Septic Shock: Causes and Effects

Septic Shock: Causes and Effects Bacteria are microscopic single celled organisms known to reside in a large proportion of the body as natural flora. They help in normal processes such as digestion and production of nutrients. However if taken out of their natural environment they can become pathogenic and in some cases fatal. These organisms are divided into two main groups namely gram positive and gram negative bacteria (this essay places its emphasis on gram negative bacteria). They can be differentiated into these groups according to their cell wall structure and their ability to retain two stains; safranin in the case of gram negatives and crystal violet in the case of gram positives. This ability lies in the bacterial cell wall (http://micro.digitalproteus.com). Septic shock is the most common killer in intensive care units and gram negative bacteria are the main known cause of this condition (Engel, C. et al, 2007). Innate immunity also known as non-specific immunity is the first line defensive response against such an infection and the most basic resistance responsible for defending the body against infections and foreign organisms. In order to do this wholly, it has a number of characteristics which help it summon cells and use different mechanisms. Just as its name suggests, cells and mechanisms of the non-specific immune system act on pathogens in a generic way. Furthermore this branch of the immune system is unable to produce long-lasting immunity against these threats. In the case of gram negative bacterial infection, the innate immune system is activated by certain motifs found on bacteria. Once discovered it calls upon certain molecules which are able to detect and deal with these pathogens appropriately (www.pathmicro.med.sc.edu). As well as fighting foreign pathogens, the innate immune system regulates inflammatory and immune responses tightly in order to prevent overpowering inflammat ion and or overgrowth of invading pathogens (Norton, J. A. et al, 2008). Gram negative bacteria possess specific components in their cell walls that strengthen their capabilities as pathogens. The main components of their cell wall include a variable capsule, a complex lipopolysaccharide layer, a rigid membrane mucopeptide layer and a cytoplasmic membrane. During infection the most important of these constituents is the lipopolysaccharide layer (LPS) also known as the endotoxin layer; so called because its lipid fraction has the ability to act as a toxin (Engel, C. et al, 2007). This conserved bacterial motif consists of a basal portion called lipid A. Lipid A is a glucosamine-based phospholipid, it is linked by keto-deoxyoctonate to the core lipopolysaccharide. It is in fact this component of LPS that is known as the endotoxin because it is this constituent of gram negative bacteria that causes such immense consequences to the immune system. Lipid A remains the most toxic moiety of gram negative toxins produced. This constituent of LPS makes up the outer monolayer of the outer membrane of most gram-negative bacteria. The core of LPS comprises of N-acetyl glucosamine, glucose, galactose and heptose fractions (Raetz, C. R. H., 1990). Finally the terminal segment encompasses repeating oligosaccharide units known to be the cause for O-antigenetic specificity. Unlike lipid A, it was found that the O-antigen does not bring about an inflammatory response; instead it hinders the detection of lipid A (Nishitani C, 2005) which can be very dangerous, as recognition of lipid A is of great importance to the recognition of such an infection. One bacterium is known to contain approximately 2 x 106 lipid A molecules (Fig.1) and about one-quarter of the fatty acyl chains of the bacterial envelope are connected with LPS (Raetz, C. R. H., 1990). The events leading to the activation of macrophages which in turn leads to the production and release of cytokines is thus very important in the understanding of how things work. As demonstrated by Galanos et al using chemically synthesized material, it can be seen that lipid A brings about most of the effects of endotoxins on these cells (Galanos, C. et al, 1985). The fact that lipid A has such a high potency (Raetz, C. R. H., 1990), coupled with the existence of unresponsive mutants as shown by Sibley et al (Sibley, C. H. et al., 1988), and the detection of an antagonist of endotoxin bioactivity (Takayama, K.. et al, 1989) suggested that a receptor (or receptors) for lipid A exists. During infection with this type of bacteria, LPS is the main activator of the innate immune response. If this toxin finds its way into the blood stream, a series of events can cause host toxicity which can lead to a condition known as systemic inflammatory response syndrome (sirs) and in some serious cases gram-negative septic shock syndrome a serious condition characterized