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Treatment shortens the duration of rarely in patients with certain terminal complement carriage and may diminish the severity of coughing parox? deficiencies erectile dysfunction research cheap top avana 80 mg with amex. These same regimens are indicated for prophylaxis of contacts to impotence young adults order top avana 80mg free shipping an active case of pertussis that are exposed erectile dysfunction doctor new orleans cheap 80mg top avana overnight delivery. Updated High fever erectile dysfunction medication costs discount 80 mg top avana overnight delivery, chills, and headache; back, abdominal, and recommendations for use of tetanus toxoid, reduced diphthe? extremity pains; and nausea and vomiting are typical. Association of Tdap vaccination with acute with thehip at 90-degree fexion; Brudzinski sign is fexion events and adverse birth outcomes among pregnant women of the knee in response to flexion of the neck) are specific with prior tetanus-containing immunizations. Petechiae may vary in size from pinpoint lesions to meningococcal disease (eg, military recruits, microbiolo? large ecchymoses or even skin gangrene that may later gists, or travelers to an epidemic or highly endemic coun? slough if the patient survives. Laboratory Findings 10 years of age or older who are at increased risk for meningococcal disease. These persons include those with Lumbar puncture tyically reveals a cloudy or purulent persistent complement component deficiencies; persons cerebrospinal fluid, with elevated pressure, increased pro? with anatomic or functional asplenia; microbiologists tein, and decreased glucose content. The fuid usually routinely exposed to isolates of Neisseria meningitidis; contains greater than 1000 cells/meL, with polymorpho? and persons identified to be at increased risk because of a nuclear cells predominating and containing gram-negative serogroup B meningococcal disease outbreak. The absence of organisms in a tion of persons aged 16-23 years may provide short-term Gram-stained smear of the cerebrospinal fuid sediment protection against most strains of serogroup B meningo? does not rule out the diagnosis. The capsular polysaccha? coccal disease; the MenB vaccine is preferred for persons ride can be demonstrated in cerebrospinal fuid or urine by aged 16-18 years. The organism is is an effective prevention strategy in closed populations usually demonstrated by smear and culture of the cerebro? and to prevent secondary cases in household or otherwise spinal fuid, oropharynx, blood, or aspirated petechiae. Rifampin, 600 mg orally twice a day for Disseminated intravascular coagulation is an important 2 days, ciprofloxacin, 500 mg orally once, or one intramus? complication of meningococcal infection and is typically cular 250-mg dose ofceftriaxone is effective. Differential Diagnosis remains a recommended empiric agent for eradication of nasopharyngeal carriage. School and work contacts ordi? Meningococcal meningitis must be differentiated from narily need not be treated. In small infants and in the elderly, apy only if intense exposure has occurred (eg, fever or stiff neck is often missing, and altered mental sta? mouth-to-mouth resuscitation). Prevention Blood cultures must be obtained and intravenous antimi? crobial therapy started immediately. The two vaccines effective penicillin G is the antibiotic ofchoice (24 million units/24 h for meningococcal serogroups A, C, Y, and W-135 are the intravenously in divided doses every 4 hours). At what level of resis? the two vaccines against meningococcal serogroup B are tance penicillin treatment failure can occur is not known. In penicillin-allergic preadolescents ages 11-12 with a booster at age 16 (see patients or those in whom Haemophilus infuenzae or For ease of program implementation, persons 2 g intravenously every 12 hours, should be used. If the primary dose was adminis? as few as 4 days if ceftriaxone is used-are also effective. Prevention and control of meningococcal disease: recommendations ofthe Advisory Committee on Immunization time when intubation can be performed promptly. Use of roquinolone (see above for dosage) may be used in the serogroup B meningococcal vaccines in persons aged 210 patient with serious penicillin allergy. Use of serogroup B meningococcal vaccines in until the strain is proved not to produce beta-lactamase. Nontypeable M catarrhalis is a gram-negative aerobic coccus morpho? strains are responsible for most disease in adults. It causes ism, smoking, chronic lung disease, advanced age, and sinusitis, bronchitis, and pneumonia. Haemophilus species colo? meningitis have also been reported in immunocompro? nize the upper