Search

Cardiac amyloidosis is indeed a condition characterized by the deposition of amyloid proteins in the myocardium, leading to thickening and stiffening of the heart muscle. These abnormal protein deposits can interfere with the heart's normal functioning and may pose diagnostic challenges due to its varied clinical presentation and resemblance to other heart condition. Here, we present a case of 55-year-old female patient of uncontrolled hypertensions for 15 years. About 15 years ago, she presented with chest pain and was diagnosed with cardiomyopathy (CM) characterized by low left ventricle (LV) function of unknown cause. Despite being on antihypertensive treatment, the patient continued to experience chest heaviness with persistent elevate blood pressure. An echocardiogram revealed increased LV septal wall thickness, valvular thickening, and biatrial dilation. Subsequently, cardiac magnetic resonance imaging (CMR) was performed, which revealed left atrium enlargement and asymmetrical myocardial wall thickening, particularly at the septum. White blood axial image revealed thickened inter atrial septum, while late gadolinium enhancement (LGE) magnetic resonance (LGE MR) images showed patchy LGE at the base relative to the apex of the myocardium, highlighting the base-to-apex gradient, subendocardial pattern enhancement at apical lateral wall, and transmural pattern enhancement of the mid anteroseptal and inferoseptal wall. Additionally, a short axis time to invert T1 scout image of left ventricle displayed an abnormal nulling pattern initially in the myocardium, followed by the blood pool, and finally the spleen. These findings collectively led to the diagnosis of cardiac amyloidosis.

Khat is an evergreen plant and its fresh green leaves and buds are chewed for several hours a day for its psychostimulant response. This study aimed to review the effects of khat chewing on the body. PubMed was searched for literature on the different aspects of khat chewing to summarize its effects on different body systems. The major effects of khat chewing are those on the cardiovascular system including increased blood pressure, increased heart rate, and increased risk of myocardial infarction. It causes insomnia, stress, depression, hallucination, and increased risk of brain stroke. It causes dental caries, bad oral hygiene, periodontitis, increased oral mucosal ulcers, and increased gingival bleeding and recession. Khat chewing causes loss of appetite, gastritis, constipation, and hemorrhoids, and increased risk of hepatotoxicity and liver cirrhosis. Ultimately, it causes weak micturition, decreased sperm motility and count, and low birth-weight offspring in khat chewing mothers. The published articles about khat chewing in journals indexed in the PubMed was reviewed. Inclusion criteria involved each article available with English language and have a reported new effect of khat chewing.

Enjy Abouzeid,1 Sally Fouad,1 Nourhan F Wasfy,1 Rania Alkhadragy,1 Mohamed Hefny,2 Doaa Kamal1 1Medical Education Department, Faculty of Medicine, Suez Canal University, Ismailia, Egypt; 2Department of Physical Medicine, Rheumatology and Rehabilitation, Faculty of Medicine, Suez Canal University, Ismailia, EgyptCorrespondence: Nourhan F WasfyMedical Education Department, Faculty of Medicine, Suez Canal University, Ismailia, EgyptEmail nourhan_f_wasfy@med.suez.edu.egPurpose: Learning focus has shifted from conventional teacher-centered to student-centered; therefore, methods used to support and encourage learners must be considered. Meanwhile, the individual differences between learners should be taken into consideration by medical educators. Aiming to achieve a better learning experience, the current study investigates the relationship between personality traits and learning styles and their effect on students’ academic achievement.Subjects and Methods: An analytical, cross-sectional study, encompassing a sample of 333 undergraduate first-year medical students, at the Faculty of Medicine, Suez Canal University in Egypt was conducted. The Big Five personality traits test and VARK learning styles questionnaires were used to assess students’ personality traits and learning styles, respectively, in the medical education module which is a part of the Foundation II module. The former is five weeks’ duration and is followed by a summative exam at the end. Students’ academic achievement was determined from their grades in Foundation II module by the end of the semester.Results: Study findings generally indicate that the highest domain of learning styles among students is the kinesthetic domain. A statistically significant difference between males and females regarding their learning style preferences was detected. Also, there was a statistically significant relationship between auditory and kinesthetic learning styles and academic achievement. Though there was a significant relationship between kinesthetic learning style with both openness traits and academic achievement, no significant statistical relationship was found between any of the personality traits and academic achievement.Conclusion: This study concludes that learning style could affect students’ academic achievement. It reveals that the kinesthetic learning style is the most preferred learning style among our medical students, also the agreeableness and openness traits were the most common personality traits among them. No significant relationship was detected between personality traits and academic achievement.Keywords: learning styles, personality traits, academic achievement, active learning, medical education

