Prognostic factors of surgical management for heart failure patients with reduced left ventricular ejection fraction.

Objectives: There are many available pharmaceutical and surgical management for Coronary artery disease (CAD) patients. However, coronary artery bypass grafting (CABG) is the preferred treatment modality for CAD patients with low ejection fraction (EF) in view of the more favorable outcomes. This study aimed to determine the associated factors of poor outcomes post-CABG for heart failure patients with reduced left ventricular ejection fraction who underwent on-pump and off-pump CABG. Methods: A retrospective review of CAD patients who underwent isolated on-pump CABG (ONCAB) or off-pump CABG (OPCAB) in Beijing Anzhen Hospital Affiliated with Capital Medical University from January 2013 to March 2021. Only those with confirmed reduced left ventricular ejection fraction (LVEF) ≤40% on preoperative echocardiography were included. By analyzing the clinical and surgical data, postoperative mortality and morbidity, as well as major cardiovascular and cerebrovascular adverse events (MACCE) as endpoints, certain risk factors of the postoperative complications were identified. Results: Out of the 500 patients, 64 developed MACCE, of which 14 (13.6%) occurred in the ONCAB group and 50 (14.0%) in the OPCAB group. Univariate COX regression analysis showed that age ≥65 years, history of diabetes, and preoperative renal insufficiency were independent risk factors for postoperative primary endpoint events in CAD patients with heart failure with reduced ejection fraction (HFrEF). Following the multivariate COX regression analysis, in addition to the above three risk factors, a history of previous percutaneous coronary angiography (PCI) intervention was also a risk factor for the occurrence of the primary endpoints post-CABG. Conclusion: Based on the analysis, significant predictors of post-CABG MACCE in patients with HFrEF included being older than 65 years old, having diabetes, preoperative renal insufficiency, and having previous PCI.

Handover Management for Drones in Future Mobile Networks-A Survey.

Drones have attracted extensive attention for their environmental, civil, and military applications. Because of their low cost and flexibility in deployment, drones with communication capabilities are expected to play key important roles in Fifth Generation (5G), Sixth Generation (6G) mobile networks, and beyond. 6G and 5G are intended to be a full-coverage network capable of providing ubiquitous connections for space, air, ground, and underwater applications. Drones can provide airborne communication in a variety of cases, including as Aerial Base Stations (ABSs) for ground users, relays to link isolated nodes, and mobile users in wireless networks. However, variables such as the drone's free-space propagation behavior at high altitudes and its exposure to antenna sidelobes can contribute to radio environment alterations. These differences may render existing mobility models and techniques as inefficient for connected drone applications. Therefore, drone connections may experience significant issues due to limited power, packet loss, high network congestion, and/or high movement speeds. More issues, such as frequent handovers, may emerge due to erroneous transmissions from limited coverage areas in drone networks. Therefore, the deployments of drones in future mobile networks, including 5G and 6G networks, will face a critical technical issue related to mobility and handover processes due to the main differences in drones' characterizations. Therefore, drone networks require more efficient mobility and handover techniques to continuously maintain stable and reliable connection. More advanced mobility techniques and system reconfiguration are essential, in addition to an alternative framework to handle data transmission. This paper reviews numerous studies on handover management for connected drones in mobile communication networks. The work contributes to providing a more focused review of drone networks, mobility management for drones, and related works in the literature. The main challenges facing the implementation of connected drones are highlighted, especially those related to mobility management, in more detail. The analysis and discussion of this study indicates that, by adopting intelligent handover schemes that utilizing machine learning, deep learning, and automatic robust processes, the handover problems and related issues can be reduced significantly as compared to traditional techniques.

Mobility Management of Unmanned Aerial Vehicles in Ultra-Dense Heterogeneous Networks.

