Postnatal circulation in patients with aortic stenosis undergoing fetal aortic valvuloplasty: systematic review and meta-analysis.

OBJECTIVES: Fetal aortic valvuloplasty (FAV) has become a treatment option for critical fetal aortic stenosis (AS) with the goal of preserving biventricular circulation (BVC); however, to date, it is unclear how many patients undergoing FAV achieve BVC. The aim of this systematic review and meta-analysis was to investigate the type of postnatal circulation achieved following FAV. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. MEDLINE, EMBASE, Web of Science and the Cochrane Library were searched systematically for studies investigating postnatal circulation in patients with AS following FAV. Eligible for inclusion were original papers in the English language, published from 2000 to 2020, with at least 12 months of follow-up after birth. Review papers, abstracts, expert opinions, books, editorials and case reports were excluded. The titles and abstracts of all retrieved literature were screened, duplicates were excluded and the full texts of potentially eligible articles were obtained and assessed. The primary endpoint was type of postnatal circulation. Additional assessed outcomes included fetal death, live birth, neonatal death (NND), termination of pregnancy (TOP) and technical success of the FAV procedure. The quality of articles was assessed using the Critical Appraisal Skills Programme (CASP) tool. To estimate the overall proportion of each endpoint, meta-analysis of proportions was employed using a random-effects model. RESULTS: The electronic search identified 579 studies, of which seven were considered eligible for inclusion in the systematic review and meta-analysis. A total of 266 fetuses underwent FAV with median follow-up per study from 12 months to 13.2 years. There were no maternal deaths and only one case of FAV-related maternal complication was reported. Hydrops was present in 29 (11%) patients. The pooled prevalence of BVC and univentricular circulation (UVC) among liveborn patients was 45.8% (95% CI, 39.2-52.4%) and 43.6% (95% CI, 33.9-53.8%), respectively. The pooled prevalence of technically successful FAV procedure was 82.1% (95% CI, 74.3-87.9%), of fetal death it was 16.0% (95% CI, 11.2-22.4%), of TOP 5.7% (95% CI, 2.0-15.5%), of live birth 78.8% (95% CI, 66.5-87.4%), of NND 8.7% (95% CI, 4.7-15.5%), of palliative care 4.0% (95% CI, 1.9-8.4%) and of infant death 10.3% (95% CI, 3.6-26.1%). The pooled prevalence of BVC and UVC among liveborn patients who had technically successful FAV was 51.9% (95% CI, 44.7-59.1%) and 39.8% (95% CI, 29.7-50.9%), respectively. CONCLUSIONS: This study showed a BVC rate of 46% among liveborn patients with AS undergoing FAV, which improved to 52% when subjects underwent technically successful FAV. Given the lack of randomized clinical trials, results should be interpreted with caution. Currently, data do not suggest a true benefit of FAV for achieving BVC. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Increased risk of acute stroke among patients with severe COVID-19: a multicenter study and meta-analysis.

BACKGROUND AND PURPOSE: Recent observations linked coronavirus disease 2019 (COVID-19) to thromboembolic complications possibly mediated by increased blood coagulability and inflammatory endothelial impairment. We aimed to define the risk of acute stroke in patients with severe and non-severe COVID-19. METHODS: We performed an observational, multicenter cohort study in four participating hospitals in Saxony, Germany to characterize consecutive patients with laboratory-confirmed COVID-19 who experienced acute stroke during hospitalization. Furthermore, we conducted a systematic review using PubMed/MEDLINE, Embase, Cochrane Library and bibliographies of identified papers following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines including data from observational studies of acute stroke in COVID-19 patients. Data were extracted by two independent reviewers and pooled with multicenter data to calculate risk ratios (RRs) and 95% confidence intervals (95% CIs) for acute stroke related to COVID-19 severity using a random-effects model. Between-study heterogeneity was assessed using Cochran's Q and I2 statistics. International Prospective Register of Systematic Reviews registration number: CRD42020187194. RESULTS: Of 165 patients hospitalized for COVID-19 (49.1% males, median age = 67 years [57-79 years], 72.1% severe or critical) included in the multicenter study, overall stroke rate was 4.2% (95% CI: 1.9-8.7). Systematic literature search identified two observational studies involving 576 patients that were eligible for meta-analysis. Amongst 741 pooled COVID-19 patients, overall stroke rate was 2.9% (95% CI: 1.9-4.5). Risk of acute stroke was increased for patients with severe compared to non-severe COVID-19 (RR = 4.18, 95% CI: 1.7-10.25; P = 0.002) with no evidence of heterogeneity (I2  = 0%, P = 0.82). CONCLUSIONS: Synthesized analysis of data from our multicenter study and previously published cohorts indicates that severity of COVID-19 is associated with an increased risk of acute stroke.

