% (ns). In unimplanted samples, there was a higher but not significant rate of extracted lipids in CP: 5.7 ± 1.8 vs 9.5 ± 3.8 nanomoles in PS fraction and 11.3 ± 3.7 vs 19 ± 7.7 nanomoles in total fatty acids, in BP and CP samples respectively. All results were in conjunction and demonstrated a higher but not significant rate of mineralization in camel pericardium after implantation, which could be related to a higher but not significant basic rate of phospholipid and fatty acids. Conclusion: This experiment study in a subcutaneous rat model has failed to valid our hypothesis. Because the differences observed between bovine and camel pericardium did not reach the significance, at the best, there is no difference between both species and at the worst, camel pericardium has a higher rate of the phosphatidylserine fraction of phospholipid, and is more sensitive and prompt to calcification.展开更多
Substance use disorders(SUDs)are a growing problem among older adults.Acamprosate,disulfiram,and naltrexone are United States Food and Drug Administration(referred to as FDA)approved for the treatment of alcohol use d...Substance use disorders(SUDs)are a growing problem among older adults.Acamprosate,disulfiram,and naltrexone are United States Food and Drug Administration(referred to as FDA)approved for the treatment of alcohol use disorder,and buprenorphine is approved for the treatment of opiate use disorder among adults.However,the data on the use of these medications for the treatment of SUDs among older adults are unclear from randomized controlled trials(referred to as RCTs).A review of the literature indicates that there are only two RCTs that evaluated the use of pharmacologic agents for SUDs among older adults(≥50 years).One trial evaluated the use of naltrexone when compared to placebo for the treatment of alcohol use disorder among individuals,50-70 years in age.The other trial evaluated the use of naltrexone or placebo as adjuncts with sertraline in the treatment of alcohol use disorder among individuals older than 55 years in age.Both trials indicated that the use of naltrexone reduced the rates of relapse among older adults with alcohol use disorder.However,we did not identify any RCTs that studied the use of buprenorphine,acamprosate,or disulfiram for SUDs among older adults.Based on available evidence,it would be safe to conclude that limited data indicate some efficacy for naltrexone in the treatment of alcohol use disorder among older adults.However,data from controlled trials on the use of other medications that are FDA approved for the treatment of SUDs among younger adults are nonexistent among older adults with SUDs.展开更多
Accurate and reproducible analysis of murine small and large intestinal tissue is key for preclinical models involving intestinal pathology.Currently,there is no easily ac-cessible,standardized method that allows rese...Accurate and reproducible analysis of murine small and large intestinal tissue is key for preclinical models involving intestinal pathology.Currently,there is no easily ac-cessible,standardized method that allows researchers of different skill levels to con-sistently dissect intestines in a time-efficient manner.Here,we describe the design and use of the 3D-printed“Mouse Intestinal Slicing Tool”(MIST),which can be used to longitudinally dissect murine intestines for further analysis.We benchmarked the MIST against a commonly used procedure involving scissors to make a longitudinal cut along the intestines.Use of the MIST halved the time per mouse to prepare the intestines and outperformed alternative methods in smoothness of the cutting edge and overall reproducibility.By sharing the plans for printing the MIST,we hope to contribute a uniformly applicable method for saving time and increasing consistency in studies of the mouse gastrointestinal tract.展开更多
Behavioral and psychological symptoms including agitation are common in dementia,and are associated with decreased quality of life,increased risk of institutionalization,and greater patient and caregiver distress.Phar...Behavioral and psychological symptoms including agitation are common in dementia,and are associated with decreased quality of life,increased risk of institutionalization,and greater patient and caregiver distress.Pharmacological agents used for management of behavioral and psychological symptoms of dementia are limited by their tolerability,prompting a need for identifying efficacious and safe pharmacological treatments for managing agitation in dementia.The combination of dextromethorphan and quinidine sulfate is approved for pseudobulbar affect,and may be effective in managing agitation in dementia.A review of literature found only one randomized controlled trial that evaluated the use of dextromethorphan-quinidine for the management of agitation in dementia when compared to placebo.Data from this trial demonstrated that dextromethorphan-quinidine decreased agitation in dementia,and was well tolerated.Although promising,further research is needed before dextromethorphan-quinidine combination can be accepted as a standard treatment for agitation in dementia.展开更多
The ideal range for tracheal tube cuff pressures is usually taken to be between 20 to 30 cm H2 O. This is easily measured with a cuff pressure manometer and should be measured in each instance. The importanceof trache...The ideal range for tracheal tube cuff pressures is usually taken to be between 20 to 30 cm H2 O. This is easily measured with a cuff pressure manometer and should be measured in each instance. The importanceof tracheal tube cuff pressures is highlighted by the spectrum of airway complications that can occur with incorrect cuff pressures. High cuff pressures can result in complications ranging from sore throat and hoarseness to tracheal stenosis, necrosis, and even rupture. In such cases, the postulated causative factor is diminished blood flow to tracheal mucosa due to excessive cuff pressure on the tracheal wall. This hypothesized ischemic injury then produces healing fibrosis months or even years later. On the other hand, cuff pressures that are too low place the patient at risk for aspiration of gastric contents and consequently, aspiration pneumonitis and pneumonia. This is why the authors recommend that cuff pressures be measured following all intubations.展开更多