A pharyngeal hairy polyp (HP) is a rare benign mass that can be surgical detached with few complications. In this report, we describe a hairy polyp in a 7-day-old neonate presented with intermittent respiratory distress and feeding difficulties since birth. Neck computed tomography was performed, and demonstrated a well-defined pedunculated heterogeneous mass arising from the right lateral wall of the nasopharynx extending downward and nearly completely obstructing of the nasopharynx and oropharynx. The central part of the mass was found relatively dense surrounded by low attenuation fatty components with enhancement of the outer wall of the mass. The provisional diagnosis was pharyngeal HP. After autoamputation at the seventh day old, HP was analyzed via histopathology examination that showed a mixture of various ectodermal and mesodermal tissues including skin, cartilage, adipose and fibrous tissue. The patient fully recovered with no residual clinical features. We report this case to elucidate the possibility of this strange behavior of pharyngeal HP.

Background: Coronary artery disease (CAD) is a common medical problem that remains a great cause of morbidity and mortality. Based on clinical manifestation, CAD span from chronic stable angina to acute coronary syndrome (ACS), which encompasses (1) unstable angina (UA), (2) non-ST-elevation myocardial infarction (NSTEMI), and (3) ST-elevation myocardial infarction (STEMI). Objective: This study was conducted to describe the risk stratification and prognosis of CAD in Yemeni patients undergoing an exercise stress test. Method: A retrospective descriptive study involved the records of 302 patients who undergoing exercise stress testing by the Bruce protocol of Treadmill (TMT). Results: Out of 302 patients, the mean age was 43.29 years, (range, 22–70 years), and 79.80% were males. The majority of patients (86.75%) were normal. Most of the affected patients (82.50%) were males. All of the affected peoples were more than 30 years old with predominance in more than 50 years old. Results showed that 45% of the positive (+ve) patients were in high-risk group, and 55% were in intermediate and low-risk groups. Conclusions: CAD affects males more than females. It affects patients older than 30 years and predominates in elderly patients. Most of the affected patients were in the high, intermediate, and low-risk groups and rarely were in the very high-risk group.

Hydatid cyst is a common name for the larval stage of a tapeworm species of Echinococcus granulosus, which is transmitted from animals to humans via the fecal–oral route. Hydatid cysts predominantly affect the liver (75%), followed by the lung (15%), and they can affect many organs in the human body. Medical imaging modalities are the keystone for the diagnosis of hydatid cysts with high sensitivity and specificity. Ultrasound imaging with high resolution is the first choice for diagnosis, differential diagnosis, staging, establishing a role in interventional management, and follow-up, and it can differentiate Type I hydatid cysts from simple liver cysts. Unenhanced computed tomography (CT) is indicated where or when an ultrasound is unsatisfactory, such as with chest or brain hydatid cysts, when detecting calcification, and in obese patients. Magnetic resonance imaging (MRI) is superior for demonstrating cyst wall defects, biliary communication, neural involvement, and differentiating hydatid cysts from simple cysts using diffusion-weighted imaging (DWI) sequences. According to the phase of growth, hydatid cysts occur in different sizes and shapes, which may mimic benign or malignant neoplasms and may create diagnostic challenges in some cases. Hydatid cysts can mimic simple cysts, choledochal cysts, Caroli’s disease, or mesenchymal hamartomas of the liver. They can mimic lung cystic lesions, mycetoma, blood clots, Rasmussen aneurysms, and even lung carcinomas. Differential diagnosis can be difficult for arachnoid cysts, porencephalic cysts, pyogenic abscesses, and even cystic tumors of the brain, and can create diagnostic dilemmas in the musculoskeletal system.