respiratory tract in patients with chronic mised patients. The organism frequently colonizes the obstructive pulmonary disease and frequently cause puru? respiratory tract, making differentiation of colonization lent bronchitis. If M catarrhalis is the predomi? Beta-lactamase-producing strains are less common in nant isolate, therapy is directed against it. For adults with sinusitis, otitis, or typically produces beta-lactarase and therefore is usually respiratory tract infection, oral amoxicillin, 750 mg twice resistant to ampicillin and amoxicillin. For beta-lactamase? amoxicillin-davulanate, ampicillin-sulbactam, trime? producing strains, use of the oral fixed-drug combination thoprim-sulfarethoxazole, ciprofoxacin, and second and of amoxicillin, 875 mg, with clavulanate, 125 mg, is indi? third-generation cephalosporins. Azithromycin, 500 mg orally once followed by 250 mg daily for 4 days, is preferred over clarithromycin when a macrolide is the preferred agent. Patients are often immunocompromised, smok? daily) can be considered, but resistance rates have been ers, or have chronic lung disease. Scant sputum production, pleuritic chest pain, In the more seriously ill patient (eg, the toxic patient toxic appearance. Chest radiograph: focal patchy infiltrates or nously is recommended pending determination of whether consolidation. Gram stain of sputum: polymorphonuclear leuko? quinolone (see above for dosages) can be used for the peni? cytes and no organisms. Epiglottitis is characterized by an abrupt onset of high fever, drooling, and inability to handle secretions. General Considerations important clue to the diagnosis is complaint of a severe sore throat despite an unimpressive examination ofthe pharynx. Legionella infection ranks among the three or four most Stridor and respiratory distress result from laryngeal common causes of community-acquired pneumonia and obstruction. The diagnosis is best made by direct visualiza? is considered whenever the etiology of a pneumonia is in tion of the cherry-red, swollen epiglottis at laryngoscopy. Outbreaks have been associated with Patients with potentially fatal underlying conditions in contaminated water sources, such as showerheads and the short term such as neutropenia or immunoparesis have faucets in patient rooms and air conditioning cooling a mortality rate of 40-60%; those with serious underlying towers. Clinical Findings individuals with no underlying diseases have a mortality rate of 5% or less. Clinical Findings called because a Gram-stained smear of sputum does not show organisms. Symptoms and Signs disease are more like typical pneumonia, with high fevers, Most patients have fevers and chills, often with abrupt a toxic patient, pleurisy, and grossly purulent sputum. However, 15% of patients are hypothermic (tem? sically, this pneumonia is caused by Legionella pneumoph? perature 36. Hypotension and shock, Several laboratory abnormalities can be associated with which occur in 20-50% of patients, are unfavorable prog? Legionnaires disease, which include hyponatremia, elevated nostic signs. Laboratory Findings lar enriched medium is the most sensitive method (80-90% Neutropenia or neutrophilia, often with increased numbers sensitivity) for diagnosis andpermits identification ofinfec? ofimmature forms ofpolymorphonuclear leukocytes, is the tions caused by species and serotypes other than L pneu? most common laboratory abnormality in septic patients. Dieterle silver staining of tissue, pleural Thrombocytopenia occurs in 50% of patients, laboratory fuid, or other infected material is also a reliable method for evidence of coagulation abnormalities in 10%, and overt detecting Legionella species. Both clini? stains and serologic testing are less sensitive because these cal manifestations and the laboratory abnormalities are will detect only L pneumophila serotype l. In addition, nonspecific and insensitive, which accounts for the rela? making a serologic diagnosis requires that the host respond tively low rate of blood culture positivity (approximately with sufcient specific antibody production. If possible, three blood cultures from separate gen tests, which are targeted for detection ofL pneumophila sites should be obtained in rapid succession before starting serotype 1, are also less sensitive than culture. The chance of recovering the organ? ism in at least one of the three blood cultures is greater than. The false-negative rate for a single culture of 5-10 mL Azithromycin (500 mg orally once daily), clarithromycin ofblood is 30%. This may be reduced to 5-10% (albeit with (500 mg orally twice daily), or a fuoroquinolone (eg, levo? a slight false-positive rate due to isolation of contaminants) floxacin, 750 mg