BACKGROUND Due to development of an immune-dysregulated phenotype,advanced liver disease in all forms predisposes patients to sepsis acquisition,including by opportunistic pathogens such as fungi.Little data exists on...BACKGROUND Due to development of an immune-dysregulated phenotype,advanced liver disease in all forms predisposes patients to sepsis acquisition,including by opportunistic pathogens such as fungi.Little data exists on fungal infection within a medical intensive liver unit(MILU),particularly in relation to acute on chronic liver failure.AIM To investigate the impact of fungal infections among critically ill patients with advanced liver disease,and compare outcomes to those of patients with bacterial infections.METHODS From our prospective registry of MILU patients from 2018-2022,we included 27 patients with culture-positive fungal infections and 183 with bacterial infections.We compared outcomes between patients admitted to the MILU with fungal infections to bacterial counterparts.Data was extracted through chart review.RESULTS All fungal infections were due to Candida species,and were most frequently blood isolates.Mortality among patients with fungal infections was significantly worse relative to the bacterial cohort(93%vs 52%,P<0.001).The majority of the fungal cohort developed grade 2 or 3 acute on chronic liver failure(ACLF)(90%vs 64%,P=0.02).Patients in the fungal cohort had increased use of vasopressors(96%vs 70%,P=0.04),mechanical ventilation(96%vs 65%,P<0.001),and dialysis due to acute kidney injury(78%vs 52%,P=0.014).On MILU admission,the fungal cohort had significantly higher Acute Physiology and Chronic Health Evaluation(108 vs 91,P=0.003),Acute Physiology Score(86 vs 65,P=0.003),and Model for End-Stage Liver Disease-Sodium scores(86 vs 65,P=0.041).There was no significant difference in the rate of central line use preceding culture(52%vs 40%,P=0.2).Patients with fungal infection had higher rate of transplant hold placement,and lower rates of transplant;however,differences did not achieve statistical significance.CONCLUSION Mortality was worse among patients with fungal infections,likely attributable to severe ACLF development.Prospective studies examining empiric antifungals in severe ACLF and associations between fungal infections and transplant outcomes are critical.展开更多
Epilepsy is a complex neurologic condition which affects over 50 million people worldwide.Pharmacotherapy,primarily involving the use of anti-seizure drugs(ASDs),is an essential part of controlling seizures.However,ne...Epilepsy is a complex neurologic condition which affects over 50 million people worldwide.Pharmacotherapy,primarily involving the use of anti-seizure drugs(ASDs),is an essential part of controlling seizures.However,nearly 30%of patients develop drug-resistant epilepsy,clinically defined as the persistence of seizure following trials of two ASDs(Kwan et al.,2010).Although several hypotheses have been proposed to explain this phenomenon,the mechanism of drug-resistant epilepsy still remains unclear.展开更多
Which signaling pathway and protein to selea to mitigate the patient's expected drug resistance?The number of possibilities facing the physician is massive,and the drug combination should fit the patient status.He...Which signaling pathway and protein to selea to mitigate the patient's expected drug resistance?The number of possibilities facing the physician is massive,and the drug combination should fit the patient status.Here,we briefly review current approaches and data and map an innovative patient-specific strategy to forecast drug resistance targets that centers on parallel(or redundant)proliferation pathways in specialized cells.It considers the availability of each protein in each pathway in the specific cell,its activating mutations,and the chromatin accessibility of its encoding gene.The construction of the resulting Proliferation Pathway Network Atlas will harness the emerging exascale computing and advanced artificial intelligence(Al)methods for therapeutic development.Merging the resulting set of targets,pathways,and proteins,with current strategies will augment the choice for the attending physicians to thwart resistance.展开更多
Airway complications after lung transplantation remain a significant cause of morbidity and mortality. Many of these occur at the anastomotic sites, which are susceptible due to poor collateral circulation. Of the pos...Airway complications after lung transplantation remain a significant cause of morbidity and mortality. Many of these occur at the anastomotic sites, which are susceptible due to poor collateral circulation. Of the possible complications, bronchial dehiscence is particularly formidable. These cases have been successfully treated bronchoscopically with metallic stents, which likely promote healing through granulation tissue formation. However, limited options exist in cases where the dehiscence fails to heal following stent placement. Here, we present the case report of a 65-year-old male who developed bronchial dehiscence status post bilateral lung transplantation for idiopathic pulmonary fibrosis that failed to heal with simple stent placement. Eventually, the patient underwent amniotic membrane grafting with stenting as a novel therapy for non-healing bronchial dehiscence, for which we describe the anesthetic management. His anesthetic plan included inhalational induction with sevoflurane, propofol infusion for total intravenous anesthesia, rocuronium for muscle relaxation, and closed-circuit assisted ventilation. His existing tracheostomy was used as the airway for oxygenation and induction. In summary, our anesthetic plan for the lung transplant patient was effective; future amniotic membrane grafting for bronchial dehiscence through bronchoscopy may follow a similar technique. Ultimately, the choice of anesthesia in this patient population requires judicious consideration of the requirements of the procedure as well as the pathophysiology of the transplanted lung.展开更多