The rapid growth of mobile data traffic will lead to the deployment of Ultra-Dense Networks (UDN) in the near future. Various networks must overlap to meet the massive demands of mobile data traffic, causing an increase in the number of handover scenarios. This will subsequently affect the connectivity, stability, and reliability of communication between mobile and serving networks. The inclusion of Unmanned Aerial Vehicles (UAVs)-based networks will create more complex challenges due to different mobility characterizations. For example, UAVs move in three-dimensions (3D), with dominant of line-of-sight communication links and faster mobility speed scenarios. Assuring steady, stable, and reliable communication during UAVs mobility will be a major problem in future mobile networks. Therefore, this study provides an overview on mobility (handover) management for connected UAVs in future mobile networks, including 5G, 6G, and satellite networks. It provides a brief overview on the most recent solutions that have focused on addressing mobility management problems for UAVs. At the same time, this paper extracts, highlights, and discusses the mobility management difficulties and future research directions for UAVs and UAV mobility. This study serves as a part of the foundation for upcoming research related to mobility management for UAVs since it reviews the relevant knowledge, defines existing problems, and presents the latest research outcomes. It further clarifies handover management of UAVs and highlights the concerns that must be solved in future networks.

Diaphragmatic excursion by ultrasound: reference values for the normal population; a cross-sectional study in Egypt.

Background: Measurement of diaphragmatic motion by ultrasound is being utilized in different aspects of clinical practice. Defining reference values of the diaphragmatic excursion is important to identify those with diaphragmatic motion abnormalities. This study aimed to define the normal range of diaphragmatic motion (reference values) by Mmode ultrasound for the normal population. Methods: Healthy volunteers were included in this study. Those with comorbidities, skeletal deformity, acute or chronic respiratory illness were excluded. Diaphragmatic ultrasound in the supine position was performed using a lowfrequency probe. The B-mode was applied for diaphragmatic identification, and the M-mode was employed for the recording of the amplitude of diaphragm contraction during quiet breathing, deep breathing and sniffing. Results: The study included 757 healthy subjects [478 men (63.14%) and 279 women (36.86%)] with normal spirometry and negative history of previous or current respiratory illness. Their mean age and BMI were 45.17 ±14.84 years and 29.36±19.68 (kg/m2). The mean right hemidiaphragmatic excursion was 2.32±0.54, 5.54±1.26 and 2.90±0.63 for quiet breathing, deep breathing and sniffing, respectively, while the left hemidiaphragmatic excursion was 2.35±0.54, 5.30±1.21 and 2.97±0.56 cm for quiet breathing, deep breathing and sniffing, respectively. There was a statistically significant difference between right and left diaphragmatic excursion among all studied subjects. The ratio of right to left diaphragmatic excursion during quiet breathing was (1.009±0.19); maximum 181% and minimum 28%. Only 19 cases showed a right to left ratio of less than 50% (5 men and 14 women). The diaphragmatic excursion was higher in males than females. There was a significant difference in diaphragmatic excursion among age groups. Age, sex and BMI significantly affected the diaphragmatic motion. Conclusions: Diaphragmatic excursion values presented in this study can be used as reference values to detect diaphragmatic dysfunction in clinical practice. Diaphragmatic motion is affected by several factors including age, sex and body mass index.

Handover Parameters Optimisation Techniques in 5G Networks.

The massive growth of mobile users will spread to significant numbers of small cells for the Fifth Generation (5G) mobile network, which will overlap the fourth generation (4G) network. A tremendous increase in handover (HO) scenarios and HO rates will occur. Ensuring stable and reliable connection through the mobility of user equipment (UE) will become a major problem in future mobile networks. This problem will be magnified with the use of suboptimal handover control parameter (HCP) settings, which can be configured manually or automatically. Therefore, the aim of this study is to investigate the impact of different HCP settings on the performance of 5G network. Several system scenarios are proposed and investigated based on different HCP settings and mobile speed scenarios. The different mobile speeds are expected to demonstrate the influence of many proposed system scenarios on 5G network execution. We conducted simulations utilizing MATLAB software and its related tools. Evaluation comparisons were performed in terms of handover probability (HOP), ping-pong handover probability (PPHP) and outage probability (OP). The 5G network framework has been employed to evaluate the proposed system scenarios used. The simulation results reveal that there is a trade-off in the results obtained from various systems. The use of lower HCP settings provides noticeable enhancements compared to higher HCP settings in terms of OP. Simultaneously, the use of lower HCP settings provides noticeable drawbacks compared to higher HCP settings in terms of high PPHP for all scenarios of mobile speed. The simulation results show that medium HCP settings may be the acceptable solution if one of these systems is applied. This study emphasises the application of automatic self-optimisation (ASO) functions as the best solution that considers user experience.