orally once daily), and not erythromycin, if a single volume of 30 mL is inoculated into several blood are the drugs of choice for treatment of legionellosis culture bottles. Because blood cultures maybe falsely nega? because of their excellent intracellular penetration and in tive, when a patient with presumed septic shock, negative vitro activity, as well as desirable pharmacokinetic proper? blood cultures, and inadequate explanation for the clinical ties that permit oral administration and once or twice daily course responds to antimicrobials, therapy should be con? dosing. Treatment Several factors areimportant in themanagement ofpatients Del Castillo M et a!. Identifying the Source of Bacteremia sites, the most common being the genitourinary system, hepatobiliary tract, gastrointestinal tract, and lungs. Less By simply finding the source of bacteremia and removing common sources include intravenous lines, infusion fuids, it (central venous catheter) or draining it (abscess), a fatal surgical wounds, drains, and pressure ulcers.
As seen from this overview erectile dysfunction doctors jacksonville fl generic top avana 80 mg free shipping, after the insertion of the membrane protein it is inevitable to erectile dysfunction drugs and heart disease purchase 80 mg top avana with mastercard properly equilibrate the lipid bilayer again erectile dysfunction prescription drugs order 80 mg top avana otc. Subsequently erectile dysfunction psychological causes cheap top avana 80mg without prescription, the whole system has to undergo an extensive equilibration procedure. A production run for membrane proteins typically resides somewhere in between 50 ns and hundreds of nanoseconds. The limiting factor is the maximum timestep that can be used for the integration, determined by the fastest motion in the system. Thus, it is not able to study slow? biological processes without taking advantage of enhanced sampling techniques. As outlined in an excellent review of Christen and van Gunsteren (Christen & van Gunsteren, 2008) we have to distinguish three different types of search and sampling enhancement techniques: deformation or smoothening of the potential energy surface. Coarse-graining the model by reducation of the number of interaction sites), scaling of system parameters. Such pathways are often characterized by high-energy barriers separating meta-stable states along the ligand/substrate transition. Subsequently, the potential of mean force required to induce the transition can be used to estimate free energy barriers. This method is well established and has been used in many applications (Isralewitz et al. By gradually reducing the constrained target distance to zero, the system is driven from the reactant to product state without explicitly defining the reaction pathway (Schlitter et al. Besides their physiologically important protecting function of exporting xenotoxins, these efflux pumps affect pharmacokinetic profiles of many drugs. P-gp is encoded by the mdr1 gene and is expressed in epithelial cells of the blood brain barrier, liver, kidney and intestine, where it is located at the apical side of the membrane (Szakacs et al. However, as hydrophobic substances might diffuse through the membrane, it is the role of P-gp to keep those out as well (Neuhaus & Noe, 2009). Collies are extremely susceptible to neurotoxic drugs and thus show dramatic adverse reactions after treatment with the antiparasitic drug ivermectin (Mealey et al. Molecular Modeling and Simulation of Membrane Transport Proteins 385 this detoxifying role of P-gp can be observed at other barriers as well. However, in drug research P-gp poses a large problem, since it highly influences pharmacokinetic properties of drugs. Because of the efflux behavior in the intestinal epithelium the oral bioavailability of drugs is hindered. There are a number of compounds that are able to modulate P-gp activity, which results in modified P-gp concentrations in the target tissue. As a consequence this can lead to adverse drug-drug interactions, when therapeutics are administered at the same time. One way to overcome these negative effects associated with P-gp activity would be the development of P-gp inhibitors that should restore sensitivity to therapeutics. Already 30 years ago, the reversal of resistance against the vinca alkaloids vincristine and vinblastine by the calcium channel blocker verapamil was identified (Tsuruo et al. This can be explained by its important physiological functions, rendering them rather antitargets than targets (Ecker & Chiba, 2009). Half-transporters express each protein half separately and thus need to homo-dimerize to yield functional full transporters. During drug transport P-gp