Aim: Breast cancer (BCA) in women is a leading cause of mortality and morbidity;distant metastases occur in ~40% of cases. Here, as an alternative to ionizing radiation therapy and chemotherapy and their associated si...Aim: Breast cancer (BCA) in women is a leading cause of mortality and morbidity;distant metastases occur in ~40% of cases. Here, as an alternative to ionizing radiation therapy and chemotherapy and their associated side effects, we explored a new combination approach using capecitabine (CPBN) and aminolevulinate-based photodynamic therapy (PDT). We had previously developed a combination PDT approach in which 5-fluorouracil (5FU), a differentiation-promoting agent, increases the levels of protoporphyrin IX (PpIX) in cancer cells when given as a neoadjuvant prior to aminolevulinic acid (ALA). However, 5FU can be toxic when administered systemically at high levels. We reasoned that CPBN, a known chemotherapeutic for BCA and less toxic than 5FU (because CPBN is metabolized to 5FU specifically within tumor tissues), might work equally well as a PDT neoadjuvant. Methods: Murine 4T1 BCA cells harboring a luciferase transgene were injected into breast fat pads of female nude mice. CPBN (600 mg/kg/day) was administered by oral gavage for 3 days followed by intraperitoneal ALA administration and PDT with red light (633 nm) on day 4. Tumor growth and regression were monitored in vivo using bioluminescence imaging. Histological changes in primary tumors and metastases were assessed by immunohistochemistry after necropsy. ;Results: CPBN pretreatment of 4T1 tumors increased cellular differentiation, reduced proliferation, raised PpIX levels, enhanced tumor cell death, and reduced metastatic spread of 4T1 cells post-PDT, relative to vehicle-only controls. Conclusion: The use of CPBN as a non-toxic PDT neoadjuvant for treatment of BCA represents a novel approach with significant potential for translation into the clinic.展开更多
“Let’s Move!”is a comprehensive initiative,launched by the First Lady,Michelle Obama,dedicates to solving problems of obesity,which is growing in child.The life behaviors do affect obesity;however,the mechanistic i...“Let’s Move!”is a comprehensive initiative,launched by the First Lady,Michelle Obama,dedicates to solving problems of obesity,which is growing in child.The life behaviors do affect obesity;however,the mechanistic insight in molecular level is still not clear.In this study,by continually monitoring mouse body weight under chow and high fat western diets as well as metabolic,physical activity and food intake behaviors assessed in a CLAMS Comprehensive Lab Animal Monitoring System,we demonstrated that the platelet-activating factor receptor(PTAFR)contributes to modification of life behaviors.PTAFR does not affect metabolism of ingested dietary fat and carbohydrate in young animals;however,Ptafr ablation dramatically increased weight gain without affecting adipose tissue accumulation.Ptafr/mice possess new habits that increased food intake and decreased movement.Our studies suggest that regulation of PTAFR activity may be a novel strategy to control obesity in children or young adults.展开更多
Ileal pouch-anal anastomosis surgery can be complicated by anastomotic leaks,leading to the formation of abscess and chronic sinus that have been routinely managed by a surgical approach.We developed the endoscopic ne...Ileal pouch-anal anastomosis surgery can be complicated by anastomotic leaks,leading to the formation of abscess and chronic sinus that have been routinely managed by a surgical approach.We developed the endoscopic needle knife sinusotomy(NKSi)technique,which has become a valid alternative.The basic principle of endoscopic NKSi is dissection and drainage of the sinus through its orifice internally into the lumen of pouch body.The success of NKSi requires an access to the sinus from the pouch side.One of the most challenging situations for NKSi is a closed orifice of the sinus,which leaves an isolated chronic abscess cavity.Here we report a case of complicated presacral sinus with a closed orifice that was not amenable to NKSi,necessitating a CT-guided guide wire placement and subsequent NKSi.展开更多
The PIK3C3/VPS34 subunit of the class III phosphatidylinositol 3-kinase(PtdIns3K)complex plays a role in both canonical and noncanonical autophagy,key processes that control immune-cell responsiveness to a variety of ...The PIK3C3/VPS34 subunit of the class III phosphatidylinositol 3-kinase(PtdIns3K)complex plays a role in both canonical and noncanonical autophagy,key processes that control immune-cell responsiveness to a variety of stimuli.Our previous studies found that PIK3C3 is a critical regulator that controls the development,homeostasis,and function of dendritic and T cells.In this study,we investigated the role of PIK3C3 in myeloid cell biology using myeloid cell-specific Pik3c3-deficient mice.We found that Pik3c3-deficient macrophages express increased surface levels of major histocompatibility complex(MHC)class I and class II molecules.In addition,myeloid cell-specific Pik3c3 ablation in mice caused a partial impairment in the homeostatic