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Hereditary dysfibrinogenemia is a rare clotting disorder due to a structural defect in the fibrinogen molecule that results in a tendency for bleeding and thrombosis, as well as obstetric complications. We describe the laboratory results and clinical manifestations for 50 patients with a diagnosis of dysfibrinogenemia. Various different laboratory measurements of fibrinogen were performed on samples from these patients, including fibrinogen (Clauss), heat fibrinogen precipitation according to Schulz and immunological fibrinogen. Fifty patients were found with dysfibrinogenemia (52% female; median age 52, range 9–89 years). The fibrinogen level according to Clauss was low, with a median of 51 mg/dL (range 15–86 mg/dL; normal range 150–450 mg/dL). Determination of other fibrinogen levels revealed normal results: heat fibrinogen precipitation according to Schulz, 240 mg/dL; and immunological fibrinogen, 244 mg/dL. The median reptilase time was longer than normal, at 55 s (normal 20 s). Some 50% of the patients reported a distinct bleeding tendency, mostly a tendency for hematoma (60%) and secondary bleeding (44%). Thirteen patients had thrombotic events, of which 54% were located arterially. Some 12% of the patients reported a tendency for bleeding and for thrombosis, whereas 19% had miscarriages, sometimes recurrent. We found that functional fibrinogen levels (Clauss) were generally lower in patients with bleeding manifestations (43 vs. 57 mg/dL in other patients).
Varicella zoster virus (VZV) belongs to one of the eight herpes viruses known to infect humans. While primary VZV infection (chickenpox) is generally a disease of childhood, herpes zoster occurs primarily in elderly persons (>50 years). Herpes zoster, also called shingles, is a neurocutaneous disease resulting from reactivation of latent VZV infection within dorsal root ganglia. Severe complications may occur in elderly persons and immunocompromised of any age, including severe complication of the eye, ear, skin and internal organs, and the peripheral and central nervous systems. A progressive decline of VZV-specific cell-mediated immunity and age are associated with an increased incidence and severity of herpes zoster and postherpetic neuralgia (PHN). PHN is the most common complication of herpes zoster causing chronic, debilitating pain. In cases with characteristic signs and symptoms (presence of prodromal pain, eruptions, grouped vesicles, segmental pain), the diagnosis is almost distinctive enough and no laboratory investigations are required. However, for patients lacking no characteristic pathology, a rapid laboratory diagnosis may be helpful to begin antiviral therapy as soon as possible. Antiviral therapy should be initiated immediately within 72 h after rash onset, particularly in older patients. The main aim of treatment is to control and reduce acute zoster pain, shorten virus replication, avoid dissemination of skin lesions and prevent PHN and other severe complications. The aim of the present review is to outline advantages and disadvantages of different herpes zoster laboratory methods (microscopy, direct immunofluorescence assay, detection of viral DNA, virus isolation and serological methods). A live attenuated VZV vaccine has been developed to prevent herpes zoster and PHN in individuals >60 years of age (Shingles Prevention Study). This review summarises the epidemiology, pathogenesis, clinical aspects, complications, therapy and prevention of varicella zoster.
Das Varizella-Zoster-Virus (VZV) gehört zu einem der acht bisher bekannten humanpathogenen Herpesviren.
Während Windpocken (Primärinfektion) eine typische Erkrankung im Kindes- und Jugendalter sind, tritt der Zoster (endogene Reaktivierung) gehäuft bei älteren Menschen jenseits des fünften Lebensjahrzehnts auf. Der Zoster, auch Gürtelrose genannt, ist eine neurokutane Entzündungskrankheit, die als endogene Reaktivierung der latent in den (Hinterwurzel-) Ganglienzellen persistierenden Varizella-Zoster-Viren definiert ist.
