Tracy D Vannorsdall, Ph.D.

• Assistant Professor of Psychiatry and Behavioral Sciences

https://www.hopkinsmedicine.org/profiles/results/directory/profile/0021398/tracy-vannorsdall

Homozygosity for this mutation excludes neuronopathic disease arteries 2012 order procardia with american express, but even a single 370 allele in a compound leads to an absence of neurologic disease [76]; compound heterozygotes tend to have more severe somatic disease than N370S homozygotes heart disease 6 serious medical symptoms generic 30 mg procardia fast delivery. The Norrbottnian population of Gaucher patients in northern Sweden are homozygous for the L444P mutation and have type 3 disease of variable severity [82] cardiovascular disease fingernails 30 mg procardia with mastercard. The L444P mutation is also found in other populations blood vessels in neck buy procardia 30 mg without a prescription, and though it is associated with severe somatic symptoms and generally with neurologic manifestations cardiovascular journal of nursing generic procardia 30mg amex, in some patients neuronopathic disease may be absent [64] cardiovascular system grade 6 buy procardia 30 mg visa. An index of complexity, and the power of molecular techniques to unravel it, is a family [84] in which two Amino acid substitution Asn Ser Leu Pro Type of mutation Point mutation Frameshift insertion Point mutation Splice junction mutation 684 Gaucher disease children died of type 2 disease, and a son had relatively indolent type 1 disease. Molecular analysis revealed the mother, asymptomatic at 62 years, and the son to be S370N/L444P compounds. It was assumed that the infants who died by one year of age had inherited two L444P alleles. In ceramide, there is a long-chain fatty acid amide linkage at the carbon 2 of sphingosine. Glycosphingolipids with longer oligosaccharide moieties are successively degraded to glycosylceramide. The procedure may be essentially curative in type 1 disease, but there is a risk of mortality from the procedure. Meanwhile, enzyme replacement therapy has become a major advance in the management of this disease. Gaucher disease was the first lysosomal storage disease for which this approach became available. The major breakthrough in permitting successful therapy was the recognition that lipid-laden macrophages have a mannose receptor [87]; modifying the glycoprotein glucocerebrosidase to expose a terminal mannose permits the enzyme to attach to and be incorporated into the macrophage [48]. A modified form of the enzyme purified from human placenta was approved for treatment in 1991 under the name Ceredase (algucerase), and then in 1994, a form of human glucocerebrosidase produced in cultured Chinese hamster ovary cells was approved under the name Cerezyme (imiglucerase). Clinical responses to enzyme replacement therapy have been clearly evident in hematologic (anemia and thrombocytopenia), visceral, and even (with longer courses of treatment) bony disease. The dose generally employed is 60 U/kg every two weeks [48], but 30 U/kg every two weeks may also be effective. Experience with 26 years of the use with imiglucerase [88] has led to excellent safety and efficiency. Dosage varied from 15 to 120 U/kg every other week, but the usual dosage was 60 U/kg. Enzyme replacement therapy has been judged [89] ineffective in intraalveolar pulmonary disease. It is possible that maintenance requirements for enzyme will be lower after the initial removal of accumulated glycolipid [90], but there is a risk of relapse in some patients. The expense of treatment ($100,000 to $200,000 per year) requires judicious use [19]. Studies are underway using a more specific glucosylceramide synthase inhibitor, eliglustat tartrate [94]. An alternative approach is to use pharmacologic chaperones to stabilize products of missense mutations, and there are efforts to develop such agents, including isofagomine [95]. It is generally agreed that enzyme replacement is not effective in type 2 disease, while in the type 3 disease, systemic improvement is accompanied by no change in cerebral manifestations [96]. A variety of modalities are used to monitor the progress of therapy in Gaucher disease. Preferred method is quantitative chemical shift imaging [99], but that is not widely available. Other approaches for semi-quantitative estimation of bone marrow burden of disease have used a scoring system [100]. The most sensitive biomarker that correlates with the disease activity is chitotriosidase [69], but approximately 6 percent of the general population has References 685 no activity, resulting from a panethnic inactivating 24-bp duplication [101]. A variety of supportive measures may be rendered unnecessary by the early use of enzyme replacement. There is, in general, no longer a place for splenectomy, but it might be considered in a patient with extensive thrombocytopenia or cardiopulmonary symptoms from a massive spleen. The frequency and severity of crises of bone pain and fractures were reported to improve in patients treated with biphosphonates [103], which are analogs of pyrophosphate that bind to hydroxyapatite, inhibiting resorption. A placebo-controlled trial of alendronate showed significant benefit as an adjuvant to enzyme replacement, with improvement in bone density and bone mineral content within 18 months [104]. Assignment of the gene coding for human beta-glucocerebrosidase to the region q21-q31 of chromosome 1 using monoclonal antibodies. Nine-year experience in Gaucher disease diagnosis at the Spanish reference center Fundacion Jimenez Diaz. Phenotypic manifestations of Gaucher disease: clinical features in 48 biochemically verified type 1 patients and comment on type 2 patients. The 1226G (N370S) Gaucher mutation among patients with Legg-Calve-Perthes disease. Kummell disease: delayed collapse of the traumatised spine in a patient with Gaucher type 1 disease. Cauda equina syndrome due to an intra-dural sacral cyst in type-1 Gaucher disease. Gaucher disease with parkinsonian manifestations: does glucocerebrosidase deficiency contribute to a vulnerability to parkinsonism Malignancies and monoclonal gammopathy in Gaucher disease; a systematic review of the literature. Homozygosity for a non-pseudogene comple glucocerebrosidase allele as cause of an atypical neuronopathic form of Gaucher disease. Molecular screening for diseases frequent in Ashkenazi Jews: lessons learned from more than 100,000 tests performed in a commercial laboratory. Genetic heterogeneity in type 1 Gaucher disease: multiple genotypes in Ashkenazic and non-Ashkenazic individuals. Identification