maintenance of macrophages expressing the apoptotic cell uptake receptor TIM-4.Pik3c3 deficiency caused phenotypic changes in myeloid cells that were dependent on the early machinery(initiation/nucleation)of the classical autophagy pathway.Consequently,myeloid cell-specific Pik3c3-deficient animals showed significantly reduced severity of experimental autoimmune encephalomyelitis(EAE),a primarily CD4^(^(+))T-cell-mediated mouse model of multiple sclerosis(MS).This disease protection was associated with reduced accumulation of myelin-specific CD4^(^(+))T cells in the central nervous system and decreased myeloid cell IL-1βproduction.Further,administration of SAR405,a selective PIK3C3 inhibitor,delayed disease progression.Collectively,our studies establish PIK3C3 as an important regulator of macrophage functions and myeloid cell-mediated regulation of EAE.Our findings also have important implications for the development of small-molecule inhibitors of PIK3C3 as therapeutic modulators of MS and other autoimmune diseases.展开更多
Hyperbaric oxygen therapy(HBOT)has been shown to be efficacious in treating various conditions,including perianal Crohn’s disease.Here we present a case of a 59-year-old male with a history of ulcerative colitis,who ...Hyperbaric oxygen therapy(HBOT)has been shown to be efficacious in treating various conditions,including perianal Crohn’s disease.Here we present a case of a 59-year-old male with a history of ulcerative colitis,who underwent a total proctocolectomy and two-stage J-pouch construction.He later developed chronic antibiotic-refractory pouchitis with endoscopic features of ischemia.At the completion of HOBT-a total of 20 sessions of 100%oxygen at 2.5-3.0 atmospheres absolute for 60-90 minutes per session-a repeat pouchoscopy showed marked improvement of endoscopic mucosal inflammation.HBOT is known to increase tissue oxygenation,reduce tissue hypoxia,alter inflammatory pathways and promote tissue healing.This case demonstrated the therapeutic role of HBOT as well as the possible disease mechanism in chronic antibiotic-refractory pouchitis.展开更多
Sex differences in the susceptibility of SARS-CoV-2 infection and severity have been controversial,and the underlying mechanisms of COVID-19 in a sex-specific manner remain understudied.Here we inspected sex differenc...Sex differences in the susceptibility of SARS-CoV-2 infection and severity have been controversial,and the underlying mechanisms of COVID-19 in a sex-specific manner remain understudied.Here we inspected sex differences in SARS-CoV-2 infection,hospitalization,admission to the intensive care unit(ICU),sera inflammatory biomarker profiling,and single-cell RNA-sequencing(scRNA-seq)profiles across nasal,bronchoalveolar lavage fluid(BALF),and peripheral blood mononuclear cells(PBMCs)from COVID-19 patients with varying degrees of disease severities.Our propensity score-matching observations revealed that male individuals have a 29%elevated likelihood of SARS-CoV-2 positivity,with a hazard ratio(HR)1.32(95%confidence interval[Cl]1.18-1.48)for hospitalization and HR 1.51(95%Cl 1.24-1.84)for admission to ICU.Sera from male patients at hospital admission had elevated neutrophil-lymphocyte ratio and elevated expression of inflammatory markers(C-reactive protein and procalcitonin).We found that SARS-CoV-2 entry factors,including ACE2,TMPRSS2,FURIN,and NRP1,have elevated expression in nasal squamous cells from male individuals with moderate and severe COVID-19.We observed male-biased transcriptional activation in SARS-CoV-2-infected macrophages from BALF and sputum samples,which offers potential molecular mechanism for sex-biased susceptibility to viral infection.Cell-cell interaction network analysis reveals potential epithelium-immune cell interactions and immune vulnerability underlying male-elevated disease severity and mortality in COVID-19.Mechanistically,monocyte-elevated expression of Toll-like receptor 7{TLR7)and Bruton tyrosine kinase{BTK)is associated with severe outcomes in males with COVID-19.In summary,these findings provide basis to decipher immune responses underlying sex differences and designing sex-specific targeted interventions and patient care for COVID-19.展开更多
文摘Gastrointestinal stromal tumors (GISTs) are rare gastrointestinal malignancies. They are rarely seen near the urinary tract. In a literature review, only one case of GIST presenting as a left adrenal tumor was reported. We report two documented cases of gastric GISTs mimicking left adrenal tumors which were successfully treated with pure laparoscopic adrenalectomy and wedge resection of the stomach by excising the tumor from the stomach with serial fi ring of endoscopic gastrointestinal staplers. The surgical margins were clear, and the patients recovered smoothly. No adjuvant therapy with imatinib was prescribed. During the surveillance for 9 mo and 44 mo respectively, no tumor recurrence and metastasis were documented. Laparoscopic tumor excision, when adhering to the principles of surgical oncology, seems feasible and the prognosisis favorable for such tumors.
文摘The aim of this editorial is to evaluate the evidence for using pimavanserin for the treatment of Parkinson's disease psychosis(PDP)from randomized controlled trials(RCTs).We only identified two published trials that evaluated the use of pimavanserin among individuals with PDP.Both studies found that pimavanserin improved psychotic symptoms among individuals with PDP when compared to placebo.Pimavanserin was fairly well tolerated in both studies and did not appear to cause significant sedation or worsen motor symptoms among individuals with PDP.However,given the limited data,additional confirmatory studies are required before pimavanserin can be considered as a first line agent for the treatment of psychotic symptoms among individuals with PD.