Surgical outcomes in cardiogenic shock patients with preoperative extracorporeal membrane oxygenation (ECMO).

OBJECTIVES: To summarise the surgical outcomes in patients with cardiogenic shock supported by preoperative extracorporeal membrane oxygenation (ECMO). METHODS: Between May 2012 and August 2017, eight patients with cardiogenic shock, who were supported by ECMO, underwent emergency surgery; four of them had isolated coronary artery bypass grafting, three had coronary artery bypass grafting with mitral replacement, and one had mitral valve replacement with left ventricular posterior wall repair. RESULTS: All eight patients were successfully weaned off from ECMO after their surgeries. Postoperative ECMO time ranged from 6.8 to 228.0 h, with a median of 68.4 h. Two patients died postoperatively while another six survived. The follow up time for the six patients ranged from three to 66 months, whereby one of them died in the third month due to septicaemia. The remaining five patients survived with good cardiac function based on the NYHA classification. CONCLUSION: ECMO is a vital bridge in the preparation of critically-ill patients for cardiac surgery. It is associated with acceptable outcomes among most of the patients.

Emergency and Disaster Preparedness at a Tertiary Medical City.

OBJECTIVE: The aim of this study was to evaluate the readiness of a tertiary medical city's response to a disaster by assessing the hospital resources and knowledge, attitudes, practices, and familiarity of health care providers toward disaster and emergency preparedness. METHODS: All KFMC (King Fahad Medical City) staff with > 1 year of clinical experience were eligible to participate in a cross-sectional study. Participants responded to the Emergency Preparedness Information Questionnaire (EPIQ), knowledge and practice questionnaires, and a disaster planning attitude checklist. Data about resources were collected using the hospital disaster preparedness self-assessment tool. RESULTS: The overall mean knowledge score for disaster and emergency preparedness was 4.4 ± 1.1, and the mean overall familiarity score was 3.43 ± 0.97. Most participants knew that disaster drills (90.2%) and training (74.6%) are ongoing. Sixty-six (21.0%) agreed that KFMC is unlikely to experience a disaster. The highest and lowest EPIQ familiarity scores were for decontamination (83.0%) and accessing critical resources and reporting (64.3%), respectively. Most participants (99.4%) have access to work computers; however, only 53.0% used the Internet to access information on bioterrorism and/or emergency preparedness. The hospital is ready to respond in case of a disaster according to the used tool. CONCLUSIONS: The participants' levels of knowledge, practices, and overall familiarity toward emergency and disaster preparedness were satisfactory; however, participant attitudes and familiarity with where and how to access critical resources in the event of an emergency or disaster situations require reinforcement.

Impact of a mobile phone app on adherence to treatment regimens among hypertensive patients: A randomised clinical trial study.