and its homologues undergo large conformational changes, converting an open-inward drug-binding state into an open-outward drug-releasing state (Rosenberg et al. The detailed mechanism of the energy driven drug transport, rendering the high-affinity into a low-affinity binding site, is currently hypothesized in two different ways and has been extensively reviewed in (Seeger & van Veen, 2009). A non-functional MsbA leads to accumulation of lipopolysaccharide and phospholipids in the inner membrane of gram-negative bacteria. At this time these structures were the only source for structure-based design on MsbA and its homologues. However, with the publication of the X-ray structure of the Staphylococcus aureus transporter Sav1866, an MsbA homologue (Dawson & Locher, 2006), the previous MsbA and two additional EmrE structures had to be retracted (Chang et al. According to Chang, an error in the in-house software that should process the crystallographic data resulted in a sign change and therefore to a momentous misinterpretation of the data (Matthews, 2007). This incident became the center of numerous discussions, often referred to as the pentaretraction? (Davis et al. In contrast to the retracted MsbA models, the architecture of Sav1866 shows a helix arrangement that is analogous to domain swapping in other enzymes. In addition, this structure also fulfills most of the structural restraints that were obtained by cross-linking studies. The corrected MsbA coordinates cover different catalytic states, including a nucleotide-free ligand-binding conformation. Unfortunately these structures are resolved at resolutions far from being suitable for docking experiments, with some templates only represented by C? Models on basis of the MsbA structures were therefore mainly used for exploring the conformational changes during the catalytic cycle. Furthermore the high sequence identity of 87% with human P-gp highly facilitates the modeling process. So far, it has been assumed that there is a large binding cavity in the transmembrane region (Loo & Clarke, 1999), which comprises distinct active sites. Furthermore, cysteine-scanning mutagenesis studies showed that the protein is able to bind at least two different molecules simultaneously (Loo et al. By using biochemical techniques a more detailed characterization of concrete binding sites for distinct substrates was possible (extensively reviewed in (Crowley et al. This led to the characterization of the interaction regions of Rhodamine 123 and Hoechst 33342, named R and the H site (Loo & Clarke, 2002; Qu & Sharom, 2002), together with a regulatory site, which binds prazosin/progesterone (Shapiro et al. Since the co-crystallized enantiomers showed distinct binding patterns, this information raised the assumption of stereoselectivity of P-gp in its ligand binding quality (Aller et al. Thus, as for niguldipine and verapamil both enantiomers showed equivalent activities (Hollt et al. As the resolution of the hitherto available templates used for constructing protein homology models is quite low, only very few docking studies have been conducted so far. The binding site they used was defined by the co-crystallized ligands and was extended by 14A. However, none of the drugs was able to contact every identified residue, which favors the hypothesis of distinct interactions sites forming one binding cavity. In this study there was a major interest in considering the high flexibility of P-gp. Therefore the induced fit protocol of the Schrodinger Suite was applied (Sherman et al. However, the discrimination between binders and non-binders can be more efficiently performed on basis of physicochemical properties than different binding mechanisms. In our group, docking into a homology model based on mouse P-gp was used for explaining the stereoselective P-gp modulating activity of tricyclic benzopyranooxazines (Jabeen et al. Besides from activity differences, compounds with 4aS,10bR configuration showed a clear logP-activity correlation (r2=0. The analysis of the docking poses by agglomerative hierarchical clustering resulted in distinct clusters for the different diastereomers. Therefore it has been hypothesized, that activity differences of the diastereomers is due to their different binding modes in the P-gp binding cavity. In addition, molecules with 4aR,10bS chirality were found close to the entry path of the protein, wherefore activity is primarily affected by the molecules? partition coefficient. On the other hand compounds of the 4aS,10bR series also showed docking poses at an active site in the binding pocket of P-gp, thus suggesting that the activity is dependent on multiple factors. Furthermore, we were able to propose reliable binding hypotheses of propafenone analogs in P-gp by applying a knowledge driven docking protocol (Klepsch et al. With this protocol a high number of docking poses could be reduced to two reliable binding modes. In order to terminate a synaptic signal after neural firing, transporter proteins have to remove about 105-fold of basal concentrations (Chen et al. The transporters practically have to act as selective molecular vacuum cleaners to deal with such huge loads of neurotransmitters in order to re-establish pre-signaling conditions within milliseconds. Furthermore, very recently a double mutant stabilized in an inward-open conformation was published (Krishnamurthy & Gouaux, 2012).