of the second common Jewish Gaucher disease mutation makes possible population-based screening for the heterozygous state. Adult and infantile Gaucher disease in one family: mutational studies and clinical update. Accumulation of glucosylceramide and glucosylsphingosine (psychosine) in cerebrum and cerebellum in infantile and juvenile Gaucher disease. Imiglucerase in the management of Gaucher disease type 1: an evidence-based review of its place in therapy. Histological characterisation of visceral changes in a patient with type 2 Gaucher disease treated with enzyme replacement therapy. A randomized trial comparing the efficacy and safety of imiglucerase (Cerezyme) infusions every 4 weeks versus every 2 weeks in the maintenance therapy of adult patients with Gaucher disease type 1. Chemical chaperones increase the cellular activity of N370S -glucosidase: A therapeutic strategy for Gaucher disease. The role of the iminosugar N-butyldeoxynojirimycin (miglustat) in the management of type I (non-neuronopathic) Gaucher disease: a position statement. A phase 2 study of eliglustat tartrate (Genz-112638), an oral substrate reduction therapy for Gaucher disease type 1. The pharmacological chaperone isofagomine increases the activity of the Gaucher disease L444P mutant form of betaglucosidase. Gaucher disease: alendronate disodium improves bone mineral density in adults receiving enzyme therapy. Type B: Hepatosplenomegaly, pulmonary infiltration, foam cells, storage of sphingomyelin and deficiency of sphingomyelinase. Phenotypic variation became apparent with additional reports [4, 5], especially of adults with hepatosplenomegaly, but no neurologic abnormality in what has come to be called type B [6]. The discovery of the enzyme permitted the categorization of other patients classified as Niemann-Pick disease who clearly did not have sphingomyelinase deficiency as their molecular etiology, such as type C (Chapter 92). The separation of type C is an important distinction, but now that the nature of mutation has begun to be defined, separation into types A and B begins to appear artificial. There are certainly some very distinct phenotypes among the deficiencies of sphingomyelinase; soon the genotype for each will be known. Type A disease is relatively rare except in Ashkenazi Jews [5, 10, 11], in whom type B is quite rare. The liver and spleen may be enlarged at birth, and storage of lipid has been documented in the liver, brain, kidney, and placenta prior to birth [19, 23, 24]. Placental enlargement has been shown by ultrasound [25], and it is thought that storage in the placenta may lead to fetal loss [19]. Somatic cell hybridization indicated clearly that types A and B represented allelic variation in a single gene [13] and that type C was different. A number of mutations have been identified in both type A and type B patients [12, 17, 18]. Distinct mutations have been found in the ethnic groups in which Niemann-Pick disease is common. He had jaundice and acholic stools at six months, and repeated pulmonary infections. We have seen Niemann-Pick patients w it h hepatosplenomegaly whose history was that the spleen was not palpable early. There may be prolonged neonatal jaundice, and episodes of unexplained jaundice later. We have seen patients who presented in early infancy with acute jaundice, abnormal liver function tests, and hepatomegaly, suggesting a diagnosis of acute hepatocellular disease rather than a lipid storage disease. We have also seen a patient in whom two liver biopsies had been done in another institution and interpreted as fatty metamorphosis. At least one patient with Niemann-Pick disease was thought, on biopsy, to have glycogenosis [27]. Jaundice is a common terminal finding and some patients have developed disseminated intravascular coagulopathy. Some episodes are clear-cut infections, such as bronchiolitis or pneumonia but, in others, infection is not obvious. Chest film may reveal diffuse interstitial infiltrates in a reticular or finely nodular pattern [29]. Anorexia may be complicated by vomiting, and there may be some diarrhea [30, 31] or constipation. Neurologic involvement may be first evidenced in a failure to achieve milestones, such as sitting, but some have developed normally for six months [28], or as long as one year [6]. Neurologic degeneration is progressive to a rigid state with spasticity in which there appears to be no consciousness of the environment. In one series of patients, [19] all patients had cherry red spots by one year of age. A hypochromic, microcytic anemia may be followed with time by thrombocytopenia or granulocytopenia. Nevertheless, the type A phenotype is much more common and accounts for about three-fourths of all patients. We suspect that among the type B patients, there are a number of distinct phenotypes that are beginning to correlate with genotype. Some of these patients have had sea-blue histiocytes in marrow [37] or tissues [39] and this type has been called the Lewis variant [37]. Impaired mental development was reported in unrelated patients at nine and 18 years [43]. Evidence of abnormal neural storage has been observed despite absence of neurologic abnormalities [48]. Terminal events include bleeding, anemia, and thrombocytopenia, often requiring daily transfusion of platelets, and hepatic failure. In a series of Saudi patients, some of whose pictures are shown in this chapter, five died between 18 and 36 months; one survivor to 4. Pulmonary infiltration is evident in roentgenograms as miliary nodular lesions [50]. Liver function tests, alanine aminotransferase, and aspartate aminotransferase may be elevated, along with triglycerides. Liver disease, either biliary cirrhosis [51] or cirrhosis, may be life-threatening, and portal hypertension and ascites may develop [52]. In addition to the diffuse infiltration seen on roentgenograms, there may be exertional dyspnea and decreased pO2 because of diminished diffusion. In a series of type B patients in the United States, in whom sphingomyelinase deficiency and the mutation were documented, height and weight were usually low; 39 percent and 21 percent were below the fifth percentile for height and weight, and these correlated with large organ volumes [54]. As a reticuloendothelial cell, it is found widely in the spleen, liver, lymph nodes, and lungs. In stained preparations, the cells have a foamy appearance that results from the stored material, which stains positively with stains for lipids. The lipid droplets are uniform in size, and the appearance has been called honeycomb-like or mulberry-like.