Food allergen sensitization patterns in a large allergic population in Mexico

INTRODUCTION AND OBJECTIVES: Although food allergy is recognized as a growing worldwide public health problem, there continues to be limited data on prevalence rates in developing and emerging countries. Most prevalence estimates are based on self-reports, with only few studies using objective assessments. The aim was to analyze the frequency of sensitization to food allergens by serum specific IgE in a large group of unselected allergic patients in Mexico. MATERIALS AND METHODS: We analyzed data registries from patients of all ages with suspected food allergy referred to a specialized laboratory in Mexico City from January 2016 to April 2018. A descriptive analysis, and an age/food-group comparison were made. RESULTS: A total of 2633 subjects tested for food allergy were identified during the study period; 1795 subjects fulfilled the inclusion criteria. The overall positivity (sIgE ≥ 0.35 kUA/L) to at least one food was 24%. The most frequently positive foods were hazelnut, apple, shrimp, peanut, egg white, egg yolk, peach, almond, tomato, bean, milk, strawberry, kiwi, maize and wheat. Positivity for some foods was more frequent across different age groups, in young children (≤ 5 years) milk; in older children (6-17 years): peanut, almond, wheat, soy and maize; in adults: apple. We also found other foods with high positivity but less than 50 samples: rye 60%, mango 42.9%, carrot 37.5%, cashew 27.3%, banana 21.1% and oat 20.6%. CONCLUSION: Our study reported the presence of a differential regional IgE sensitization pattern as compared with the internationally reported one, highlighting the importance of local staple foods

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Food allergen sensitization patterns in a large allergic population in Mexico.

INTRODUCTION AND OBJECTIVES: Although food allergy is recognized as a growing worldwide public health problem, there continues to be limited data on prevalence rates in developing and emerging countries. Most prevalence estimates are based on self-reports, with only few studies using objective assessments. The aim was to analyze the frequency of sensitization to food allergens by serum specific IgE in a large group of unselected allergic patients in Mexico. MATERIALS AND METHODS: We analyzed data registries from patients of all ages with suspected food allergy referred to a specialized laboratory in Mexico City from January 2016 to April 2018. A descriptive analysis, and an age/food-group comparison were made. RESULTS: A total of 2633 subjects tested for food allergy were identified during the study period; 1795 subjects fulfilled the inclusion criteria. The overall positivity (sIgE≥0.35kUA/L) to at least one food was 24%. The most frequently positive foods were hazelnut, apple, shrimp, peanut, egg white, egg yolk, peach, almond, tomato, bean, milk, strawberry, kiwi, maize and wheat. Positivity for some foods was more frequent across different age groups, in young children (≤5 years) milk; in older children (6-17 years): peanut, almond, wheat, soy and maize; in adults: apple. We also found other foods with high positivity but less than 50 samples: rye 60%, mango 42.9%, carrot 37.5%, cashew 27.3%, banana 21.1% and oat 20.6%. CONCLUSION: Our study reported the presence of a differential regional IgE sensitization pattern as compared with the internationally reported one, highlighting the importance of local staple foods.

Long-term study analysis of contrast-enhanced ultrasound in the diagnosis of focal nodular hyperplasia.