by a series of clinical conditions caused by the presence of infection which leads to a successive widespread inflammatory response and results in physiologic alterations that occur at the capillary endothelial level. The infected suffers from a sharp rise in temperature, respiration, heart rate and a sudden fall in blood pressure. A combination of these symptoms can be very severe and in some cases fatal (R.L. Paterson and N.R. Webster, 2000). Sepsis has a similar reaction to infection; however instead of the reaction being contained in one place, its effects are on a systemic level, the consequence being wide spread endothelial dysfunction. Stage one in the development of septic shock is the presence of bacteria in the blood a condition known as bacteremia. The bacterial cells become autolysed, their outer membrane fall apart releasing lipopolysaccharide (LPS) (Baumgarten, G., et al., 2006). As mentioned before, during gram negative bacterial infection, the provocative cause is the interaction of the host immune cells with the endotoxin LPS. In this process, LPS binds to a serum protein known as LPS binding protein (LBP) forming an LBP-LPS complex. This complex then binds unto receptors on the macrophages and causes regulatory proteins [Nuclear Factor Kappa B (NFkB)] to be activated. This complex is then assembled by the CDreceptors unto the surface of the cell, and finally the signal is translated into the cells by the TLR receptors. This response brings about the production of a number of pro-inflammatory cytokines namely; tumor necrosis factor (TNF), Interleukins 1, 6 and 12 and Interferon gamma (IFN gamma), casing a direct effect on organ function and an indirect one through the use of secondary mediators (Bosshart, H. and M. Heinzelmann, 2007). Examples of secondary mediators called upon include, complement and platelet-activating factor. Overproduction of these pro-inflammatory cytokines can lead to the production of tissue-factor causing the deposi tion of fibrin which can in turn cause disseminated intravascular coagulation (DIC) (Bosshart, H. and M. Heinzelmann, 2007). A major advance in our comprehension of the molecular mechanisms of septic shock is the recognition that CD14 is a receptor for LPS. Its accessory molecules and how they can come together to give a tragic result are also important in recognizing how it works. The most important component to take heed of during an infection with gram negative bacteria is CD14. CD14 is the part of the LPS receptor complex which binds ligands, it is made up of two parts namely Toll-like receptor 4 (TLR4) and the extracellular protein myeloid differentiation-2 (MD-2), (Miyake K, 2004). This receptor is a membrane bound glycosyl phosphatidylinositol surface-anchored molecule and a pattern recognition receptor expressed by myeloid cells primarily monocytes and macrophages. It is a critical part of the LPS recognition system which is able to interrelate with a variety of bacterial ligands and is able to recognize major fragments of the gram negative bacterial wall primarily lipopolysaccharide It has a two m ajor roles, firstly it instigates an immune response finally has a fundamental role in systemic inflammation bracause it has the ability to recognize lipopolysaccharide and to a lesser extent other bacterial motifs in the cell wall of gram negative bacteria (SD Wright et al, 1990). During infection, the first line of defense is the extraction of Lipopolysaccharide (LPS) monomers from the membranes of the bacteria. This is done by the serum protein LPS-binding protein (LBP) an acute-phase protein produced by hepatocytes in the liver as a 50-kDa single polypeptide but released as a larger 60-kDa glycosylated form (Ramadori, G., et al.1990). This protein has a very high affinity for the lipid A moiety in LPS. LPB has two main functions; firstly in the presence of lipopolyscaccharide binding protein, particles containing LPS undergo opsonisation. This process causes leukocytes to be more sensitive to LPS. Secondly, lipopolysaccharide binding protein channels LPS-coated particles to macrophages by binding to the lipid A portion of LPS and then to macrophages (Wright, S. D et al, 1989). LBP acts as a ligand for CD14 by transferring the LPS monomer to a lipid-binding site on CD14 in the membrane of phagocytes. Membrane-bound CD14 does not have an intracellular domain, making it incomplete on its own right. Thus it has to interrelate with other cell receptors before signal transduction takes place (Bosshart, H. and M. Heinzelmann, 2007). When LPS is recognised by CD14 the innate immune system is stimulated by TLR4. TLR4 receptors bind the foreign antigen and internalize it resulting in signal transduction and innate immune cell activation the final result being cytokine production. This couple contribute to a valuable host defense mechanism against intact