文摘Objective: To validate the hypothesis that camel pericardium could be more protected than bovine pericardium against calcification process according to the huge difference in their respective lifestyle and lifetime. Methods: Glutaraldehyde (GA) fixed bovine and camel pericardium samples (BP and CP respectively) were both implanted in 30 New Zealand white rats (2 BP and 2 CP matched specimens in each animal) and explanted after 60 days. Unimplanted GA-fixed samples of both species served as control. Matched implanted samples and unimplanted samples were randomly submitted to elemental analysis by spectroscopy, phospholipid extraction, macroscopic and X-ray examination and histology. Results: At 60 days, calcium and phosphorus content were respectively 9.54% ± 3.1% and 4.79% ± 1.4% of tissue dry weight in BP, and 12.52% ± 2.7% and 6.14% ± 1.3% of tissue dry weight in CP (ns). In X-ray analysis, the calcification score was 1.28 ± 0.45 and 2.14 ± 0.98 in BP and CP samples respectively without significant difference (p < 0.08). In histology, calcifications were lower in BP than in CP: 1.37 ± 0.85 vs 2.28 ± 0.83 (ns);collagen fibers were better conserved in BP than in CP: 2.4 ± 0.48 vs 1.87 ± 0.78 (ns), and less disoriented: 25% vs 62% (ns). In unimplanted samples, there was a higher but not significant rate of extracted lipids in CP: 5.7 ± 1.8 vs 9.5 ± 3.8 nanomoles in PS fraction and 11.3 ± 3.7 vs 19 ± 7.7 nanomoles in total fatty acids, in BP and CP samples respectively. All results were in conjunction and demonstrated a higher but not significant rate of mineralization in camel pericardium after implantation, which could be related to a higher but not significant basic rate of phospholipid and fatty acids. Conclusion: This experiment study in a subcutaneous rat model has failed to valid our hypothesis. Because the differences observed between bovine and camel pericardium did not reach the significance, at the best, there is no difference between both species and at the worst, camel pericardium has a higher rate of the phosphatidylserine fraction of phospholipid, and is more sensitive and prompt to calcification.
文摘Substance use disorders(SUDs)are a growing problem among older adults.Acamprosate,disulfiram,and naltrexone are United States Food and Drug Administration(referred to as FDA)approved for the treatment of alcohol use disorder,and buprenorphine is approved for the treatment of opiate use disorder among adults.However,the data on the use of these medications for the treatment of SUDs among older adults are unclear from randomized controlled trials(referred to as RCTs).A review of the literature indicates that there are only two RCTs that evaluated the use of pharmacologic agents for SUDs among older adults(≥50 years).One trial evaluated the use of naltrexone when compared to placebo for the treatment of alcohol use disorder among individuals,50-70 years in age.The other trial evaluated the use of naltrexone or placebo as adjuncts with sertraline in the treatment of alcohol use disorder among individuals older than 55 years in age.Both trials indicated that the use of naltrexone reduced the rates of relapse among older adults with alcohol use disorder.However,we did not identify any RCTs that studied the use of buprenorphine,acamprosate,or disulfiram for SUDs among older adults.Based on available evidence,it would be safe to conclude that limited data indicate some efficacy for naltrexone in the treatment of alcohol use disorder among older adults.However,data from controlled trials on the use of other medications that are FDA approved for the treatment of SUDs among younger adults are nonexistent among older adults with SUDs.
基金This study was supported by a research grant from the Prevent Cancer Foundation(PCF2019J.C.)+8 种基金seed funding from the Cleveland Clinic Foundation(J.C.)a National Institutes of Health grant(R01 AI153173J.C.)an American Cancer Society Institutional Research Grant(IRG-16-186-21J.C.)a Jump Start Award from the Case Comprehensive Cancer Center(CA043703J.C.)funding from the Office of the Assistant Secretary of Defense for Health Affairs through the Congressionally Directed Medical Research Programs Peer Reviewed Medical Research Program under award no.W81XWH-19-1-0488(PR181846C.M.)。
文摘Accurate and reproducible analysis of murine small and large intestinal tissue is key for preclinical models involving intestinal pathology.Currently,there is no easily ac-cessible,standardized method that allows researchers of different skill levels to con-sistently dissect intestines in a time-efficient manner.Here,we describe the design and use of the 3D-printed“Mouse Intestinal Slicing Tool”(MIST),which can be used to longitudinally dissect murine intestines for further analysis.We benchmarked the MIST against a commonly used procedure involving scissors to make a longitudinal cut along the intestines.Use of the MIST halved the time per mouse to prepare the intestines and outperformed alternative methods in smoothness of the cutting edge and overall reproducibility.By sharing the plans for printing the MIST,we hope to contribute a uniformly applicable method for saving time and increasing consistency in studies of the mouse gastrointestinal tract.
