Abdo Jurjus

Thymoquinone reduces mouse colon tumor cell invasion and inhibits tumor growth in murine colon cancer models

We have shown that thymoquinone (TQ) is a potent antitumor agent in human colorectal cancer cells. In this study, we evaluated TQs therapeutic potential in two different mice colon cancer models [ 1,2 ‐dimethyl hydrazine (DMH) and xenografts]. We also examined TQ effects on the growth of C26 mouse colorectal carcinoma spheroids and assessed tumor invasion in vitro. Mice were treated with saline, TQ, DMH, or combinations once per week for 30 weeks and the multiplicity, size and distribution of aberrant crypt foci (ACF) and tumors were determined at weeks 10, 20 and 30. TQ injected intraperitoneally (i.p.) significantly reduced the numbers and sizes of ACF at week 10; ACF numbers were reduced by 86%. Tumor multiplicity was reduced at week 20 from 17.8 in the DMH group to 4.2 in mice injected with TQ. This suppression was observed at week 30 and was long‐term; tumors did not re‐grow even when TQ injection was discontinued for 10 weeks. In a xenograft model of HCT116 colon cancer cells, TQ significantly (P < 0.05) delayed the growth of the tumor cells. Using a matrigel artificial basement membrane invasion assay, we demonstrated that sub‐cyto‐toxic doses of TQ (40μM) decreased C26 cell invasion by 50% and suppressed growth in three‐dimensional spheroids. Apoptotic signs seen morphologically were increased significantly in TQ‐treated spheroids. TUNEL staining of xenografts and immunostaining for caspase 3 cleavage in DMH tumors confirmed increased apoptosis in mouse tumors in response to TQ. These data should encourage further in vivo testing and support the potential use of TQ as a therapeutic agent in human colorectal cancer.

The prevalence of hypertension and its association with other cardiovascular disease risk factors in a representative sample of the Lebanese population.

Hypertension is a well-known major risk factor for cardiovascular diseases. This study has been designed to assess the prevalence of hypertension, its co-occurrence with other cardiovascular risk factors and its association with cardiovascular diseases in a representative sample of Lebanese population. A pretested questionnaire was administered to 2125 adults aged equal or above 30 years old from all regions in Lebanon and proportionate with the respective population density. Data revealed that 23.1% of the respondents admitted being hypertensive, with no statistically significant difference between male and female patients. Prevalence of hypertension increased with age (P<0.01) and hypertension tended to occur more in the less educated and the unemployed (P<0.01). Only 45.7% of hypertensive patients followed a low fat diet while 14.7% exercised daily. The prevalence of hypertension increased significantly with an increase in body mass index particularly in female patients. Among the hypertensive respondents, 23.9% were diabetic, 38.1% were hyperlipidaemic and 9.1% were both diabetic and hyperlipidaemic. Co-occurrence of hypertension with diabetes, hyperlipidaemia or both was more common in female patients compared to male patients. In addition, stroke, myocardial infarction (MI) and atherothrombosis occurred in hypertensive respondents at rates of 2.4, 4.3 and 9.5%, respectively. Hypertensive female patients reported more stroke and atherothrombotic episodes compared to male patients, whereas hypertensive male patients had more MIs. Based on these results it is very important to address the issue of lifestyle modification for the prevention and treatment of hypertension and awareness campaigns should stress the fact that cardiovascular diseases are not only restricted to men.