The signaling mechanisms by which dietary fat and cholesterol signals regulate central pathways of glucose homeostasis are not completely understood. By using a hepatocyte-specific PKCβ-deficient (PKCβHep–/–) mouse model, we demonstrated the role of hepatic PKCβ in slowing disposal of glucose overload by suppressing glycogenesis and increasing hepatic glucose output. PKCβHep–/– mice exhibited lower plasma glucose under the fed condition, modestly improved systemic glucose tolerance and mildly suppressed gluconeogenesis, increased hepatic glycogen accumulation and synthesis due to elevated glucokinase expression and activated glycogen synthase (GS), and suppressed glucose-6-phosphatase expression compared with controls. These events were independent of hepatic AKT/GSK-3α/β signaling and were accompanied by increased HNF-4α transactivation, reduced FoxO1 protein abundance, and elevated expression of GS targeting protein phosphatase 1 regulatory subunit 3C in the PKCβHep–/– liver compared with controls. The above data strongly imply that hepatic PKCβ deficiency causes hypoglycemia postprandially by promoting glucose phosphorylation via upregulating glucokinase and subsequently redirecting more glucose-6-phosphate to glycogen via activating GS. In summary, hepatic PKCβ has a unique and essential ability to induce a coordinated response that negatively affects glycogenesis at multiple levels under physiological postprandial conditions, thereby integrating nutritional fat intake with dysregulation of glucose homeostasis.

Objective: Nonalcoholic hepatic steatosis, also known as fatty liver, is a uniform response of the liver to hyperlipidic-hypercaloric diet intake. However, the post-ingestive signals and mechanistic processes driving hepatic steatosis are not well understood. Emerging data demonstrate that protein kinase C beta (PKCβ), a lipid-sensitive kinase, plays a critical role in energy metabolism and adaptation to environmental and nutritional stimuli. Despite its powerful effect on glucose and lipid metabolism, knowledge of the physiological roles of hepatic PKCβ in energy homeostasis is limited. Methods: The floxed-PKCβ and hepatocyte-specific PKCβ-deficient mouse models were generated to study the in vivo role of hepatocyte PKCβ on diet-induced hepatic steatosis, lipid metabolism, and mitochondrial function. Results: We report that hepatocyte-specific PKCβ deficiency protects mice from development of hepatic steatosis induced by high-fat diet, without affecting body weight gain. This protection is associated with attenuation of SREBP-1c transactivation and improved hepatic mitochondrial respiratory chain. Lipidomic analysis identified significant increases in the critical mitochondrial inner membrane lipid, cardiolipin, in PKCβ-deficient livers compared to control. Moreover, hepatocyte PKCβ deficiency had no significant effect on either hepatic or whole-body insulin sensitivity supporting dissociation between hepatic steatosis and insulin resistance. Conclusions: The above data indicate that hepatocyte PKCβ is a key focus of dietary lipid perception and is essential for efficient storage of dietary lipids in liver largely through coordinating energy utilization and lipogenesis during post-prandial period. These results highlight the importance of hepatic PKCβ as a drug target for obesity-associated nonalcoholic hepatic steatosis.

Tuberculosis (TB) is a bacterial infection with Mycobacterium tuberculosis; it is a public health problem worldwide and one of the leading causes of mortality. Since December 2019, the COVID-19 pandemic has created unprecedented health challenges and disrupted the TB health services, especially in high-burden countries with ever-increasing prevalence. Extrapulmonary and even pulmonary TB are an important cause of nonspecific clinical and radiological manifestations and can masquerade as any benign or malignant medical case, thus causing disastrous conditions and diagnostic dilemmas. Clinical manifestations and routine laboratory tests have limitations in directing physicians to diagnose TB. Medical-imaging examinations play an essential role in detecting tissue abnormalities and early suspecting diagnosis of TB in different organs. Radiologists and physicians should be familiar with and aware of the radiological manifestations of TB to contribute to the early suspicion and diagnosis of TB. The purpose of this article is to illustrate the common radiologic patterns of pulmonary and extrapulmonary TB. This article will be beneficial for radiologists, medical students, chest physicians, and infectious-disease doctors who are interested in the diagnosis of TB.

Natural plant products have been used for centuries for health maintenance and treatment of a variety of diseases in various traditional systems of medicine in Egypt and other African countries, India, China, and other countries around the world. Over the past several decades, the popularity of herbal and other natural products has gradually increased in many western countries. Despite the increasing popularity of natural products, both the public and the professionals are skeptical about the use of these products. Reasons for this skepticism include, but are not limited to, the lack of proper documentation about the source and formulations used; standardization of the composition, batch-to-batch consistency, documented safety of herbal products; and information about the mechanisms of action of these products. The 1st Euro-Mediterranean Workshop: Natural Products in Health and Diseases was organized by the Euro-Mediterranean Association of Life Sciences (EMALS) and various other local organizations to review and discuss the above-mentioned strengths and limitations of the use of natural products. The aim of this workshop was to share best practices and expertise about natural products, and to identify opportunities for collaboration among researchers, health professionals, and business personnel in a productive atmosphere.