Pathogenesis of tuberculosis: interaction of Mycobacterium tuberculosis with macrophages cardiovascular system blood vessels youtube buy cheap procardia 30mg online. Essential roles of methionine and S-adenosylmethionine in the autarkic lifestyle of Mycobacterium tuberculosis coronary artery ulceration buy cheap procardia 30 mg on-line. L-Arginine availability modulates local nitric oxide production and parasite killing in experimental trypanosomiasis arteries 95 blocked best procardia 30mg. Cationic amino acid transporters and Salmonella Typhimurium ArgT collectively regulate arginine availability towards intracellular Salmonella growth coronary artery branches proven 30 mg procardia. Augenstreich J arteries main function order procardia 30 mg, Arbues A cardiovascular labeling quiz cheap procardia online amex, Simeone R, Haanappel E, Wegener A, Sayes F, Le Chevalier F, Chalut C, Malaga W, Guilhot C, Brosch R, Astarie-Dequeker C. Infection by tubercular mycobacteria is spread by nonlytic ejection from their amoeba hosts. Mycobacterium marinum: the generalization and specialization of a pathogenic mycobacterium. Survival of Mycobacterium tuberculosis in host macrophages involves resistance to apoptosis dependent upon induction of antiapoptotic Bcl-2 family member Mcl-1. The efficiency of the translocation of Mycobacterium tuberculosis across a bilayer of epithelial and endothelial cells as a model of the alveolar wall is a consequence of transport within mononuclear phagocytes and invasion of alveolar epithelial cells. Mycobacterium tuberculosis infection and inflammation: what is beneficial for the host and for the bacterium Alveolar epithelial cells in Mycobacterium tuberculosis infection: active players or innocent bystanders The mechanisms and consequences of the extra-pulmonary dissemination of Mycobacterium tuberculosis. Alveolar macrophages provide an early Mycobacterium tuberculosis niche and initiate dissemination. Tuberculous granuloma induction via interaction of a bacterial secreted protein with host epithelium. Wang Y, Hu M, Liu Q, Qin J, Dai Y, He L, Li T, Zheng B, Zhou F, Yu K, Fang J, Liu X, Otto M, Li M. Type I interferons in the pathogenesis of tuberculosis: molecular drivers and immunological consequences. Systematic, multiparametric analysis of Mycobacterium tuberculosis intracellular infection offers insight into coordinated virulence. Host-directed therapy of tuberculosis based on interleukin-1 and type I interferon crosstalk. A modular transcriptional signature identifies phenotypic heterogeneity of human tuberculosis infection. Identification of human T cell antigens for the development of vaccines against Mycobacterium tuberculosis. Modeling Mycobacterium tuberculosis early granuloma formation in experimental human lung tissue. Undetected multidrugresistant tuberculosis amplified by first-line therapy in mixed infection. Spatio-temporal distribution of Mycobacterium tuberculosis complex strains in Ghana. These models, using defined cell lines or expanded primary cell cultures, have been invaluable in the generation of the knowledge base on which the field currently relies. However, the models artificially compress the heterogeneity that exists for all these pathogens in their natural in vivo infection cycle. Mycobacterium tuberculosis is a human pathogen and is the largest single cause of death by a single infectious agent. Such drug regimens are a serious strain on the resources of the health care systems in many resourcechallenged nations, and drug-resistant strains emerge with disturbing frequency in many countries. Understanding the consequences of bacterial heterogeneity in vivo with respect to both drug action and immune containment remains a serious challenge to the field. This proinflammatory response persists until the development of an acquired immune response, which in the murine model system is delayed until 3 to 4 weeks postinfection because it is dependent on dendritic cells carrying M. In non-human primates and, by inference, in humans, the infection is paucibacillary, whereas in mice there is a much greater bacterial burden. At this point, the acquired immune response has developed and controls the bacterial burden at a subclinical level but is unable to clear the infection. In vaccinated hosts, this transition to control of the bacterial burden is achieved at around 1 log fewer bacilli. While resolution of infection is theoretically possible, it is virtually impossible to demonstrate. Progression from latent disease to active disease appears to occur in the face of a robust systemic immune response that is Th1 dominant. While there are candidate indicators of early disease progression, the field lacks immunological markers to detect vaccine-induced protection. The center of the granuloma is caseous and rich in lipids, thought to be derived from the lipids present in foamy macrophages. The caseum is surrounded by a macrophage-rich layer that contains foamy macrophages, multinucleated giant cells, and epithelioid macrophages. This structure is frequently encased in a fibrous capsule of collagen and other extracellular matrix proteins. Lymphocytes tend to be restricted to the periphery of the granuloma outside the fibrous outer layer. During this phase of containment and cellular consolidation, new macrophage phenotypes, such as epithelioid macrophages, multinucleated giant cells, and foamy macrophages, appear within the granuloma (20). In non-human primates and humans, the granuloma is a highly stratified structure with distinct transcriptional signatures associated with the different regions. The central, caseous region of the granuloma has a proinflammatory signature, while the region surrounding the caseum shows marked enrichment for transcripts associated with anti-inflammatory programs (21, 22). Intriguingly, each granuloma functions like an independent entity, and while the systemic immune response appears to be unchanged, some granulomas may progress to active disease while others continue to control the infection, or even progress to a sterile state (23). The factors that determine the localized progression to active disease have remained elusive (24). Increasingly sensitive indicators of early disease progression have been reported (25), but these indicators require initiation of the tissue damage that accompanies actual disease, so they are not useful indicators of protective immune status. Mycobacterial growth inhibition assays are the most utilized peripheral indicator of protective immunity (26). The data look compelling