BACKGROUND: Hypertension is one of the most prevalent long-term diseases seen in many countries, including Palestine. Patients with poorly controlled blood pressure are more likely to develop several complications. Therefore; it is imperative to control their blood pressure by improving their adherence to the treatment regimen. AIM: The objective of this study was to evaluate the impact of using a mobile phone app on the level of adherence to treatment regimens among hypertensive patients in the Gaza Strip. METHODS AND RESULTS: This study used an experimental design with a pre and post-intervention assessment. Using the Hill-Bone compliance to high blood pressure therapy scale, 191 participants completed the study: 94 in the control group and 97 in the intervention group. The intervention group used a phone app which reminds participants to take their medication, reminding them about their follow-up appointments and sending educational information about hypertension management. After 3 months of intervention, the level of adherence to treatment was reassessed. Results showed that participants in both groups showed a significant improvement in adherence levels, with higher improvements in the intervention group in the total score as well as all three domain scores: adherence to medication, diet and keeping appointments. CONCLUSION: The use of a mobile phone app resulted in improvements in adherence to hypertension treatment. Thus, this study confirms the potential effectiveness of mobile technology in improving treatment adherence in hypertension and an opportunity to reduce cardiovascular mortality and morbidity. However, wider adoption has to be accompanied by ongoing evaluation and integration in public health systems.

Assessing Barriers to and Level of Adherence to Hypertension Therapy among Palestinians Living in the Gaza Strip: A Chance for Policy Innovation.

INTRODUCTION: Hypertension is a major health concern, especially in low-income countries. Nonadherence and poor or no persistence in adhering to hypertension treatment regimens result in uncontrolled high blood pressure, increasing rates of mortality and morbidity, and preventable healthcare costs. The aim of this study was to assess the level of adherence and barriers to treatment regimens among hypertensive patients living in the Gaza Strip, Palestine. METHODS: A convenience sample of 648 participants completed the Hill-Bone Compliance to High Blood Pressure Therapy Scale. The great majority of participants (n = 521, 80.4%) was highly adherent to their treatment regimen, 123 participants (18.98%) were classified as moderately nonadherent, and 4 (0.62%) participants were classified as highly nonadherent to their hypertension treatment regimen. Participants of this study showed the highest adherence rate to the domain of medication adherence (mean of 1.42 out of 4) followed by appointment keeping (mean 1.8), while they were least adherent to diet (mean of 2.18). The greatest three barriers to adherence to the recommended treatment regimen reported by participants were inability to exercise, inability to resist fast and fried food, and inability to keep themselves away from salty foods. CONCLUSION: Overall adherence to medication in Gaza was surprisingly good in patients with a diagnosis of hypertension for at least one year. However, adherence to lifestyle advice or dietary regimes remains poor. A combination of interventions using low-cost mobile technology, combined with face-to-face interventions by healthcare professionals, can be applied to improve adherence to hypertension treatment regimens in order to reduce the consequences of uncontrolled blood pressure.

Repair of a type B aortic dissection with a re-vascularization of the aberrant right subclavian artery in an adult patient.

BACKGROUND: An aberrant right subclavian artery which arises from the proximal descending aorta may result in aortic dissection. The dissection may occur at either the site of the primary intimal tear or from an aortic branch. These conditions may lead to blood flow limitation and possible aneurysmal degeneration in the future. CASE PRESENTATION: We described the clinical presentation and management of a 54-year old patient diagnosed with a rare case of an aberrant right subclavian artery with Stanford Type B aortic dissection. A hybrid surgical approach was successfully performed and the patient had an uneventful recovery. CONCLUSION: Even though aortic dissection is often an incidental finding, this case highlighted that in rare situations, it can be associated with an aberrant right subclavian artery. It is important to disseminate this association as it has profound diagnostic and therapeutic implications in safeguarding the clinical outcomes of patients with such condition.

Epicardial cardiac cavernous Haemangioma-a case report.

BACKGROUND: Cardiac haemangiomas are exceptionally rare. They are usually solitary growths. Cardiac haemangiomas can be classified as capillary, cavernous, or arteriovenous in nature. They can occur in any chambers of the heart, but are predominantly found at the intramural or endocardial layers. CASE PRESENTATION: This is a rare case of a cardiac haemangioma located on the epicardium of a 52-year-old male patient. The patient complained of 1-year duration of chest tightness and shortness of breath. The haemangioma was removed successfully. For symptomatic lesions, surgical removal remains the preferred treatment. CONCLUSION: The pathological diagnosis was primary cardiac cavernous haemangioma. In this case, the haemangioma was successfully resected with invasive surgery. No recurrence was detected on follow up.