gram-negative bacteria and is so effective that removal of CD14 has been found to aid an over development of a number of gram-negative pathogens in vivo as shown in knockout mice (SD Wright et al, 1990) CD14 exists in two forms the first being a soluble protein and the second a membrane bound form. Furthermore, two isoforms of the soluble protein have been identified; one form is produced by detaching itself from the cell surface and the other is released before the glycosyl phosphatidylinositol anchor is added to cells (Labeta MO, et al, 1993). Two further molecules come together to form a complex which is able to recognize a variety of Pathogen-Associated Molecular Patterns (PAMPs), LPS being one of them. PAMPs are relatively invariant molecular structures that the bacteria have but are not found in the host. These structures are recognized by Pattern Recognition Receptors (PRRs. PRRs are transmembrane receptors which are able to distinguish a variety of PAMPs. In the case of gram negative bacterial infection, PRRs are found on cell-surface receptors of cells. They bind the pathogen and set off a signal causing effector molecules to be released. These receptors are Toll-like receptors (TLRs). Toll-like receptors (TLRs) are vital for the regulation of innate immune responses during infection. A number of toll like receptors have been found as well as the PAMPS they are associated with (Takeda K et al, 2003). The most important TLR in gram negative infection is TLR4 involved in the recognition of the PAMP lipopolyssacharide. With the support of accessory molecules, TLR4 specializes in the recognition of LPS. It requires MD-2 (myeloid differentiation-2) to respond efficiently to LPS. Its amino-terminal region which consists of Glu(24)-Pro(34) is critical for MD-2 binding and LPS signaling(4). This transmembrane protein contains an extracellular region made up of a protein pattern called leucine-rich repeats (LRR). LRR forms a complex with MD-2 an extracellular molecule who has a role in surface expression of TLR4 on cells as well as its interaction with LPS. CD14 promotes the binding of LPS to the TLR4–MD-2 complex, which signals to the cell interior. Reseasch has shown that membrane bound TLR4 is the PRR for LPS as it encourages responsiveness of cells to LPS (Nishitani C, 2005). During gram negative infection, the TLR4–MD-2 complex recognizes gram negative bacteria and activates an effector response causing a signaling cascade which in turn causes NF-ÃŽ ºB to be activated. NF-ÃŽ ºB is a transcription factor which activates many cytokine genes, examples of which are tumor necrosis factor-alpha (TNF-ÃŽ ±) gene, Interleukin-1 (IL-1) and chemokines, (molecules which cause migration of leukocytes to the site of infection), these molecules are all known to cause inflammation at the site of infection. NF-ÃŽ ºB is found in the cytosol of cells where it is bound to IÃŽ ºB its inhibitor. Binding of ligands to the receptor causes IÃŽ ºB to be phosphorylation and destroyed. NF-ÃŽ ºB can then move into the nucleus where the genes required are activated. Genes encoding IL-1 and other cytokines are turned on by this effector molecule resulting in inflammation and other cell precesses such as processes such as cell adhesion cell proliferation, and angiogenesis (http: //users.rcn.com/). The TLR4-MD-2 complex plays an important role in suppressing Gram-negative bacterial infection by activating innate immune responses (Engel, C. et al, 2007). Even though TLR4-MD-2 recognizes LPS, not much is known about the physical interaction between LPS and TLR4-MD-2. It is known that CD14 significantly enhances the formation of LPS-TLR4-MD-2 complexes by loading LPS onto TLR4-MD-2 complexes. In the absence of CD14, the TLR4–MD-2 complex can still function with some forms of LPS in the presence of high concentrations of LPS (Nishitani C, 2005). The effect that the presence of endotoxins brings on the immune system is not as important as the effect which overproduction of cytokines has on the host. The latter caused by over reaction of the hosts immune system is what brings about such dire consequences. Prolonged harm to individual organ systems results in mul ­tiple organ failure, transitioning into the final stage known as refractory septic shock. Past experiments have shown that protein C levels are low during sepsis. Protein C plays a vital role in the inhibition of coagulation. Low levels thus suggest that during sepsis protein C is inhibited causing coagulation to take place on a systematic level. The collective consequence of such a cascade is an imbalanced state, where inflammation prevails over anti-inflammation and coagulation prevails over fibrinolysis. The end result being conditions such as ischemia, and high scale tissue destruction; severe sepsis, shock, and multiple organ failure may follow which could eventually lead to death.