Surgical Anatomy of the Infratemporal Fossa: The Styloid Diaphragm Revisited

INTRODUCTION The infratemporal fossa (ITF) gives passage to most major cerebral vessels and cranial nerves. Dissection of the ITF is essential in many of the lateral cranial base approaches and in exposure of the high cervical internal carotid artery (ICA). We reviewed the surgical anatomy of this region. METHODS Direct foraminal measurements were made in seven dry skulls (14 sides), and the relationship of these foramina to each other and various landmarks were determined. Ten ITF dissections were performed using a preauricular subtemporal-infratemporal approach. Preliminary dissections of the extracranial great vessels and structures larger than 1 cm were performed using standard macroscopic surgical techniques. Dissection of all structures less than 1 cm was conducted using microsurgical techniques and instruments, including the operating microscope. The anatomic relationships of the muscles, nerves, arteries, and veins were carefully recorded, with special emphasis regarding the relationship of these structures to the styloid diaphragm. The dissection was purely extradural. RESULTS The styloid diaphragm was identified in all specimens. It divides the ITF into the prestyloid region and the retrostyloid region. The prestyloid region contains the parotid gland and associated structures, including the facial nerve and external carotid artery. The retrostyloid region contains major vascular structures (ICA, internal jugular vein) and the initial exocranial portion of the lower Cranial Nerves IX through XII. Landmarks were identified for the different cranial nerves. The bifurcation of the main trunk of the facial nerve was an average of 21 mm medial to the cartilaginous pointer and an average of 31 mm medial to the tragus of the ear. The glossopharyngeal nerve was found posterior and lateral to stylopharyngeus muscle in nine cases and medial in only one. The vagus nerve was consistently found in the angle formed posteriorly by the ICA and the internal jugular vein. The spinal accessory nerve crossed anterior to the internal jugular vein in five cases and posterior in another five cases. It could be located as it entered the medial surface of the sternocleidomastoid muscle 28 mm (mean) below the mastoid tip. The hypoglossal nerve was most consistently identified as it crossed under the sternocleidomastoid branch of the occipital artery 25 mm posterior to the angle of the mandible and 52 mm anterior and inferior to the mastoid tip. CONCLUSION The styloid diaphragm divides the ITF into prestyloid and retrostyloid regions and covers the high cervical ICA. Using landmarks for the exocranial portion of the lower cranial nerves is useful it identifying them and avoiding injury during approaches to the high cervical ICA, the upper cervical spine, and the ITF.

Dismicrobism in inflammatory bowel disease and colorectal cancer: Changes in response of colocytes

Patients with inflammatory bowel disease (IBD) have an increased risk of 10%-15% developing colorectal cancer (CRC) that is a common disease of high economic costs in developed countries. The CRC has been increasing in recent years and its mortality rates are very high. Multiple biological and biochemical factors are responsible for the onset and progression of this pathology. Moreover, it appears absolutely necessary to investigate the environmental factors favoring the onset of CRC and the promotion of colonic health. The gut microflora, or microbiota, has an extensive diversity both quantitatively and qualitatively. In utero, the intestine of the mammalian fetus is sterile. At birth, the intestinal microbiota is acquired by ingesting maternal anal or vaginal organisms, ultimately developing into a stable community, with marked variations in microbial composition between individuals. The development of IBD is often associated with qualitative and quantitative disorders of the intestinal microbial flora (dysbiosis). The healthy human gut harbours about 10 different bacterial species distributed in colony forming units which colonize the gastrointestinal tract. The intestinal microbiota plays a fundamental role in health and in the progression of diseases such as IBD and CRC. In healthy subjects, the main control of intestinal bacterial colonization occurs through gastric acidity but other factors such as endoluminal temperature, competition between different bacterial strains, peristalsis and drugs can influence the intestinal microenvironment. The microbiota exerts diverse physiological functions to include: growth inhibition of pathogenic microorganisms, synthesis of compounds useful for the trophism of colonic mucosa, regulation of intestinal lymphoid tissue and synthesis of amino acids. Furthermore, mucus seems to play an important role in protecting the intestinal mucosa and maintaining its integrity. Changes in the microbiota composition are mainly influenced by diet and age, as well as genetic factors. Increasing evidence indicates that dysbiosis favors the production of genotoxins and metabolites associated with carcinogenesis and induces dysregulation of the immune response which promotes and sustains inflammation in IBD leading to carcinogenesis. A disequilibrium in gut microflora composition leads to the specific activation of gut associated lymphoid tissue. The associated chronic inflammatory process associated increases the risk of developing CRC. Ulcerative colitis and Crohns disease are the two major IBDs characterized by an early onset and extraintestinal manifestations, such as rheumatoid arthritis. The pathogenesis of both diseases is complex and not yet fully known. However, it is widely accepted that an inappropriate immune response to microbial flora can play a pivotal role in IBD pathogenesis.