Case report: synovial sarcoma of the axilla with brachial plexus involvement.

BACKGROUND: Synovial sarcoma is a rare soft tissue sarcoma which most commonly affects the extremities of young adults. Axilla involvement by this sarcoma is very rare especially with involvement of the brachial plexus. This combination adds to the challenge in approaching such tumors which might significantly affect survival and function. CASE PRESENTATION: Herein, we present a 48-year-old female patient who presented with an isolated painless lump in her right axilla. Initially, her workup, looking for possible breast cancer, included fine-needle aspiration (FNA) which did not provide the diagnosis. Core-needle biopsy, performed later, revealed monophasic synovial sarcoma. Her workup studies revealed no metastasis. Then, through extensile deltopectoral approach, the tumor was dissected out from within the brachial plexus. Ulnar nerve was sacrificed in order not to compromise the surgical margins which were confirmed tumor free by final pathology. The patient did not receive chemotherapy or radiation upon consultations with medical and radiation oncology teams. Her follow-up revealed no tumor recurrence with no restriction of her right shoulder motion. CONCLUSION: Our case report represents a very rare occurrence of synovial sarcoma in the axilla with involvement of the brachial plexus. When clinical and radiological findings are suggestive of soft tissue sarcoma of the axilla, we recommend getting core-needle biopsy rather than fine-needle aspiration for earlier diagnosis. Early referral and multidisciplinary approach may contribute to better management.

Post-Traumatic Stress Disorder Among Health Care Providers Following the Israeli Attacks Against Gaza Strip in 2014: A Call for Immediate Policy Actions.

PURPOSE: This study aimed to assess the level of posttraumatic stress disorder and to examine the relationship between exposure to war stress and posttraumatic symptoms among health care providers following Israeli offensives against Gaza Strip in 2014. METHODOLOGY: A cross-sectional design was used for this study. We targeted all nurses and doctors working in three governmental hospitals in the Gaza Strip and worked with victims of the last war, more specifically, those who were working in emergency departments, intensive care units, operating rooms, surgical departments, and burn units. A demographic sheet and Impact Event Scale-Revised were used in this study. The Impact Event Scale-Revised has three sub-scales; intrusion, avoidance, and hyper-arousal. RESULTS: The results showed that 291 (89.8%) of 324 participants had scores more than 35 (threshold cut-off point) on the Impact Event Scale-Revised. Scores ranged from zero to 80 with a mean of 52.13. Females had higher levels of stress (55.79) than males (51.63) and nurses (54.85) had more stress than physicians (47.38). The most frequent symptoms of trauma subscales was "avoidance" (mean=20.04), followed by "intrusion" (mean=17.83), and then "hyper-arousal" (mean=14.27). Levels of trauma symptoms were not affected by place of living, hospital of work, while level of education had impacted level of trauma. CONCLUSION: The findings showed that health care providers suffered from severe posttraumatic symptoms after exposure to prolonged war stress. This level of trauma among health care providers warrants intervention programs to reduce stress and trauma among Gaza health care providers after the war.

Tyrosine kinase inhibitors as a first-line treatment in patients with newly diagnosed chronic myeloid leukemia in chronic phase: A mixed-treatment comparison.

