Karolina Akinosoglou

Native valve right sided infective endocarditis

Right-sided infective endocarditis (RSIE) accounts for 5-10% of all cases of infective endocarditis (IE), and is predominantly encountered in the injecting drug user (IDU) population, where HIV and HCV coinfections often coexist. Staphylococcus aureus is the most common pathogen. The pathogenesis of RSIE is still not well understood. RSIE usually presents as a persistent fever with respiratory symptoms whilst signs of systemic embolisation as seen in left-sided IE are notably absent. The prompt diagnosis of RSIE thus requires a high index of suspicion. Transthoracic echocardiography (TTE) can detect the majority of RSIE, whilst transoesophageal echocardiography (TOE) can increase sensitivity. Virulence of the causative organism and vegetation size are the major determinants of prognosis. Most cases of RSIE resolve with appropriate antibiotic administration.

Characterization of Plasmodium developmental transcriptomes in Anopheles gambiae midgut reveals novel regulators of malaria transmission.

The passage through the mosquito is a major bottleneck for malaria parasite populations and a target of interventions aiming to block disease transmission. Here, we used DNA microarrays to profile the developmental transcriptomes of the rodent malaria parasite Plasmodium berghei in vivo, in the midgut of Anopheles gambiae mosquitoes, from parasite stages in the midgut blood bolus to sporulating oocysts on the basal gut wall. Data analysis identified several distinct transcriptional programmes encompassing genes putatively involved in developmental processes or in interactions with the mosquito. At least two of these programmes are associated with the ookinete development that is linked to mosquito midgut invasion and establishment of infection. Targeted disruption by homologous recombination of two of these genes resulted in mutant parasites exhibiting notable infection phenotypes. GAMER encodes a short polypeptide with granular localization in the gametocyte cytoplasm and shows a highly penetrant loss‐of‐function phenotype manifested as greatly reduced ookinete numbers, linked to impaired male gamete release. HADO encodes a putative magnesium phosphatase with distinctive cortical localization along the concave ookinete periphery. Disruption of HADO compromises ookinete development leading to significant reduction of oocyst numbers. Our data provide important insights into the molecular framework underpinning Plasmodium development in the mosquito and identifies two genes with important functions at initial stages of parasite development in the mosquito midgut.

Immune-modulating therapy in acute pancreatitis: Fact or fiction

Acute pancreatitis (AP) is one of the most common diseases of the gastrointestinal tract, bearing significant morbidity and mortality worldwide. Current treatment of AP remains unspecific and supportive and is mainly targeted to aggressively prevent systemic complications and organ failure by intensive care. As acute pancreatitis shares an indistinguishable profile of inflammation with sepsis, therapeutic approaches have turned towards modulating the systemic inflammatory response. Targets, among others, have included pro- and anti-inflammatory modulators, cytokines, chemokines, immune cells, adhesive molecules and platelets. Even though, initial results in experimental models have been encouraging, clinical implementation of immune-regulating therapies in acute pancreatitis has had a slow progress. Main reasons include difficulty in clinical translation of experimental data, poor understanding of inflammatory response time-course, flaws in experimental designs, need for multimodal approaches and commercial drawbacks. Whether immune-modulation in acute pancreatitis remains a fact or just fiction remains to be seen in the future.

Hyperamylasaemia and dual paraneoplastic syndromes in small cell lung cancer.

We hereby describe the rare case of a 59-year-old patient presenting with marked hyperamylasaemia mimicking acute pancreatitis upon admission. Investigation of co-existent hypokalemia revealed the presence of ectopic adrenocorticotropic hormone secretion, leading to the final diagnosis of small cell lung cancer, exhibiting dual paraneoplastic syndromes including Cushing Syndrome and hyperamylasaemia. Although, paraneoplastic syndromes occur commonly, paraneoplastic hyperamylasaemia especially in the context of dual paraneoplastic syndromes occurring simultaneously, is extremely rare. Such misleading manifestations require a high index of suspicion on behalf of the physician, so that an underlying malignancy is not missed, and a final diagnosis combining all clinical and laboratory findings is reached. In turn, in rare cases common biochemical markers such as amylase can be used as a useful follow up index driving further management.