Ernsthafte Komplikationen, die im Zusammenhang mit dem Zoster beschrieben werden, treten vor allem bei älteren und immunsupprimierten Patienten auf. Diese können sich an Haut, Auge, Ohr, an verschiedenen inneren Organen sowie am zentralen und peripheren Nervensystem manifestieren. Ein fortschreitendes Nachlassen der VZV-spezifischen zellvermittelten Immunität ist mit dem Alter assoziiert, ebenso wie der gleichzeitige Anstieg von Inzidenz und Schweregrad einer Zosterinfektion sowie das Auftreten einer postzosterischen Neuralgie (PZN).
Die postzosterische Neuralgie (PZN), die einen chronischen Schmerzzustand beschreibt, stellt die häufigste Komplikation des Zosters dar. Im Fall einer eindeutigen klinischen Situation (Prodromalschmerzen, charakteristische Hauteffloreszenzen (Eruptionen, Bläschen), dermatomabhängige Schmerzen) werden keine laboratoriumsdiagnostischen Nachweisverfahren benötigt. Aber gerade bei Patienten, die keine „Zoster-typische Klinik“ aufzeigen, kann eine schnelle Diagnosesicherung durch verschiedene Nachweismethoden hilfreich sein, um schnellstmöglich eine antivirale Therapie einzuleiten. Es wird empfohlen, diese so früh wie möglich, d.h. innerhalb von 72 Stunden nach Auftreten der ersten Effloreszenzen, zu beginnen. Das Hauptziel der Therapie sollte die Kontrolle und Reduktion des akuten Zosterschmerzes, die verkürzte Virusreplikation, die Verhinderung der Ausbreitung der Hautläsionen sowie die Prävention der postzosterischen Neuralgie und weiterer ernsthafter Komplikationen sein. In der vorliegenden Arbeit werden Vor- und Nachteile verschiedener Nachweisverfahren (Mikroskopie, Immunofluoreszenztechnik, DNA-Nachweisverfahren, Virusisolierung und Serologie) beschrieben. Eine attenuierte VZV-Lebendvakzine wurde entwickelt, um Herpes Zoster und die PZN bei über 60- jährigen zu verhindern (Shingles Prevention Study). Es wird ein Überblick über die Epidemiologie, Pathogenese, klinischen Aspekte, Komplikationen, therapeutischen Möglichkeiten sowie die Prävention eines Herpes Zoster gegeben.
Einleitung: Medizinisches Personal ist dem Risiko ausgesetzt, sich an kontaminierten Instrumenten zu verletzen. Nadelstichverletzungen (NSV) können zu ernsthaften und möglicherweise schwerwiegenden Infektionen wie Hepatitis B (HBV), Hepatitis C (HCV) und HIV-Infektionen führen. Dieses Risiko betrifft auch Medizinstudenten im Verlaufe ihrer klinischen Ausbildung. Jede NSV sollte als Arbeitsunfall gemeldet werden, damit postexpositionelle Maßnahmen eingeleitet sowie etwaige Infektionen frühzeitzeitig erkannt und behandelt werden können. Im Falle einer Infektion können versicherungsrechtliche Ansprüche gegenüber den Berufsgenossenschaften geltend gemacht werden. Ziel unserer Studie war die Erhebung der Häufigkeit und Melderate von NSV bei Medizinstudenten.
Methoden: Anonyme Fragebogenerhebung bei Medizinstudenten vor Beginn des Praktischen Jahres.
Ergebnisse: Von den befragten Studenten gaben 58,8% (n=183/311) mindestens eine NSV im Rahmen des Studiums an. Insgesamt 284 NSV wurden von den befragten Studenten gemeldet. Lediglich 38,3% der Studenten hatten alle NSV gemeldet. Die häufigste Ursache für das Nichtmelden der NSV war Schamgefühl aufgrund der Verletzung (54,0%).
Schlussfolgerungen: Expositionen gegenüber Blut sind eine häufige und ernstzunehmende Gefährdung von Medizinstudenten. Es sollten Maßnahmen ergriffen werden, um die Häufigkeit von NSV zu reduzieren und das Meldeverhalten der Studenten zu optimieren. Entsprechende Schulungen sollten sowohl die technischen Fertigkeiten der Studenten als auch das Bewusstsein über die Gefährdung durch NSV vermitteln.