BACKGROUND: Focal nodular hyperplasia (FNH) is a hyperplastic mass of vascular abnormality and the second most common benign liver lesion. It can be discovered incidentally or during a surveillance examination in patients at risk for hepatic malignancy, mostly by conventional ultrasound. CEUS has been used as an additional alternative method for the rapid diagnosis of FNH. However, none of the previous studies compared the diagnostic performance of CEUS to MRI retrospectively in a 10-year observation. OBJECTIVE: The aim of this long-term retrospective study is to assess the diagnostic performance of CEUS in the imaging of FNH and compare the results to MRI. MATERIAL AND METHODS: A single experienced physician performed CEUS examinations in 244 patients between 2009 and 2019 with suspected focal nodular hyperplasia after conventional ultrasound. A second-generation blood pool agent (SonoVue®, Bracco, Milan, Italy) was administered. Additional dynamic MRI with contrast agent was performed in a subgroup of 95 patients. RESULTS: Out of 244 patients, FNH could be displayed in 221 patients on CEUS. A subgroup of 95 patients had CEUS examinations and CEMRI for diagnosis comparison. In comparison with CEMRI, CEUS presented a sensitivity of 97%, a specificity of 76%, a positive predictive value of 93% and a negative predictive value of 89%. CONCLUSION: CEUS is a safe and feasible approach that assess the diagnosis of focal nodular hyperplasia equally to MRI. The focal lesion enhancement can be depicted in real-time in the arterial, venous and late phase facilitating the prompt diagnosis.

Unexpectedly high incidences of chronic non-bacterial as compared to bacterial osteomyelitis in children.

Historically, osteomyelitis was considered an infectious disorder. More recently, inflammatory mechanisms were recognized causing a significant proportion of pediatric osteomyelitis. This study was to compare characteristics of children with chronic non-bacterial (CNO) and bacterial osteomyelitis (BOM). A chart review of osteomyelitis patients from the departments of pediatrics, pediatric surgery, orthopedic surgery, and oral and maxillofacial surgery was conducted in a tertiary referral center, covering the years 2004-2014. Institutional incidences of CNO (n = 49) and BOM (n = 56) were comparable. Differentiation between CNO and BOM based on clinical or laboratory findings was mostly impossible. However, children with BOM more frequently presented with local inflammatory signs (47 vs. 68 %, p = 0.040), fever (12 vs. 38 %, p = 0.003), and abscesses (0 vs. 39 %, p < 0.001). Peripheral arthritis (14 vs. 0 %, p < 0.001), inflammatory bowel disease (10 vs. 2 %, p = ns), and hyperostosis (29 vs. 4 %, p = 0.001) were more common in CNO. Whole-body MRI was performed in 76 % of CNO patients, unveiling multifocal lesions in 80 % (CRMO). Though considered a rare disorder, institutional incidences of CNO were comparable to BOM, and the discrimination between CNO and BOM solely based on clinical aspects was mostly impossible. This is of special interest, since a correct and timely diagnosis is of utmost importance for long-term outcomes in both disorders. Whole-body MRIs should be considered in chronic osteomyelitis to (1) detect clinically inapparent lesions in CNO and (2) indirectly exclude (usually unifocal) chronic bacterial infections. Prospective studies are warranted to establish evidence-based diagnostic and therapeutic approaches to CNO.

[Organized Post-Stroke Care through Case Management on the Basis of a Standardized Treatment Pathway : Results of a Single-Centre Pilot Study]. / Koordinierte Schlaganfallnachsorge durch Case Management auf der Basis eines standardisierten Behandlungspfades : Ergebnisse einer monozentrischen Pilotstudie.