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All patients were examined in the Surugadai Nihon University Hospital erectile dysfunction drugs natural top avana 80mg without a prescription, Tokyo erectile dysfunction treatment food order discount top avana on line, between April 2005 and March 2007 erectile dysfunction young adults 80 mg top avana visa. The study was approved in advance by the Ethics Committee of the hospital erectile dysfunction 34 buy top avana 80mg on-line, and was conducted in accordance with the Helsinki Declaration. All study participants provided written informed consent prior to participation in this study. Examination of MoAb reactivity revealed that hybridoma clone 5 had the highest sensitivity. Clonal sensitivity was ranked in the following order: clone 5 > clone 8 > clone 7 > clone 9 > clone 3 > clone 4 > clone 1. The MoAb 1 produced from hybridoma clone 1 and clones 3, 5, 7, 8, and 9 were IgG1? The MoAbs recognized a protein band at a molecular weight of approximately 11,500 Da. In each case, the relative molecular weight corresponded to the predicted size of the recombinant peptide fragments. However, these epitope regions include helix and loop structures, and there have been only a few reports of cross-reaction with these epitopes. Preparation of latex reagent with amino acid spacers was synthesized using glycine at concentrations of 1. Thus, latex responsiveness was improved by the combination of the amino acid and latex at a concentration of 0. The result of each reagent using glycine (Gly), alanine (Ala), valine (Val), leucine (Leu), and peptide synthesized by Fmoc solid phase (5 molecule bond of glycine: Gly5) are shown in Fig. Each amino acid produced a gentle sloping curve, and Gly5 produced a good reaction curve. This study demonstrates that a latex reagent made by using 5 types of amino acid spacer molecules increased reactiveness by 40% as compared to using only 1 glycine molecule. It is possible that the long amino acid spacer reduces steric hindrance in the antigen-antibody reaction with the latex and thus reactiveness to the antibody is increased. Because the reactiveness is examined by using the amino acid, the position of the carboxyl group is the same as the amino group necessary for the peptide bond formation. Because the alkyl group of the amino acid used is aliphatic, the hydrophobe of the amino acid, and the volume of the molecule are chiefly different (Table 4), the difference in reactiveness may be due to the side chain of the amino acid. Therefore, it is suggested that the reactiveness is due to the interaction of the aliphatic amino acid spacer with the hydrophobe. Comparison of reactivity in various concentration of glycine spacer 168 Medicinal Chemistry and Drug Design 100 80 60 40 20 0 0. Comparison of reactivity in various types of amino acid spacers Glycine Concentration 0 1. Amino acid spacers 120 100 80 60 40 20 0 Gly Ala Leu Val amino acid(%) antibody(%) Fig. Amount of conjugated amino acid and antibody 170 Medicinal Chemistry and Drug Design 3. The immunoreactivity curve of the latex agglutination rates using the various antibodies is shown in Fig. The reactivity of these reagents was ranked in the following order: MoAb 5 > MoAb 8 > MoAb 7. The detection limit, which was calculated as the concentration equivalent to 3 standard deviations above the mean signal from 10 replicates of the zero standard, was calculated at 10 ng/ml. The sensitivity of the latex reagents containing MoAb 5 was found to be the highest, and the latex reagents with the oligoclonal antibody were more sensitive than the mixed latex reagents. The mixed latex reagents containing MoAb 5 were found to have higher activity than the others. Comparison of Latex Reagent Reactivity Following Mixing of Two Types of Latex Reagents Containing Different MoAbs. Two types of latex reagents sensitizing MoAb 5 were found to have higher sensitivity than the rest. When MoAbs for two different epitopes were used, the resulting latex reagent exhibited higher