Introduction: Healthcare workers (HCWs) are exposed to bloodborne pathogens (e.g., contaminated devices). In the healthcare environment, needlestick injuries (NSI) represent a major risk factor in the transmission of hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV). Medical students are at risk of occupational exposure to bloodborne viruses following needlestick injuries during medical education. Reporting of needlestick injuries is an important step for initiating early prophylaxis or treatment. In the case of a bloodborne infection, pursuant to insure law could result in a claim. The objective of the present study was to describe occupational blood exposure of medical students through needlestick injuries.
Methods: Sixth-year medical students were invited to complete an anonymous questionnaire.
Results: In our study, 58.8% (n=183/311) of medical students recalled at least one needlestick injury during their studies. Overall, 284 needlestick injuries were reported. Only 38.3% of medical students reported all NSI to the appropriate hospital personnel. The main reason (54.0%) for not reporting NSI was being ashamed of having an NSI.
Conclusions: Occupational exposure to blood is a common problem among medical students. Efforts are required to ensure greater awareness among medical students about the risk of bloodborne pathogens. Proper training in procedures and how to act in case of injury should be offered to reduce the number of needlestick injuries.
Human serum albumin (HSA) nanoparticles represent a promising tool for targeted drug delivery to tumor cells. The coupling of the antibody trastuzumab to nanoparticles uses the capability of human epidermal growth factor receptor 2 (HER2)-positive cells to incorporate agents linked to HER2. In our present study, we developed targeted nanoparticles loaded with antisense oligonucleotides (ASOs) against polo-like kinase 1 (Plk1). We evaluated the receptor-mediated uptake into HER2-positive and -negative breast cancer and murine cell lines. We performed quantitative real-time PCR and Western blot analyses to monitor the impact on Plk1 expression in HER2-positive breast cancer cells. Antibody-conjugated nanoparticles showed a specific targeting to HER2-overexpressing cells with cellular uptake by receptor-mediated endocytosis and a release into HER2-positive BT-474 cells. We observed a significant reduction of Plk1 mRNA and protein expression and increased activation of Caspase 3/7. Thus, this is the first report about ASO-loaded HSA nanoparticles, where an impact on gene expression could be observed. The data provide the basis for the further development of carrier systems for Plk1-specific ASOs to reduce off-target effects evoked by systemically administered ASOs and to achieve a better penetration into primary and metastatic target cells. Treatment of tumors using trastuzumab-conjugated ASO-loaded HSA nanoparticles could be a promising approach to reach this goal.
GTPase-activating proteins are required to terminate signaling by Rap1, a small guanine nucleotide-binding protein that controls integrin activity and cell adhesion. Recently, we identified Rap1GAP2, a GTPase-activating protein of Rap1 in platelets. Here we show that 14-3-3 proteins interact with phosphorylated serine 9 at the N terminus of Rap1GAP2. Platelet activation by ADP and thrombin enhances serine 9 phosphorylation and increases 14-3-3 binding to endogenous Rap1GAP2. Conversely, inhibition of platelets by endothelium-derived factors nitric oxide and prostacyclin disrupts 14-3-3 binding. These effects are mediated by cGMP- and cAMP-dependent protein kinases that phosphorylate Rap1GAP2 at serine 7, adjacent to the 14-3-3 binding site. 14-3-3 binding does not change the GTPase-activating function of Rap1GAP2 in vitro. However, 14-3-3 binding attenuates Rap1GAP2 mediated inhibition of cell adhesion. Our findings define a novel crossover point of activatory and inhibitory signaling pathways in platelets.
