Sustained inflammation, coagulation activation and elevated endothelin-1 levels without macrovascular dysfunction at 3 months after COVID-19.

INTRODUCTION: Endothelial damage and thrombosis caused by COVID-19 may imperil cardiovascular health. More than a year since the WHO declared COVID-19 pandemic, information on its effects beyond the acute phase is lacking. We investigate endothelial dysfunction, coagulation and inflammation, 3 months post-COVID-19. MATERIALS AND METHODS: A cohort study was conducted including 203 patients with prior COVID-19. Macrovascular dysfunction was assessed by measuring the carotid artery diameter in response to hand immersion in ice-water. A historic cohort of 312 subjects served as controls. Propensity score matching corrected for baseline differences. Plasma concentrations of endothelin-1 were measured in patients post-COVID-19, during the acute phase, and in matched controls. Coagulation enzyme:inhibitor complexes and inflammatory cytokines were studied. RESULTS AND CONCLUSIONS: The prevalence of macrovascular dysfunction did not differ between the COVID-19 (18.6%) and the historic cohort (22.5%, RD -4%, 95%CI: -15-7, p = 0.49). Endothelin-1 levels were significantly higher in acute COVID-19 (1.67 ± 0.64 pg/mL) as compared to controls (1.24 ± 0.37, p < 0.001), and further elevated 3 months post-COVID-19 (2.74 ± 1.81, p < 0.001). Thrombin:antithrombin(AT) was high in 48.3%. Markers of contact activation were increased in 16-30%. FVIIa:AT (35%) and Von Willebrand Factor:antigen (80.8%) were elevated. Inflammatory cytokine levels were high in a majority: interleukin(IL)-18 (73.9%), IL-6 (47.7%), and IL-1ra (48.9%). At 3 months after acute COVID-19 there was no indication of macrovascular dysfunction; there was evidence, however, of sustained endothelial cell involvement, coagulation activity and inflammation. Our data highlight the importance of further studies on SARS-CoV-2 related vascular inflammation and thrombosis, as well as longer follow-up in recovered patients.

Disturbed sleep in cluster headache is not the result of transient processes associated with the cluster period.

BACKGROUND AND PURPOSE: Cluster headache (CH) is characterized by severe, unilateral attacks of pain and a high nocturnal attack burden. It remains unknown whether perturbations of sleep are solely present during the CH bout. Therefore, we aimed to investigate differences in sleep between the bout and remission period in patients with episodic CH and, secondly, to compare patients in the two phases with controls. METHODS: Patients with episodic CH (aged 18-65 years), diagnosed according to the International Classification of Headache Disorders 2nd edition, were admitted for polysomnography at the Danish Center for Sleep Medicine in bout and in remission. The macrostructure of sleep, including arousals, breathing parameters, limb movements and periodic limb movements, was compared with 25 age-, sex- and body mass index-matched healthy controls. RESULTS: There were no differences in any of the sleep parameters for patients in bout (n = 32) compared with patients in remission (n = 23). Attacks were unrelated to sleep stages, presence of apnea episodes, periodic limb movements, limb movements and arousals. In bout, patients had longer sleep latency (18.8 vs. 11.7 min, P < 0.05) and rapid eye movement sleep latency (1.7 vs. 1.2 h, P < 0.05) than controls and sleep efficiency was lower (82.5% vs. 86.5%, P < 0.05). Patients in remission only had a longer sleep latency compared with controls (17.5 vs. 11.7 min, P < 0.01). CONCLUSIONS: The results support the presence of a continuing or slowly recovering disturbance of sleep outside the bout rather than a disturbance occurring secondary to attacks. Further, we confirm that there is no relation between CH attacks and specific sleep stages or between CH and breathing parameters.

Value of 18F-FDG PET/CT in diagnosing chronic Q fever in patients with central vascular disease.