BACKGROUND: Post-stroke care programs based on a standardized treatment pathway supported by case management may prevent secondary stroke and minimize risk factors. OBJECTIVES: We aimed to determine the feasibility of a standardized treatment pathway and its impact on risk factor control, life-style changes and adherence to secondary prevention medication. METHODS: We conducted a prospective pilot study in consecutive stroke patients. The 12-month post-stroke care program included regular perosnal and phone contact with a certified case manager. Target values for vascular risk factors following current recommendations of stroke guidelines were monitored and treated if necessary. In the case of deviations from the treatment pathway the case manager intervened. Patients were screened for recurrent stroke at the end of the program after 12 months. RESULTS: We enrolled 101 patients: 57.4 % were male, the median age was 72 (IQR, 62-80) years, median baseline NIHSS score was 2(IQR, 1-5), 79.2 % had an ischemic stroke, 3 % a hemorrhagic stroke, and 17.8 % a transient ischemic attack (TIA). Eighty-six (85.1 %) patients completed the program, 12 (11.9 %) withdrew from the program and 3 died of malignant diseases. In total, 628 personal (6.2/patient) and 2,683 phone contacts (26.6/patient) were conducted by the case manager. Three hundred-seventy-nine specific interventions were necessary mostly because of missing medication, non-compliance, and social needs. After 12 months, target goals for blood pressure, body mass index, nicotine use, and cholesterol were more frequently (p < 0.05) achieved than at baseline. No recurrent stroke occurred during the program. CONCLUSIONS: Our pilot data demonstrate that case management-based post-stroke care is feasible and may contribute to effective secondary prevention of stroke.

The influence of polypharmacy on grade III/IV toxicity, prior discontinuation of chemotherapy and overall survival in ovarian cancer.

BACKGROUND: Ovarian cancer is mostly diagnosed in the elderly woman who is likely to have comorbid disease and to take several comedications on a regular basis. Aim of this study was to evaluate the influence of polypharmacy on grade III/IV toxicity, prior discontinuation of chemotherapy and survival. PATIENTS AND METHODS: In this individual participant data meta-analysis the original data of three phase II/III studies of the North-Eastern German Society of Gynecological Oncology (NOGGO) were analyzed using multivariate logistic and Cox regression. RESULTS: Overall, 1213 patients with recurrent ovarian cancer were included in these analyses. An increasing amount of medication was associated with overall grade III/IV toxicity (p<0.001; OR 1.120), and hematological (p<0.001; OR 1.056) and non-hematological (p<0.001; OR 1.134) toxicities. Prior discontinuation of chemotherapy was not influenced by an increasing amount of medication (p=0.196). There was no association of polypharmacy with overall survival (p=0.068). CONCLUSION: As polypharmacy does not influence survival ovarian cancer patients taking several comedications may be included in clinical trials and should not be deprived of adequate cancer treatment. However, a thorough monitoring is mandatory due to the increased risk of toxicities.

The influence of comorbidity and comedication on grade III/IV toxicity and prior discontinuation of chemotherapy in recurrent ovarian cancer patients: An individual participant data meta-analysis of the North-Eastern German Society of Gynecological Oncology (NOGGO).

BACKGROUND: Ovarian cancer is usually a cancer of the older age group. Comorbidities and comedications increase with rising age. Aim of this study was to evaluate association of comorbidity and comedication with grade III/IV toxicities and prior cessation of chemotherapy in ovarian cancer patients. PATIENTS AND METHODS: As an individual participant data meta-analysis this study analyzes the original data of three phase II/III chemotherapy studies of the North-Eastern German Society of Gynecological Oncology (NOGGO). Risk scores for certain combinations of risk factors were calculated based on stepwise regression analyses. RESULTS: Altogether, 1213 patients were included in the study. Cardiovascular disease was the most frequent comorbidity (47.5%). In multivariate analyses it was associated with hematological, non-hematological, pulmonary and renal grade III/IV toxicities (p=0.002; p<0.001; p=0.005; p<0.001). Renal toxicity was more frequent when using diuretics and ACE-inhibitors (p<0.001; p=0.002). Prior cessation of therapy was e.g. associated with use of diuretics, insulin and digitalis (p=0.001; p=0.04; p=0.03). The risk for renal grade III/IV toxicities was more than 16 times higher when using both a diuretic and an ACE-inhibitor. CONCLUSIONS: Regimens of ovarian cancer treatment should not be restricted to direct cancer therapy but rather include additional individualized treatment of comorbidities. Comedications such as diuretics increase grade III/IV toxicities and patients at risk should be closely monitored.

TIDILAP: Treatment of iron deficiency in lipoprotein apheresis patients --A prospective observational multi-center cohort study comparing efficacy, safety and tolerability of ferric gluconate with ferric carboxymaltose.