Tyrosine kinase inhibitors (TKI) are the initial treatment for majority of newly diagnosed patients with chronic myelogenous leukemia (CML) in chronic phase (CP) and are associated with marked improvement in hematological, cytogenetic, molecular response and survival rates compared with other therapies. In this review, we summarize the evidence of TKI efficacy for patients with newly diagnosed CP-CML. Six trials at low risk of bias evaluating TKIs as an initial treatment in adults with newly diagnosed CP-CML and enrolling 2,456 patients were included. Follow-up times ranged from a median of 3 months to 5 years. Direct comparison showed statistically higher rates of major molecular response (MMR ≤ 0.1%(IS)) achievement with second-generation TKIs at 12 months which was sustained throughout treatment period. Bayesian mixed-treatment comparison (MTC) analysis demonstrated superiority of both nilotinib and dasatinib over imatinib in terms of efficacy. Nilotinib was associated with higher deeper molecular responses (MR(4.5) ≤ 0.0032%(IS)) at 60 months than dasatinib but no difference in MMR. The differences between nilotinib and dasatinib are likely clinically trivial. Among TKIs, nilotinib was found to have the best survival profile. Both nilotinib and dasatinib are associated with significantly better MMR compared to imatinib that is sustained over 60 months. This analysis shows that new-generation TKIs are not only showing faster response but also maintaining a more potent one through longer follow-up period. It is important to note out that MTC is not a substitute for well-conducted RCTs investigating direct comparisons.

Predictors of acute diarrhoea among hospitalized children in Gaza Governorates: a case-control study.

This study aims to determine the predictors of acute diarrhoea among hospitalized children in the Gaza Governorates. The case-control design included 140 children (70 cases and 70 controls) in a stratified cluster sample from Naser Medical Complex and Alnasser Pediatric Hospital. An interview questionnaire was used, and face and content validations were performed. Multiple logistic regression was used for the multivariate analysis of risk factors of diarrhoea in children aged less than five years. Results showed a significant association between diarrhoea and family income, residence, complementary feeding, and age of weaning (p<0.05). Children living in villages had lower odds of having diarrhoea by 53.2% than children living in cities. Children of families with incomes between US$ 485 and 620 had lower odds of having diarrhoea by 80.8% than children of families with incomes less than US$ 485. Moreover, children who did not receive complementary feeding had lower odds of having diarrhoea by 59.0%. We found that, for one month increase in weaning age, the odds of diarrhoea decreased by 1.06 times (adjusted OR=1.05, 95% CI 1.0180-1.100). The study concludes that urban residence, lower family income, complementary feeding, and lower age of weaning are risk factors of diarrhoea among children aged less than five years in the Gaza Strip. The results of the study suggest that children of low-income families and those who were not naturally breastfed may warrant more attention for prevention and/or treatment of diarrhoea.

Dietary lecithin protects against cholestatic liver disease in cholic acid-fed Abcb4- deficient mice.

Mutations in multidrug resistance 3 gene (MDR3 or ABCB4) underlie progressive familial intrahepatic cholestasis type 3 (PFIC3), a severe pediatric liver disease progressing to cirrhosis. Abcb4-/- mice exhibit slowly developing hepatic lesions that can be accelerated by feeding a cholic acid (CA)-supplemented diet. We investigated the beneficial effects of a soybean lecithin (L)-supplemented diet in this model of liver disease. Abcb4-/- mice and wild-type (WT) controls were divided in four groups by the diet they were fed: control (C) diet, L-supplemented diet, CA-supplemented diet, and L- and CA-supplemented (L+CA) diet. After 2 wk on these regimens, liver enzymes and bilirubin were measured in serum with bile flow, total bile acids, and cholesterol (CHOL) and phospholipid (PL) concentrations in bile. Ductular hyperplasia, portal fibroblastic cell proliferation, myofibroblast activation, and hepatic fibrosis were quantified on liver sections. Abcb4-/- mice fed the C diet exhibited mild liver damage. CA produced very high elevations of serum liver enzymes and bilirubin with significant bile duct proliferation, peribiliary fibroblast activation, and fibrosis. The L-supplemented diet dramatically mitigated the hepatic damage in CA-supplemented diet animals. We conclude that L is protective against liver disease in Abcb4-/- mice and suggest that it could offer potential benefit in PFIC3.

Cholemic transgenic mice: a novel animal model to investigate the effects of bile acids.