Type I interferons (IFNs) signal for their diverse biological effects by binding a common receptor on target cells, composed of the two transmembrane IFNAR1 and IFNAR2 proteins. We have previously differentially enhanced the antiproliferative activity of IFN by increasing the weak binding affinity of IFN to IFNAR1. In this study, we further explored the affinity interdependencies between the two receptor subunits and the role of IFNAR1 in differential IFN activity. For this purpose, we generated a panel of mutations targeting the IFNAR2 binding site on the background of the IFNalpha2 YNS mutant, which increases the affinity to IFNAR1 by 60-fold, resulting in IFNAR2-to-IFNAR1 binding affinity ratios ranging from 1000:1 to 1:1000. Both the antiproliferative and antiviral potencies of the interferon mutants clearly correlated to the in situ binding IC(50) values, independently of the relative contributions of the individual receptors, thus relating to the integral lifetime of the complex. However, the antiproliferative potency correlated throughout the entire range of affinities, as well as with prolonged IFNAR1 receptor down-regulation, whereas the antiviral potency reached a maximum at binding affinities equivalent to that of wild-type IFNalpha2. Our data suggest that (i) the specific activity of interferon is related to the ternary complex binding affinity and not to affinity toward individual receptor components and (ii) although the antiviral pathway is strongly dependent on pSTAT1 activity, the cytostatic effect requires additional mechanisms that may involve IFNAR1 down-regulation. This differential interferon response is ultimately mediated through distinct gene expression profiling.
The neuronal adaptor protein Fe65 is involved in brain development, Alzheimer disease amyloid precursor protein (APP) signaling, and proteolytic processing of APP. It contains three protein-protein interaction domains, one WW domain, and a unique tandem array of phosphotyrosine-binding (PTB) domains. The N-terminal PTB domain (Fe65-PTB1) was shown to interact with a variety of proteins, including the low density lipoprotein receptor-related protein (LRP-1), the ApoEr2 receptor, and the histone acetyltransferase Tip60. We have determined the crystal structures of human Fe65-PTB1 in its apo- and in a phosphate-bound form at 2.2 and 2.7A resolution, respectively. The overall fold shows a PTB-typical pleckstrin homology domain superfold. Although Fe65-PTB1 has been classified on an evolutionary basis as a Dab-like PTB domain, it contains attributes of other PTB domain subfamilies. The phosphotyrosine-binding pocket resembles IRS-like PTB domains, and the bound phosphate occupies the binding site of the phosphotyrosine (Tyr(P)) within the canonical NPXpY recognition motif. In addition Fe65-PTB1 contains a loop insertion between helix alpha2 and strand beta2(alpha2/beta2 loop) similar to members of the Shc-like PTB domain subfamily. The structural comparison with the Dab1-PTB domain reveals a putative phospholipid-binding site opposite the peptide binding pocket. We suggest Fe65-PTB1 to interact with its target proteins involved in translocation and signaling of APP in a phosphorylation-dependent manner.
Precursor protein translocation across the outer chloroplast membrane depends on the action of the Toc complex, containing GTPases as recognizing receptor components. The G domains of the GTPases are known to dimerize. In the dimeric conformation an arginine contacts the phosphate moieties of bound nucleotide in trans. Kinetic studies suggested that the arginine in itself does not act as an arginine finger of a reciprocal GTPase-activating protein (GAP). Here we investigate the specific function of the residue in two GTPase homologues. Arginine to alanine replacement variants have significantly reduced affinities for dimerization compared with wild-type GTPases. The amino acid exchange does not impact on the overall fold and nucleotide binding, as seen in the monomeric x-ray crystallographic structure of the Arabidopsis Toc33 arginine-alanine replacement variant at 2.0A. We probed the catalytic center with the transition state analogue GDP/AlF(x) using NMR and analytical ultracentrifugation. AlF(x) binding depends on the arginine, suggesting the residue can play a role in catalysis despite the non-GAP nature of the homodimer. Two non-exclusive functional models are discussed: 1) the coGAP hypothesis, in which an additional factor activates the GTPase in homodimeric form; and 2) the switch hypothesis, in which a protein, presumably the large Toc159 GTPase, exchanges with one of the homodimeric subunits, leading to activation.