because they show a functional readout linked to bacterial survival. However, recent comprehensive evaluation of extensive data sets for the application of mycobacterial growth inhibition assays to different human populations indicates that, while the data are indicative of trained innate immunity, they do not correlate with the protection status of the individual (27). Escape from the phagosome appears to precipitate the necrotic death of the infected macrophage and a marked growth spurt in the intracellular bacterial population (38, 39). This transient event may have significance with respect to the pathology observed in late-stage disease but may be of less significance to long-term survival of the pathogen in its host. Moreover, the assumption that disease progression is the consequence of failure of Th1dependent immune control, while widely held, is actually unsubstantiated. Inert particles phagocytosed by macrophages are delivered to the acidic, hydrolytic environment of the phagolysosome, but M. The phenotype of the bacterium at individual cell level was determined on cell suspensions from infected tissue (44). Neither treatment impacted the neutrophil population within the infected lung tissue. A functional link between host cell metabolism and bacterial growth was demonstrated through the manipulation of M. Inhibition of glycolysis in the infected bone marrow-derived macrophages enhanced bacterial growth, while inhibition of fatty acid oxidation with etomoxir led to a reduction in bacterial growth. Neither compound had any impact on bacterial growth in rich Middlebrook 7H9 bacterial broth. These tissue-resident cells are selfmaintaining and capable of replication, albeit at a low rate during homeostasis. A subsequent model suggests that the ratio of M1 to M2 macrophage subsets is an accurate predictor of whether any individual granuloma is likely to progress to active disease (59). Analysis of peripheral blood mononucleocyte-derived macrophages and tissue-resident macrophages under homeostatic conditions suggests that the bias towards M1-like and M2-like phenotypes in these different macrophage lineages exists prior to any insult or infection (60, 61). How macrophages function in the reprogramming model (Model 1) is determined by immune signaling within the tissue niche. In the proposed preprogramming model (Model 2), the function of coexisting macrophage lineages in the lung in M. The Mce family of lipid transporters is conserved across the bacterial kingdom (67) and is present in M. Mce1 and Mce4 are the preferred uptake transporters for fatty acids and for cholesterol, respectively (69). The linking of fatty acid and cholesterol acquisition is not surprising given the requirement for the balanced production of downstream intermediates to feed the tricarboxylic acid cycle and provide building blocks for the synthesis of complex cell wall lipids (63, 66). Thin-layer chromatography and mass spectrometry analysis of the lipid species in the human granuloma demonstrated that the major lipid species were triacylglycerols, cholesterol, and cholesterol ester (21). The presence of abundant cholesterol ester in the caseum is strong evidence that these lipids came from lipid droplets present in the foamy macrophages that typically surround the caseous center of the granuloma (72, 73). When cells accumulate cholesterol, they usually esterify the sterol prior to transport from the endoplasmic reticulum and incorporation into the lipid droplet. The absence of green stain in uninfected cells at 48 h indicates loss of oleate-induced lipid droplets. The mycobacterial cell wall lipid trehalose dimycolate has been shown to induce this behavior (72). It is thought that the prolonged, chronic activation of the proinflammatory pathways in macrophages drives this transformation into foamy cells. The challenges remain, but our increased knowledge of the physiology and metabolism of intracellular M. Asymmetry and aging of mycobacterial cells lead to variable growth and antibiotic susceptibility. Deletion of a mycobacterial divisome factor collapses single-cell phenotypic heterogeneity. Exploitation of Mycobacterium tuberculosis reporter strains to probe the impact of vaccination at sites of infection. Mycobacterium tuberculosis responds to chloride and pH as synergistic cues to the immune status of its host cell. The importance of first impressions: early events in Mycobacterium tuberculosis infection influence outcome. Protective immunity against tuberculosis: what does it look like and how do we find it Role of chemokine ligand 2 in the protective response to early murine pulmonary tuberculosis. Depletion of alveolar macrophages exerts protective effects in pulmonary tuberculosis in mice. Initiation of the adaptive immune response to Mycobacterium tuberculosis depends on antigen production in the local lymph node, not the lungs. Caseation of human tuberculosis granulomas correlates with elevated host lipid metabolism. Sterilization of granulomas is common in active and latent tuberculosis despite within-host variability in bacterial killing. Correlates of tuberculosis risk: predictive biomarkers for progression to active tuberculosis. In vitro mycobacterial growth inhibition assays: a tool for the assessment of protective immunity and evaluation of tuberculosis vaccine efficacy. Cytokine activation leads to acidification and increases maturation of Mycobacterium avium-containing phagosomes in murine macrophages. Identification of nitric oxide synthase as a protective locus against tuberculosis. Disruption of phagosomal membranes of normal alveolar macrophages by the H37Rv strain of Mycobacterium tuberculosis. Phagosomal rupture by Mycobacterium tuberculosis results in toxicity and host cell death. Intracellular growth of Mycobacterium tuberculosis after macrophage cell death leads to serial killing of host cells. Interferon gamma release assays for monitoring the response to treatment for tuberculosis: a systematic review. Linking the transcriptional profiles and the physiological states of Mycobacterium tuberculosis during an extended intracellular infection. Mycobacterium tuberculosis arrests host cycle at the G1/S transition to establish long term infection. Quantitative and qualitative profiles of circulating monocytes may help identifying tuberculosis infection and disease stages. Ratio of monocytes to lymphocytes in peripheral blood in patients diagnosed with active tuberculosis. Cell origin dictates programming of resident versus recruited macrophages during acute lung injury.