INTRODUCTION: Laboratory investigations into cholestatic liver disease and the effects of cholemia on organ function are long-standing subjects of scientific enquiry. A widely-used strategy to investigate these topics relies on animal-based research using experimental animal models. Targeted inactivation of the spgp gene, the gene responsible for expressing the bile salt export pump (BSEP) in the hepatocyte canalicular membrane impairs the canalicular secretion of bile salts resulting in systemic cholemia. The results of in vitro experiments have established bile acids as pro-oxidants and the collection of unambiguous in vivo data on the pro-oxidant activity of bile acids in the existing models of cholemia cannot be done. Therefore, we decided to use these genetically modified mice to determine whether this model of cholemia has evidence of extrahepatic or systemic oxidative stress, one of the features of cholestatic liver disease. METHODS: The extent of lipid peroxidation in livers, kidneys, hearts and brains harvested from cholemic homozygous (spgp -/-) mice using the thiobarbituric acid reactive substances (TBARS) assay. The data were compared to equivalent data collected from heterozygous (spgp +/-) and control mice. RESULTS: We found (1) substantial increases in malondialdehyde (MDA) levels in the brains and hearts; (2) a moderate increase in MDA levels in the kidneys; and (3) no change in MDA levels in the livers of the homozygous cholemic mice compared to the control and heterozygous mice. DISCUSSION: The transgenic mouse model of cholemia has an intact enterohepatic circulation and is uncomplicated by the adverse consequences of hepatotoxins or biliary surgery. Hepatocellular injury, as well as plasma and tissue accumulation of bilirubin and other liver-derived compounds are also negligible. Although this preliminary study could not establish a causal relationship between cholemia and oxidative stress, we believe this model is worthy of further investigation to study the impact of short-term and long-term cholemia on diverse physiological and biochemical functions such as trying to establish a causal role for bile acids in the development of oxidative stress in cholestatic liver disease.

The role of mdr2 in manganese-bilirubin induced cholestasis in mice.

The pathogenesis of manganese-bilirubin (Mn-BR) induced cholestasis has only been studied in rats and is associated with alteration in the hepatic homeostasis of cholesterol and phospholipids. Multidrug resistance-2 (mdr2) transporter, which mediates excretion of these lipids, is suggested to be involved in this phenomenon. The present study was undertaken to examine if Mn-BR induced cholestasis is reproducible in mice, then to clarify the role of mdr2 in its pathogenesis, using mice with disrupted mdr2 gene (mdr2 (-/-)). Results showed that Mn-BR combination decreased bile flow in mice. This reduction in bile flow was similar in mdr2 (-/-) and the wild type mdr2 (+/+). Furthermore, the change in biliary lipid excretion was comparable in both genotypes. These data indicate that Mn-BR induced cholestasis is reproducible in mice and provide evidence that mdr2 alteration is not a primary event in this form of cholestasis.

Severe cholestasis induced by cholic acid feeding in knockout mice of sister of P-glycoprotein.

Intrahepatic cholestasis is often associated with impairment of biliary bile acid secretion, a process mediated by the sister of P-glycoprotein (Spgp or Abcb11) also known as the bile salt export pump (Bsep). In humans, mutations in the Spgp gene are associated with a fatal childhood disease, type 2 progressive familial intrahepatic cholestasis (PFIC2). However in mice, the "knockout" of Spgp only results in mild cholestasis. In this study, we fed spgp(-/-) knockout mice with a cholic acid (CA)-supplemented diet to determine whether a more pronounced PFIC2-like phenotype could be induced. Such mice developed severe cholestasis characterized by jaundice, weight loss, elevated plasma bile acid, elevated transaminase, cholangiopathy (proliferation of bile ductules and cholangitis), liver necrosis, high mortality, and wide-ranging changes in the mRNA expression of major liver genes (16/36 examined). A surprising observation was that the bile acid output and bile flow in CA-fed mutant mice was significantly higher than anticipated. This suggests that the spgp(-/-) mice are able to utilize an alternative bile salt transport system. However, unlike Spgp, this system is insufficient to protect the knockout mice from cholestasis despite its high capacity. In conclusion, the spgp(-/-) mice provide a unique model to investigate molecular pathways associated with cholestasis and related diseases.