Treatment predictors are important tools for the management of therapy in patients with chronic hepatitis B and C virus (HBV, HCV) infection. In chronic hepatitis B, several pretreatment parameters have been identified for prediction of virologic response to interferon alfa-based antiviral therapies or treatment with polymerase inhibitors. In interferon alfa and pegylated interferon alfa-treated patients, low baseline HBV DNA concentrations, HBV genotype A (B), and high baseline ALT levels are significantly associated with treatment response. In patients treated with nucleos(t)ide analogues, low baseline HBV DNA but not viral genotype is positively associated with virologic response. During treatment the best predictor of response is HBV DNA kinetics. Early viral suppression is associated with favourable virologic response and reduced risk for subsequent resistance mutations. For the current standard treatment with pegylated interferon alfa and ribavirin in patients with chronic hepatitis C, infection with HCV genotypes 2 and 3, baseline viral load below 400,000–800,000 IU/ml, Asian and Caucasian ethnicity, younger age, low GGT levels, absence of advanced fibrosis/cirrhosis, and absence of steatosis in the liver have been identified as independent pretreatment predictors of a sustained virologic response. After initiation of treatment, initial viral decline with undetectable HCV-RNA at week 4 of therapy (RVR) is the best predictor of sustained virologic response independent of HCV genotype.
Aufgrund der leichten Handhabung und des Nachweises einer Mortalitätssenkung gilt der Nachweis von okkultem Blut (FOBT) im Stuhl derzeit als das am weitesten verbreitete Screeningverfahren für das kolorektale Karzinom. Als nachteilig erweisen sich allerdings eine unzureichende Sensitivität, insbesondere beim Nachweis früher Stadien und eine nach wie vor geringe Akzeptanz in der Bevölkerung. Vorläufige Daten zum Nachweis von Calprotectin oder der Tumor-M2-PK im Stuhl ließen bessere Screeningeigenschaften erwarten. Aber auch hierschränkt die geringe Sensitivität für frühe Vorstufen und unzureichende Spezifität mit zu erwartenden hohen Folgekosten die Tauglichkeit der Tests deutlich ein. Die kürzlich entwickelten immunologischen FOBTs (I-FOBT)erweisen sich als spezifischer und sensitiver. Sie beruhen auf dem Nachweis von humanem Hämoglobin mittels spezifischer Antikörper und sind somit unabhängig von diätetischen oder medikamentösen Faktoren, was zu einer deutlich besseren Akzeptanz führt. Sie gelten derzeit als kosteneffektivste Verfahren unter den nichtinvasiven Screeningmaßnahmen. Der Nachweis von Tumor-DNA im Stuhl eröffnet eine neue Ära zum frühzeitigen Nachweis kolorektaler Karzinome. Erste kleinere Studien weisen auf eine sehr gute Sensitivität dieser Verfahren hin. Sie lagen für kolorektale Karzinome zwischen 62–91% und für Adenome zwischen 26–73% bei mit 93–100% sehr guter Spezifität. Als nachteilig im Ver-gleich zu den derzeit verfügbaren Screeningtests erweisen sich allerdings die vergleichsweise hohen Kosten.
Given the simplicity of the method and how it can be applied, as well as proof that it lowers the mortality rate, fecal occult blood testing (FOBT) is currently the most commonly used screening method for colorectal cancer (CRC). However, the test suffers from poor sensitivity, particularly with respect to detecting early stages, as well as low acceptance among the population. Preliminary data on detecting calprotectin and tumour-M2-PK in the stool indicated that a better screening performance could be expected. But these tests also suffer from low sensitivity in detecting early stages and from poor specificity, thus limiting the usefulness of the tests as a result of high follow-up costs. Recently developed immunological tests (I-FOBT) demonstrate significantly increased sensitivity and specificity. I-FOBTs use antibodies specific to human hemoglobin and are therefore not affected by diet and drugs, leading to improved patient partipication. At present, I-FOBTs seem to be the most cost-effective approach for non-invasive screening. The detection of tumour-DNA in the stool opens up a new era in early diagnosis of colorectal cancer. Small trials have pointed to a very high sensitivity of these methods: 62–91% for colorectal cancer and between 26% and 73% for adenomas, with a very high level of specificity (93–100%). The major drawback of this type of testing, compared with other screening tests available today, is its high cost.