OBJECTIVES: Iron deficiency (ID) and iron deficiency anemia (IDA) are common findings in patients undergoing lipoprotein apheresis (LA). Different intravenous (iv) formulations are used to treat ID in LA patients, however guidelines and data on ID/IDA management in LA patients are lacking. We therefore performed a prospective observational multi-center cohort study of ID/IDA in LA patients, comparing two approved i.v. iron formulations, ferric gluconate (FG) and ferric carboxymaltose (FCM). METHODS: Inclusion criteria were a) serum ferritin <100 µg/L or b) serum ferritin <300 µg/L and transferrin saturation <20%. Patients received either FG (62.5 mg weekly) or FCM (500 mg once in ID or up to 1000 mg if IDA was present) i.v. until iron deficiency was resolved. Efficacy and safety were determined by repeated laboratory and clinical assessment. Iron parameters pre and post apheresis were measured to better understand the pathogenesis of ID/IDA in LA patients. RESULTS: 80% of LA patients treated at the three participating centers presented with ID/IDA; 129 patients were included in the study. Serum ferritin and transferrin levels were reduced following apheresis (by 18% (p < 0.0001) and by 13% (p < 0.0001) respectively). Both FG and FCM were effective and well tolerated in the treatment of ID/IDA in LA patients. FCM led to a quicker repletion of iron stores (p < 0.05), while improvement of ID/IDA symptoms was not different. Number and severity of adverse events did not differ between FG and FCM, no severe adverse events occurred. CONCLUSIONS: Our results suggest that FG and FCM are equally safe, well-tolerated and effective in treating ID/IDA in LA patients. These data form the basis for follow-up randomized controlled trials to establish clinical guidelines.

[Axon-reflex based nerve fiber function assessment in the detection of autonomic neuropathy]. / Axon-Reflex-basierte Nervenmessverfahren in der Diagnostik autonomer Neuropathie.

Axon-reflex-based tests of peripheral small nerve fiber function including techniques to quantify vasomotor and sudomotor responses following acetylcholine iontophoresis are used in the assessment of autonomic neuropathy. However, the established axon-reflex-based techniques, laser Doppler flowmetry (LDF) to assess vasomotor function and quantitative sudomotor axon-reflex test (QSART) to measure sudomotor function, are limited by technically demanding settings as well as interindividual variability and are therefore restricted to specialized clinical centers. New axon-reflex tests are characterized by quantification of axon responses with both temporal and spatial resolution and include "laser Doppler imaging (LDI) axon-reflex flare area test" to assess vasomotor function, the quantitative direct and indirect test of sudomotor function (QDIRT) to quantify sudomotor function, as well as the quantitative pilomotor axon-reflex test (QPART), a technique to measure pilomotor nerve fiber function using adrenergic cutaneous stimulation through phenylephrine iontophoresis. The effectiveness of new axon-reflex tests in the assessment of neuropathy is currently being investigated in clinical studies.

[Statins and ASS for primary prevention of cardiovascular and cerebrovascular disease]. / Medikamentöse Primärprävention kardiovaskulärer und zerebrovaskulärer Erkrankungen.

Whereas statins and acetylsalicylic acid (ASA) are considered gold standard for secondary prevention following myocardial infarction or atherotrombotic stroke, there are inconsistent data on the use of these drugs for primary prevention in patients with increased cardiovascular risk. Some meta-analyses indicated that the use of statins and ASA for primary prevention of cardiovascular disease can reduce the risk of cardiovascular events such as ischemic stroke or myocardial infarction. However, the effects of primary prevention with statins and ASA on mortality varied in the data included in these meta-analyses. Therefore the guidelines of the German College of General Practitioners and Family Physicians recommend primary prevention with statins and ASA only in those patients who have a 10-year risk of cardiovascular events which exceeds 20 %. Divergently, primary prevention with ASA is not recommended by the European Society of Cardiology. Observational studies suggested that treatment success of primary prevention with statins and ASA depends on various factors such as adherence to medication and prescription behavior of physicians. This review summarizes the current literature on primary prevention of cardiovascular events with ASA and statins.