文摘Behavioral and psychological symptoms including agitation are common in dementia,and are associated with decreased quality of life,increased risk of institutionalization,and greater patient and caregiver distress.Pharmacological agents used for management of behavioral and psychological symptoms of dementia are limited by their tolerability,prompting a need for identifying efficacious and safe pharmacological treatments for managing agitation in dementia.The combination of dextromethorphan and quinidine sulfate is approved for pseudobulbar affect,and may be effective in managing agitation in dementia.A review of literature found only one randomized controlled trial that evaluated the use of dextromethorphan-quinidine for the management of agitation in dementia when compared to placebo.Data from this trial demonstrated that dextromethorphan-quinidine decreased agitation in dementia,and was well tolerated.Although promising,further research is needed before dextromethorphan-quinidine combination can be accepted as a standard treatment for agitation in dementia.
文摘The ideal range for tracheal tube cuff pressures is usually taken to be between 20 to 30 cm H2 O. This is easily measured with a cuff pressure manometer and should be measured in each instance. The importanceof tracheal tube cuff pressures is highlighted by the spectrum of airway complications that can occur with incorrect cuff pressures. High cuff pressures can result in complications ranging from sore throat and hoarseness to tracheal stenosis, necrosis, and even rupture. In such cases, the postulated causative factor is diminished blood flow to tracheal mucosa due to excessive cuff pressure on the tracheal wall. This hypothesized ischemic injury then produces healing fibrosis months or even years later. On the other hand, cuff pressures that are too low place the patient at risk for aspiration of gastric contents and consequently, aspiration pneumonitis and pneumonia. This is why the authors recommend that cuff pressures be measured following all intubations.
文摘BACKGROUND Due to development of an immune-dysregulated phenotype,advanced liver disease in all forms predisposes patients to sepsis acquisition,including by opportunistic pathogens such as fungi.Little data exists on fungal infection within a medical intensive liver unit(MILU),particularly in relation to acute on chronic liver failure.AIM To investigate the impact of fungal infections among critically ill patients with advanced liver disease,and compare outcomes to those of patients with bacterial infections.METHODS From our prospective registry of MILU patients from 2018-2022,we included 27 patients with culture-positive fungal infections and 183 with bacterial infections.We compared outcomes between patients admitted to the MILU with fungal infections to bacterial counterparts.Data was extracted through chart review.RESULTS All fungal infections were due to Candida species,and were most frequently blood isolates.Mortality among patients with fungal infections was significantly worse relative to the bacterial cohort(93%vs 52%,P<0.001).The majority of the fungal cohort developed grade 2 or 3 acute on chronic liver failure(ACLF)(90%vs 64%,P=0.02).Patients in the fungal cohort had increased use of vasopressors(96%vs 70%,P=0.04),mechanical ventilation(96%vs 65%,P<0.001),and dialysis due to acute kidney injury(78%vs 52%,P=0.014).On MILU admission,the fungal cohort had significantly higher Acute Physiology and Chronic Health Evaluation(108 vs 91,P=0.003),Acute Physiology Score(86 vs 65,P=0.003),and Model for End-Stage Liver Disease-Sodium scores(86 vs 65,P=0.041).There was no significant difference in the rate of central line use preceding culture(52%vs 40%,P=0.2).Patients with fungal infection had higher rate of transplant hold placement,and lower rates of transplant;however,differences did not achieve statistical significance.CONCLUSION Mortality was worse among patients with fungal infections,likely attributable to severe ACLF development.Prospective studies examining empiric antifungals in severe ACLF and associations between fungal infections and transplant outcomes are critical.
基金The present work is supported in part by the National Institute of Neurological Disorders and Stroke/National Institutes of Health grants R01NS095825(to CG).
文摘Epilepsy is a complex neurologic condition which affects over 50 million people worldwide.Pharmacotherapy,primarily involving the use of anti-seizure drugs(ASDs),is an essential part of controlling seizures.However,nearly 30%of patients develop drug-resistant epilepsy,clinically defined as the persistence of seizure following trials of two ASDs(Kwan et al.,2010).Although several hypotheses have been proposed to explain this phenomenon,the mechanism of drug-resistant epilepsy still remains unclear.
基金This project has been funded in whole or in part with federal funds from the National Cancer Institute,National Institutes of Health,under contract HHSN261200800001EThis research was supported[in part]by the Intramural Research Program of NIH,National Cancer Institute,Center for Cancer Research.
文摘Which signaling pathway and protein to selea to mitigate the patient's expected drug resistance?The number of possibilities facing the physician is massive,and the drug combination should fit the patient status.Here,we briefly review current approaches and data and map an innovative patient-specific strategy to forecast drug resistance targets that centers on parallel(or redundant)proliferation pathways in specialized cells.It considers the availability of each protein in each pathway in the specific cell,its activating mutations,and the chromatin accessibility of its encoding gene.The construction of the resulting Proliferation Pathway Network Atlas will harness the emerging exascale computing and advanced artificial intelligence(Al)methods for therapeutic development.Merging the resulting set of targets,pathways,and proteins,with current strategies will augment the choice for the attending physicians to thwart resistance.