Autoimmune diseases such as rheumatoid arthritis (RA) cause significant morbidity and loss of productivity. Many potent conventionally used drugs are available for these diseases, but their prolonged use is accompanied by severe adverse effects besides a high cost. Therefore, there is an unmet need for effective but less expensive medications for RA and other autoimmune diseases. Natural plant products belonging to the traditional systems of medicine, such as the traditional Chinese medicine and Indian Ayurvedic medicine, offer a vast and promising resource in this regard. However, herbal medicinal products are often poorly characterized for their composition as well as mechanisms of action. We review here the results of our systematically performed studies aimed at defining the anti-arthritic activity of three herbal extracts, namely, modified Huo-luo-xiao-ling dan (HLXL), Celastrus aculeatus Merr., and polyphenolic fraction of green tea (Camellia sinensis), as well as a purified compound Celastrol, a bioactive component of Celastrus. Specifically, we examined the effects of these herbal products on the immunological, biochemical and molecular biological effector pathways in autoimmune arthritis. We have also reviewed here related studies on these herbal products by other investigators. Taken together, we suggest further testing of these herbal products in RA patients.

The 4th Euro-Mediterranean Conference of Natural Products and Drug Discovery: Back to Mother Nature (BioNat-IV) was recently (from March 3rd through 7th, 2015) convened in Cairo and Sharm El-Sheikh along the Red Sea coast of Egypt. Overall, the meeting provided a platform for scientists from different nations to discuss emerging ideas that focused on cell signaling in cancer; the pathogenesis of autoimmune diseases; the identification and use of natural products as well as novel drug delivery approaches for the treatment of cancer, arthritis, diabetes, tuberculosis, fungal infection, etc.; and untapped or unconventional sources for natural products. This fourth in a row conference tried to bridge the gap not only between basic research and clinical applications, but also between developed nations and developing countries. With the continuing success of these past meetings, the fifth Euro-Mediterranean Conference of Natural Products and Drug Discovery (BioNat-V) is slated to be in February 2017.

Bone marrow stromal cells (BMSCs) produce long-lasting attenuation of pain hypersensitivity. This effect involves BMSC’s ability to interact with the immune system and activation of the endogenous opioid receptors in the pain modulatory circuitry. The nuclear factor kappa B (NF-κB) protein complex is a key transcription factor that regulates gene expression involved in immunity. We tested the hypothesis that the NF-κB signaling plays a role in BMSC-induced pain relief. We focused on the rostral ventromedial medulla (RVM), a key structure in the descending pain modulatory pathway, that has been shown to play an important role in BMSC-produced antihyperalgesia. In Sprague-Dawley rats with a ligation injury of the masseter muscle tendon (TL), BMSCs (1.5 M/rat) from donor rats were infused i.v. at 1 week post-TL. P65 exhibited predominant neuronal localization in the RVM with scattered distribution in glial cells. At 1 week, but not 8 weeks after BMSC infusion, western blot and immunostaining showed that p65 of NF-κB was significantly increased in the RVM. Given that chemokine signaling is critical to BMSCs’ pain-relieving effect, we further evaluated a role of chemokine signaling in p65 upregulation. Prior to infusion of BMSCs, we transduced BMSCs with Ccl4 shRNA, incubated BMSCs with RS 102895, a CCR2b antagonist, or maraviroc, a CCR5 antagonist. The antagonism of chemokines significantly reduced BMSC-induced upregulation of p65, suggesting that upregulation of p65 was related to BMSCs’ pain-relieving effect. We then tested the effect of a selective NF-κB activation inhibitor, BAY 11-7082. The mechanical hyperalgesia of the rat was assessed with the von Frey method. In the pre-treatment experiment, BAY 11-7082 (2.5 and 25 pmol) was injected into the RVM at 2 h prior to BMSC infusion. Pretreatment with BAY 11-7082 attenuated BMSCs’ antihyperalgesia, but post-treatment at 5 weeks post-BMSC was not effective. On the contrary, in TL rats receiving BAY 11-7082 without BMSCs, TL-induced hyperalgesia was attenuated, consistent with dual roles of NF-κB in pain hypersensitivity and BMSC-produced pain relief. These results indicate that the NF-κB signaling pathway in the descending circuitry is involved in initiation of BMSC-produced behavioral antihyperalgesia.