Requiring School Uniform :: miscellaneous

Requiring School Uniform If the school considering requiring all students to wear uniform during school, this is not a good idea that all students think. It is because nowadays, teenager want to have their own style and wear whatever they want. They don't want anyone to force them wear the uniform. And they want to give any others students or friends saw their best look, best look can take give other students or friends' attention, they can attract other students by the look or style they wear. So most students will think wear their clothes are better than the school uniform. First, some of the students think wear their clothes are the habit they they do that everyday. So they won't like to wear the uniform. And most the girls like to wear some clothes that can attract other boys to look at them and their friends will said they are so cool. Then the boys will date them and the girls will feel so happy and have another boyfriend. And in the other way, some of the boys always want to wear their clothes and look so cool to attract other girls, so they can have the other girlfriends. That is one reason they students like to wear their clothes and not uniform. Second, some of the uniform in other school was so ugly or outdate. It is because the school teacher or principal don't know what the students like or what style do the students want to wear. Every students have their own style and their won't have the same idea as the other students. So the school cannot make a uniform to content all the students. And the other things is the students will think wear the school uniform was so dumb and stupid, and they think that the people in outside will laugh at them or make fun on them. Third, the students want to be free, they want to have all the freedom. United state is a freedom country, they think they can wear the clothes in their way. It is because uniform maybe is some pressure for the students, they don't want school to force them to wear it. Uniform give the students a uncomfortable feeling, they will feel not comfortable to wear it, and now all teenager like to buy many clothes and wear different everyday. Maybe some students don't want people to know what school they are and if they wear uniform, the other people will know what school they are.

Girl Interrupted Character Analysis Essay

Borderline personality disorder is characterized by intense shifts in mood. This is often accompanied by periods of intense aggression, substance abuse, and self damaging behaviors. People with borderline personality disorder will sometimes attempt suicide impulsively in periods of extreme depression or anger. Often times people with borderline personality disorder feel extremely bored, empty, mistreated and alone. Intense feelings of loneliness usually are followed by frantic efforts to avoid being alone. Suzanne is initially institutionalized for taking a bottle of aspirin with a bottle of vodka. She claims that she was not trying to kill herself, but only get rid of a headache. At the beginning Suzanne claimed that she had no bones in her hand. This fits more with a delusional disorder. Suzanne often exhibits spontaneous damaging behavior that is mainly sexual. Other spontaneous behaviors include breaking out of the hospital, stealing her medical files, and not taking medication. She also aids in drugging a nurse and steals a guitar from the art room to help cheer up another patient. Spontaneous dangerous behavior is one of the major signs of borderline personality disorder. Suzanne has strange ideas about her symptoms and diagnosis, the major example being the bones in her hand disappearing and then reappearing. She often seeks to be alone; shows many social anxieties around people and had a lack of close friends on outside of the hospital. These symptoms go along with schizotypal personality disorder. Contradictions to the possible schizotypal personality disorder would include that she is sometimes the â€Å"life of the party† which falls in line more with borderlines. She also desperately seeks male attention leading to her promiscuous sexual behavior that goes against the seeking of complete isolation often exhibited by others with scizotypal personality disorder. Her social anxieties are not clear in the movie and it is unknown whether they are because of negative feelings about her or whether she has paranoid fears. Despite the schizotypal possibility it is more likely that she has borderline personality disorder. This is because she clearly exhibits the majority of the signs of someone with borderline personality disorder including self destructive behavior, feelings of emptiness, intense shifts in mood lasting only a short period of time, consistent suicide ideation, feelings of â€Å"rejection and not fitting in.† Even the schizotypal symptoms can be explained by borderline personality disorder. People with borderline personality disorder often have odd thinking, quasipsychosis, and unusual perceptions. Although Suzanne showed symptoms of many types of disorders, the Borderline that she was diagnosed with was the most fitting and prevelant in her actions in the movie.