Conservation of the D-mannose-adhesion protein among type 1 fimbriated members of the family Enterobacteriaceae cardiovascular symptoms generic procardia 30mg overnight delivery. Evolution of the chaperone/usher assembly pathway: fimbrial classification goes Greek cardiovascular disease board certification order 30 mg procardia with amex. Host-specific induction of Escherichia coli fitness genes during human urinary tract infection cardiovascular group snellville ga purchase discount procardia on-line. Modulating effects of the plug blood vessels of the brain cheap procardia line, helix heart disease youth of robeson county 2012 order cheap procardia line, and N- and C-terminal domains on channel properties of the PapC usher omega 7 arteries cheap procardia online visa. Fiber formation across the bacterial outer membrane by the chaperone/usher pathway. Domain activities of PapC usher reveal the mechanism of action of an Escherichia coli molecular machine. Functional role of the type 1 pilus rod structure in mediating host-pathogen interactions. Structure of a chaperone-usher pilus reveals the molecular basis of rod uncoiling. Role of the K2 capsule in Escherichia coli urinary tract infection and serum resistance. Polysaccharide capsule and sialic acid-mediated regulation promote biofilm-like intracellular bacterial communities during cystitis. The antigen 43 structure reveals a molecular Velcro-like mechanism of autotransporter-mediated bacterial clumping. Functional analysis of antigen 43 in uropathogenic Escherichia coli reveals a role in long-term persistence in the urinary tract. Structure-function analysis of the curli accessory protein CsgE defines surfaces essential for coordinating amyloid fiber formation. Urinary tract infection in a small animal model: transurethral catheterization of male and female mice. Antibody-based therapy for enterococcal catheter-associated urinary tract infections. Bladder catheterization increases susceptibility to infection that can be prevented by prophylactic antibiotic treatment. Catheterization alters bladder ecology to potentiate Staphylococcus aureus infection of the urinary tract. Genome-wide transposon mutagenesis of Proteus mirabilis: essential genes, fitness factors for catheterassociated urinary tract infection, and the impact of polymicrobial infection on fitness requirements. Prevention of mucosal Escherichia coli infection by FimH-adhesin-based systemic vaccination. Siderophore vaccine conjugates protect 98 against uropathogenic Escherichia coli urinary tract infection. Antivirulence C-mannosides as antibiotic-sparing, oral therapeutics for urinary tract infections. Treatment and prevention of urinary tract infection with orally active FimH inhibitors. Lead optimization studies on FimH antagonists: discovery of potent and orally bioavailable ortho-substituted biphenyl mannosides. Piatek R, Zalewska-Piatek B, Dzierzbicka K, Makowiec S, Pilipczuk J, Szemiako K, Cyranka-Czaja A, Wojciechowski M. Design and synthesis of C-2 substituted thiazolo and dihydrothiazolo ring-fused 2-pyridones: pilicides with increased antivirulence activity. Quorum-sensing Escherichia coli regulator A: a regulator of the LysR family involved in the regulation of the locus of enterocyte effacement pathogenicity island in enterohemorrhagic E. The broadly conserved regulator PhoP links pathogen virulence and membrane potential in Escherichia coli. The Cpx stress response system potentiates the fitness and virulence of uropathogenic Escherichia coli. Strong cross-system interactions drive the activation of the QseB response regulator in the absence of its cognate sensor. Distinguishing the contribution of type 1 pili from that of other QseB-misregulated factors when QseC is absent during urinary tract infection. Regulation of hemolysin in uropathogenic Escherichia coli fine-tunes killing of human macrophages. Toxin-antitoxin systems are important for niche-specific colonization and stress resistance of uropathogenic Escherichia coli. The extraintestinal pathogenic Escherichia coli factor RqlI constrains the genotoxic effects of the RecQ-like helicase RqlH. The rhomboid protease GlpG promotes the persistence of extraintestinal pathogenic Escherichia coli within the gut. The repeat-in-toxin family member TosA mediates adherence of uropathogenic Escherichia coli and survival during bacteremia. As such, these bacteria have experienced a long-standing coevolution with eukaryotic hosts that has likely shaped their biology. The genus Brucella is composed of an increasing number of species that infect a wide variety of mammals as primary hosts, such as bovines (Brucella abortus), goats (B. Most species cause in their hosts a disease named brucellosis, which manifests as abortion, sterility, and lameness in animals and which can also be transmitted to humans via inhalation of aerosolized bacteria or via ingestion of, or contact with, contaminated tissues or derived products, classically by the most pathogenic species, B. Human brucellosis is characterized by nonspecific flu-like symptoms during an early acute phase, which is followed by a chronic infection with debilitating consequences, including recurrent fever, osteomyelitis, arthritis, neurological symptoms, and endocarditis, if not treated with antibiotic therapy in a timely manner (4). Animal and human brucellosis share common pathophysiological features at the cellular level, where bacteria undergo an intracellular cycle that ensures their survival, proliferation, and persistence within phagocytic cells of various tissues, including 1 macrophages and dendritic cells (4, 5). Initially described in placental tissues of infected animals (6), the ability of B. Hence, significant efforts have been made in the last 2 decades to understand the underlying mechanisms that define these stages and how the bacterium exploits the corresponding cellular pathways to complete its intracellular cycle. Using live-cell imaging of fluorescent fluid-phase markers that were chased to terminal lysosomes, as a method that precludes any issue with detection of soluble lysosomal antigens, Starr et al. The underlying mechanisms, host functions, and bacterial effectors that mediate this process have been the subject of