Background & Aims: Dietary factors are likely an important determinant of gallstone development, and difficulty in adapting to lithogenic diets may predispose individuals to gallstone formation. Identification of the critical early diet-dependent metabolic markers of adaptability is urgently needed to prevent gallstone development. We focus on the interaction between diet and genes, and the resulting potential to influence gallstone risk by dietary modification. Methods: Expression levels of hepatic protein kinase C (PKC) isoforms were determined in lithogenic diet-fed mice, and the relationship of hepatic cholesterol content and PKCβ expression and the effect of hepatic PKCβ overexpression on intracellular signaling pathways were analyzed. Results: Lithogenic diet feeding resulted in a striking induction of hepatic PKCβ and PKCδ mRNA and protein levels, which preceded the appearance of biliary cholesterol crystals. Unlike PKCβ deficiency, global PKCδ deficiency did not influence lithogenic diet-induced gallstone formation. Interestingly, a deficiency of apolipoprotein E abrogated the diet-induced hepatic PKCβ expression, whereas a deficiency of liver X receptor-α further potentiated the induction, suggesting a potential link between the degree of hepatic PKCβ induction and the intracellular cholesterol content. Furthermore, our results suggest that PKCβ is a physiologic repressor of ileum basal fibroblast growth factor 15 (FGF15) expression and activity of hepatic proto-oncogene serine/threonine-protein kinase Raf-1/mitogen-activated protein (MAP) kinase kinase/extracellular signal-regulated kinases 1/2 (Raf-1/MEK/ERK1/2) cascade proteins, and the complex interactions between these pathways may determine the degree of hepatic ERK1/2 activation, a potent suppressor of cholesterol 7α-hydroxylase and sterol 12α-hydroxylase expression. We found that PKCβ regulated Raf-1 activity by modulating the inhibitory Raf-1Ser259 phosphorylation. Conclusions: Our results demonstrate a novel interaction between the hepatic PKCβ/Raf-1 regulatory axis and ileum PKCβ/FGF15/ERK axis, which could modulate the bile lithogenecity of dietary lipids. The data presented are consistent with a two-pronged mechanism by which intestine and liver PKCβ signaling converges on the liver ERK1/2 pathway to control the hepatic adaptive response to a lithogenic diet. Elucidating the impact and the underlying mechanism(s) of PKCβ action could help us understand how different types of dietary fat modify the risk of gallstone formation, information that could help to identify novel targets for therapeutic approaches to combat this disease. Keywords: Hepatic Cholesterol Metabolism, Lithogenic Diet, Signal Transduction, Protein Kinase Cβ

To explore the role of leptin in PKCβ action and to determine the protective potential of PKCβ deficiency on profound obesity, double knockout (DBKO) mice lacking PKCβ and ob genes were created, and key parameters of metabolism and body composition were studied. DBKO mice had similar caloric intake as ob/ob mice but showed significantly reduced body fat content, improved glucose metabolism, and elevated body temperature. DBKO mice were resistant to high-fat diet-induced obesity. Moreover, PKCβ deficiency increased β-adrenergic signaling by inducing expression of β1- and β3-adrenergic receptors (β-ARs) in white adipose tissue (WAT) of ob/ob mice. Accordingly, p38MAPK activation and expression of PGC-1α and UCP-1 were increased in WAT of DBKO mice. Consistent with results of in vivo studies, inhibition of PKCβ in WAT explants from ob/ob mice also increased expression of above β-ARs. In contrast, induction of PGC-1α and UCP-1 expression in brown adipose tissue of DBKO mice was not accompanied by changes in the expression of these β-ARs. Collectively, these findings suggest that PKCβ deficiency may prevent genetic obesity, in part, by remodeling the catabolic function of adipose tissues through β-ARs dependent and independent mechanisms.