BACKGROUND: The aim of this study is to describe the value of 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) in diagnosing chronic Q fever in patients with central vascular disease and the added value of 18F-FDG PET/CT in the diagnostic combination strategy as described in the Dutch consensus guideline for diagnosing chronic Q fever. METHODS: 18F-FDG PET/CT was performed in patients with an abdominal aortic aneurysm or aorto-iliac reconstruction and chronic Q fever, diagnosed by serology and positive PCR for Coxiella burnetii DNA in blood and/or tissue (PCR-positive study group). Patients with an abdominal aortic aneurysm or aorto-iliac reconstruction without clinical and serological findings indicating Q fever infection served as a control group. Patients with a serological profile of chronic Q fever and a negative PCR in blood were included in additional analyses (PCR-negative study group). RESULTS: Thirteen patients were evaluated in the PCR-positive study group and 22 patients in the control group. 18F-FDG PET/CT indicated vascular infection in 6/13 patients in the PCR-positive study group and 2/22 patients in the control group. 18F-FDG PET/CT demonstrated a sensitivity of 46% (95% CI: 23-71%), specificity of 91% (95% CI: 71-99%), positive predictive value of 75% (95% CI:41-93%) and negative predictive value of 74% (95% CI: 55-87%). In the PCR-negative study group, 18F-FDG PET/CT was positive in 10/20 patients (50%). CONCLUSION: The combination of 18F-FDG PET/CT, as an imaging tool for identifying a focus of infection, and Q fever serology is a valid diagnostic strategy for diagnosing chronic Q fever in patients with central vascular disease.

Vascular chronic Q fever: quality of life.

The aim of this study was to evaluate the quality of life in patients with vascular chronic Q fever at time of diagnosis and during follow-up. Based upon the SF-36 questionnaire, the mean physical and mental health of each patient were assessed at 3-month intervals for up to 18 months. A total of 26 patients were included in the study. At time of diagnosis, the mean physical health and mental health score was 50·6 [95% confidence interval (CI) 46·7-54·4] and 44·6 (95% CI 41·6-47·5), respectively. During treatment, the mean physical health score declined significantly by 1·7 points each 3 months (P < 0·001) to 40·8 (95% CI 34·4-45·1). The mean mental health score significantly and steadily increased towards 51·2 (95% CI 46·9-54·3) during follow-up (P = 0·026). A total of 23% of patients were cured after 18 months of follow-up. In conclusion, quality of life at time of diagnosis for patients with vascular chronic Q fever is lower compared to a similar group of patients, matched for age and gender, with an aortic abdominal aneurysmal disease, and physical health decreases further after starting treatment. Considering the low percentage of cure, the current treatment of vascular chronic Q fever patients may require a separate strategy from that of endocarditis in order to increase survival.

Serological follow-up in patients with aorto-iliac disease and evidence of Q fever infection.

The aim of this study was to provide data on the risk of developing chronic Q fever in patients with aorto-iliac disease and evidence of previous Q fever infection. Patients with an aortic and/or iliac aneurysm or aorto-iliac reconstruction (aorto-iliac disease) and evidence of previous Q fever infection were included. The presence of phase I and II Coxiella burnetii IgG antibodies was assessed periodically using immunofluorescence assay. A total of 111 patients with aorto-iliac disease were divided into three groups, based upon the serological profile [mean follow-up: 16 ± 9 months (mean ± standard deviation)]. Group 1 consisted of 30 patients with a serological trace of C. burnetii infection (negative IgG phase I, IgG phase II titer of 1:32). Of these, 36.7% converted to serological profile matching past resolved Q fever. Group 2 included 49 patients with negative IgG phase I titer and IgG phase II titer ≥1:64. No patients developed chronic Q fever, but 14.3% converted to a positive IgG phase I titer. Group 3 consisted of 32 patients with positive IgG phase I and positive IgG phase II titers, of which 9.4% developed chronic Q fever (significantly different from group 2, p = 0.039). The IgG phase I titer increased in 28.1% of patients (from 1:64 to 1:4,096). The risk of developing chronic Q fever in patients with aorto-iliac disease and previous Q fever infection with a positive IgG phase I titer was 9.4%. The IgG phase I titer increases or becomes positive in a substantial number of patients. A standardized serological follow-up is proposed.

CRAdRGDflt-IL24 virotherapy in combination with chemotherapy of experimental glioma.

Malignant forms of glioma, the most common primary brain tumors, remain poorly responsive to multimodality therapeutic interventions, including chemotherapy. Suppressed apoptosis and extraordinary invasiveness are important distinctive features that contribute to the malignant phenotype of glioma. We have developed the vascular endothelial growth factor receptor 1 (VEGFR-1/flt-1) conditional replicating adenoviral vector (CRAdRGDflt-IL24) encoding the interleukin-24 (IL-24) gene. We investigated whether a combination of CRAdRGDflt-IL24-mediated oncolytic virotherapy and chemotherapy using temozolomide (TMZ) produces increased cytotoxicity against human glioma cells in comparison with these agents alone. Combination of CRAdRGDflt-IL24 and TMZ significantly enhanced cytotoxicity in vitro, inhibited D54MG tumor growth and prolonged survival of mice harboring intracranial human glioma xenografts in comparison with CRAdRGDflt-IL24 or TMZ alone. These data indicate that combined treatment with CRAdRGDflt-IL24-mediated oncolytic virotherapy and TMZ chemotherapy provides a promising approach for glioma therapy.