extensive research. Autophagy is a membrane-based process that normally captures intracellular contents, whether cytosolic contents, damaged organelles, or microorganisms, into double-membrane vesicles called autophagosomes, to deliver them for degradation to the lysosomal compartment. While it can act as an innate immune antibacterial mechanism, it can also be beneficial to some pathogens (44, 45). While the modes of action of BspA and BspF are unknown, that of BspB has been elucidated. Whether bacteria are released in a free state or contained within a membrane-bound vacuole remains to be established, but the maintenance of the originally infected cells argues that bacterial release is a nonlytic event, suggesting an exocytic process. Unlike many pathogens, which cause cell death to exit the cells in which they have replicated, Brucella prevents cell death programs from being carried out (60, 61), thus preserving its intracellular niche. Penetration and intracellular growth of Brucella abortus in nonphagocytic cells in vitro. Essential role of the VirB machinery in the maturation of the Brucella abortus-containing vacuole. Early acidification of phagosomes containing Brucella suis is essential for intracellular survival in murine macrophages. Brucella intracellular replication requires trafficking through the late endosomal/lysosomal compartment. Selective subversion of autophagy complexes facilitates completion of the Brucella intracellular cycle. VirB3 to VirB6 and VirB8 to VirB11, but not VirB7, are essential for mediating persistence of Brucella in the reticuloendothelial system. Future characterization of these proteins not only will reveal unsuspected aspects of Brucella intracellular strategies but also will teach us a great deal about host cell functions and their roles in many aspects of bacterial pathogenesis. Brucella abortus transits through the autophagic pathway and replicates in the endoplasmic reticulum of nonprofessional phagocytes. Brucella evades macrophage killing via VirB-dependent sustained interactions with the endoplasmic reticulum. Identification and characterization of in vivo attenuated mutants of Brucella melitensis. Virulent Brucella abortus prevents lysosome fusion and is distributed within autophagosomelike compartments. Integration host factor is involved in transcriptional regulation of the Brucella abortus virB operon. Deghelt M, Mullier C, Sternon J-F, Francis N, Laloux G, Dotreppe D, Van der Henst C, Jacobs-Wagner C, Letesson J-J, De Bolle X. G1-arrested newborn cells are the predominant infectious form of the pathogen Brucella abortus. Taguchi Y, Imaoka K, Kataoka M, Uda A, Nakatsu D, Horii-Okazaki S, Kunishige R, Kano F, Murata M. Brucella induces an unfolded protein response via TcpB that supports intracellular replication in macrophages. Legionella subvert the functions of Rab1 and Sec22b to create a replicative organelle. Chlamydia trachomatis interrupts an exocytic pathway to acquire endogenously synthesized sphingomyelin in transit from the Golgi apparatus to the plasma membrane. Cirl C, Wieser A, Yadav M, Duerr S, Schubert S, Fischer H, Stappert D, Wantia N, Rodriguez N, Wagner H, 111 Svanborg C, Miethke T. Subversion of Toll-like receptor signaling by a unique family of bacterial Toll/interleukin-1 receptor domain-containing proteins. Brucella infection inhibits macrophages apoptosis via Nedd4-dependent degradation of calpain2. In vitro Brucella suis infection prevents the programmed cell death of human monocytic cells. Failure to eradicate this age-old disease is the result of an ineffective vaccine and extended, often insufficient, chemotherapy. The spontaneous deletion (Rv3871 to Rv3878) from esx-1 found in the vaccine strains of M. Interestingly, a recently isolated clinical strain defective in this region has shown similar results, where there is no significant difference in bacterial count but pathology and cytokine response are remarkably different (15). Although these studies did not lead to novel vaccine candidates, they did provide tools to study M. A lengthy investigation attributed the disaster to negligent vaccine preparation, leading to contamination with virulent tubercle bacilli. The culture was passaged every 3 weeks on a medium containing potato, glycerine, and ox bile. By 1919, 230 subcultures had resulted in a strain that failed to produce tuberculous disease when injected into guinea pigs, rabbits, cattle, and horses (17). More recently, the EspD to -F and EspH proteins were shown to be stabilized by the chaperone EspL (24). EspC has been shown to form filaments in the membrane (18), whereas EspE localizes to the cell wall. However, no cell lysis was observed, until the missing link of low pH was identified (38, 39). Nutrient-rich cytoplasm seems an attractive environment for proliferation, providing an advantage to intracellular pathogens that develop mechanisms to permeabilize, and escape from, the phagosome. This finding was noteworthy, as mouse plasma has an arginine concentration of 200 M under normal conditions, and M. However, by utilizing nutrients from the host in this manner, these pathogens also alert the host immune system. In this instance, a growth-permissive naive macrophage serves as the perfect host where M. It has been reported to attract naive macrophages to the lung, and fractalkine production from M. Early establishment of infection and subsequent bacillary dissemination relies upon the availability of permissive "niche" cells. Therefore, a chemotactic signal would be a requisite for increasing the number of the cells from the approximate one macrophage per every 9 ml of lung volume (72). The immunogenicity of this vaccine candidate has been boosted by using a Toll-like receptor 4 agonist as an adjuvant, resulting in the induction of a humoral Why Do We Need a New Vaccine Current vaccine candidates in the pipeline include protein/adjuvant-based, attenuated/killed or cell extract-based, and viral vector-based vaccines. Although this candidate includes an alternative agonist and is designed to promote T cell and antibody responses, we do not know if these are the only correlates that will protect. There are also questions regarding the role of chemokines in the vaccine response.