Background: Air pollution due to road traffic is a serious health hazard and thus the persons who are continuously exposed, may be at an increased risk. Although several studies have confirmed the ill effects of air pollutants on the lung function of traffic policemen, only a few have investigated the relationship between respiratory health and duration of exposure in this category of occupationally exposed persons. Aim: The study was carried out with the aim of evaluating the extent of impairment in lung function in traffic policemen in respect to an unexposed control group having the same age group. Materials and Methods: A cross-sectional study was conducted in which the spirometric parameters of a group of 100 nonsmoking traffic policemen, aged 20-55 years, working in and around Patiala city, were compared with those obtained in an age-matched control group, consisting of 100 healthy males, serving in the Punjab Police, who have never done traffic duty and are thus not exposed to traffic pollution. Lung function was done with MEDSPIROR. The data on the overall health status of the subjects was collected using the standard Respirator Medical Evaluation Questionnaire. The statistical analysis was carried out with SPSS PC software version 13. Results: Traffic policemen recorded a significant decline in various parameters, such as forced vital capacity (FVC), forced expiratory volume in one second (FEV 1 ), and peak expiratory flow rate (PEFR) when compared with controls, and is probably due to exposure to vehicular pollution. It was also observed that in traffic policemen with >8 years of exposure, the values of FVC (2.7 L), FEV 1 (1.8 L), and PEFR (7.5 L/s) were significantly lower than those obtained in traffic policemen with

Histone modification is emerging as a major regulatory mechanism for modulating gene expression by altering the accessibility of transcription factors to DNA. This study unravels the relationship between histone H3 modifications and LDL receptor induction, focusing also on routes by which phosphorylation is mediated in human hepatoma HepG2 cells. We show that while histone H3 is constitutively acetylated at LDL receptor chromatin, 12-O -tetradecanoylphorbol-13-acetate (TPA) causes rapid hyperphosphorylation of histone H3 on serine 10 (histone H3-Ser10), despite global reduction in its phosphorylation levels. Ser10 hyperphosphorylation precedes LDL receptor induction and is independent of the p42/44MAPK, p38MAPK, pp90RSK, or MSK-1 cascade. Interestingly, inhibition of protein kinase C (PKC) blocks Ser10 hyperphosphorylation and also compromises LDL receptor induction by TPA. Consistent with its role, recombinant purified PKC phosphorylate purified histone H3-Ser10.Collectively, our findings highlight a novel role for PKC in regulating histone H3-Ser10 phosphorylation and suggest that histone modification provides numerous regulatory opportunities to set the overall range of control attainable for LDL receptor gene induction.

We have previously shown that different extracellular stimuli require signaling through the Raf/MEK/p42/44MAPK cascade to induce LDL receptor expression. The present studies were designed to delineate the molecular mechanisms underlying p42/44MAPK-induced LDL receptor transcription in HepG2-ΔRaf-1:ER cells, a modified HepG2 cell line in which the Raf-1/MEK/p42/44MAPK cascade can be specifically activated by anti-estradiol ICI182,780 in an agonist-specific manner. Using these cells, we show that: a) LDL receptor induction was reduced in reporter constructs containing mutation in either Sp1 or sterol-regulatory element-1 (SRE-1) sites, whereas inactivation of both sites abolished the induction; b) E1A, which inhibits CREB binding protein (CBP), a common activator of SRE-1 binding protein and Sp1, strongly repressed the induction; c) intracellular inhibition of the 90 kDa ribosomal S6 kinase (pp90RSK) cascade reduced LDL receptor induction; d) highly selective protein kinase C (PKC) inhibitors effectively abrogated the induction without affecting activation of pp90RSK; and e) overexpression of PKCβ significantly induced LDL receptor promoter activity.Taken together, these results demonstrate that pp90RSK and PKCβ are downstream effectors and Sp1, SRE-1 binding protein, and CBP are part of the transcriptional complex resulting in induction of LDL receptor expression in response to activation of the Raf/MEK/p42/44MAPK cascade. These findings identify for the first time a role for PKCβ in determining the specificity of p42/44MAPK signaling by participating with pp90RSK in regulating gene expression.

Protein kinase C beta (PKCβ) expression in breast cancer is associated with a more aggressive tumor phenotype, yet the mechanism for how PKCβ is pro-tumorigenic in this disease is still unclear. Interestingly, while it is known that PKCβ mediates angiogenesis, immunity, fibroblast function and adipogenesis, all components of the mammary tumor microenvironment (TME), no study to date has investigated whether stromal PKCβ is functionally relevant in breast cancer. Herein, we evaluate mouse mammary tumor virus-polyoma middle T-antigen (MMTV-PyMT) induced mammary tumorigenesis in the presence and absence of PKCβ. We utilize two model systems: one where PKCβ is deleted in both the epithelial and stromal compartments to test the global requirement for PKCβ on tumor formation, and second, where PKCβ is deleted only in the stromal compartment to test its role in the TME. MMTV-PyMT mice globally lacking PKCβ live longer and develop smaller tumors with decreased proliferation and decreased macrophage infiltration. Similarly, when PKCβ is null exclusively in the stroma, PyMT-driven B6 cells form smaller tumors. These experiments reveal for the first time a tumor promoting role for stromal PKCβ in MMTV-PyMT tumorigenesis. In corroboration with these results, PKCβ mRNA (Prkcb) is increased in fibroblasts isolated from MMTV-PyMT tumors. These data were confirmed in a breast cancer patient cohort. Combined these data suggest the continued investigation of PKCβ in the mammary TME is necessary to elucidate how to effectively target this signaling pathway in breast cancer.