Clinical significance of splanchnic artery stenosis.

BACKGROUND: The clinical relevance of splanchnic artery stenosis is often unclear. Gastric exercise tonometry enables the identification of patients with actual gastrointestinal ischaemia. A large group of patients with splanchnic artery stenosis was studied using standard investigations, including tonometry. METHODS: Patients referred with possible intestinal ischaemia were analysed prospectively, using duplex imaging, conventional abdominal angiography and tonometry. All results were discussed within a multidisciplinary team. RESULTS: Splanchnic stenoses were found in 157 (49.7 percent) of 316 patients; 95 patients (60.5 percent) had one-vessel, 54 (34.4 percent) two-vessel and eight (5.1 percent) had three-vessel disease. Chronic splanchnic syndrome was diagnosed in 107 patients (68.2 percent), 54 (57 percent) with single-vessel, 45 (83 percent) with two-vessel and all eight with three-vessel stenoses. Treatment was undertaken in 95 patients, 62 by surgery and 33 by endovascular techniques. After a median follow-up of 43 months, 84 percent of patients were symptom free. CONCLUSION: Gastric exercise tonometry proved crucial in the evaluation of possible intestinal ischaemia. Comparing patients with single- and multiple-vessel stenoses, there were significant differences in clinical presentation and mortality rates.

Endovascular treatment of chronic splanchnic syndrome.

OBJECTIVE: The technical and clinical outcome of endovascular revascularization was analyzed in patients with suspicion of chronic splanchnic syndrome (CSS). METHODS: Medical history, duplex, angiography and exercise gastric tonometry suggested CSS in 97 patients. Twenty-seven of them were treated endovascular (one patient had 3-vessel, 12 patients had 2-vessels, 14 patients had 1-vessel CSS). Five patients received previous splanchnic revascularization. Twenty-three patients (85%) had severe co-morbidity: cardiac, pulmonary or cachexia. Endovascular treatment consisted of percutaneous transluminal angiography (PTA) of the coeliac artery (CA) or superior mesenteric artery (SMA) in three and primary balloon expandable stenting in 24 patients (13 CA and 10 SMA solitary, two CA and SMA both, 31 splanchnic arteries in total). RESULTS: Three patients showed procedure related complications (11%). Mean follow-up was 19, range 2-76 months. Two patients died during follow up, both not procedure or CSS related. Five patients had no improvement of symptoms, without evidence of re- or residual stenosis. The primary clinical success was 67%, secondary clinical success was 81%. The primary patency was 81% and secondary patency was 100%. CONCLUSION: Endovascular treatment of CSS has a reasonable outcome. It is an alternative to operative treatment, especially in patients with high co-morbidity or limited life expectancy.

Clinical approach to chronic gastrointestinal ischaemia: from 'intestinal angina' to the spectrum of chronic splanchnic disease.

Stenotic disorders of the splanchnic arteries are not rare, and it is generally assumed that symptoms are rare in patients with a single splanchnic stenosis, and even in patients with multiple-vessel stenoses. Currently, only gastric exercise tonometry aids the diagnostic evaluation, as it indicates actual ischaemia. Patients with stenotic disorders without complaints are referred to as having chronic splanchnic disease (CSD) and those with ischaemic complaints as having chronic splanchnic syndrome (CSS). The classical presentation of CSS, including the triad postprandial pain, weight loss and upper abdominal bruit, is also known as 'intestinal angina'. From the experience of our multidisciplinary working team on gastrointestinal ischaemia in 110 patients with stenoses of at least one splanchnic artery, two different clinical patterns were observed. In our series approximately 60% of patients with single-vessel stenoses, including the coeliac artery compression syndrome, have CSS. They have fewer complications, very low mortality, but most can be successfully treated by stenting or surgical treatment. Patients with multivessel splanchnic stenoses have more classical ischaemic complaints. Progression to a bowel infarction was seen in 34%, and mortality was 21%, mostly from bowel or myocardial infarction. Treatment should be tailored based upon perioperative risk assessment and local vascular anatomy. This may consist of autologous arterial bypass of one or two vessels, preferably antegrade. stenting or a combination of both. This differentiation between single- and multivessel splanchnic disease has considerable consequences for optimal work-up and treatment.