sensitivity than the MoAbs for two nearby epitopes. We suggest that latex reagents can be further increased in sensitivity through the use of MoAbs directed against remote epitopes. Chronic high blood sugar in diabetic patients increases the risk of arteriosclerosis. The latex reagents constructed using these MoAbs were found to be highly sensitive. Moreover, the latex reagents, containing a cocktail of MoAbs specific for different epitopes, were also found to be highly sensitive. We suggest that latex reagents can be increased in sensitivity and specificity through the use of MoAbs directed against remote epitopes. The results from this study might also prove to be applicable to additional substances such as interleukin, etc. Introduction Infectious, cancer and allergic diseases have always been scourge for humans and. As immunization helps to inhibit the spread of disease, many people can be protected from illness and death. It has been proved beyond doubt that with the exception of pure drinking water, no other human endeavor rivals immunization in combating infectious diseases. Millions of lives have been saved, with considerably reduced mortality rates, millions have the chance of a longer healthier life. The purpose of prophylactic vaccination is to generate a strong immune response providing long term protection against infection. The considerable success achieved in the eradication of smallpox and the reduction of polio, measles, pertussis, tetanus and meningitis, were among the most notable achievements of the 20th century (Wack and Rappuoli 2005). Some of the existing vaccines do not induce complete protection and therefore, the development of effective vaccines towards these diseases is needed. This topic was extensively studied in last one decade and thousands of high quality publication and high quality reviews are reported in the literature. Need for immune adjuvants Traditional vaccines mainly consisted of live attenuated pathogens, whole inactivated organisms, or inactivated bacterial toxins. Many traditional vaccines based on pathogen whole cells often contain components that can cause toxicity related side effects. As a result 178 Medicinal Chemistry and Drug Design of these safety limitations of conventional vaccines, several new approaches to vaccine development have emerged that may have significant advantages over more traditional approaches. These approaches include 1) recombinant protein subunits 2) synthetic peptides and 3) protein polysaccharide conjugates. By contrast, these vaccines although offering considerable advantages over traditional vaccines in terms of safety and cost of production, in most cases they have limited immunogenicity and therefore are use less as prophylactic or therapeuticvaccines on their own. These pitfalls have intensified the search of external agents that can synergistically boost the immune response of otherwise weakly immunogenic subunit vaccines. Such molecularly defined immune boosters, popularly known as adjuvants, ideally should constitute a non-immunogenic entities, however, able to stimulate humoral and cellular immunity in presence of a vaccine antigen and most importantly, being non toxic, suitable for animals and humans use. Immune system: Innate and adaptive the immune system in higher animals can be broadly classified into the innate and the adaptive immune systems(Janeway 2001; Janeway and Medzhitov 2002). The innate immune system was long thought to be a non-specific inflammatory response generated during exposure to foreign antigen. However, studies conducted in recent years indicate the innate immune response is able to discriminate between pathogen classes and direct innate and adaptive immune responses toward elimination of the invading pathogen(Akira, Uematsu et al. Improved understanding of innate immunity in recent years, has led to the identification of immune pathways and adjuvant formulations more suitable for clinical advancement. The 2011 Noble Prize for Medicine was awarded to three scientists who have done more than anyone to lay bare the two-tier structure of the immune system. Adaptive immune responses are essential for the control of pathogens that escape elimination by the innate immune response(Schwartz 2000). Because of its role in immune memory, the adaptive immune systems contributions to pathogen elimination and vaccine development have been widely studied. Adaptive immunity mediates a delayed, specific response to foreign antigen while innate immunity is not antigen specific and develops immediately following exposure to immune stimuli i. Pattern Recognition Receptors Based Immune Adjuvants: Their Role and Importance in Vaccine Design 179 2009; Blasius and Beutler 2010; Kawai and Akira 2010; Takeuchi and Akira 2010). This creates an inflammatory environment in tandem, that leads to the establishment of the adaptive immune response(Iwasaki and Medzhitov 2004). A number of these are now in clinical or late preclinical stages of development for multiple applications and have been the subject of research to clarify the basis of their adjuvant activity.