文摘Airway complications after lung transplantation remain a significant cause of morbidity and mortality. Many of these occur at the anastomotic sites, which are susceptible due to poor collateral circulation. Of the possible complications, bronchial dehiscence is particularly formidable. These cases have been successfully treated bronchoscopically with metallic stents, which likely promote healing through granulation tissue formation. However, limited options exist in cases where the dehiscence fails to heal following stent placement. Here, we present the case report of a 65-year-old male who developed bronchial dehiscence status post bilateral lung transplantation for idiopathic pulmonary fibrosis that failed to heal with simple stent placement. Eventually, the patient underwent amniotic membrane grafting with stenting as a novel therapy for non-healing bronchial dehiscence, for which we describe the anesthetic management. His anesthetic plan included inhalational induction with sevoflurane, propofol infusion for total intravenous anesthesia, rocuronium for muscle relaxation, and closed-circuit assisted ventilation. His existing tracheostomy was used as the airway for oxygenation and induction. In summary, our anesthetic plan for the lung transplant patient was effective; future amniotic membrane grafting for bronchial dehiscence through bronchoscopy may follow a similar technique. Ultimately, the choice of anesthesia in this patient population requires judicious consideration of the requirements of the procedure as well as the pathophysiology of the transplanted lung.
基金P01CA084203(Tayyaba Hasan and Edward Maytin)from the National Cancer Institute,National Institutes of Health,USAVelosano pilot award grant,Cleveland ClinicNIH shared instrument grant award S100D018205(IVIS Spectrum)to Imaging Core,Lerner Research Institute,Cleveland Clinic,Cleveland,Ohio
文摘Aim: Breast cancer (BCA) in women is a leading cause of mortality and morbidity;distant metastases occur in ~40% of cases. Here, as an alternative to ionizing radiation therapy and chemotherapy and their associated side effects, we explored a new combination approach using capecitabine (CPBN) and aminolevulinate-based photodynamic therapy (PDT). We had previously developed a combination PDT approach in which 5-fluorouracil (5FU), a differentiation-promoting agent, increases the levels of protoporphyrin IX (PpIX) in cancer cells when given as a neoadjuvant prior to aminolevulinic acid (ALA). However, 5FU can be toxic when administered systemically at high levels. We reasoned that CPBN, a known chemotherapeutic for BCA and less toxic than 5FU (because CPBN is metabolized to 5FU specifically within tumor tissues), might work equally well as a PDT neoadjuvant. Methods: Murine 4T1 BCA cells harboring a luciferase transgene were injected into breast fat pads of female nude mice. CPBN (600 mg/kg/day) was administered by oral gavage for 3 days followed by intraperitoneal ALA administration and PDT with red light (633 nm) on day 4. Tumor growth and regression were monitored in vivo using bioluminescence imaging. Histological changes in primary tumors and metastases were assessed by immunohistochemistry after necropsy. ;Results: CPBN pretreatment of 4T1 tumors increased cellular differentiation, reduced proliferation, raised PpIX levels, enhanced tumor cell death, and reduced metastatic spread of 4T1 cells post-PDT, relative to vehicle-only controls. Conclusion: The use of CPBN as a non-toxic PDT neoadjuvant for treatment of BCA represents a novel approach with significant potential for translation into the clinic.
基金This work was supported by National Institute on Alcohol Abuse and Alcoholism(NIAAA)017748.
文摘“Let’s Move!”is a comprehensive initiative,launched by the First Lady,Michelle Obama,dedicates to solving problems of obesity,which is growing in child.The life behaviors do affect obesity;however,the mechanistic insight in molecular level is still not clear.In this study,by continually monitoring mouse body weight under chow and high fat western diets as well as metabolic,physical activity and food intake behaviors assessed in a CLAMS Comprehensive Lab Animal Monitoring System,we demonstrated that the platelet-activating factor receptor(PTAFR)contributes to modification of life behaviors.PTAFR does not affect metabolism of ingested dietary fat and carbohydrate in young animals;however,Ptafr ablation dramatically increased weight gain without affecting adipose tissue accumulation.Ptafr/mice possess new habits that increased food intake and decreased movement.Our studies suggest that regulation of PTAFR activity may be a novel strategy to control obesity in children or young adults.
文摘Ileal pouch-anal anastomosis surgery can be complicated by anastomotic leaks,leading to the formation of abscess and chronic sinus that have been routinely managed by a surgical approach.We developed the endoscopic needle knife sinusotomy(NKSi)technique,which has become a valid alternative.The basic principle of endoscopic NKSi is dissection and drainage of the sinus through its orifice internally into the lumen of pouch body.The success of NKSi requires an access to the sinus from the pouch side.One of the most challenging situations for NKSi is a closed orifice of the sinus,which leaves an isolated chronic abscess cavity.Here we report a case of complicated presacral sinus with a closed orifice that was not amenable to NKSi,necessitating a CT-guided guide wire placement and subsequent NKSi.