Bilateral double axillary artery: Embryological basis and clinical implications

An unusual bilateral variation in the arterial pattern of the axilla was observed in an embalmed cadaver. Each axilla contained two axillary arteries of similar origins but different patterns of branching and fate. The first part of each axillary artery was a single vessel as is the norm. It gave off a supreme thoracic artery and then bifurcated into two medium‐sized arteries hence referred to as regular and variant. The variant artery ran in an antero‐medial course, partly covered by the one axillary vein. The regular artery gave off the thoracoacromial and two posterior branches from its second part, the anterior and posterior humeral circumflex arteries from its third part, and then continued as the brachial artery with all the usual branches except the profunda brachii on the right side. The variant gave off five arteries from the second part, a thoracoacromial artery, two separate long thoracic arteries each with a branch that ran along the intercostobrachial nerve to the arm, and two posterior branches. In the third part of the variant, the subscapular artery arose with its usual branches plus a common origin for two additional humeral circumflex arteries. The variant terminated as the profunda brachii artery to the right side while on the left side it terminated in muscular branches to the triceps. Hence, the arterial blood supply to the upper limb, and the axillary region in particular, was shared on both sides by two major arteries instead of one. These two arteries emanated from the first part of the axillary artery and may represent persisting branches of the capillary plexus of the developing limb buds. The findings have an embryological basis and clinical relevance considering the frequency of procedures in this region. Clin. Anat. 12:135–140, 1999.

Nociceptive behaviour induced by dental application of irritants to rat incisors: a new model for tooth inflammatory pain.

Animal models simulating acute human pulpitis are still lacking. The rat incisors present a particular situation where most of their innervation is considered to be unmyelinated and concentrated mainly in the tooth pulp. This study reports on a new model for dental pain induced by inflammatory agents applied to the tooth pulps of incisors. In different groups of rats, artificial crowns were fixed on the lower incisors, after cutting 1–2 mm of their distal extremities. A volume of 7–10 μl of solutions of saline, capsaicin (1–10 mg/ml) or formalin (2.5% or 5%) was injected in the crown cavity, and the nociceptive behaviour was quantitated following a devised scoring method of four scales. Intradental application of capsaicin produced nociceptive scores in the form of one plateau for 1–2 h depending on the concentration used. Similar results were obtained with intradental application of formalin 2.5%. The one plateau of nociceptive scores obtained with formalin contrasts with the biphasic aspect of nociceptive behaviour described with the intradermal formalin test. This discrepancy could be attributed to a difference in the types of afferent fibres involved in each situation. Pretreatment with morphine (2 mg/kg) attenuated, in a naloxone‐reversible manner, the nociceptive behaviour observed following intradental application of capsaicin. Pretreatment with meloxicam (a cyclo‐oxygenase‐2 inhibitor) exerted a less pronounced attenuation of the nociceptive scores when compared with morphine. These results provide evidence for the validity of the described model for the simulation of tooth pulp inflammatory pain in awake animals.

Hyperalgesia and upregulation of cytokines and nerve growth factor by cutaneous leishmaniasis in mice.

&NA; Classical description of syndromes produced by cutaneous leishmaniasis (CL) does not include sensory manifestations such as pain and/or itching, despite the evident upregulation of proinflammatory cytokines. Using a murine model of CL we report on evident hyperalgesia, as assessed by acute pain tests, and sustained upregulation of interleukin (IL‐1&bgr;) and nerve growth factor (NGF). This upregulation, especially that of NGF, may explain the observed hyperalgesia, in the light of recent evidence on the role of cytokines in the sensitization of nerve afferents and the subsequent hyperalgesia.

Inflammatory bowel disease, colorectal cancer and type 2 diabetes mellitus: The links