[Autonomic neuropathies]. / Formen autonomer nervenkrankheiten.

Autonomic neuropathies are a heterogeneous group of diseases that involve damage of small peripheral autonomic Aδ- and C-fibers. Causes of autonomic nerve fiber damage are disorders such as diabetes mellitus and HIV-infection. Predominant symptoms of autonomic neuropathy are orthostatic hypotension, gastro-intestinal problems, urogenital dysfunction, and cardiac arrhythmia, which can severely impair the quality of life in affected patients. Furthermore, autonomic neuropathies can be induced by autoimmune diseases such as acute inflammatory demyelinating polyneuropathy, hereditary disorders such as the lysosomal storage disorder Fabry disease and hereditary sensory and autonomic neuropathies, as well as certain toxins and drugs.

[Autonomic neuropathies--diagnosis and evidence based treatment]. / Autonome nervenkrankheiten--früherkennung und leitliniengerechte behandlung.

Among the few well-established techniques to diagnose autonomic dysfunction are head-up-tilt table testing, heart rate variability measurement and axon-reflex based sudomotor testing. Recent research focused on the development of novel techniques to assess autonomic function based on axon-reflex testing in both vasomotor and pilomotor nerve fibers. However, these techniques are clinically not widely used due to technical limitations and the lack of data on their utility to detect autonomic dysfunction in patients with neuropathy. The treatment of autonomic neuropathies should focus on the management of the underlying disease. In addition, symptomatic treatment of autonomic dysfunction should be provided in an individual patient-centered multimodal regimen that may incorporate both pharmacological and non-pharmacological strategies. The use of medication in autonomic dysfunction requires a careful risk-benefit assessment and should be individually adjusted based on both therapeutic success and occurrence of adverse effects.

The effects of venlafaxine on cognitive functions and quantitative EEG in healthy volunteers.

Antidepressants that selectively block serotonin uptake may cause unwanted effects on cognitive functions such as impairment of vigilance and memory. A double-blind, randomized, placebo-controlled cross-over trial was performed to examine the effects of venlafaxine, a selective serotonin and noradrenaline reuptake inhibitor (SSNRI), on cognitive functions and quantitative EEG (qEEG) in humans. 12 healthy male subjects aged 23-32 years (26+/-3 years mean+/-sd) orally received 37.5 mg venlafaxine b.i.d. for 7 days and subsequently 75 mg b.i.d. for another 7 days. After a 14-day wash-out phase, placebo was administered to the subjects for 14 days under randomized double-blind cross-over conditions. Venlafaxine did not influence cognitive functions such as choice reaction, memory, psychomotor performance and subjective mood. Placebo resulted in an increase in slow alpha power (p<0.05) whereas venlafaxine had no effect on qEEG. In conclusion, multiple dosing with venlafaxine did not influence cognitive functions in healthy humans.

[Fever, nosebleeding and myalgic abdominal pain]. / Fieber, Nasenbluten und myalgiforme abdominale Schmerzen.

A 38 year old patient presented with fever, myalgic abdominal pain, nose bleeding and acute renal failure since five days. A combination of thrombocytopenia, proteinuria, elevated CrP and creatinin is common in hemorrhagic fever with renal syndrome (HFRS) due to Hantavirus infection. The benigne form is called Nephropathia epidemica. Dialysis is infrequently required by patients with the Puumala virus. Other infection (e.g. malaria, leptospirosis, yellow fever) and systemic diseases (e.g. collagenosis or vasculitis) are considered.

N-end rule specificity within the ubiquitin/proteasome pathway is not an affinity effect.