There is a hydrophilic phospholipid coat in which one large protein (apoprotein B-100) is embedded heart disease day generic procardia 30mg without a prescription. This apoprotein is recognized and bound by the receptor cardiovascular kansas city buy generic procardia line, which is an acidic glycoprotein heart disease from smoking purchase genuine procardia line. It is synthesized as a precursor with an apparent molecular weight of 120 kDa and arteries going to the heart generic 30 mg procardia fast delivery, 30 minutes after synthesis heart disease grants cheap procardia amex, it is converted to the apparently larger form and inserted into the plasma membrane 5 arteries where it is possible to palpate a pulse procardia 30 mg. Intracellular cholesterol regulates its own intracellular concentration by means of an elegant system of feedback controls [53]. Some is required in the synthesis of cell surface membranes and in specialized cells, such as the adrenal and liver, and some is converted to steroid hormones and bile acids. Regulation occurs at this level in that cholesterol suppresses the synthesis of this enzyme, thus turning off cholesterol biosynthesis [55]. The protein is synthesized in the endoplasmic reticulum and then migrates to the Golgi complex; in the process, the mannose-rich portion of the precursor protein is reduced and O-linked sugars, including sialic acid, are added to the core N-acetylgalactosamine [57]. Next, the receptor moves to the cell surface to cluster in the coated pits, which are lined by a surface protein, clathrin [58]. The coated pits invaginate to form endocytic vesicles, which fuse to form endosomes. At least one class 1 allele was found in over half of 128 fibroblast lines studied. Among 32 of these alleles studied, 12 had large deletions [12] recognizable on Southern blots. Four FrenchCanadian homozygotes were found to have a deletion over 10 kb involving the promoter and exon 1 [61]. In patients with two null alleles, there is no immunoprecipitable protein and receptors cannot be seen electron microscopically [12, 50]. In class 2 mutations, the proteins synthesized fail to be transported to the Golgi and the receptors accumulate 630 Familial hypercholesterolemia intracellularly. A nonsense mutation in which a single nucleotide substitution produces a stop codon that leads to a truncated protein has been called the Lebanese allele and has been found in several unrelated Arab patients [65]. Among mutations identified early, there were two deletions, an insertion, a nonsense mutation, and a missense mutation [66]. The stop codon in the nonsense mutation leaves only two of the normal 50 amino acids in the cytoplasmic domain. The insertion adds eight amino acids in this domain and the missense mutation changes a tyrosine to a cysteine at the 80th amino acid of this domain [67]. These observations suggested that this area is critical for binding to a protein as a requirement for movement into the clathrin-coated pits. This was the first evidence that clustering in the pits was required for transport into cells. The two deletions appear to constitute a different subclass of defects in which the membrane spacing domain is altered, and the truncated receptors are largely secreted into the medium of cultured cells [66]. Class 5 mutations code for receptors that cannot discharge the ligand in the endosome and thus cannot recycle to the cell surface. R3500W was found in eight probands of many Taiwanese families; of them, 25 were missense, five nonsense, and six frameshift mutations in 52; 11 probands were novel. In a series of pregnancies at risk, one was homozygous affected, two were heterozygotes, and one was normal. Prenatal diagnosis of an affected fetus has also been made by fetal blood sampling and analysis of cholesterol [79]. Heterozygosity for the Lebanese mutation has been documented in chorionic villus material [80]. Heterozygosity has been diagnosed in cord blood [13], as well as prenatally, but the assay of cord blood is not a reliable method of screening the general public. Patients with autosomal recessive hypercholesterolemia have severe elevations of cholesterol and had large xanthomas on the tendons [84]. In another patient successfully transplanted, lesions in the coronary arteries regressed, as did xanthomas [20]. Homozygotes are generally resistant to the drugs and diet that are effective in heterozygotes, but those with some functional receptor activity may respond. These procedures lower blood concentrations of cholesterol appreciably, and xanthomas have been observed to regress, as have lesions in the coronary arteries, which were limiting flow. Lowering of cholesterol levels has also been reported following portacaval anastomosis [90]. In this ex vivo technique, hepatocytes were isolated from the patient and grown in culture, transfected with the normal gene, and reinjected into the portal circulation. Heterozygotes Two major approaches have been developed for the treatment of heterozygotes. The first group of drugs to be employed is anionbinding resins such as cholestyramine and colestipol. This was enough to reduce the incidence of myocardial infarctions by 20 percent in a ten-year prospective study [38]. The first of these drugs was mevastatin (Compactin), a compound isolated from Penicillium [95] that has a side chain resembling mevalonic acid. A more potent inhibitor isolated from Aspergillus differs in structure only in the substitution of a methyl for hydrogen group and is called mevinolin or lovastatin [96]. They are not without side effects, including hepatic toxicity and myopathy, which may manifest as rhabdomyolysis. The addition of nicotinic acid to the regimen may further improve the effect on levels of cholesterol [97]. The average age of onset of coronary disease was significantly higher after widespread use of statins in Japan [99]. Anion exchange resins, such as cholestyramine and colestipol may be effective, but they are unpalatable and poorly tolerated. In a search of statin trials reviewed from Medline, eight randomized, doubleblind, controlled studies were found involving 897 patients less than 18 years of age. Safety was evident in no differences in transaminases or creatine kinase, but long-term safety remains to be determined [101]. A double heterozygote for familial hypercholesterolemia and familial defective apolipoprotein B-100. Fat transport in lipoproteins: an integrated approach to mechanisms and