The protein synthesis inhibitor anisomycin activates stress-related mitogen-activated protein kinases (MAPKs), namely, c-jun NH2-terminal kinase (p46/54JNK) and p38MAPK in mammalian cells. In this paper, we show that although exposure to anisomycin resulted in rapid and strong activation of p46/54JNK and p38MAPK, with a delayed low level dual-phosphorylation of mitogen/extracellular protein kinase (p42/44MAPK), low density lipoprotein (LDL) receptor induction depends solely on the mild activation of p42/44MAPK signaling cascade in HepG2 cells. Unlike hepatocyte growth factor (HGF) which caused LDL receptor induction via rapid, strong, and Ras-dependent p42/44MAPK activation, anisomycin-induced p42/44MAPK activity and increased LDL receptor expression in a Ras-independent manner. Finally, we examined the role of the p42/44MAPK signaling cascade in LDL receptor induction by activating this kinase independently of anisomycin or HGF. By using estrogen-dependent human Raf-1 protein kinase in transient transfection assays, we show that the exclusive activation of the Raf-1/MEK-1/p42/44MAPK signaling cascade with antiestrogen ICI 182,780 caused induction of LDL receptor expression to the same level as observed with either HGF or anisomycin. Consistent with the role of p42/44MAPK, induction was strongly inhibited by pretreatment with the MEK-1/2 inhibitor PD98059. Our observation that anisomycin can use p42/44MAPK signaling cascade is a departure from established thinking, and the results presented shows that activation of the p42/44MAPK alone is sufficient to fully induce LDL receptor transcription.—Dhawan, P., A. Bell, A. Kumar, C. Golden, and K. D. Mehta. Critical role of p42/44MAPK activation in anisomycin and hepatocyte growth factor-induced LDL receptor expression: activation of Raf-1/MEK-1/p42/44MAPK cascade alone is sufficient to induce LDL receptor expression. J. Lipid Res. 1999. 40: 1911–1919.

The delta isoform of the p110 catalytic subunit (p110δ) of phosphoinositide 3-kinase is expressed primarily in hematopoietic cells and plays an essential role in B-cell development and function. Studies employing mice lacking a functional p110δ protein, as well as the use of highly-selective chemical inhibitors of p110δ, have revealed that signaling via p110δ-containing PI3K complexes (PI3Kδ) is critical for B-cell survival, migration, and activation, functioning downstream of key receptors on B cells including the B-cell antigen receptor, chemokine receptors, pro-survival receptors such as BAFF-R and the IL-4 receptor, and co-stimulatory receptors such as CD40 and Toll-like receptors. Similarly, this PI3K isoform plays a key role in the survival, proliferation, and dissemination of B-cell lymphomas. Herein we summarize studies showing that these processes can be inhibited in vitro and in vivo by small molecule inhibitors of p110δ enzymatic activity, and that these p110δ inhibitors have shown efficacy in clinical trials for the treatment of several types of B-cell malignancies including chronic lymphocytic leukemia and non-Hodgkins lymphoma. PI3Kδ also plays a critical role in the activation, proliferation, and tissue homing of self-reactive B cells that contribute to autoimmune diseases, in particular innate-like B-cell populations such as marginal zone B cells and B-1 cells that have been strongly linked to autoimmunity. We discuss the potential utility of p110δ inhibitors, either alone or in combination with B-cell depletion, for treating autoimmune diseases such as lupus, rheumatoid arthritis, and type 1 diabetes. Because PI3Kδ plays a major role in both B-cell-mediated autoimmune inflammation and B-cell malignancies, PI3Kδ inhibitors may represent a promising therapeutic approach for treating these diseases.