Plasmodium berghei PIMMS2 Promotes Ookinete Invasion of the Anopheles gambiae Mosquito Midgut

ABSTRACT Mosquito midgut stages of the malaria parasite present an attractive biological system to study host-parasite interactions and develop interventions to block disease transmission. Mosquito infection ensues upon oocyst development that follows ookinete invasion and traversal of the mosquito midgut epithelium. Here, we report the characterization of PIMMS2 (Plasmodium invasion of mosquito midgut screen candidate 2), a Plasmodium berghei protein with structural similarities to subtilisin-like proteins. PIMMS2 orthologs are present in the genomes of all plasmodia and are mapped between the subtilisin-encoding genes SUB1 and SUB3. P. berghei PIMMS2 is specifically expressed in zygotes and ookinetes and is localized on the ookinete surface. Loss of PIMMS2 function through gene disruption by homologous recombination leads to normal development of motile ookinetes that exhibit a severely impaired capacity to traverse the mosquito midgut and transform to oocysts. Genetic complementation of the disrupted locus with a mutated PIMMS2 allele reveals that amino acid residues corresponding to the putative subtilisin-like catalytic triad are important but not essential for protein function. Our data demonstrate that PIMMS2 is a novel ookinete-specific protein that promotes parasite traversal of the mosquito midgut epithelium and establishment of mosquito infection.

Sepsis favors high-on-clopidogrel platelet reactivity

Abstract High-on-treatment platelet reactivity (HPR) is associated with ischemic events in patients on antiplatelet therapy with a history of cardiovascular disease. On the other hand, recent data have associated sepsis with adverse cardiovascular events in patients admitted with bacteremia or respiratory infection. We aimed to assess P2Y12-mediated platelet reactivity (PR) during sepsis and recovery in patients under clopidogrel. This was a prospective observational study. Incoming patients presenting with signs/symptoms of sepsis already on a maintenance dose of clopidogrel of 75 mg qd for cardiovascular events were included in this study. Patients were assessed for their PR on presentation and following septic syndrome, using the VerifyNow point-of-care P2Y12 assay. Patients were excluded in the presence of evidence of noncompliance to antiplatelet regimen or in need of discontinuation during this study. Twenty-two septic patients on clopidogrel were included in this study (Supplemental Figure S1). Clopidogrel was administered for previous stroke, coronary, and peripheral artery disease in 27.3, 40.9, and 31.8% of patients, respectively. The main site of infection was respiratory tract followed by urinary tract, while the same amounts of gram-negative and -positive pathogens were isolated. HPR was noted in 77% and 29% of patients during sepsis and recovery, respectively, presenting a significant decrease in P2Y12 reaction units values during follow-up [240.7 ± 58.3 versus 179.5 ± 58.4, 95% CI (–102.7, –39.76), p = 0.0002]. Five patients died of infection, while no adverse cardiovascular events were noted in our study. Our study shows that sepsis may favor HPR, which is reversed when recovery occurs. This finding may underlie the adverse cardiovascular events in patients admitted with sepsis, possibly requiring alteration of antiplatelet regimen during the inflammation period.

Neisseria meningitidis presenting as acute abdomen and recurrent reactive pericarditis.

Meningococcal meningitis is a well established potential fatal infection characterized by fever, headache, petechial rash, and vomiting in the majority of cases. However, protean manifestations including abdominal pain, sore throat, diarrhea and cough, even though rare, should not be overlooked. Similarly, although disseminated infection could potentially involve various organ-targets, secondary immune related complications including joints or pericardium should be dealt with caution, since they remain unresponsive to appropriate antibiotic regimens. We hereby report the rare case of an otherwise healthy adult female, presenting with acute abdominal pain masking Neisseria meningitidis serotype B meningitis, later complicated with recurrent reactive pericarditis despite appropriate antibiotic treatment. There follows a review of current literature.

Ets-2 Acts As a Transcriptional Repressor of the Human Immunodeficiency Virus Type 1 through Binding to a Repressor–Activator Target Sequence of 5′-LTR