disorders. Binding and degradation of low density lipoprotein by cultured human fibroblasts: comparison of cells from a normal subject and from a patient with homozygous familial hypercholesterolemia. A world wide web site for low-density lipoprotein receptor gene mutations in familial hypercholesterolemia: Sequence-based tabular and direct submission data handling. Multiple crmmutations in familial hypercholesterolemia: evidence for 13 alleles including four deletions. Xanthomatosis and coronary heart disease: necropsy study of two affected siblings. Natural history and cardiac manifestations of homozygous familial hypercholesterolaemia. Supravalvular aortic stenosis and coronary ostial stenosis in familial hypercholesterolemia: two-dimensional echocardiographic assessment. Ischemic optic neuropathy as the first manifestation of elevated cholesterol levels in young patients. Familial hypercholesterolemia: genetic biochemical and pathophysiologic considerations. Mode of inheritance in 55 families with essential hyperlipidaemia and xanthomatosis. Familial hypercholesterolemia: defective binding of lipoproteins to cultured fibroblasts associated with impaired regulation of 3-hydroxy-3methylglutaryl coenzyme A reductase activity. Inhibition of lipoprotein binding to cell surface receptors of fibroblasts following selective modification of arginyl residues in arginine-rich and B-apoproteins. Partial purification and characterization of the low density lipoprotein receptor from bovine adrenal cortex. Purification of the low density lipoprotein receptor an acidic glycoprotein of 164,000 molecular weight. Localization of low density lipoprotein receptors on plasma membrane of normal human fibroblasts and their absence in cells from a familial hypercholesterolemia homozygote. Role of the coated endocytic vesicle in the uptake of receptor-bound low density lipoprotein in human fibroblasts. Occurrence of low density lipoprotein receptors within large pits on the surface of human fibroblasts as demonstrated by freeze-etching. Esterification of low density lipoprotein in human fibroblasts and its absence in homozygous familial hypercholesterolemia. Regulation of 3-hydroxy3-methylglutaryl coenzyme A reductase activity in cultured human fibroblasts: comparison of cells from a normal subject and from a patient with homozygous familial hypercholesterolemia. Regulation of the activity of the low density lipoprotein receptor in human fibroblasts. ExonAlu recombination deletes 5 kilobases from low density lipoprotein receptor gene producing null phenotype in familial hypercholesterolemia. Common lowdensity lipoprotein receptor mutations in the French Canadian population. Analysis of a recycling-impaired mutant of low density lipoprotein receptor in familial hypercholesterolemia. A single-base substitution in the proximal Sp1 site of the human low density lipoprotein receptor promoter as a cause of heterozygous familial hypercholesterolemia. Detection of mutations and large rearrangements of the low-density liprotein receptor gene in Taiwanese patients with familial hypercholesterolemia. A novel mutation in proprotein convertase subtilisin/kexin tupe 9 gene leads to familial hypercholesterolemia in a Chinese family. Prenatal diagnosis of homozygous familial hypercholesterolaemia: expression of a genetic receptor disease in utero. Direct fetal blood examination for prenatal diagnosis of homozygous familial hypercholesterolemia. Dyslipidemia of mothers with familial hypercholesterolemia deteriorates lipids in adult offspring. Liver transplantation to provide low-density-lipoprotein receptors and lower plasma cholesterol in a child with homozygous familial hypercholesterolemia. Long-term effects of low-density lipoprotein apheresis using an automated dextran sulfate cellulose adsorption system. Low-density lipoprotein apheresis decreases ferritin, transferrin and vitamin B12, which may cause anemia in serially treated patients. Metabolic studies in familial hypercholesterolaemia: evidence for a gene-dosage effect in vivo. Gene therapy in a humanized mouse model of familial hypercholesterolemia leads to marked regression of atherosclerosis. Efficacy and safety of cholestyramine therapy in peripubertal and prepubertal children with familial hypercholesterolemia. Complementarity of colestipol, niacin and lovastatin in treatment of severe familial hypercholesterolemia. Antihyperlipidemic agents cause a decrease in von Willebrand factor levels in pediatric patients with familial hyperlipidemia. Rosuvastatin lowers coenzyme Q10 levels, but not mitochondrial adenosine triphosphate synthesis, in children with familial hypercholesterolemia. Homozygous familial hypercholesterolemia: new insights and guidance for clinicians to improve detection and clinical management. Effect of mipomersen, an apolipoprotein B synthesis inhibitor, on lowdensity lipoprotein cholesterol in patients with familial hypercholesterolemia. Dilemmas in treatment of women with familial hypercholesterolaemia during pregnancy. Efficacy and safety of the cholesteryl ester transfer protein inhibitor anacetrapib in Japanese patients with heterozygous familial hypercholesterolemia. The compound spontaneously cyclizes to form the lactone under the acidic conditions usually employed in liquid partition chromatography, extraction, and other forms of preparation for organic acid analysis. Less severely impaired patients have had developmental delay, ataxia, and hypotonia. Most have had recurrent crises of fever, tender lymphadenopathy, increase in liver and spleen size, arthralgia, and a morbilliform eruption. An even more attenuated presentation was observed in a five-year-old with cerebellar ataxia and retinal dystrophy and no febrile crises or hyperimmunoglobulin D elevation [7]. Our first patient [1] presented with severe failure to thrive, diarrhea, and hepatosplenomegaly, a picture that led to referral to gastroenterologists. Failure to thrive was present in nearly all the early reported patients: it was described as severe in two [1, 16], moderate in five, and mild in two [6]. Psychomotor impairment has been characteristic of each of the early patients described. It was of such severity in the most severely affected patients that no social interaction was possible [1, 6, 8, 9]. Most mutations appear to affect stability or folding of the enzyme rather than its catalytic properties [5].

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