Influence of gender on proximal gastric motor and sensory function.

OBJECTIVE: Gender-related differences have been demonstrated with regard to GI motility: gallbladder contraction, colonic transit, and gastric emptying are delayed in women. It is not known whether gender influences proximal gastric motility and perception. METHODS: We have studied the influence of gender on proximal gastric motility and perception under fasting and postprandial conditions by retrospective analysis of data obtained in 99 healthy volunteers (42 men, 57 women) who participated in barostat studies performed according to standardized protocols at the Leiden University Medical Center (Leiden, The Netherlands) between 1996 and 2000. RESULTS: Minimal distending pressure (MDP) was significantly higher in women than in men (respectively, 6.8+/-0.2 vs 5.5+/-0.2 mm Hg; p < 0.001). During stepwise pressure distensions pressure-volume curves were similar in both sexes after correction for MDP, whereas perception of fullness and abdominal pressure increased significantly (p < 0.05) more rapidly in women. Before the meal intragastric volumes (at MDP + 2 mm Hg) did not differ between sexes. After the meal gastric relaxation in the first 30 min did not differ in women and men (respectively, 186+/-23 ml and 140+/-32 ml). However, from 30 until 90 min after the meal a significantly (p < 0.05) delayed return of intragastric volume to basal was seen in women. Perception of postprandial nausea was significantly (p < 0.01) increased in women. Perception of postprandial fullness remained increased for a longer period of time in women. CONCLUSIONS: Proximal gastric motility and perception are influenced by gender. Gender-related differences in postprandial proximal gastric motility and perception should be taken into account in barostat studies comparing patients with controls.

Post-thymic T-cell development in the rat.

The presence or absence of CD4, CD8, Thy-1, RT6 and CD45RC revealed a number of T-cell subpopulations in the rat. Vascular thymus transplantation was used in RT7 congenics to establish the lineage relationship between these subpopulations by following phenotypic changes after thymus emigration. We found that recent thymic emigrants exhibit the Thy-1+/RT6-/CD45RC- phenotype and express either CD4 or CD8. Within 11 days after emigration, these cells differentiated into Thy-1-/RT6+/CD45RC+ cells. From 33 to 76 days following transplantation, a proportion of the latter lost RT6 and/or CD45RC expression, suggesting further differentiation. The pathway of 'mature' T-cell differentiation could be reconstructed from these data and analysis of the differences between T-cell subsets in thymectomized and normal control rats. End-stages of post-thymic T-cell differentiation in the rat were most likely to be Thy-1-/RT6+/CD45RC- and Thy-1-/RT6-/CD45RC+ T cells.

Nonword pronunciation and models of word recognition.

Nonword pronunciation is a form of generalization behavior that has been at the center of debates about models of word recognition, the role of rules in explaining behavior, and the adequacy of the parallel distributed processing approach. An experiment yielded data concerning the pronunciation of a large corpus of nonwords. The data were then used to assess 2 models of naming: a model developed by D. C. Plaut and J. L. McClelland (1993), which is similar to the one described by M. S. Seidenberg and J. L. McClelland (1989) but uses improved orthographic and phonological representations, and the grapheme-phoneme correspondence rules of M. Coltheart, B. Curtis, P. Atkins, and M. Haller's (1993) dual-route model. Both models generate plausible nonword pronunciations and match subjects' responses accurately. The dual-route model does so by using rules that generate correct output for most words but mispronounce a significant number of exceptions. The parallel distributed processing model does so by finding a set of weights that allow it to generate correct output for both "rule-governed" items and exceptions. Some ways in which the two approaches differ and other issues facing them are also discussed.

Prophylactic one-dose treatment with clindamycin and gentamicin in transurethral prostatic resection. A double-blind placebo controlled study.

One hundred and sixty-eight patients scheduled for transurethral prostatic resection were randomly assigned to treatment either with a combination of clindamycin and gentamycin or with placebo, administered preoperatively as a single bolus infusion. The patients were stratified into a group of 35 with preoperative bacteriuria, and a group of 133 with preoperative sterile urine. Postoperatively the frequency of bacteriuria and bacteriaemia, the maximum body temperature measured, the number of patients with antibiotic therapy instituted, and the duration of hospitalization were significantly lower in the treated than in the placebo group. This applied both to the group with preoperative sterile urine and to the group with preoperative bacteriuria.