HIV-1 is transcriptionally active in activated T helper (Th)-cells and inactive in naive or resting memory Th-cells. Ets-2 is a preinduction transcriptional repressor of the IL-2 gene in naive Th-cells and a candidate transcriptional repressor of HIV-1 in the same cells, because the −279 to −250 upstream region of HIV-1-LTR [repressor–activator target sequence (RATS)], that participates in HIV-1-LTR transcriptional silencing, encompasses the AAGGAG Ets-2 binding site. In this proof of concept study, we investigated whether Ets-2 represses the expression of HIV-1. To assess whether Ets-2 can repress HIV-1 transcriptional activation acting through RATS, we transfected Jurkat cells with an Ets-2 overexpression plasmid (pCDNA3-ets-2) or Ets-2 silencing plasmids (ets-2-shRNA) and, as target genes, plasmids carrying the whole HIV-1-LTR sequence (HIV-1-LTR-CAT) or two copies of the RATS sequence (2× RATS-CAT) or a point mutation in the Ets-2 binding site (2× mutantRATS-CAT) or CMV-CAT (control). Ets-2 overexpression resulted in a significant reduction of HIV-1-LTR-CAT and 2× RATS-CAT activities in stimulated cells, but not of the 2× mutantRATS-CAT or CMV-CAT. Ets-2 silencing led to increased activities of HIV-1-LTR-CAT and 2× RATS-CAT in unstimulated cells, but had no effect on the activities of 2× mutantRATS-CAT and CMV-CAT. To assess Ets-2 binding to HIV-1-LTR–RATS in naive Th-cells, we isolated naive Th-cell nuclear proteins and passed them through an Ets-2 antibody column; electrophoretic mobility shift assays were performed using an RATS probe mixed with consecutive protein eluates. Ets-2 bound to the HIV-1-LTR–RATS in a dose-dependent manner. To assess Ets-2 binding to RATS in vivo, Jurkat cells were transfected with 2× RATS-CAT and stained for the Ets-2 protein and the RATS sequence by combining immunofluorescence and fluorescence in situ hybridization techniques. In unstimulated cells, Ets-2 bound to RATS, whereas no binding was observed in stimulated cells. To test for RATS specificity, the same experiments were performed with 2× mutantRATS-CAT, and no binding of Ets-2 was observed. The results were corroborated by chromatin immunoprecipitation assays performed with the same cells. Our results show that Ets-2 is a transcriptional repressor of HIV-1. Repression of HIV-LTR-RATS mediated by Ets-2 may account for the low-level transcription and replication of HIV-1 in naive Th-cells, and contribute to the viral latency and maintenance of viral reservoirs in patients, despite long-term therapy.

How well does qSOFA correspond to underlying systemic inflammatory response

HighlightsqSOFA score has been recently introduced to quickly identify patients in need for more intensive care.However, qSOFA score sensitivity remains poor in non‐ICU patients.Association of qSOFA with underlying inflammatory response remains unclear.Levels of IL‐6, IL‐10 and TNF‐a are similar between patients with qSOFA ≥ or <2.Presence of systemic inflammatory response, rather than organ dysfunction per se, should prompt for more intensive care. &NA; Need for prompt recognition and management of sepsis recently led to the introduction of qSOFA score. However, its association with underlying host inflammatory response remains unclear, while previous studies have challenged its performance in non – intensive care unit (ICU) patients comparing to previously used systemic inflammatory response syndrome (SIRS) criteria. Between June 2016 and April 2017, we performed a prospective observational study in the medical ward of a tertiary hospital to explore the relation of qSOFA ≥ 2 and <2 to underlying inflammatory response, as this is mirrored in levels of serum pro‐ and anti‐inflammatory mediators i.e. IL‐6, IL‐10 and TNF‐&agr;. A total of 100 consecutive patients were finally included in this study. Comparable levels [(pg/ml) median (IQR)] of IL‐6 [200 (53–200) vs 65.1 (17.3–200)], IL‐10 [ 7 (2.3–170.6) vs 2.3 (2.3–27.7)], and TNF‐&agr; [4 (4–46.1) vs 46.06 (4–227.2)] were noted between group of patients with qSOFA ≥ 2 or <2. Nevertheless, prognosis was worse in patients with qSOFA ≥ 2 showing longer length of stay [10 (7–25) vs 5 (3–7) days, p = .03] and lower recovery rates (41 vs 93%, p < .0001). Our results underline the need for prompt management of critically ill patients in presence of systemic inflammatory response regardless of qSOFA score, partly reflecting its low sensitivity comparing to previously used SIRS criteria.

Hereditary Angioedema: How Long Should We Treat?

We have read with interest the article by Loudin et al concerning their case of hereditary angioedema and its rapid improvement following intravenous C1 inhibitor concentrate (C1INH). C1INH remains the mainstay of therapy in any hereditary angioedema attack, while rapid response to the regimen has been well demonstrated. In response, we report our experience with a 30-year-old man with hereditary angioedema under danazol, who presented to our department with a 4-day history of vomiting and diarrhea. Initial examination revealed a patient in poor condition, exhibiting severe diffuse abdominal pain with rebound tenderness, in absence of fever, arthritis, or edema. Laboratory tests showed mild leukocytosis and hypokalemia but markedly elevated C-reactive protein: 37 mg/dL (<0.5), otherwise normal. Noncontrast-enhanced computed tomography—in the fear of exacerbating angioedema—was