Requirements for the interaction of mouse Polkappa with ubiquitin and its biological significance
(2008)
Polkappa protein is a eukaryotic member of the DinB/Polkappa branch of the Y-family DNA polymerases, which are involved in the tolerance of DNA damage by replicative bypass. Despite universal conservation through evolution, the precise role(s) of Polkappa in this process has remained unknown. Here we report that mouse Polkappa can physically interact with ubiquitin by yeast two-hybrid screening, glutathione S-transferase pulldown, and immunoprecipitation methods. The association of Polkappa with ubiquitin requires the ubiquitin-binding motifs located at the C terminus of Polkappa. In addition, Polkappa binds with monoubiquitinated proliferating cell nuclear antigen (PCNA) more robustly than with non-ubiquitinated PCNA. The ubiquitin-binding motifs mediate the enhanced association between monoubiquitinated PCNA and Polkappa. The ubiquitin-binding motifs are also required for Polkappa to form nuclear foci after UV radiation. However, the ubiquitin-binding motifs do not affect Polkappa half-life. Finally, we have examined levels of Polkappa expression following the exposure of mouse cells to benzo[a]pyrene-dihydrodiol epoxide or UVB radiation.
Glucokinase (GK) is a key enzyme of glucose metabolism in liver and pancreatic beta-cells, and small molecule activators of GK (GKAs) are under evaluation for the treatment of type 2 diabetes. In liver, GK activity is controlled by the GK regulatory protein (GKRP), which forms an inhibitory complex with the enzyme. Here, we performed isothermal titration calorimetry and surface plasmon resonance experiments to characterize GK-GKRP binding and to study the influence that physiological and pharmacological effectors of GK have on the protein-protein interaction. In the presence of fructose-6-phosphate, GK-GKRP complex formation displayed a strong entropic driving force opposed by a large positive enthalpy; a negative change in heat capacity was observed (Kd = 45 nm, DeltaH = 15.6 kcal/mol, TDeltaS = 25.7 kcal/mol, DeltaCp = -354 cal mol(-1) K(-1)). With k(off) = 1.3 x 10(-2) s(-1), the complex dissociated quickly. The thermodynamic profile suggested a largely hydrophobic interaction. In addition, effects of pH and buffer demonstrated the coupled uptake of one proton and indicated an ionic contribution to binding. Glucose decreased the binding affinity between GK and GKRP. This decrease was potentiated by an ATP analogue. Prototypical GKAs of the amino-heteroaryl-amide type bound to GK in a glucose-dependent manner and impaired the association of GK with GKRP. This mechanism might contribute to the antidiabetic effects of GKAs.
Cytotoxic T lymphocytes eliminate infected cells upon surface display of antigenic peptides on major histocompatibility complex I molecules. To promote immune evasion, UL49.5 of several varicelloviruses interferes with the pathway of major histocompatibility complex I antigen processing. However, the inhibition mechanism has not been elucidated yet. Within the macromolecular peptide-loading complex we identified the transporter associated with antigen processing (TAP1 and TAP2) as the prime target of UL49.5. Moreover, we determined the active oligomeric state and crucial elements of the viral factor. Remarkably, the last two residues of the cytosolic tail of UL49.5 are essential for endoplasmic reticulum (ER)-associated proteasomal degradation of TAP. However, this process strictly requires additional signaling of an upstream regulatory element in the ER lumenal domain of UL49.5. Within this new immune evasion mechanism, we show for the first time that additive elements of a small viral factor and their signaling across the ER membrane are essential for targeted degradation of a multi-subunit membrane complex.