Under pathologic conditions erectile dysfunction pills cape town cheap 80mg top avana overnight delivery, the spleen may become the There is generalised hyperplasia of tissue macrophages in site of extramedullary haematopoiesis erectile dysfunction or cheating generic 80mg top avana otc. Being the Microscopically impotence vs sterile 80 mg top avana mastercard, the involved organs contain aggregates largest lymphoreticular organ erectile dysfunction needle injection video top avana 80 mg low price, it is involved secondarily in of macrophages which are pleomorphic and show nuclear a wide variety of systemic disorders which manifest most atypia. The cytoplasm of these cells contains vacuoles and commonly as splenic enlargement (splenomegaly) described rod-shaped histiocytosis-X bodies. Enlargement of the spleen termed splenomegaly, occurs in a Intense chemotherapy helps to control Letterer-Siwe disease wide variety of disorders which increase the cellularity and but intercurrent infections result in fatal outcome in many vascularity of the organ. Portal vein obstruction Moderate enlargement (upto umbilicus) occurs in hepatitis, 3. Splenic vein obstruction cirrhosis, lymphomas, infectious mononucleosis, haemolytic 4. Primary and metastatic splenic tumours bodies resulting in fibrocongestive splenomegaly, also called 3. The mechanism for excessive removal is followed by significant haematologic alterations. The criteria for hypersplenism autoimmune haemolytic anaemia or thrombocytopenia, the are as under: respective blood cell counts are increased following 1. Splenic destruction of one or more of the cell types in the as under: peripheral blood causing anaemia, leucopenia, thrombo 1. Red cells: There is appearance of target cells in the blood cytopenia, or pancytopenia. Splenectomy is followed by improvement in the severity shows increased resistance to haemolysis. There is shift-to-left of the myeloid medulla composed of onion skin-like concentrically arranged cells with appearance of some myelocytes. Platelets: Within hours after splenectomy, there is rise in Thymocytes are predominantly present in the cortex. These cells include immature T lymphocytes in the cortex and mature T lymphocytes in the medulla. The most common cause of splenic rupture or laceration is the main function of the thymus is in the cell-mediated blunt trauma. Non immunity by T-cells and by secretion of thymic hormones traumatic or spontaneous rupture occurs in an enlarged such as thymopoietin and thymosin-? In acute Thymic lesions are associated with diverse conditions infections, the spleen can enlarge rapidly to 2 to 3 times its which may be immunologic, haematologic or neoplastic. Some of the other common causes of involvement in myasthenia gravis is discussed in spontaneous splenic rupture are splenomegaly due to chronic Chapter 28. Sometimes Thymic hypoplasia and agenesis are acquired and congenital fragments of splenic tissue are autotransplanted within the disorders respectively in which the gland is either unusually peritoneal cavity and grow into tiny spleens there (splenosis). Acquired hypoplasia occurs as an Primary tumours of the spleen are extremely rare. The ageing phenomenon or may occur in the young due to severe only notable benign tumours are haemangiomas and stress, malnutrition, irradiation, therapy with cytotoxic drugs lymphangioma, while examples of primary malignant and glucocorticoids. Enlargement of the thymus or failure to involute produces Secondary tumours occur late in the course of disease thymic hyperplasia. Hyperplasia is usually associated with and represent haematogenous dissemination of the appearance of lymphoid follicles in the medulla of the thymus malignant tumour. Splenic metastases appear as multiple and is called thymic follicular hyperplasia. The most frequent primary sites include: lung, of follicular hyperplasia of the thymus is myasthenia gravis. Although thymus is a lymphoepithelial organ, the term thymoma is used for the the thymus gland is a complex lymphoreticular organ lying tumour of epithelial origin. At birth, the gland weighs In about half the cases, thymoma remains asymptomatic and 10-35 gm and grows in size upto puberty, following which is accidentally discovered in X-rays. In the adult, associated conditions like myasthenia gravis or local thymus