The N-end rule relates the amino terminus to the rate of degradation through the ubiquitin/26 S proteasome pathway. Proteins bearing basic (type 1) or large hydrophobic (type 2) amino termini are assumed to be targeted through this pathway by their higher affinity for binding to the responsible E3 ligase compared with proteins bearing other residues (type 3). Paradoxically, a significant fraction of eukaryotic protein degradation occurs through the N-end rule pathway, although the majority of cellular proteins are type 3 substrates. We have exploited specific interactions between ubiquitin carrier proteins (E2/Ubc) and their cognate E3 ligases to purify for the first time the mammalian N-end rule ligase E3alpha/Ubr1 to near homogeneity. In vitro studies show that E3alpha forms lysine 48-linked polyubiquitin degradation signals on type 1-3 substrates and is absolutely dependent on Ubc2/Rad6 orthologs. Biochemically defined kinetic studies show that the basis of N-end rule specificity is a k(cat) rather than the K(m) effect originally proposed, since all three substrate classes show similar binding affinities (K(m) approximately 5 microm) but V(max) values that are 100- and 50-fold greater for type 1 and 2 versus type 3 model substrates, respectively. In addition, the N-end rule dipeptides lysylalanine and phenylalanylalanine are general noncompetitive inhibitors for E3alpha-catalyzed ubiquitination of type 1-3 substrates rather than type-specific competitive inhibitors as predicted. These observations are consistent with a model in which the N-end rule effect reflects substrate binding-induced transitions in E3alpha to a catalytically competent conformer, the equilibrium for which depends on the identity of the amino terminus or the presence of basic or hydrophobic surface features. The model reconciles conflicts between specific predictions and empirical observations relating N-end rule targeting in addition to explicating the efficacy of selected dipeptides as potent in vivo inhibitors of this pathway.

Pathways of ubiquitin conjugation.

The covalent attachment of the polypeptide ubiquitin to proteins marks them for degradation by the ubiquitin/26S proteasome-dependent degradation pathway. This pathway functions in regulating many fundamental processes required for cell viability. Phylogenetic analysis of ubiquitin sequences reveals greater variability among lower eukaryotes and defines essential residues, many of which are conserved among the three ubiquitin-like proteins known to undergo parallel ligation pathways. The hierarchical design of the ubiquitin conjugation mechanism provides great flexibility for the divergent evolution of new functions mediated by this posttranslational modification. Within this hierarchy, a single ubiquitin-activating enzyme provides charged intermediates to multiple targeting pathways defined by cognate ubiquitin carrier protein (E2)/ligase (E3) pairs. Sequence analysis of E2 isozymes shows that the E2 superfamily is composed of distinct function-specific families. The apparent lack of E2/E3 specificity suggested in the literature results from the presence of multiple isozymes within many E2 families and erroneous family assignments based on incomplete data sets. Other apparent inconsistencies are explained by interfamily sequence relationships among some E2 isoforms.

[In vitro study of platelet concentrate preparations from whole blood using N-(2-mercaptopropionyl)-glycine]. / In-vitro-Untersuchungen zur Herstellung von Thrombozytenkonzentraten aus Vollblut mit N-(2-Mercaptopropionyl)-glycin.

The sulfhydryl group containing drug N-(2-mercaptopropionyl)-glycine (MPG) which inhibits platelet aggregation in a reversible manner permits to prepare platelet concentrates in non-siliconized glass containers at pH 7.4. Resuspension of platelets is possible immediately after centrifugation. In vitro platelets tests were carried out after washing out the MPG in MPG-free plasma. Thereafter, no inhibitory effects on platelet functions were found. Platelets concentrated in presence of MPG were significantly better with respect to yield, maintenance of discoid shape, aggregability, and hypotonic shock response compared with control platelets concentrated in absence of MPG.

The use of N-(2-mercaptopropionyl)-glycine (MPG) for preparation and storage of platelets.

The SH group containing drug MPG which inhibits platelet aggregation in a reversible manner was used as a cytoprotective substance in some experiments on preparation and storage of human platelets for transfusion. In vitro (n = 6): concentration, morphology score, HSR and aggregation of stored platelets were measured after simulating in vitro the post transfusional conditions by resuspension of stored platelets in fresh drawn plasma (pH 7.4, 37 degrees C). In vivo (n = 2): Autologous platelets stored for 48 h at 22 degrees C were labelled with 111In and retransfused. The results obtained from platelets prepared and stored in plasma containing MPG were compared with those obtained from control platelets without MPG.