The global nephrology community recognizes the need for a cohesive strategy to address the growing problem of end-stage kidney disease (ESKD). In March 2018, the International Society of Nephrology hosted a summit on integrated ESKD care, including 92 individuals from around the globe with diverse expertise and professional backgrounds. The attendees were from 41 countries, including 16 participants from 11 low- and lower-middle-income countries. The purpose was to develop a strategic plan to improve worldwide access to integrated ESKD care, by identifying and prioritizing key activities across 8 themes: (i) estimates of ESKD burden and treatment coverage, (ii) advocacy, (iii) education and training/workforce, (iv) financing/funding models, (v) ethics, (vi) dialysis, (vii) transplantation, and (viii) conservative care. Action plans with prioritized lists of goals, activities, and key deliverables, and an overarching performance framework were developed for each theme. Examples of these key deliverables include improved data availability, integration of core registry measures and analysis to inform development of health care policy; a framework for advocacy; improved and continued stakeholder engagement; improved workforce training; equitable, efficient, and cost-effective funding models; greater understanding and greater application of ethical principles in practice and policy; definition and application of standards for safe and sustainable dialysis treatment and a set of measurable quality parameters; and integration of dialysis, transplantation, and comprehensive conservative care as ESKD treatment options within the context of overall health priorities. Intended users of the action plans include clinicians, patients and their families, scientists, industry partners, government decision makers, and advocacy organizations. Implementation of this integrated and comprehensive plan is intended to improve quality and access to care and thereby reduce serious health-related suffering of adults and children affected by ESKD worldwide.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the joints and it affects over 18 million people worldwide. Despite the availability of a variety of potent drugs for RA, over 30–40 percent of patients fail to achieve adequate remission, and many patients suffer from systemic adverse effects. Thus, there is an urgent need for a joint-targeted drug delivery system. Nanotechnology-based drug delivery methods offer a promising resource that is largely untapped for RA. Using the T cell-driven rat adjuvant-induced arthritis (AA) model of human RA, we developed a peptide-targeted liposomal drug delivery system for arthritis therapy. It was based on a novel joint-homing peptide ART-2 to guide liposomes entrapping dexamethasone (Dex) to arthritic joints of rats, and this approach was more effective in suppressing arthritis than the unpackaged (free) drug. To de-risk the translation of our innovative drug delivery technology to RA patients, we undertook the validation of ART-2-liposomal delivery in a genetically and mechanistically distinct arthritis model in mice, the collagen antibody-induced arthritis (CAIA) model. Using live imaging for tissue distribution of liposomes in vivo, immunohistochemistry of paws for cellular binding of ART-2, and liposomal Dex delivery, our results fully validated the key findings of the rat model, namely, preferential homing of peptide-functionalized liposomes to arthritic joints compared to healthy joints, and higher efficacy of liposomal Dex than free Dex. These results offer a proof-of-concept for the benefits of targeted drug delivery to the joints and its potential translation to RA patients. [ABSTRACT FROM AUTHOR]

Background: Malnutrition and suboptimal food intake are common concerns among chronic kidney disease (CKD) patients. Medical nutrition therapy plays a significant role in ensuring the well-being of CKD patients undergoing maintenance hemodialysis (MHD). The present study explored the dietary intake and quality of life (QOL) of CKD patients on MHD. Materials and Methods: Adult CKD patients (n = 107, >20 years, 72% male) on MHD were conveniently selected from dialysis centers across India. This cross-sectional exploratory study elicited information on general profile, height, dry body weight, biochemical parameters, food intake, and QOL of the patients. Nutrient intake was compared with Kidney Disease Outcomes Quality Initiative (KDOQI) Guidelines. Results: The average energy and protein intake per kg body weight was below the recommendations (energy ~21 kcal/kg vs. 30-35 kcal/kg body weight and protein ~0.7g/kg vs. 1-1.2 g/kg body weight). Majority of them (>75%) had inadequate energy and protein intake. The sodium intake of the participants (3109.42 ± 1012.31 mg) was higher than the suggested limit. The energy and protein intake/kg ideal body weight of female patients was significantly higher than male patients (p < 0.05). Overall, their QOL was satisfactory. However, nearly half of them (47%) reported moderate-level problem in the pain and discomfort dimension. Conclusion: Patients were not meeting the recommendations especially for energy and protein. Patient-specific customized nutrition counseling along with routine nutrition assessment, follow-up of patients and continued nutrition education, and motivation and support from the medical care team, especially the dietitian is needed for better dietary compliance and overall improvement of QOL. [ABSTRACT FROM AUTHOR]