The co-occurrence of the three disease entities, inflammatory bowel disease (IBD), colorectal cancer (CRC), type 2diabetes mellitus (T2DM) along with inflammation and dismicrobism has been frequently reported. Some authors have even suggested that dysbiosis could be the link through a molecular crosstalk of multiple inflammatory loops including TGFβ, NFKB, TNFα and ROS among others. This review focuses on the inflammatory process along with the role of microbiota in the pathophysiology of the three diseases. The etiology of IBD is multifactorial, and like CRC and T2DM, it is associated with a widespread and sustained GI inflammation and dismicrobism, whereby an array of pro-inflammatory mediators and other related biomolecules are up-regulated, both locally and systematically. Such a persistent or an inadequately resolved chronic inflammation may be a causative agent, in the presence other factors, leading to several pathologies such as IBD, CRC and T2DM. TGFβ plays a crucial role in pancreatic β cell malfunctioning as glucotoxicity stimulates its signaling cascade through smad 3, IL-6 and epithelial to mesenchymal transition. Such a cascade could lead to macrophages and other cells recruitment, inflammation, then IBD and CRC. NFkB is also another key regulator in the crosstalk among the pathways leading to the three disease entities. It plays a major role in linking inflammation to cancer development through its ability to up regulate several inflammatory and tumor promoting cytokines like: IL-6, IL-1 α and TNF α, as well as genes like BCL2 and BCLXL. It activates JAK/STAT signaling network via STAT3 transcription factors and promotes epithelial to mesenchymal transition. It also increases the risk for T2DM in obese people. In brief, NFKB is a matchmaker between inflammation, IBD, cancer and diabetes. In addition, TNFα plays a pivotal role in systemic inflammation. It is increased in the mucosa of IBD patients and has a central role in its pathogenesis. It also activates other signaling pathways like NFKB and MAPK leading to CRC. It is also overexpressed in the adipose tissues of obese patients thus linking it to T2DM, chronic inflammation and consequently CRC. On the other hand, increasing evidence suggests that dysbiosis plays a role in initiating, maintaining and determining the severity of IBD. Actually, among its functions, it modulates genotoxic metabolites which are able to induce CRC, a fact proven to be sustained by stool transfer from patients with CRC. Probiotics, however, may actively prevent CRC as well as IBD and results in a significant decrease in fasting glycemia in T2DM patients. In conclusion, IBD, CRC and T2DM are commonly occurring interrelated clinical problems. They share a common basis influenced by an inflammatory process, an imbalance in intestinal microbiota, and a crosstalk between various signaling pathways. Would probiotics interrupt the crosstalk or orient it in the physiological direction?

Vaccines Through Centuries: Major Cornerstones of Global Health

Multiple cornerstones have shaped the history of vaccines, which may contain live-attenuated viruses, inactivated organisms/viruses, inactivated toxins, or merely segments of the pathogen that could elicit an immune response. The story began with Hippocrates 400 B.C. with his description of mumps and diphtheria. No further discoveries were recorded until 1100 A.D. when the smallpox vaccine was described. During the eighteenth century, vaccines for cholera and yellow fever were reported and Edward Jenner, the father of vaccination and immunology, published his work on smallpox. The nineteenth century was a major landmark, with the “Germ Theory of disease” of Louis Pasteur, the discovery of the germ tubercle bacillus for tuberculosis by Robert Koch, and the isolation of pneumococcus organism by George Miller Sternberg. Another landmark was the discovery of diphtheria toxin by Emile Roux and its serological treatment by Emil Von Behring and Paul Ehrlih. In addition, Pasteur was able to generate the first live-attenuated viral vaccine against rabies. Typhoid vaccines were then developed, followed by the plague vaccine of Yersin. At the beginning of World War I, the tetanus toxoid was introduced, followed in 1915 by the pertussis vaccine. In 1974, The Expanded Program of Immunization was established within the WHO for bacille Calmette–Guerin, Polio, DTP, measles, yellow fever, and hepatitis B. The year 1996 witnessed the launching of the International AIDS Vaccine Initiative. In 1988, the WHO passed a resolution to eradicate polio by the year 2000 and in 2006; the first vaccine to prevent cervical cancer was developed. In 2010, “The Decade of vaccines” was launched, and on April 1st 2012, the United Nations launched the “shot@Life” campaign. In brief, the armamentarium of vaccines continues to grow with more emphasis on safety, availability, and accessibility. This mini review highlights the major historical events and pioneers in the course of development of vaccines, which have eradicated so many life-threatening diseases, despite the vaccination attitudes and waves appearing through history.

The Use of Stem Cells in Burn Wound Healing: A Review

Burn wound healing involves a series of complex processes which are subject to intensive investigations to improve the outcomes, in particular, the healing time and the quality of the scar. Burn injuries, especially severe ones, are proving to have devastating effects on the affected patients. Stem cells have been recently applied in the field to promote superior healing of the wounds. Not only have stem cells been shown to promote better and faster healing of the burn wounds, but also they have decreased the inflammation levels with less scar progression and fibrosis. This review aims to highlight the beneficial therapeutic effect of stem cells in burn wound healing and to discuss the involved pathways and signaling molecules. The review covers various types of burn wound healing like skin and corneal burns, along with the alternative recent therapies being studied in the field of burn wound healing. The current reflection of the attitudes of people regarding the use of stem cells in burn wound healing is also stated.