Nathaniel Alexander, Inventor of a Folding Chair

On July 7, 1911, an African-American man named Nathaniel Alexander of Lynchburg, Virginia patented a folding chair. According to his patent, Nathaniel Alexander designed his chair to be used in schools, churches, and other auditoriums. His design included a book rest that was usable for the person sitting in the seat behind and was ideal for church or choir use.​ Fast Facts: Nathaniel Alexander Known For: African-American patent holder for a folding chairBorn: UnknownParents: UnknownDied: UnknownPublished Works: Patent 997,108, filed March 10, 1911, and granted July 4 the same year Little Biographical Data Alexanders invention is found on many lists for black American inventors. However, he has escaped having much biographical information known about him. What can be found confuses him with an early governor of the state of North Carolina, who was not a black American. One says he was born in the early 1800s in North Carolina and died several decades before the date of the patent of the folding chair. Another one, which is written as satire, says he was born the same year as the patent was issued. These seem obviously erroneous. Patent 997108 is the only invention on record for Nathaniel Alexander, but on March 10, 1911, his application was witnessed by two people: James R.L. Diggs and C.A. Lindsay. James R.L. Diggs was a Baptist minister from Baltimore (born in 1865), who was a member of the Niagara Movement, and holder of an MA from Bucknell University and a PhD in Sociology from Illinois Wasleyan in 1906—in fact, Diggs was the first African-American to hold a Sociology Ph.D. in the United States. The Niagara Movement was a black civil rights movement led by W.E.B. DuBois and William Monroe Trotter, who assembled in Niagara Falls, Ontario (American hotels barred blacks), to discuss Jim Crow laws following the Reconstruction. They met annually between 1905 and 1910: in between 1909 and 1918, Diggs corresponded with DuBois about a possible history of the movement, among other things. There may have only been a passing connection between Alexander and Diggs. Foldable Chairs for Churches and Choirs Alexanders folding chair is not the first folding chair patent in the United States. His innovation was that it included a book rest, making it suitable for use in places where the back of one chair could be used as a desk or shelf by the person seated behind. This would certainly be convenient when setting up rows of chairs for choirs, so they could rest music on the chair ahead of each singer, or for churches where a prayer book, hymnal, or Bible could be placed on the reading shelf during the service. Folding chairs allow the space to be used for other purposes when there is not a class or church service. Today, many congregations meet in spaces that used to be large big box stores, supermarkets, or other large, cavernous rooms, Using folding chairs set up only during services, they are able to quickly turn the space into a church. In the early part of the 20th century, congregations likewise might have met outdoors, in warehouses, barns, or other spaces that didnt have fixed seating or pews. Earlier Folding Chair Patents Folding chairs have been in use for thousands of years in many cultures, including ancient Egypt and Rome. They were even commonly used in churches as liturgical furniture in the Middle Ages. Here are some other patents for folding chairs that were granted prior to that of Nathaniel Alexander: M.S. Beach of Brooklyn, New York patented a folding chair for pews, U.S. Patent No. 18377 on October 13, 1857. However, this design appears to be a drop-down seat such as an airplane jump seat rather than a chair you can fold, stack, and store away.J.P.A.  Spaet, W.F. Berry and J.T. Snoddy of Mount Pleasant, Iowa were granted U.S. Patent No. 383255 on May 22,  1888, for a folding chair designed to look much like a regular chair when in use. It could be folded up to be stored away and save space.C. F. Batt patented a folding chair for steamers on June 4, 1889, U.S. Patent No. 404,589. Batts patent notes that he was seeking improvements on longstanding folding chair designs, especially avoiding having a hinge at the side arms that can pinch your fingers when folding or unfolding the chair. Sources Alexander, Nathaniel. Chair. Patent 997108. 1911.Batt, C.F. Folding Chair. Patent 383255. 1888.Beach, M.S. Char. Patent 18377. 1857.Pipkin, James Jefferson. James R.L. Diggs. The Negro in Revelation, in History and in Citizenship: What the Race has Done and is Doing. St. Louis: N.D. Thompson Publishing Company, 1902Spaet, J.P.A., W. F. Berry and J.T. Snoddy. Folding Chair for Steamers. Patent 404,589. 1889.WEB DuBois Correspondence with J.R.L. Diggs, Special Collections, University of Massachusetts at Amherst.