基金Work in the authors’lab was supported by grants from the NIH(AI139046 to L.V.K.and 1ZIAES10328601 to J.M.)the National Multiple Sclerosis Society(60006625 to L.V.K.)+3 种基金Core Services were performed through the Vanderbilt Digestive Disease Research Center(NIH grant P30DK058404)the Vanderbilt Ingram Cancer Center(NIH grant P30CA68485)the Vanderbilt Diabetes Research and Training Center(NIH grant P60DK020593)J.L.P.was supported by predoctoral NIH training grants(T32HL069765 and T32AR059039).
文摘The PIK3C3/VPS34 subunit of the class III phosphatidylinositol 3-kinase(PtdIns3K)complex plays a role in both canonical and noncanonical autophagy,key processes that control immune-cell responsiveness to a variety of stimuli.Our previous studies found that PIK3C3 is a critical regulator that controls the development,homeostasis,and function of dendritic and T cells.In this study,we investigated the role of PIK3C3 in myeloid cell biology using myeloid cell-specific Pik3c3-deficient mice.We found that Pik3c3-deficient macrophages express increased surface levels of major histocompatibility complex(MHC)class I and class II molecules.In addition,myeloid cell-specific Pik3c3 ablation in mice caused a partial impairment in the homeostatic maintenance of macrophages expressing the apoptotic cell uptake receptor TIM-4.Pik3c3 deficiency caused phenotypic changes in myeloid cells that were dependent on the early machinery(initiation/nucleation)of the classical autophagy pathway.Consequently,myeloid cell-specific Pik3c3-deficient animals showed significantly reduced severity of experimental autoimmune encephalomyelitis(EAE),a primarily CD4^(^(+))T-cell-mediated mouse model of multiple sclerosis(MS).This disease protection was associated with reduced accumulation of myelin-specific CD4^(^(+))T cells in the central nervous system and decreased myeloid cell IL-1βproduction.Further,administration of SAR405,a selective PIK3C3 inhibitor,delayed disease progression.Collectively,our studies establish PIK3C3 as an important regulator of macrophage functions and myeloid cell-mediated regulation of EAE.Our findings also have important implications for the development of small-molecule inhibitors of PIK3C3 as therapeutic modulators of MS and other autoimmune diseases.
文摘Hyperbaric oxygen therapy(HBOT)has been shown to be efficacious in treating various conditions,including perianal Crohn’s disease.Here we present a case of a 59-year-old male with a history of ulcerative colitis,who underwent a total proctocolectomy and two-stage J-pouch construction.He later developed chronic antibiotic-refractory pouchitis with endoscopic features of ischemia.At the completion of HOBT-a total of 20 sessions of 100%oxygen at 2.5-3.0 atmospheres absolute for 60-90 minutes per session-a repeat pouchoscopy showed marked improvement of endoscopic mucosal inflammation.HBOT is known to increase tissue oxygenation,reduce tissue hypoxia,alter inflammatory pathways and promote tissue healing.This case demonstrated the therapeutic role of HBOT as well as the possible disease mechanism in chronic antibiotic-refractory pouchitis.
基金This work was supported by the National Institute of Aging(R01AG066707 and 3R01AG066707-01S1)the National Heart,Lung,and Blood Institute(R00HL138272)to F.C+1 种基金This work has been also supported in part by the VeloSano Pilot Program(Cleveland Clinic Taussig Cancer Institute)to F.C.and J.D.LThis work was partly supported by NIH P01 CA245705 and NIH R01 NS109742 to J.D.L.
文摘Sex differences in the susceptibility of SARS-CoV-2 infection and severity have been controversial,and the underlying mechanisms of COVID-19 in a sex-specific manner remain understudied.Here we inspected sex differences in SARS-CoV-2 infection,hospitalization,admission to the intensive care unit(ICU),sera inflammatory biomarker profiling,and single-cell RNA-sequencing(scRNA-seq)profiles across nasal,bronchoalveolar lavage fluid(BALF),and peripheral blood mononuclear cells(PBMCs)from COVID-19 patients with varying degrees of disease severities.Our propensity score-matching observations revealed that male individuals have a 29%elevated likelihood of SARS-CoV-2 positivity,with a hazard ratio(HR)1.32(95%confidence interval[Cl]1.18-1.48)for hospitalization and HR 1.51(95%Cl 1.24-1.84)for admission to ICU.Sera from male patients at hospital admission had elevated neutrophil-lymphocyte ratio and elevated expression of inflammatory markers(C-reactive protein and procalcitonin).We found that SARS-CoV-2 entry factors,including ACE2,TMPRSS2,FURIN,and NRP1,have elevated expression in nasal squamous cells from male individuals with moderate and severe COVID-19.We observed male-biased transcriptional activation in SARS-CoV-2-infected macrophages from BALF and sputum samples,which offers potential molecular mechanism for sex-biased susceptibility to viral infection.Cell-cell interaction network analysis reveals potential epithelium-immune cell interactions and immune vulnerability underlying male-elevated disease severity and mortality in COVID-19.Mechanistically,monocyte-elevated expression of Toll-like receptor 7{TLR7)and Bruton tyrosine kinase{BTK)is associated with severe outcomes in males with COVID-19.In summary,these findings provide basis to decipher immune responses underlying sex differences and designing sex-specific targeted interventions and patient care for COVID-19.