weighs 5-10 gm. The gland consists of right and left encapsulated lobes, joined together by fibrous connective tissue. Grossly, the tumour is tissue septa pass inwards from the capsule and subdivide spherical, measuring 5-10 cm in diameter with an average the lobe into large number of lobules. Sectioned surface is soft, yellowish, of the lobule shows outer cortex and inner medulla. Both cortex lobulated and may be either homogeneous or contain cysts and medulla contain two types of cells: epithelial cells and due to the presence of haemorrhage and necrosis. Microscopically, the tumour has a thick fibrous capsule Epithelial cells are similar throughout the thymus gland. The histology of lobule shows network in which thymocytes and macrophages are found. The tumour consists of neoplastic epithelial cells and variable number of non-neoplastic features of cancer. Thymoma may be of following types: malignancy may be squamous cell type (most common) Benign thymoma is more common. These include: myasthenia gravis Malignant thymoma is less common and is further of 2 (most common), hypogammaglobulinaemia, erythroid types: hypoplasia (pure red cell aplasia), peripheral T cell leukae Type 1 is cytologically benign looking but aggressive and mia/lymphoma, multiple myeloma, other autoimmune invades the mediastinal structures locally. The outer coat of arteries is the tunica from the left heart to the metabolising cells, and then back to adventitia. The blood containing oxygen, nutrients and some elastic fibres that merge with the adjacent tissues. This metabolites is routed through arteries, arterioles, capillaries, layer is rich in lymphatics and autonomic nerve fibres. These blood vessels differ from each other the layers of arterial wall receive nutrition and oxygen in their structure and function. Thus, there are structural variations Histologically, all the arteries of the body have 3 layers in the three types of arteries: in their walls: the tunica intima, the tunica media and the Large, elastic arteries such as the aorta, innominate, tunica adventitia. These layers progressively decrease common carotid, major pulmonary, and common iliac with diminution in the size of the vessels. The internal elastic lamina appears as Endothelium is a layer of flattened cells adjacent to the a single wavy line while the external elastic lamina is less flowing blood. The media primarily consists of smooth muscle endothelial cells through which certain materials pass. Structurally, they consist of the three layers as in the most important event in the initiation of thrombus forma muscular arteries but are much thinner and cannot be tion at the site. The arterioles consist of a layer of endothelial cells in the intima, one or two smooth muscle cells in the Subendothelial tissue consists of loose meshwork of media and small amount of collagen and elastic tissue connective tissue that includes myointimal cells, collagen, comprising the adventitia. The elastic laminae are virtually proteoglycans, elastin and matrix glycoproteins. Tunica media is the middle coat of the capillaries returns to the heart via post-capillary venules and arterial wall, bounded internally by internal elastic lamina thence into venules and then veins. This layer is the In the following pages, diseases of arteries are discussed thickest and consists mainly of smooth muscle cells and under 3 major headings: arteriosclerosis, arteritis (vasculitis) elastic fibres. This is followed by brief account of diseases condensed elastic tissue is less well defined than the internal of veins and lymphatics, while the vascular tumours are elastic lamina. All 391 the three types are common in hypertension but may occur due to other causes as well. Hyaline Arteriolosclerosis Hyaline sclerosis is a common arteriolar lesion that may be seen physiologically due to aging, or may occur pathologically in benign nephrosclerosis in hypertensives and as a part of microangiopathy in diabetics; the subject is discussed again in Chapter 22. Microscopically, the thickened vessel wall shows structureless, eosinophilic, hyaline material in the intima Figure 15. This is the following morphologic entities are included under substantiated by the demonstration of immunoglobulins, arteriosclerosis: complement, fibrin and lipids in the lesions. Atherosclerosis ii) An alternate possibility is that the lesions may be due to the last-named, atherosclerosis, is the most common and immunologic reaction. The changes are non the hyperplastic or proliferative type of arteriolosclerosis is selective and affect most of the arteries. These are possibly a characteristic lesion of malignant hypertension; other induced by stress and strain on vessel wall during life.